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Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density. 褪黑素可减轻顺铂诱导的大鼠认知障碍并改善海马树突棘密度。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI: 10.1097/WNR.0000000000002049
Shahd Qutifan, Tareq Saleh, Nisreen Abu Shahin, Maha ELBeltagy, Fatimah Obeidat, Duaa Qattan, Heba Kalbouneh, Noor A Barakat, Mohammad Alsalem

Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.

顺铂诱发的认知障碍(化疗脑)影响着相当一部分癌症患者,目前尚无成熟的药物治疗方法。化脑可能与神经炎症和氧化应激有关。褪黑激素是一种松果体激素,具有抗氧化、抗炎和保护神经的作用。在这项研究中,我们调查了顺铂诱导的大鼠认知功能损害,以及褪黑激素是否能改善或逆转这种损害。行为测试包括在顺铂或顺铂+褪黑激素治疗条件下使用新位置识别测试(NLRT)测量工作记忆,然后收集大鼠大脑。随后用高尔基-考克斯染色法对大鼠大脑进行染色,然后检查每只大鼠的海马CA3区,并计算树突棘密度。顺铂治疗会导致大鼠在 NLRT 中的表现出现缺陷(P<0.05)。
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引用次数: 0
The miR-23b-3p from adipose-derived stem cell exosomes alleviate inflammation in mice experiencing kainic acid-induced epileptic seizures. 脂肪源性干细胞外泌体中的 miR-23b-3p 可减轻凯尼酸诱发的癫痫小鼠的炎症反应。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-09 DOI: 10.1097/WNR.0000000000002044
Xue Yang, Xiaxin Yang, Anqi Sun, Si Chen, Xiaotang Wang, Xiuhe Zhao

Epilepsy is a common neurologic disorder. While a good clinical solution is still missing, studies have confirmed that exosomes (Exos) derived from adipose-derived stem cells (ADSCs) had a therapeutic effect on various diseases, including neurological diseases. Therefore, this study aimed to reveal whether ADSC-Exo treatment could improve kainic acid (KA)-induced seizures in epileptic mice. ADSCs and Exos were isolated. Mice were generated with KA-induced epileptic seizures. ELISA was used to detect inflammatory factor expression. Luciferase reporter analysis detection showed a relationship among miR-23b-3p, STAT1, and glyoxylate reductase 1 (GlyR1). ADSC-Exos had a protective effect on KA-induced seizures by inhibiting inflammatory factor expression and the M1 microglia phenotype. The result showed that miR-23b-3p played an important role in the Exo-mediated protective effect in KA-induced seizures in epileptic mice by regulating STAT1 and GlyR1. Luciferase reporter analysis confirmed that miR-23b-3p interacted with the 3'-UTR of STAT1 and GlyR1. The miR-23b-3p inhibited M1 microglia-mediated inflammatory factor expression in microglial cells by regulating STAT1 and GlyR1. The downregulation of miR-23b-3p decreased the protective effect of ADSC-Exos on KA-induced seizures in epileptic mice. The miR-23b-3p from ADSC-Exos alleviated inflammation in mice with KA-induced epileptic seizures.

癫痫是一种常见的神经系统疾病。虽然目前还没有很好的临床解决方案,但已有研究证实,从脂肪源性干细胞(ADSCs)中提取的外泌体(Exos)对包括神经系统疾病在内的多种疾病有治疗作用。因此,本研究旨在揭示ADSC-Exo治疗是否能改善凯尼酸(KA)诱导的癫痫小鼠癫痫发作。研究分离了 ADSCs 和 Exos。生成 KA 诱导癫痫发作的小鼠。用ELISA检测炎症因子的表达。荧光素酶报告分析检测显示了 miR-23b-3p、STAT1 和乙醛酸还原酶 1 (GlyR1) 之间的关系。ADSC-Exos 通过抑制炎症因子的表达和 M1 小胶质细胞表型,对 KA 诱导的癫痫发作有保护作用。研究结果表明,miR-23b-3p通过调节STAT1和GlyR1,在Exo介导的对KA诱导的癫痫小鼠发作的保护作用中发挥了重要作用。荧光素酶报告分析证实,miR-23b-3p 与 STAT1 和 GlyR1 的 3'-UTR 相互作用。miR-23b-3p 通过调节 STAT1 和 GlyR1 抑制了 M1 小胶质细胞介导的小胶质细胞炎症因子的表达。miR-23b-3p 的下调降低了 ADSC-Exos 对 KA 诱导的癫痫小鼠癫痫发作的保护作用。来自 ADSC-Exos 的 miR-23b-3p 减轻了 KA 诱导的癫痫小鼠的炎症反应。
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引用次数: 0
Danshen injection mitigated the cerebral ischemia/reperfusion injury by suppressing neuroinflammation via the HIF-1α/CXCR4/NF-κB signaling pathway. 丹参注射液通过HIF-1α/CXCR4/NF-κB信号通路抑制神经炎症,从而减轻脑缺血再灌注损伤。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI: 10.1097/WNR.0000000000002043
Gao Chen, Zhan Jin, Xi Wang, Qi-Hui Yu, Gao-Bo Hu

Danshen injection (DI) is effective in treating cardiovascular and cerebrovascular diseases, including ischemic stroke (IS), including IS, but its mechanism is unclear. A middle cerebral artery occlusion model was used to simulate ischemia/reperfusion (I/R) injury in SD rats. Overexpression of hypoxia-inducible factor 1α (HIF-1α) was achieved by AAV-HIF-1α. Rats were treated with DI or saline. Neurological scores and infarction rates were assessed. I/R damage was examined by HE, 2,3,5-triphenyltetrazolium and Nissl stainings. Expression levels of relative proteins [TNF-α, IL-6, IL-1β, SOD, MDA, ROS, HIF-1α, CXC chemokine receptor 4 (CXCR4) and NF-κB] were measured. DI treatment improved neurological scores and reduced infarction rates, suggesting that it inhibits inflammation and oxidative stress. The expression levels of HIF-1α, CXCR4 and NF-κB were decreased. However, the effectiveness of DI on inflammation inhibition was lost after HIF-1α overexpression. DI may directly target HIF-1α to suppress neuroinflammation and reduce I/R injury by suppressing the HIF-1α/CXCR4/NF-κB signaling pathway.

丹参注射液对包括缺血性中风(IS)在内的心脑血管疾病有很好的治疗效果,但其作用机制尚不清楚。研究采用大脑中动脉闭塞模型模拟 SD 大鼠的缺血再灌注损伤。通过AAV-HIF-1α实现了缺氧诱导因子1α(HIF-1α)的过表达。大鼠接受 DI 或生理盐水治疗。评估神经系统评分和梗死率。通过 HE、2,3,5-三苯基四氮唑和 Nissl 染色检查 I/R 损伤。测量了相关蛋白质[TNF-α、IL-6、IL-1β、SOD、MDA、ROS、HIF-1α、CXC趋化因子受体4(CXCR4)和NF-κB]的表达水平。DI 治疗改善了神经系统评分,降低了梗死率,这表明它抑制了炎症和氧化应激。HIF-1α、CXCR4和NF-κB的表达水平有所下降。然而,HIF-1α过表达后,DI抑制炎症的效果就消失了。DI可能直接靶向HIF-1α,通过抑制HIF-1α/CXCR4/NF-κB信号通路来抑制神经炎症和减轻I/R损伤。
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引用次数: 0
Gastrodin combined with electroacupuncture prevents the development of cerebral ischemia via rebalance of brain-derived neurotrophic factor and interleukin-6 in stroke model rats. 天麻素联合电针通过重新平衡脑源性神经营养因子和白细胞介素-6防止中风模型大鼠脑缺血的发生。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI: 10.1097/WNR.0000000000002050
Min Liu, Rujie Gong, Lina Ding, Yingdi Zhao, Xili Yan, Liangbin Shi, Yegui Zhang, Zhiliang Xu

Traditional Chinese medicine (TCM) has long been used to treat various diseases, including cerebral ischemia. The specific molecular mechanism of TCM in the treatment of cerebral ischemia, however, is still unclear. This study investigated the effects of gastrodin, electroacupuncture and their combination on cerebral ischemic rats. We used Nissl staining, immunohistochemical staining and immunoblotting to detect the expression changes of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) in the frontal cortex. The results showed that the combination therapy of gastrodin and electroacupuncture significantly increased the number of Nissl-positive neurons and improved cell morphology compared with other groups. Mechanistically, we found that the combination of gastrodin and electroacupuncture treatment group can restore the abnormal morphology of neuronal cells caused by cerebral ischemia by rebalancing the expression levels of BDNF and IL-6. Our research indicates that gastrodin combined with electroacupuncture has a significant protective effect on cerebral ischemic injury in rats, possibly by regulating the expression of BDNF and IL-6. This combination therapy is superior to single-drug or electroacupuncture therapy.

长期以来,中医一直被用于治疗包括脑缺血在内的各种疾病。然而,中医药治疗脑缺血的具体分子机制尚不清楚。本研究探讨了天麻素、电针及其组合对脑缺血大鼠的影响。我们采用Nissl染色法、免疫组织化学染色法和免疫印迹法检测了脑源性神经营养因子(BDNF)和白细胞介素-6(IL-6)在额叶皮层的表达变化。结果显示,与其他组相比,胃复安和电针联合治疗能显著增加Nissl阳性神经元的数量,并改善细胞形态。从机理上讲,我们发现天麻素联合电针治疗组可以通过重新平衡BDNF和IL-6的表达水平来恢复脑缺血导致的神经元细胞的异常形态。我们的研究表明,天麻素联合电针对大鼠脑缺血损伤有显著的保护作用,可能是通过调节BDNF和IL-6的表达。这种联合疗法优于单一药物或电针疗法。
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引用次数: 0
Interhemispheric functional in age-related macular degeneration patient: a resting-state functional MRI study. 老年性黄斑变性患者的半球间功能:静息态功能磁共振成像研究。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-15 DOI: 10.1097/WNR.0000000000002045
Yi-Jing Jiang, Ping-Hong Lai, Xin Huang

Age-related macular degeneration (AMD) is a prevalent disease leading to severe visual impairment in the elderly population. Despite this, the pathogenesis of AMD remains largely unexplored. The application of resting-state functional MRI (rs-fMRI) allows for the detection of coherent intrinsic brain activities along with the interactions taking place between the two hemispheres. In the frame of our study, we utilize voxel-mirrored homotopic connectivity (VMHC) as an rs-fMRI method to carry out a comparative analysis of functional homotopy between the two hemispheres with the aim of further understanding the pathogenesis of AMD patients. In our study, we utilized the VMHC method to explore levels of brain activity in individuals diagnosed with AMD, planning to investigate potential links with their clinical characteristics. We extended our invitation to 20 AMD patients and 20 healthy controls from Jiangxi Provincial People's Hospital to participate in this research. rs-fMRIs were captured for each participant, and associated neural activity levels were examined using the VMHC method. Remarkably, our comparative examination with the healthy control group revealed significantly reduced VMHC in the cuneus, superior occipital lobe, precentral gyrus, and superior parietal lobule in the patient cohort. Utilizing the VMHC method allows us to identify discrepancies in the visual pathways of AMD patients compared with standard controls, potentially explaining the common challenges among AMD patients with object recognition, face recognition, and reading.

老年性黄斑变性(AMD)是一种导致老年人群严重视力损伤的常见疾病。尽管如此,老年黄斑变性的发病机理在很大程度上仍未得到探索。应用静息态功能磁共振成像(rs-fMRI)可以检测大脑固有的连贯活动以及两个半球之间的相互作用。在我们的研究框架中,我们利用体素映射同位连接(VMHC)作为一种rs-fMRI方法,对两个半球之间的功能同位性进行比较分析,旨在进一步了解AMD患者的发病机制。在我们的研究中,我们利用 VMHC 方法探讨了确诊为 AMD 患者的大脑活动水平,并计划研究其与临床特征之间的潜在联系。我们邀请了江西省人民医院的20名AMD患者和20名健康对照者参与这项研究。我们为每位参与者采集了rs-fMRI,并使用VMHC方法检测了相关的神经活动水平。值得注意的是,我们与健康对照组的对比检查发现,患者群中楔叶、枕叶上部、中央前回和顶叶上部的 VMHC 明显减少。利用VMHC方法,我们可以发现AMD患者的视觉通路与标准对照组的差异,这可能解释了AMD患者在物体识别、人脸识别和阅读方面面临的共同挑战。
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引用次数: 0
Elevated calcineurin activity in primary astrocytes leads to the dephosphorylation of connexin 43 in conjunction with increased membrane permeability. 原代星形胶质细胞中钙调素活性的升高会导致连接蛋白 43 的去磷酸化,同时增加膜的通透性。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-07-01 Epub Date: 2024-05-17 DOI: 10.1097/WNR.0000000000002051
Blaine E Weiss, Susan D Kraner, Irina A Artiushin, Christopher M Norris

Hyperactivation of the Ca2+/calmodulin-dependent phosphatase calcineurin (CN) is observed in reactive astrocytes associated with neuroinflammation and progressive degenerative diseases, like Alzheimer's disease. Apart from key transcription factors (e.g. nuclear factor of activated t cells and nuclear factor-κB) very few other CN-dependent pathways have been studied in astrocytes. The hemichannel protein, connexin 43 (Cx43) is found at high levels in astrocytes and contains a CN-sensitive Ser residue near its carboxy terminus. CN-dependent dephosphorylation of Cx43 has been reported in primary astrocytes treated with injurious stimuli, but much remains unknown about CN/Cx43 interactions in the context of neuroinflammation and disease. Western blots were used to assess total Cx43 and dephosphorylated Cx43 subtypes in rat embryonic primary astrocytes treated with a hyperactive CN fragment (ΔCN, via adenovirus), or with a proinflammatory cytokine cocktail. Under similar treatment conditions, an ethidium bromide (EtBr) uptake assay was used to assess membrane permeability. Effects of ΔCN and cytokines were tested in the presence or absence of the CN inhibitor, cyclosporin A. A connexin inhibitor, carbenoxolone was also used in EtBr assays to assess the involvement of connexins in membrane permeability. Treatment with ΔCN or cytokines increased dephosphorylated Cx43 levels in conjunction with increased membrane permeability (elevated EtBr uptake). Effects of ΔCN or cytokine treatment were blocked by cyclosporine A. Treatment-induced changes in EtBr uptake were also inhibited by carbenoxolone. The results suggest that Cx43 hemichannels could be an important mechanism through which astrocytic CN disrupts neurologic function associated with neurodegenerative disease.

在与神经炎症和渐进性退行性疾病(如阿尔茨海默病)相关的反应性星形胶质细胞中,可以观察到 Ca2+/calmodulin 依赖性磷酸酶钙调磷酸酶(CN)的过度激活。除了关键的转录因子(如活化 t 细胞核因子和核因子-κB)外,很少有人研究过星形胶质细胞中其他依赖 CN 的途径。在星形胶质细胞中发现了高水平的半通道蛋白--连接蛋白 43(Cx43),其羧基末端附近含有对 CN 敏感的 Ser 残基。据报道,在受到损伤性刺激的原代星形胶质细胞中,Cx43会发生CN依赖性去磷酸化,但在神经炎症和疾病的背景下,CN/Cx43之间的相互作用仍有很多未知之处。研究人员使用 Western 印迹来评估用高活性 CN 片段(ΔCN,通过腺病毒)或促炎细胞因子鸡尾酒处理的大鼠胚胎原代星形胶质细胞中的总 Cx43 和去磷酸化 Cx43 亚型。在类似的处理条件下,使用溴化乙锭(EtBr)摄取试验来评估膜通透性。在有或没有氯化萘抑制剂环孢素 A 的情况下,测试了ΔCN 和细胞因子的影响。用ΔCN或细胞因子处理会增加去磷酸化的Cx43水平,同时增加膜通透性(EtBr摄取量增加)。环孢素 A 可阻断ΔCN 或细胞因子处理的影响。这些结果表明,Cx43 半通道可能是星形胶质细胞 CN 干扰与神经退行性疾病相关的神经功能的重要机制。
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引用次数: 0
Danshensu reduces neuronal excitability by enhancing potassium currents in bushy cells in the mouse cochlear nucleus. 丹参素通过增强小鼠耳蜗神经核丛细胞中的钾电流来降低神经元的兴奋性。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI: 10.1097/WNR.0000000000002047
Mengfan Xu, Liqin Wang, Geng-Lin Li, Zheng-Quan Tang

Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 μm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 μm and Danshensu of 200 μm failed to cause significantly more enhancement on K+ currents when compared to that of 100 μm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.

丹参素又称丹酚酸 A,是从一种传统中草药丹参(丹参)中提取的主要活性化合物。虽然丹参素的抗氧化和神经保护作用已得到充分证实,但其潜在机制却鲜为人知。在本研究中,我们试图研究丹参素是否以及如何调节中枢神经系统的神经元兴奋性和电压门控离子电流。我们制备了小鼠脑干的脑片,并对耳蜗核前腹部的丛状细胞进行了贴片钳记录。内部使用QX-314阻断Na+电流,而四乙基铵和4-氨基吡啶则用于分离不同亚型的K+电流。我们发现,100 μm 的丹参素能使灌木细胞的输入电阻降低约 60%,并使尖峰正向电压阈值移动约 7 mV,从而显著降低了兴奋性。此外,我们还发现丹参素导致兴奋性降低的原因是这些神经元中的电压门控 K+ 电流增强,其中低电压激活的 IK,A 增强了约 100%,而高电压激活的 IK,dr 则增强了约 30%。最后,我们发现丹参素对 K+ 电流的影响是剂量依赖性的,50 μm 的丹参素对 K+ 电流没有增强作用,而 200 μm 的丹参素与 100 μm 的丹参素相比,对 K+ 电流的增强作用并不明显。我们发现丹参素通过增强电压门控K+电流来降低中枢神经系统神经元的兴奋性,为其在体内广泛存在的神经保护作用提供了机理支持。
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引用次数: 0
The activation of AMPK/PGC-1α/GLUT4 signaling pathway through early exercise improves mitochondrial function and mitigates ischemic brain damage. 通过早期运动激活 AMPK/PGC-1α/GLUT4 信号通路,可改善线粒体功能,减轻缺血性脑损伤。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-07-01 Epub Date: 2024-05-15 DOI: 10.1097/WNR.0000000000002048
Xinyue Wu, Chen Li, Changkai Ke, Chuan Huang, Bingchen Pan, Chunxiao Wan

Mitochondria play a crucial role in maintaining cellular energy supply and serve as a source of energy for repairing nerve damage following a stroke. Given that exercise has the potential to enhance energy metabolism, investigating the impact of exercise on mitochondrial function provides a plausible mechanism for stroke treatment. In our study, we established the middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats and implemented early exercise intervention. Neurological severity scores, beam-walking test score, and weight were used to evaluate neurological function. The volume of cerebral infarction was measured by MRI. Nerve cell apoptosis was detected by TUNEL staining. Mitochondrial morphology and structure were detected by mitochondrial electron microscopy. Mitochondrial function was assessed using membrane potential and ATP measurements. Western blotting was used to detect the protein expression of AMPK/PGC-1α/GLUT4. Through the above experiments, we found that early exercise improved neurological function in rats after MCAO, reduced cerebral infarction volume and neuronal apoptosis, promoted the recovery of mitochondrial morphology and function. We further examined the protein expression of AMPK/PGC-1α/GLUT4 signaling pathway and confirmed that early exercise was able to increase its expression. Therefore, we suggest that early exercise initiated the AMPK/PGC-1α/GLUT4 signaling pathway, restoring mitochondrial function and augmenting energy supply. This, in turn, effectively improved both nerve and body function in rats following ischemic stroke.

线粒体在维持细胞能量供应方面起着至关重要的作用,是中风后修复神经损伤的能量来源。鉴于运动具有增强能量代谢的潜力,研究运动对线粒体功能的影响为中风治疗提供了一种可信的机制。在我们的研究中,我们在 Sprague-Dawley 大鼠中建立了大脑中动脉闭塞(MCAO)模型,并实施了早期运动干预。神经严重程度评分、横梁行走测试评分和体重用于评估神经功能。核磁共振成像测量了脑梗塞的体积。通过 TUNEL 染色检测神经细胞凋亡。线粒体电子显微镜检测线粒体形态和结构。线粒体功能通过膜电位和 ATP 测量进行评估。用 Western 印迹法检测 AMPK/PGC-1α/GLUT4 的蛋白表达。通过以上实验,我们发现早期运动能改善 MCAO 后大鼠的神经功能,减少脑梗死体积和神经元凋亡,促进线粒体形态和功能的恢复。我们进一步检测了AMPK/PGC-1α/GLUT4信号通路的蛋白表达,证实早期运动能够增加其表达。因此,我们认为早期运动启动了AMPK/PGC-1α/GLUT4信号通路,恢复了线粒体功能并增加了能量供应。这反过来又有效改善了缺血性中风后大鼠的神经和身体功能。
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引用次数: 0
Heat stress induces IL-1β and IL-18 overproduction via ROS-activated NLRP3 inflammasome: implication in neuroinflammation in mice with heat stroke. 热应激通过ROS激活的NLRP3炎性体诱导IL-1β和IL-18过度分泌:与中暑小鼠的神经炎症有关。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-06-05 Epub Date: 2024-04-29 DOI: 10.1097/WNR.0000000000002042
Guoqiang Du, Zixi Yang, Yin Wen, Xusheng Li, Wenhong Zhong, Zhuo Li, Shiying Zhang, Ensi Luo, Hongguang Ding, Weifeng Li

Heat stroke induced cerebral damage via neuroinflammation. This study aimed to approach whether heat stress would promote NOD-like receptor protein 3 (NLRP3) inflammasome via reactive oxygen species (ROS). The mice were randomly divided into the sham group, the heat stress group, and the heat stress + TEMPOL (ROS scavenger) group. And the NLRP3 -/- mice were applied and divided into the NLRP3 -/-  + sham group and the NLRP3 -/-  + heat stress group. Furthermore, the BV2 cells were divided into four groups following the intervention measures: the heat stress + TEMPOL group, the heat stress + Z-VAD-FMK (caspase-1 inhibitor) group, the heat stress group, and the control group. ROS levels were examined. The expression levels of NLRP3, caspase-1, IL-1β, and IL-18 were detected by western blotting and double immunofluorescence. We found that heat stress attack induced excessive ROS in microglia and subsequently activated NLRP3 inflammasome in both mice and BV2 cells. When ROS scavenged, the expression level of NLRP3 was downregulated. Furthermore, with NLRP3 inflammasome activation, the expression levels of caspase-1, IL-1β, and IL-18 were increased. In NLRP3 -/- mice, however, the caspase-1, IL-1β, and IL-18 were significantly declined. Further experiments showed that pretreatment of caspase-1 inhibitor decreased the expression levels of IL-1β and IL-18. These results suggest that heat stress attack caused neuroinflammation via excessive ROS activating the NLRP3 inflammasome in microglia cells.

中暑通过神经炎症诱发脑损伤。本研究旨在探讨热应激是否会通过活性氧(ROS)促进NOD样受体蛋白3(NLRP3)炎性体。小鼠被随机分为假组、热应激组和热应激+TEMPOL(ROS清除剂)组。NLRP3-/-小鼠被应用并分为NLRP3-/-+假组和NLRP3-/-+热应激组。此外,在采取干预措施后,将 BV2 细胞分为四组:热应激 + TEMPOL 组、热应激 + Z-VAD-FMK(caspase-1 抑制剂)组、热应激组和对照组。检测 ROS 水平。通过 Western 印迹和双重免疫荧光检测了 NLRP3、caspase-1、IL-1β 和 IL-18 的表达水平。我们发现,热应激攻击会诱导小胶质细胞产生过量的 ROS,进而激活小鼠和 BV2 细胞中的 NLRP3 炎性体。清除ROS后,NLRP3的表达水平被下调。此外,随着 NLRP3 炎性体的激活,caspase-1、IL-1β 和 IL-18 的表达水平也升高了。但在 NLRP3-/- 小鼠中,caspase-1、IL-1β 和 IL-18 的表达水平明显下降。进一步的实验表明,预处理 caspase-1 抑制剂可降低 IL-1β 和 IL-18 的表达水平。这些结果表明,热应激攻击通过过量的 ROS 激活小胶质细胞中的 NLRP3 炎性体引起神经炎症。
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引用次数: 0
Caspase-1 deletion reveals pyroptosis participates in neural damage induced by cerebral ischemia/reperfusion in tMCAO model mice. Caspase-1缺失揭示了热蛋白沉积参与了tMCAO模型小鼠脑缺血/再灌注诱发的神经损伤。
IF 1.6 4区 医学 Q3 Neuroscience Pub Date : 2024-06-05 Epub Date: 2024-04-29 DOI: 10.1097/WNR.0000000000002041
Qing-Na Hao, Xiao-Bo Xue, Heng Zhou, Zhao-Li Hu

Pyroptosis, a form of programmed cell death, drives inflammation in the context of cerebral ischemia/reperfusion. The molecular mechanism of pyroptosis underlying ischemia/reperfusion, however, is not fully understood. The transient middle cerebral artery occlusion was applied to wild-type and caspase-1 knockout mice. 2,3,5-Triphenyltetrazolium chloride-staining and immunohistochemistry were used to identify the ischemic region, and western blot and immunofluorescence for the examination of neuronal pyroptosis. The expression of inflammatory factors and the behavioral function assessments were further conducted to examine the effects of caspase-1 knockout on protection against ischemia/reperfusion injury. Ischemia/reperfusion injury increased pyroptosis-related signals represented by the overexpression of pyroptosis-related proteins including caspase-1 and gasdermin D (GSDMD). Meanwhile, the number of GSDMD positive neurons increased in penumbra by immunofluorescence staining. Compared with wild-type mice, those with caspase-1 knockout exhibited decreased levels of pyroptosis-related proteins following ischemia/reperfusion. Furthermore, ischemia/reperfusion attack-induced brain infarction, cerebral edema, inflammatory factors, and neurological outcomes were partially improved in caspase-1 knockout mice. The data indicate that pyroptosis participates in ischemia/reperfusion induced-damage, and the caspase-1 might be involved, it provides some new insights into the molecular mechanism of ischemia.

在脑缺血/再灌注的情况下,嗜热细胞增多症(一种程序性细胞死亡)会引发炎症。然而,缺血/再灌注所引发的裂解热的分子机制尚未完全明了。对野生型小鼠和 caspase-1 基因敲除小鼠进行瞬时大脑中动脉闭塞实验。采用 2,3,5-三苯基氯化四氮唑染色法和免疫组化法确定缺血区域,并用 Western 印迹法和免疫荧光法检测神经元热解。为了研究caspase-1基因敲除对缺血再灌注损伤的保护作用,还进一步进行了炎症因子表达和行为功能评估。缺血/再灌注损伤增加了热蛋白沉积相关信号,表现为包括caspase-1和gasdermin D(GSDMD)在内的热蛋白沉积相关蛋白的过度表达。同时,通过免疫荧光染色,半影中 GSDMD 阳性神经元的数量增加。与野生型小鼠相比,caspase-1基因敲除的小鼠在缺血/再灌注后表现出热休克相关蛋白水平的下降。此外,缺血再灌注诱发的脑梗塞、脑水肿、炎症因子和神经系统结果在caspase-1基因敲除小鼠中得到了部分改善。这些数据表明,热蛋白沉积参与了缺血/再灌注诱导的损伤,而caspase-1可能参与其中,这为缺血的分子机制提供了一些新的见解。
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