阿尔茨海默病(Alzheimer’s disease, AD)是一种进行性的神经退行性疾病,也是最常见的痴呆症。世界上65岁及以上的老年人超过10%患有AD。AD在神经病理学上与特定脑区域中神经元和突触的进行性损失、淀粉样蛋白斑块和神经纤维缠结的沉积...阿尔茨海默病(Alzheimer’s disease, AD)是一种进行性的神经退行性疾病,也是最常见的痴呆症。世界上65岁及以上的老年人超过10%患有AD。AD在神经病理学上与特定脑区域中神经元和突触的进行性损失、淀粉样蛋白斑块和神经纤维缠结的沉积、神经炎症、血脑屏障(Blood-brain barrier, BBB)破坏、线粒体功能障碍及氧化应激相关。尽管做了大量的努力,仍然没有治愈该疾病的方法。近年来,随着科学家们对外泌体进行深入研究,发现神经源性外泌体在治疗包括AD在内的各种疾病方面具有很大的前景,因为它们含有多种抗凋亡、抗炎和抗氧化成分。不仅如此,神经源性外泌体还促进神经发生和血管生成并修复受损的BBB。因此,本文主要概述外泌体的生物发生及吸收、总结神经源性外泌体治疗AD的最新数据及讨论神经源性外泌体治疗AD的挑战和前景。Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. More than 10% of the world’s elderly people aged 65 and over have AD. AD is neuropathologically associated with progressive loss of neurons and synapses in specific brain regions, deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and oxidative stress. Despite a lot of efforts, there is still no cure for the disease. In recent years, as scientists have conducted in-depth research on exosomes, it has been found that neurogenic exosomes have great promise in the treatment of various diseases, including AD, because they contain a variety of anti-apoptotic, anti-inflammatory, and antioxidant components. Not only that, neurogenic exosomes also promote neurogenesis and angiogenesis and repair damaged BBBs. Therefore, this article mainly summarizes the biogenesis and absorption of exosomes, summarizes the latest data of neurogenic exosomes in the treatment of AD, and discusses the challenges and prospects of neurogenic exosomes in the treatment of AD.展开更多
文摘目的研究长链非编码RNA(long non-coding RNA,LncRNA)LINC01137在非小细胞肺癌(nonsmall cell lung cancer,NSCLC)免疫逃逸中的生物学功能及其潜在的调节机制。方法采集24例健康志愿者和24例NSCLC患者血液样本,并收集NSCLC肿瘤组织和癌旁组织检测LINC01137水平。利用Starbase数据库预测LINC01137与miR-22-3p的结合位点,荧光素酶报告基因分析进行验证。采用A549细胞来源的外泌体和/或sh-LINC01137干扰序列转染A549细胞,检测细胞增殖和侵袭能力;收集转染后的细胞上清液培养CD8^(+)T细胞,检测CD8^(+)T细胞耗竭标志物干扰素-γ(interfereron-γ,IFN-γ)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、颗粒霉素B(granzyme B)和白细胞介素-2(interleukin-2,IL-2)水平,以及PD-1+Tim3^(+)CD8^(+)T细胞百分比。采用外泌体和/或miR-22-3p模拟物(miR-22-3p mimic)转染CD8^(+)T细胞,检测PD-1蛋白水平。结果与癌旁组织相比,NSCLC肿瘤组织中LINC01137表达(3.357±0.548 vs 1.011±0.371)明显升高;与健康志愿者相比,NSCLC患者外周血LINC01137表达(3.216±0.342 vs 1.007±0.313)亦明显升高,差异具有统计学意义(t=-17.367,-17.147,均P<0.001)。肿瘤组织LINC01137表达与外周血中LINC01137表达呈正相关(r=0.755,P<0.05)。在A549细胞来源的外泌体中LINC01137显著富集。与Exo+sh-NC组相比,Exo+sh-LINC01137组细胞活力(65.852%±4.715%vs 100.153%±11.934%)及细胞侵袭(21.464%±3.481%vs 43.126%±1.447%)能力显著降低,差异具有统计学意义(t=4.630,9.953,均P<0.01)。NSCLC患者外周血中LINC01137表达和CD8^(+)T细胞百分比呈负相关(r=-0.520,P<0.05)。与Exo+sh-NC组相比,Exo+sh-LINC01137组IFN-γ(3865.314±543.852 pg/ml vs 1786.971±105.982 pg/ml),TNF-α(4631.930±510.715pg/ml vs 1973.242±379.623pg/ml),Granzyme B(3876.496±312.438pg/ml vs 1879.439±287.584pg/ml)和IL-2 mRNA水平(3.286±0.437 vs 1.015±0.314)升高,PD-1+Tim3^(+)CD8^(+)T细胞百分比(7.680%±2.185%vs 18.952%±3.216%)降低,差异具有统计学意义(t=-6.497,-7.237,-8.146,-7.310,5.021,均P<0.01)。miR-22-3p是LINC01137的靶基因。与Exo+NC mimic组相比,Exo+miR-22-3p组PD-1蛋白水平(0.384±0.087 vs 1.003±0.147)显著降低,差异有统计学意义(t=6.277,P<0.01)。结论NSCLC患者肿瘤组织及外周血中LINC01137表达显著上调;NSCLC细胞来源的外泌体中LINC01137通过靶向CD8^(+)T细胞中miR-22-3p并抑制其表达,诱导CD8^(+)T细胞耗竭,促进NSCLC细胞免疫逃逸。
文摘阿尔茨海默病(Alzheimer’s disease, AD)是一种进行性的神经退行性疾病,也是最常见的痴呆症。世界上65岁及以上的老年人超过10%患有AD。AD在神经病理学上与特定脑区域中神经元和突触的进行性损失、淀粉样蛋白斑块和神经纤维缠结的沉积、神经炎症、血脑屏障(Blood-brain barrier, BBB)破坏、线粒体功能障碍及氧化应激相关。尽管做了大量的努力,仍然没有治愈该疾病的方法。近年来,随着科学家们对外泌体进行深入研究,发现神经源性外泌体在治疗包括AD在内的各种疾病方面具有很大的前景,因为它们含有多种抗凋亡、抗炎和抗氧化成分。不仅如此,神经源性外泌体还促进神经发生和血管生成并修复受损的BBB。因此,本文主要概述外泌体的生物发生及吸收、总结神经源性外泌体治疗AD的最新数据及讨论神经源性外泌体治疗AD的挑战和前景。Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. More than 10% of the world’s elderly people aged 65 and over have AD. AD is neuropathologically associated with progressive loss of neurons and synapses in specific brain regions, deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and oxidative stress. Despite a lot of efforts, there is still no cure for the disease. In recent years, as scientists have conducted in-depth research on exosomes, it has been found that neurogenic exosomes have great promise in the treatment of various diseases, including AD, because they contain a variety of anti-apoptotic, anti-inflammatory, and antioxidant components. Not only that, neurogenic exosomes also promote neurogenesis and angiogenesis and repair damaged BBBs. Therefore, this article mainly summarizes the biogenesis and absorption of exosomes, summarizes the latest data of neurogenic exosomes in the treatment of AD, and discusses the challenges and prospects of neurogenic exosomes in the treatment of AD.
