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Asking one mechanism in glial cells during neuroinflammation. 神经炎症期间神经胶质细胞的一种机制。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-06-03 DOI: 10.4103/NRR.NRR-D-24-00225
Xiaoli Guo, Chikako Harada, Takayuki Harada
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引用次数: 0
Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion. 聚乙二醇对坐骨神经异体移植物具有免疫保护作用,但行为恢复和移植物耐受性需要神经出血和轴突融合。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-04-03 DOI: 10.4103/NRR.NRR-D-23-01220
Tyler A Smith, Liwen Zhou, Cameron L Ghergherehchi, Michelle Mikesh, Cathy Z Yang, Haley O Tucker, JuliAnne Allgood, Jared S Bushman, George D Bittner

JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative c

JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff由于轴突再生缓慢且不准确,使用(存活的)周围神经异体移植修复消融型(节段性缺失)周围神经损伤的行为恢复迟缓或不佳。此外,这种外周神经异体移植还会受到宿主免疫系统的免疫排斥。相比之下,通过聚乙二醇融合外周神经异体移植修复的外周神经损伤可在数周内表现出极佳的行为恢复能力,减少免疫反应,而且许多轴突不会发生沃勒变性。在本研究之前,我们还不知道神经出血和聚乙二醇融合轴突的相对作用与聚乙二醇本身的影响。我们假设,聚乙二醇可能具有一定的免疫保护作用,但聚乙二醇融合是防止沃勒里变性和功能/行为恢复所必需的。我们研究了在没有聚乙二醇诱导轴突融合的情况下,聚乙二醇溶液本身如何影响功能和行为恢复以及周围神经异体移植的形态学和免疫学反应。使用与聚乙二醇融合外周神经异体移植物相同的溶液,按照修改后的方案修复近交Sprague-Dawley大鼠的消融型坐骨神经损伤,但外周神经异体移植物被松散缝合(松散缝合聚乙二醇),并故意留出1-2毫米的间隙,以防止外周神经异体移植物轴突与宿主轴突因聚乙二醇而融合。与未经聚乙二醇处理的阴性对照外周神经异体移植物相似,与聚乙二醇融合外周神经异体移植物不同的是,使用松散缝合的聚乙二醇外周神经异体移植物的动物在术后 7 天时所有轴突均出现沃勒氏变性,髓鞘变性,在术后 42 天时坐骨神经介导的行为功能仍未恢复。聚乙二醇融合外周神经异体移植物没有出现其他排斥反应的形态学迹象,如雪旺细胞基底层管塌陷,但在阴性对照组和松散缝合的聚乙二醇外周神经异体移植物中,术后21天时可普遍观察到这种排斥反应。与阴性对照外周神经异体移植物相比,松弛缝合的聚乙二醇外周神经异体移植物具有更多的促炎巨噬细胞和更少的抗炎巨噬细胞。虽然松弛缝合的聚乙二醇外周神经异体移植物和阴性对照外周神经异体移植物的 T 细胞计数同样高,但术后 14 天时,松弛缝合的聚乙二醇外周神经异体移植物表达的一些对 T 细胞活化很重要的细胞因子/凝血因子的水平要低得多。术后 21 天时,松解缝合的聚乙二醇周围神经异体移植物的 MHCI 表达升高,但与阴性对照组相比,MHCII 表达略低。我们的结论是,虽然聚乙二醇本身会降低周围神经异体移植物的某些免疫反应,但要防止这些轴突的沃勒变性和周围神经异体移植物的免疫排斥反应,并恢复感觉/运动功能和自主行为,就必须成功地对某些轴突进行聚乙二醇融合修复。聚乙二醇融合技术的转化将改变目前临床实践中等待数天至数月才能修复消融周围神经损伤的模式。
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引用次数: 0
Corrigendum: Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer's disease. 更正:枸橘精提取物对自噬的激活可改善淀粉样β诱导的阿尔茨海默氏症细胞死亡和认知障碍。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-07-08 DOI: 10.4103/NRR.NRR-D-24-00581
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引用次数: 0
Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis. 缺氧预处理的骨髓间充质干细胞可保护神经元免受心脏骤停诱发的热休克。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-06-03 DOI: 10.4103/NRR.NRR-D-23-01922
Xiahong Tang, Nan Zheng, Qingming Lin, Yan You, Zheng Gong, Yangping Zhuang, Jiali Wu, Yu Wang, Hanlin Huang, Jun Ke, Feng Chen

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

摘要:由于炎症、线粒体功能障碍和心肺复苏后神经损伤,心脏骤停可导致严重的神经损伤。低氧预处理已被证明可改善骨髓间充质干细胞的迁移和存活,并减少心脏骤停后的热休克,但低氧预处理骨髓间充质干细胞保护心脏骤停后脑损伤的具体机制尚不清楚。为此,我们建立了骨髓间充质干细胞和缺氧-缺糖原代神经元的体外共培养模型,发现缺氧预处理增强了骨髓基质干细胞对神经元热休克的保护作用,这可能是通过抑制MAPK和核因子κB通路实现的。随后,我们在窒息诱导的心脏骤停8分钟大鼠模型中,将缺氧预处理的骨髓间充质干细胞移植到自发循环恢复后的侧脑室。结果表明,缺氧预处理的骨髓间充质干细胞可显著减少心脏骤停诱导的神经元猝死、氧化应激和线粒体损伤,而骨髓间充质干细胞中磷酸果激酶肝脏同工酶的敲除抑制了这些效应。总之,缺氧预处理骨髓间充质干细胞为心脏骤停后的神经元损伤提供了一种很有前景的治疗方法,其有益作用可能与缺氧预处理后磷酸果糖激酶肝脏同工酶的表达增加有关。
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引用次数: 0
Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats. 运动障碍大鼠皮质纹状体伽马振荡受多巴胺 D3 受体调节
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-03-01 DOI: 10.4103/NRR.NRR-D-23-01240
Pengfei Wang, Yuewei Bi, Min Li, Jiazhi Chen, Zhuyong Wang, Huantao Wen, Ming Zhou, Minjie Luo, Wangming Zhang

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia. Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia. Currently, studies have reported increased oscillation power in cases of levodopa-induced dyskinesia. However, little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia. Furthermore, the role of the dopamine D3 receptor, which is implicated in levodopa-induced dyskinesia, in movement disorder-related changes in neural oscillations is unclear. We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson's disease. Furthermore, levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components, as well as bidirectional primary motor cortex (M1) ↔ dorsolateral striatum gamma flow. Administration of PD128907 (a selective dopamine D3 receptor agonist) induced dyskinesia and excessive gamma oscillations with a bidirectional M1 ↔ dorsolateral striatum flow. However, administration of PG01037 (a selective dopamine D3 receptor antagonist) attenuated dyskinesia, suppressed gamma oscillations and cortical gamma aperiodic components, and decreased gamma causality in the M1 → dorsolateral striatum direction. These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity, and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff 长期服用左旋多巴可导致左旋多巴诱发的运动障碍。伽马振荡是左旋多巴诱发的运动障碍中神经电活动异常的一个公认标志。目前,已有研究报告称左旋多巴诱发的运动障碍会增加振荡功率。然而,人们对左旋多巴诱发的运动障碍如何改变伽马振荡的其他电生理参数知之甚少。此外,与左旋多巴诱导的运动障碍有关的多巴胺 D3 受体在运动障碍相关的神经振荡变化中的作用尚不清楚。我们发现,在帕金森病模型中,皮质-纹状体β振荡的功能连接性增强。此外,左旋多巴的应用增强了皮质-纹状体投射中的皮质伽马振荡和皮质伽马非周期性成分,以及双向初级运动皮质(M1)↔背外侧纹状体伽马流。给药 PD128907(一种选择性多巴胺 D3 受体激动剂)会诱发运动障碍和过度伽马振荡,并伴有 M1 ↔ 背外侧纹状体双向伽马流。然而,服用 PG01037(一种选择性多巴胺 D3 受体拮抗剂)可减轻运动障碍,抑制伽马振荡和皮层伽马非周期性成分,并降低 M1 → 背外侧纹状体方向的伽马因果关系。这些研究结果表明,多巴胺 D3 受体在运动障碍相关的振荡活动中发挥作用,并有可能成为左旋多巴诱发的运动障碍的治疗靶点。
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引用次数: 0
The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence. 间充质干细胞衍生的细胞外囊泡在改善青春期暴饮暴食式乙醇治疗诱发的海马NLRP3炎症中的新作用。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-06-24 DOI: 10.4103/NRR.NRR-D-23-01397
Susana Mellado, María José Morillo-Bargues, Carla Perpiñá-Clérigues, Francisco García-García, Victoria Moreno-Manzano, Consuelo Guerri, María Pascual

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff我们先前的研究报告指出,乙醇处理的星形胶质细胞和慢性酒精喂养小鼠的NLRP3(NOD-、LRR-和含吡咯啉结构域蛋白3)-炎症小体复合物的激活可能与神经炎症和脑损伤有关。研究表明,间充质干细胞衍生的细胞外囊泡(MSC-EVs)可恢复前额叶皮层的神经炎症反应以及髓鞘和突触结构改变,并缓解青少年小鼠因狂饮乙醇诱发的认知和记忆功能障碍。考虑到间充质干细胞源性细胞外囊泡所含分子的治疗作用,本研究分析了给予从脂肪组织分离的间充质干细胞源性细胞外囊泡抑制NLRP3炎性体的激活,是否能够减轻暴饮暴食治疗的青少年小鼠的海马神经炎症。我们证实,间充质干细胞衍生的细胞外囊泡能改善海马NLRP3炎性体复合体和其他NLRs炎性体(如、以及炎症基因的改变(白细胞介素-1β、白细胞介素-18、诱导型一氧化氮合酶、核因子-kappa B、单核细胞介素-1、核因子-kappa B)、核因子-kappa B、单核细胞趋化蛋白-1 和 C-X3-C motif 趋化因子配体 1)和 miRNA(miR-21a-5p、miR-146a-5p 和 miR-141-5p)的变化。生物信息学分析进一步揭示了 miR-21a-5p 和 miR-146a-5p 与炎症靶基因和 NOD 样受体信号通路的关系。综上所述,这些发现提供了新的证据,证明间充质干细胞衍生的EVs具有治疗潜力,可改善青春期暴饮暴食诱发的与NLRP3炎性体激活相关的海马神经炎症反应。
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引用次数: 0
Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future. 小鼠 Müller 胶质重编程研究:回顾过去十年,展望未来。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-04-16 DOI: 10.4103/NRR.NRR-D-23-01612
Zhiyuan Yin, Jiahui Kang, Xuan Cheng, Hui Gao, Shujia Huo, Haiwei Xu

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.

Müller胶质细胞是视网膜中最重要的胶质细胞,在维持视网膜健康和疾病状态下的平衡方面发挥着重要作用。在斑马鱼等低等脊椎动物中,这些细胞承担着自发性视网膜再生的责任,内源性Müller胶质细胞发生增殖,转化为Müller胶质细胞衍生的祖细胞,随后再生整个视网膜并恢复其功能。相反,小鼠和人类视网膜中的Müller胶质细胞则表现出有限的神经重编程能力。因此,Müller胶质细胞重编程是治疗眼部神经退行性疾病的一种很有前景的策略。通过各种技术,小鼠 Müller 胶质重编程已取得显著成功。分子、遗传、表观遗传、形态学和生理学评估方面的进步使得记录和研究小鼠Müller胶质细胞编程过程变得更加容易。然而,仍有一些问题阻碍着重编程效率和成熟度的提高。因此,了解重编程机制对于探索提高Müller胶质细胞重编程效率的因素以及开发新型Müller胶质细胞重编程策略至关重要。本综述介绍了相对成功的Müller胶质细胞重编程策略的最新进展。它还为开发新的小鼠Müller胶质细胞重编程策略提供了基础,包括表观遗传重塑、代谢调节、免疫调节、化学小分子调控、细胞外基质重塑和细胞-细胞融合,以实现小鼠Müller胶质细胞重编程。
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引用次数: 0
Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming. 全氟戊烷氧载纳米液滴通过新陈代谢重编程减少小胶质细胞活化
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-04-03 DOI: 10.4103/NRR.NRR-D-23-01299
Wanxian Luo, Chuanhui Xu, Linxi Li, Yunxiang Ji, Yezhong Wang, Yingjia Li, Yongyi Ye

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson's disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson's disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography-tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff小胶质细胞是大脑中的主要免疫细胞,已被公认为是治疗包括帕金森病在内的中枢神经系统神经退行性疾病的有希望的治疗靶点。据报道,纳米级全氟碳液滴不仅具有很高的携氧能力,还具有显著的抗炎特性。然而,人们对全氟戊烷在小胶质细胞介导的中枢炎症反应中的作用仍知之甚少。在这项研究中,我们开发了基于全氟戊烷的载氧纳米液滴(PFP-OLNDs),并发现使用这些液滴进行预处理可抑制脂多糖诱导的 M1 型小胶质细胞在体外和体内的活化,并可抑制帕金森病小鼠模型中的小胶质细胞活化。抑制小胶质细胞可降低体外炎症反应、氧化应激和细胞迁移能力。因此,神经毒性效应得到缓解,从而减轻了神经元退化。此外,超高效液相色谱-串联质谱分析表明,PFP-OLNDs 的抗炎作用主要来自于对小胶质细胞代谢重编程的调节。我们进一步发现,PFP-OLNDs 通过 AKT-mTOR-HIF-1α 通路调控小胶质细胞代谢重编程。总之,我们的研究结果表明,本研究中构建的新型 PFP-OLNDs 可通过代谢重编程缓解小胶质细胞介导的中枢炎症反应。
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引用次数: 0
Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions. 反应性星形胶质细胞中 PI3K/蛋白激酶 B 通路激活的影响:从有害影响到保护功能。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-06-03 DOI: 10.4103/NRR.NRR-D-23-01756
Ramón Pérez-Núñez, María Fernanda González, Ana María Avalos, Lisette Leyton

Astrocytes are the most abundant type of glial cell in the central nervous system. Upon injury and inflammation, astrocytes become reactive and undergo morphological and functional changes. Depending on their phenotypic classification as A1 or A2, reactive astrocytes contribute to both neurotoxic and neuroprotective responses, respectively. However, this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries. Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles, which emphasizes the heterogeneous nature of their reactivity. Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types, releasing cytokines, and influencing the immune response. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior, as evidenced by in silico , in vitro , and in vivo results. In astrocytes, inflammatory cues trigger a cascade of molecular events, where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses. Here, we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation. We highlight the involvement of various signaling pathways that regulate astrocyte reactivity, including the PI3K/AKT/mammalian target of rapamycin (mTOR), α v β 3 integrin/PI3K/AKT/connexin 43, and Notch/PI3K/AKT pathways. While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage, evidence suggests that activating this pathway could also yield beneficial outcomes. This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation. The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior. The findings should then be validated using in vivo models to ensure real-life relevance. The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage, although further studies are required to fully comprehend its role due to varying factors such as different cell types, astrocyte responses to inflammation, and disease contexts. Specific strategies are clearly necessary to address these variables effectively.

摘要:星形胶质细胞是中枢神经系统中数量最多的胶质细胞类型。在受到损伤和炎症时,星形胶质细胞会产生反应,并发生形态和功能上的变化。根据其表型分为 A1 或 A2,反应性星形胶质细胞分别有助于神经毒性反应和神经保护反应。然而,这种二元分类法并不能完全反映在不同疾病和损伤中观察到的星形胶质细胞反应的多样性。转录组分析表明,反应性星形胶质细胞具有复杂的基因表达谱,这强调了其反应性的异质性。星形胶质细胞通过与小胶质细胞和其他细胞类型相互作用、释放细胞因子和影响免疫反应,积极参与调节中枢神经系统炎症。磷酸肌酸 3- 激酶(PI3K)/蛋白激酶 B(AKT)信号通路是星形胶质细胞反应性的核心参与者,并影响星形胶质细胞行为的各个方面,这一点已在硅学、体外和体内研究结果中得到证实。在星形胶质细胞中,炎症线索触发了一系列分子事件,其中核因子κΒ是促炎症反应的核心介质。在这里,我们回顾了反应性星形胶质细胞的异质性及其激活的分子机制。我们强调了调节星形胶质细胞反应性的各种信号通路,包括 PI3K/AKT/ 哺乳动物雷帕霉素靶标(mTOR)、αvβ3 整合素/PI3K/AKT/connexin 43 和 Notch/ PI3K/AKT 通路。虽然以 PI3K/AKT 细胞信号通路的失活为目标可以控制反应性星形胶质细胞并防止中枢神经系统损伤,但有证据表明,激活该通路也能产生有益的结果。PI3K/AKT 通路的这种双重功能凸显了它在星形胶质细胞反应性和脑功能调节方面的复杂性。综述强调了采用星形胶质细胞专属模型来准确了解其功能的重要性,这些模型对于阐明星形胶质细胞的行为至关重要。然后,应使用体内模型对研究结果进行验证,以确保与现实生活的相关性。综述还强调了 PI3K/AKT 通路调节在预防中枢神经系统损伤方面的重要作用,但由于细胞类型、星形胶质细胞对炎症的反应和疾病背景等因素各不相同,要充分理解其作用还需要进一步的研究。要有效解决这些变数,显然需要特定的策略。
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引用次数: 0
Design and redesign journey of a drug for transthyretin amyloidosis. 转甲状腺素淀粉样变性病药物的设计和再设计之旅。
IF 5.9 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 Epub Date: 2024-06-03 DOI: 10.4103/NRR.NRR-D-24-00056
Francisca Pinheiro, Salvador Ventura
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引用次数: 0
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