Neurochemistry international最新文献_第2页

Neuron-selective and activity-dependent splicing of BDNF exon I–IX pre-mRNA BDNF外显子I-IX前mRNA的神经元选择性和活动依赖性剪接。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-23 DOI: 10.1016/j.neuint.2024.105889

Mamoru Fukuchi , Yumi Shibasaki , Yuto Akazawa , Hitoshi Suzuki-Masuyama , Ken-ichi Takeuchi , Yumika Iwazaki , Akiko Tabuchi , Masaaki Tsuda

Brain-derived neurotrophic factor (BDNF) is essential for numerous neuronal functions, including learning and memory. The expression of BDNF is regulated by distinctive transcriptional and post-transcriptional mechanisms. The Bdnf gene in mice and rats comprises eight untranslated exons (exons I–VIII) and one exon (exon IX) that contains the pre-proBDNF coding sequence. Multiple splice donor sites on the untranslated exons and a single acceptor site upstream of the coding sequence result in the characteristic exon skipping patterns that generate multiple Bdnf mRNA variants, which are essential for the spatiotemporal regulation of BDNF expression, mRNA localization, mRNA stability, and translational control. However, the regulation of Bdnf pre-mRNA splicing remains unclear. Here, we focused on the splicing of Bdnf exon I–IX pre-mRNA. We first constructed a minigene to evaluate Bdnf exon I–IX pre-mRNA splicing. Compared with Bdnf exon I–IX pre-mRNA splicing in non-neuronal NIH3T3 cells, splicing was preferentially observed in primary cultures of cortical neurons. Additionally, a series of overexpression and knockdown experiments suggested that neuro-oncological ventral antigen (NOVA) 2 is involved in the neuron-selective splicing of Bdnf exon I–IX pre-mRNA. Supporting this finding, endogenous Nova2 mRNA expression was markedly higher in neurons, and a strong correlation between endogenous Bdnf exon I–IX and Nova2 mRNA was observed across several brain regions. Furthermore, Bdnf exon I–IX pre-mRNA splicing was facilitated by Ca²⁺ signals evoked via L-type voltage-dependent Ca²⁺ channels. Notably, among the Bdnf pre-mRNA splicing investigated in the current study, neuron-selective and activity-dependent splicing was observed in Bdnf exon I–IX pre-mRNA. In conclusion, Bdnf exon I-IX pre-mRNA splicing is preferentially observed in neurons and is facilitated in an activity-dependent manner. The neuron-selective and activity-dependent splicing of Bdnf exon I–IX pre-mRNA may contribute to the efficient induction of Bdnf exon I–IX expression in neurons.

脑源性神经营养因子（BDNF）对包括学习和记忆在内的多种神经元功能至关重要。BDNF 的表达受独特的转录和转录后机制调控。小鼠和大鼠的 Bdnf 基因由八个非翻译外显子（外显子 I-VIII）和一个包含前前导 BDNF 编码序列的外显子（外显子 IX）组成。非翻译外显子上的多个剪接供体位点和编码序列上游的一个受体位点导致了特征性的外显子跳接模式，从而产生了多个 Bdnf mRNA 变体，这些变体对于 BDNF 的表达、mRNA 定位、mRNA 稳定性和翻译控制的时空调控至关重要。然而，Bdnf前mRNA剪接的调控仍不清楚。在这里，我们重点研究了Bdnf外显子-I-IX前mRNA的剪接。我们首先构建了一个迷你基因来评估Bdnf外显子I-IX前mRNA的剪接。与非神经元NIH3T3细胞中的Bdnf外显子I-IX前mRNA剪接相比，在皮层神经元的原代培养物中更容易观察到剪接。此外，一系列过表达和基因敲除实验表明，神经肿瘤腹侧抗原（NOVA）2参与了Bdnf外显子I-IX前mRNA的神经元选择性剪接。支持这一发现的是，内源性 Nova2 mRNA 在神经元中的表达明显较高，而且在多个脑区观察到内源性 Bdnf 外显子-I-X 和 Nova2 mRNA 之间存在很强的相关性。此外，通过 L 型电压依赖性 Ca2+ 通道诱发的 Ca2+ 信号促进了 Bdnf 外显子-I-X 预 mRNA 的剪接。值得注意的是，在本研究调查的Bdnf前mRNA剪接中，在Bdnf外显子I-IX前mRNA中观察到了神经元选择性和活动依赖性剪接。总之，Bdnf外显子I-IX前mRNA剪接优先在神经元中观察到，并以活动依赖的方式促进。Bdnf外显子I-IX前mRNA的神经元选择性和活动依赖性剪接可能有助于有效诱导Bdnf外显子I-IX在神经元中的表达。

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引用次数: 0

Supplemental oxygen alters the pentose phosphate pathway in the developing mouse brain through SIRT signaling 补充氧气可通过 SIRT 信号改变发育中小鼠大脑中的五糖磷酸途径

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-20 DOI: 10.1016/j.neuint.2024.105886

Defne Engur , Serap Cilaker Micili , Sila Soy , Gökcen Bilici , Kemal Ugur Tufekci , Cagla Kiser , İlkcan Ercan , Abdullah Kumral , Sermin Genc

Oxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood.

Purpose

of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out.

Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.

氧气支持在新生儿重症监护室早产儿的管理中起着至关重要的作用。另一方面，人们对补氧对细胞功能，特别是葡萄糖代谢可能产生的影响了解较少。目的：本研究旨在探讨补充氧气是否会改变脑组织中的葡萄糖代谢和磷酸戊糖途径（PPP）活性及其与沉默信息调节蛋白（SIRT）途径的相关性。为此，新生 C57BL/6 幼崽从出生到出生后第 7 天（PN7）一直暴露在 90% 的氧气环境中，并通过代谢组学分析研究糖酵解和磷酸戊糖途径的代谢物。通过免疫组化和分子学方法检测了大脑前额叶和海马区的 SIRT1、葡萄糖-6-磷酸脱氢酶（G6PD）和转醛酸酶（TALDO）蛋白。随后进行了 SIRT1 抑制实验。我们的研究结果表明，补充氧气会导致 PPP 代谢物的增加以及脑组织中 G6PD 酶的激活，而抑制 SIRT1 则会逆转这种情况。我们的研究强调了补氧、葡萄糖代谢、PPP 途径和 SIRT 信号转导之间的联系。了解这些错综复杂的关系不仅能加深我们对细胞生理学的认识，还能为早产儿大脑神经保护策略的治疗干预带来希望。

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引用次数: 0

Reassessment of capsaicin desensitization in the rodent spinal dorsal horn 重新评估啮齿类动物脊髓背角的辣椒素脱敏。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-20 DOI: 10.1016/j.neuint.2024.105887

Caifeng Shao , Wen-Qian Zhou , Hong-Yi Jia , Guangying Li , Yifei Ma , Mingwei Zhao , Hongjie Wu , Kun Yang , Xin Qian , Ming-Ming Zhang

Capsaicin activates primary afferent transient receptor potential vanilloid 1 (TRPV1) in the spinal dorsal horn and induces exaggerated glutamate release. This capsaicin action is followed by a lasting refractory state referred to as “capsaicin desensitization”, which is considered a presynaptic event. In this study, using whole-cell recordings and holographic photostimulation, we reassessed this notion by investigating presynaptic glutamate release and the postsynaptic glutamate response during capsaicin administration. We found that both presynaptic synchronous glutamate release and the postsynaptic glutamate response were largely attenuated in this refractory state; in contrast, asynchronous release was exaggerated. Further behavioral studies revealed a quick increase in the mechanical pain threshold with intrathecal capsaicin administration. Taken together, both presynaptic synchronous glutamate release and the postsynaptic response are downregulated during capsaicin desensitization, and this desensitization may transiently increase the pain threshold. Since both presynaptic synchronous release and postsynaptic glutamate responses are attenuated, the traditional electrophysiological evidence supporting capsaicin desensitization as a presynaptic event should be reassessed.

辣椒素可激活脊髓背角的初级传入瞬时受体电位类香草素 1（TRPV1），并诱导谷氨酸的大量释放。这种辣椒素作用之后会出现一种持久的折射状态，被称为 "辣椒素脱敏"，它被认为是一种突触前事件。在本研究中，我们使用全细胞记录和全息光刺激，通过研究辣椒素给药期间突触前谷氨酸释放和突触后谷氨酸反应，重新评估了这一概念。我们发现，在这种难治性状态下，突触前同步谷氨酸释放和突触后谷氨酸反应在很大程度上被削弱；相反，异步释放被夸大。进一步的行为学研究表明，鞘内注射辣椒素可迅速提高机械痛阈。综上所述，在辣椒素脱敏过程中，突触前同步谷氨酸释放和突触后反应都被下调，这种脱敏可能会短暂提高痛阈。由于突触前同步释放和突触后谷氨酸反应都会减弱，支持辣椒素脱敏是突触前事件的传统电生理学证据应该重新评估。

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引用次数: 0

Apelin regulates mitochondrial dynamics by inhibiting Mst1-JNK-Drp1 signaling pathway to reduce neuronal apoptosis after spinal cord injury Apelin通过抑制Mst1-JNK-Drp1信号通路调节线粒体动力学，从而减少脊髓损伤后的神经细胞凋亡。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-19 DOI: 10.1016/j.neuint.2024.105885

Qixuan Guo , Qing Liu , Shuai Zhou , Yabin Lin , Ang Lv , Luping Zhang , Liming Li , Fei Huang

In the secondary injury stage of spinal cord injury, mitochondrial dysfunction leads to decreased ATP production, increased ROS production, and activation of the mitochondria-mediated apoptosis signaling pathway. This ultimately intensifies neuronal death and promotes the progression of the injury. Apelin, a peptide produced by the APLN gene, has demonstrated promise in the treatment of spinal cord injury. The aim of this study was to investigate how Apelin protects neurons after spinal cord injury by influencing the mitochondrial dynamics. The results showed that Apelin has the ability to reduce mitochondrial fission, enhance the mitochondrial membrane potential, improve antioxidant capacity, facilitate the clearance of excess ROS, and ultimately decrease apoptosis in PC12 cells. Moreover, Apelin is overexpressed in neurons in the damaged part of the spinal cord, contributing to reduce mitochondrial fission, improve antioxidant capacity, increase ATP production, decrease apoptosis, promote spinal cord morphological repair, maintain the number of nissl bodies, and enhance signal transduction in the descending spinal cord pathway. Apelin exerts its protective effect by inhibiting the Mst1-JNK-Drp1 signaling pathway. In summary, our study further improved the effect of Apelin in the treatment of spinal cord injury, revealed the mechanism of Apelin in protecting damaged neurons after spinal cord injury by maintaining mitochondrial homeostasis, and provided a new therapeutic mechanism for Apelin in spinal cord injury.

在脊髓损伤的继发性损伤阶段，线粒体功能障碍会导致 ATP 生成减少、ROS 生成增加，并激活线粒体介导的细胞凋亡信号通路。这最终会加剧神经元的死亡，促进损伤的发展。Apelin是一种由APLN基因产生的多肽，在治疗脊髓损伤方面前景看好。本研究旨在探讨 Apelin 如何通过影响线粒体动力学来保护脊髓损伤后的神经元。结果表明，Apelin 能够减少 PC12 细胞线粒体分裂，增强线粒体膜电位，提高抗氧化能力，促进过量 ROS 的清除，并最终减少细胞凋亡。此外，Apelin 在脊髓受损部位的神经元中过表达，有助于减少线粒体分裂、提高抗氧化能力、增加 ATP 生成、减少细胞凋亡、促进脊髓形态修复、维持 nissl 体的数量以及增强脊髓下降通路的信号转导。Apelin通过抑制Mst1-JNK-Drp1信号通路发挥保护作用。综上所述，我们的研究进一步提高了Apelin治疗脊髓损伤的效果，揭示了Apelin通过维持线粒体平衡保护脊髓损伤后受损神经元的机制，为Apelin治疗脊髓损伤提供了新的治疗机制。

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引用次数: 0

Ras, RhoA, and vascular pharmacology in neurodevelopment and aging 神经发育和衰老中的 Ras、RhoA 和血管药理学。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-18 DOI: 10.1016/j.neuint.2024.105883

Ruth Nussinov , Hyunbum Jang , Feixiong Cheng

Small GTPases Ras, Rac, and RhoA are crucial regulators of cellular functions. They also act in dysregulated cell proliferation and transformation. Multiple publications have focused on illuminating their roles and mechanisms, including in immune system pathologies. Their functions in neurology-related diseases, neurodegeneration and neurodevelopment, are also emerging, as well as their potential as pharmacological targets in both pathologies. Observations increasingly suggest that these pathologies may relate to activation (or suppression) of signaling by members of the Ras superfamily, especially Ras, Rho, and Rac isoforms, and components of their signaling pathways. Germline (or embryonic) mutations that they harbor are responsible for neurodevelopmental disorders, such as RASopathies, autism spectrum disorder, and dilated cardiomyopathy. In aging, they promote neurodegenerative diseases, with Rho GTPase featuring in their pharmacology, as in the case of Alzheimer's disease (AD). Significantly, drugs with observed anti-AD activity, particularly those involved in cardiovascular systems, are associated with the RhoA signaling, as well as cerebral vasculature in brain development and aging. This leads us to suggest that anti-AD drugs could inform neurodevelopmental disorders, including pediatric low-grade gliomas pharmacology. Neurodevelopmental disorders associated with RhoA, like autism, are also connected with vascular systems, thus could be targets of vascular system-connected drugs.

小 GTP 酶 Ras、Rac 和 RhoA 是细胞功能的关键调节因子。它们还在细胞增殖和转化失调中发挥作用。已有多篇论文集中阐明了它们的作用和机制，包括在免疫系统病理学中的作用和机制。它们在神经系统相关疾病、神经变性和神经发育中的功能以及作为这两种病症的药物靶点的潜力也在不断涌现。越来越多的观察结果表明，这些病理现象可能与 Ras 超家族成员（尤其是 Ras、Rho 和 Rac 异构体）及其信号通路成分的信号激活（或抑制）有关。它们所携带的种系（或胚胎）突变是神经发育疾病的罪魁祸首，如 RAS 病、自闭症谱系障碍和扩张型心肌病。在衰老过程中，它们会促进神经退行性疾病的发生，Rho GTPase 在这些疾病的药理学中占有重要地位，阿尔茨海默病（AD）就是一例。值得注意的是，已观察到具有抗 AD 活性的药物，尤其是那些涉及心血管系统的药物，都与 RhoA 信号转导以及大脑发育和衰老过程中的脑血管有关。这使我们认为，抗 AD 药物可以为神经发育疾病（包括小儿低级别胶质瘤）的药理学提供信息。与RhoA有关的神经发育障碍，如自闭症，也与血管系统有关，因此可能成为与血管系统有关的药物的靶点。

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引用次数: 0

LASP1 in the nucleus accumbens modulates methamphetamine-induced conditioned place preference in mice 小鼠伏隔核中的 LASP1 可调节甲基苯丙胺诱导的条件性位置偏好。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-16 DOI: 10.1016/j.neuint.2024.105884

Meng-Qing Li , Xiao-Yu Lu , Jia-Yu Yao , Guang-Jing Zou , Ze-Hao Zeng , Lin-Xuan Zhang , Shi-Fen Zhou , Zhao-Rong Chen , Tian-Shu Zhao , Zi-Rui Guo , Yan-Hui Cui , Fang Li , Chang-Qi Li

Methamphetamine (METH) is a highly addictive and widely abused drug that causes complex adaptive changes in the brain's reward system, such as the nucleus accumbens (NAc). LASP1 (LIM and SH 3 domain protein 1) as an actin-binding protein, regulates synaptic plasticity. However, the role and mechanism by which NAc LASP1 contributes to METH addiction remains unclear. In this study, adult male C57BL/6J mice underwent repeated METH exposure or METH-induced conditioned place preference (CPP). Western blotting and immunohistochemistry were used to determine LASP1 expression in the NAc. Furthermore, LASP1 knockdown or overexpression using adeno-associated virus (AAV) administration via stereotactic injection into the NAc was used to observe the corresponding effects on CPP. We found that repeated METH exposure and METH-induced CPP upregulated LASP1 expression in the NAc. LASP1 silencing in the NAc reversed METH-induced CPP and reduced PSD95, NR2A, and NR2B expression, whereas LASP1 overexpression in the NAc enhanced CPP acquisition, accompanied by increased PSD95, NR2A, and NR2B expression. Our findings demonstrate an important role of NAc LASP1 in modulating METH induced drug-seeking behavior and the underlying mechanism may be related to regulate the expression of synapse-associated proteins in the NAc. These results reveal a novel molecular regulator of the actions of METH on the NAc and provide a new strategy for treating METH addiction.

甲基苯丙胺（METH）是一种极易上瘾且被广泛滥用的药物，它会导致大脑奖赏系统（如纳氏核）发生复杂的适应性变化。LASP1（LIM 和 SH 3 结构域蛋白 1）是一种肌动蛋白结合蛋白，可调节突触的可塑性。然而，NAc LASP1在METH成瘾中的作用和机制仍不清楚。在这项研究中，成年雄性 C57BL/6J 小鼠接受了反复的 METH 暴露或 METH 诱导的条件性位置偏好（CPP）。研究采用了 Western 印迹和免疫组织化学方法来确定 LASP1 在 NAc 中的表达。此外，我们还使用腺相关病毒（AAV）通过立体定向注射到 NAc 来敲除或过表达 LASP1，以观察其对 CPP 的相应影响。我们发现，重复暴露 METH 和 METH 诱导的 CPP 会上调 NAc 中 LASP1 的表达。在NAc中沉默LASP1可逆转METH诱导的CPP，并减少PSD95、NR2A和NR2B的表达，而在NAc中过表达LASP1可增强CPP的获得，同时增加PSD95、NR2A和NR2B的表达。我们的研究结果表明，NAc LASP1 在调节 METH 诱导的觅药行为中起着重要作用，其潜在机制可能与调节 NAc 中突触相关蛋白的表达有关。这些结果揭示了 METH 对 NAc 作用的新型分子调节因子，为治疗 METH成瘾提供了新策略。

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引用次数: 0

Changes in reactive oxygen species and autofluorescence under hypoxia at the hippocampal CA3 area: Role of calcium and zinc influxes 缺氧条件下海马 CA3 区活性氧和自发荧光的变化：钙和锌流入的作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-15 DOI: 10.1016/j.neuint.2024.105882

João L. Alves , Patrícia M. Reis , Rosa M. Quinta-Ferreira , M. Emília Quinta-Ferreira , Carlos M. Matias

Reactive oxygen species (ROS) have an important role in cellular biology, being involved, in a way that depends on their levels, in cell signaling processes or in oxidative stress, probably associated with neurodegenerative and other diseases. Most of the studies about ROS formation were performed in ischemic conditions, and thus, there is limited knowledge about ROS formation in less severe hypoxic conditions. This study investigates neuronal ROS generation and autofluorescence changes in hypoxic conditions, focusing on the involvement of calcium and zinc. Using hippocampal slices from Wistar rats, ROS production was monitored by the permeant fluorescent indicator H₂DCFDA under different oxygenation levels. Moderate hypoxia (40% O₂) led to a small ROS increase, while severe hypoxia (0% O₂) showed a more pronounced rise. KCl-induced depolarization significantly enhanced ROS formation, particularly under severe hypoxia. Inhibition of NMDA receptors reduced ROS generation without affecting autofluorescence, while chelation of zinc ions decreased ROS production and increased flavin adenine dinucleotide (FAD) autofluorescence. These findings suggest that, in hypoxic conditions, ROS formation is mediated by calcium entry through NMDA receptors and also by zinc influxes. Thus, these ions play a crucial role in oxidative stress, which may be related with neurodegenerative diseases associated with ROS dysregulation.

活性氧（ROS）在细胞生物学中发挥着重要作用，根据其含量参与细胞信号传导过程或氧化应激，可能与神经退行性疾病和其他疾病有关。大多数有关 ROS 形成的研究都是在缺血条件下进行的，因此对缺氧程度较轻条件下的 ROS 形成了解有限。本研究调查了缺氧条件下神经元 ROS 的生成和自发荧光的变化，重点关注钙和锌的参与。使用 Wistar 大鼠的海马切片，在不同氧合水平下通过渗透性荧光指示剂 H2DCFDA 监测 ROS 的产生。中度缺氧（40% O2）导致 ROS 少量增加，而严重缺氧（0% O2）则导致 ROS 明显增加。KCl 诱导的去极化显著增强了 ROS 的形成，尤其是在严重缺氧的情况下。抑制 NMDA 受体可减少 ROS 的产生，但不会影响自发荧光，而锌离子螯合可减少 ROS 的产生并增加黄素腺嘌呤二核苷酸（FAD）的自发荧光。这些发现表明，在缺氧条件下，ROS 的形成是通过 NMDA 受体的钙离子进入和锌离子流入介导的。因此，这些离子在氧化应激中起着至关重要的作用，而氧化应激可能与 ROS 失调相关的神经退行性疾病有关。

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引用次数: 0

MRPL41, as a target for acupuncture, promotes neuron apoptosis in models of ischemic stroke via activating p53 pathway 作为针灸靶点的MRPL41可通过激活p53通路促进缺血性中风模型中神经元的凋亡。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-13 DOI: 10.1016/j.neuint.2024.105881

Hong Guo , Yuanwei Dong , Danqing Luo , Meng Gong , Jianfeng Sun , Zhipeng Wu , Zhixiang Liu , Lei Zhong , Song Jin

Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo, MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.

神经元死亡是缺血性中风的主要原因。针灸（Acupuncture，Acu）是公认的治疗和改善脑缺血的方法。然而，针灸治疗缺血性中风的分子机制尚未得到详细阐明。根据我们的芯片分析结果，与细胞凋亡有关的线粒体核糖体蛋白 L41（MRPL41）被确定为 Acu 的靶点。MRPL41在大脑中动脉闭塞/再灌注（MCAO/R）模型中表达增加，而在Acu治疗后表达减少。随后，建立了MCAO/R模型和氧和葡萄糖剥夺/再氧合（OGD/R）模型来探讨MRPL41的作用。敲除MRPL41增加了OGD/R神经元的细胞活力和抗凋亡蛋白（Bcl-2）的表达，降低了细胞凋亡强度和促凋亡蛋白（Bax和Caspase-3）的表达。在体内，MRPL41沉默可降低神经系统严重程度评分，缩小梗死面积，减轻脑水肿和神经元凋亡。此外，MRPL41的减少会导致p53的缺失。我们的数据发现，Acu以MRPL41为靶点，通过p53通路抑制神经元凋亡，从而改善缺血性中风。

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引用次数: 0

The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice PACAP/PAC1R信号从前部岛叶皮层传导至小鼠神经节对小鼠焦虑相关行为的关键作用

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-11 DOI: 10.1016/j.neuint.2024.105879

Thi Thu Nguyen , Kohei Hashiguchi , James A. Waschek , Atsuro Miyata , Yuki Kambe

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.

神经肽垂体腺苷酸环化酶激活多肽（PACAP）及其特异性受体（PAC1R）广泛存在于中枢神经系统（CNS）中，PACAP/PAC1R 信号传导与焦虑相关行为有关。在整个中枢神经系统中具有广泛去甲肾上腺素能（NA）投射的小脑位置（LC）也与焦虑有关。虽然 LC 中 PAC1R 的表达量很高，但 PACAP/PAC1R 信号在 LC 参与焦虑中的确切作用仍不清楚。组织化学分析证实了 LC 中高水平的 PAC1R mRNA，并显示 PAC1R 基因转录物高度定位在 NA 神经元中。从这些细胞中靶向缺失 PAC1R 会导致在开阔地和高架迷宫测试中出现多动/低焦虑表型。逆行神经回路追踪表明，来自前岛皮质（aIC）和其他一些区域的PACAP神经元将轴突投射到LC。选择性激活 aIC 中的 PACAP 神经元会导致焦虑行为显著增加，而整体运动活动并无变化。此外，在野生型小鼠的 aIC 中敲除 shRNA PACAP 可选择性地减少焦虑。本研究结果确定了控制焦虑的 aIC 至 LC 神经环路，该神经环路关键需要 PACAP/PAC1R 信号。

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引用次数: 0

Protein aggregation and its affecting mechanisms in neurodegenerative diseases 神经退行性疾病中的蛋白质聚集及其影响机制

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2024-10-11 DOI: 10.1016/j.neuint.2024.105880

Junyun Wu , Jianan Wu , Tao Chen , Jing Cai , Reng Ren

Protein aggregation serves as a critical pathological marker in a spectrum of neurodegenerative diseases (NDs), including the formation of amyloid β (Aβ) and Tau neurofibrillary tangles in Alzheimer's disease, as well as α-Synuclein (α-Syn) aggregates in Parkinson's disease, Parkinson's disease-related dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A significant proportion of patients with amyotrophic lateral sclerosis (ALS) exhibit TDP-43 aggregates. Moreover, a confluence of brain protein pathologies, such as Aβ, Tau, α-Syn, and TDP-43, has been identified in individual NDs cases, highlighting the intricate interplay among these proteins that is garnering heightened scrutiny. Importantly, protein aggregation is modulated by an array of factors, with burgeoning evidence suggesting that it frequently results from perturbations in protein homeostasis, influenced by the cellular membrane milieu, metal ion concentrations, post-translational modifications, and genetic mutations. This review delves into the pathological underpinnings of protein aggregation across various NDs and elucidates the intercommunication among disparate proteins within the same disease context. Additionally, we examine the pathogenic mechanisms by which diverse factors impinge upon protein aggregation, offering fresh perspectives for the future therapeutic intervention of NDs.

蛋白质聚集是一系列神经退行性疾病（NDs）的重要病理标志，包括阿尔茨海默病中淀粉样β（Aβ）和Tau神经纤维缠结的形成，以及帕金森病、帕金森病相关痴呆（PDD）、路易体痴呆（DLB）和多系统萎缩（MSA）中α-突触核蛋白（α-Syn）的聚集。相当一部分肌萎缩侧索硬化症（ALS）患者表现出 TDP-43 聚集。此外，在个别 NDs 病例中还发现了 Aβ、Tau、α-Syn 和 TDP-43 等脑蛋白病变的汇合，突显了这些蛋白之间错综复杂的相互作用，正引起人们的高度关注。重要的是，蛋白质聚集受一系列因素的影响，越来越多的证据表明，蛋白质聚集往往是蛋白质平衡紊乱的结果，受到细胞膜环境、金属离子浓度、翻译后修饰和基因突变的影响。本综述深入探讨了各种 ND 蛋白质聚集的病理基础，并阐明了同一疾病背景下不同蛋白质之间的相互影响。此外，我们还研究了各种因素影响蛋白质聚集的致病机制，为未来非传染性疾病的治疗干预提供了新的视角。

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