Neurochemistry international最新文献_第3页

Previous strength training attenuates ouabain-induced bipolar disorder-related behaviors and memory deficits in rats: Involvement of hippocampal ERK/CREB and PI3K/AKT/mTOR pathways 先前的力量训练减弱了大鼠的维卡因诱导的双相情感障碍相关行为和记忆缺陷：海马ERK/CREB和PI3K/AKT/mTOR通路的参与

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105919

Luan Machado Maidana , Jozyê Milena da Silva Guerra , Adson Souza-Pereira , Marizabel Parente Lins , Mayckel Jean Moreira-Silva , Eduarda Goulart Paiva , Douglas Buchmann Godinho , Luis Fernando Freire Royes , Leonardo Magno Rambo

Bipolar disorder (BD) is a central nervous system condition that is typified by fluctuations in mood, oscillating between depressive and manic, and/or hypomanic episodes. The objective of this study was to test the hypothesis that strength training may act as a potent protector against behavioral and neurochemical changes induced by BD. A strength training protocol was performed with adult male Wistar rats, and seven days following the conclusion of training, a single ouabain injection was administered. Following ouabain administration, the animals were subjected to behavioral tests after the seventh (manic period) and fourteenth (depressive period) days. Subsequently, rats were euthanized and the hippocampus was collected for western blotting assays. We demonstrated that strength training provided protection against ouabain-induced behavioral changes, both during the manic and depressive periods, including increased locomotor activity, risk-taking and aggressive-like behaviors, and impaired memory performance. Furthermore, physical training protected against ouabain-induced decrease of neurogenesis/neuroplasticity-related pathways, including BDNF/TrKB/ERK/CREB and PI3K/AKT/mTOR/p70S6K. These findings suggest that strength training has a protective effect, attenuating or preventing BD-induced deficits, and may have therapeutic potential as an adjuvant treatment for this patient population in the future.

双相情感障碍（BD）是一种以情绪波动为典型特征的中枢神经系统疾病，在抑郁、躁狂和/或轻躁发作之间摇摆。本研究的目的是验证力量训练可能作为对抗双相障碍引起的行为和神经化学变化的有效保护的假设。对成年雄性Wistar大鼠进行了力量训练方案，在训练结束后7天，给予单次瓦巴因注射。给药后，分别于第7天（躁狂期）和第14天（抑郁期）进行行为测试。随后，对大鼠实施安乐死，收集海马进行免疫印迹检测。我们证明，在躁狂和抑郁期间，力量训练都可以防止瓦巴因引起的行为改变，包括运动活动增加、冒险和攻击性行为，以及记忆表现受损。此外，体育锻炼可以防止瓦苦因诱导的神经发生/神经可塑性相关通路的减少，包括BDNF/TrKB/ERK/CREB和PI3K/AKT/mTOR/p70S6K。这些研究结果表明，力量训练具有保护作用，可以减轻或预防bd引起的缺陷，并且可能在未来作为辅助治疗对这类患者群体具有治疗潜力。

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引用次数: 0

Celecoxib paradoxically induces COX-2 expression and astrocyte activation through the ERK/JNK/AP-1 signaling pathway in the cerebral cortex of rats 塞来昔布通过ERK/JNK/AP-1信号通路矛盾地诱导大鼠大脑皮层COX-2表达和星形胶质细胞活化。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105926

Kai-Che Wei , Jun-Ting Lin , Chia-Ho Lin

Previous studies have shown that celecoxib or NSAID may paradoxically induce cyclooxygenase-2 (COX-2) expression and trigger inflammation-like responses in airway smooth muscle cells and renal mesangial cells. Despite the extensive research on celecoxib, its atypical biological effect on the induction of COX-2 in astroglial cells within the central nervous system (CNS) remains unexplored. In the present study, we investigated the impact of celecoxib on COX-2 and Glial Fibrillary Acidic Protein (GFAP) expression and explored the mechanisms underlying celecoxib-regulated COX-2 expression in cortical astrocytes of rats.

Cortical astrocytes were treated with celecoxib (20 μM) for 24 h, resulting in a significant increase in COX-2 expression and up-regulation of GFAP, a marker of astrocyte activation, and the COX-2 induced by celecoxib is functionally active in prostaglandin E2 (PGE2) synthesis. Celecoxib also enhanced LPS-induced COX-2 expression, but its ability to inhibit PGE2 synthesis decreased at higher concentrations. Celecoxib induced phosphorylation of Extracellular signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) but not p38 Mitogen-Activated Protein Kinase (p38 MAPK), and inhibition of activity of ERK and JNK by U0126 and SP600125 effectively blocked COX-2 and GFAP induction by celecoxib. Celecoxib increased the accumulation of transcription factor AP-1 (composed of phosphorylated c-Jun and c-fos) in the nucleus. Inhibition of AP-1 activity with SR11302 significantly prevented celecoxib-induced COX-2 and GFAP expression. Additionally, the inhibiting activity of ERK and JNK can effectively suppress AP-1 expression and activity induced by celecoxib.

These findings demonstrated that celecoxib induces COX-2 expression and astrocyte activation through the ERK/JNK/AP-1 signaling pathway, highlighting its potential effect in modulating inflammatory responses in the central nervous system.

先前的研究表明，塞来昔布或非甾体抗炎药可能矛盾地诱导环氧化酶-2 （COX-2）表达并引发气道平滑肌细胞和肾系膜细胞的炎症样反应。尽管对塞来昔布进行了广泛的研究，但其在中枢神经系统（CNS）星形胶质细胞中诱导COX-2的非典型生物学效应仍未被探索。在本研究中，我们研究了塞来昔布对大鼠皮质星形胶质细胞中COX-2和胶质纤维酸性蛋白（GFAP）表达的影响，并探讨了塞来昔布调节COX-2表达的机制。塞来昔布（20 μM）作用皮质星形胶质细胞24小时后，COX-2表达显著升高，星形胶质细胞活化标志物GFAP表达上调，且塞来昔布诱导的COX-2在前列腺素E2 （PGE2）合成中具有功能活性。塞来昔布也增强了lps诱导的COX-2表达，但其抑制PGE2合成的能力随着浓度的升高而下降。塞来昔布诱导细胞外信号调节激酶（ERK）和c-Jun n-末端激酶（JNK）磷酸化，但不诱导p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化，U0126和SP600125抑制ERK和JNK活性可有效阻断塞来昔布诱导COX-2和GFAP。塞来昔布增加了转录因子AP-1（由磷酸化的c-Jun和c-fos组成）在细胞核中的积累。SR11302抑制AP-1活性可显著阻止塞来昔布诱导的COX-2和GFAP表达。此外，ERK和JNK的抑制活性可以有效抑制塞来昔布诱导的AP-1的表达和活性。这些发现表明塞来昔布通过ERK/JNK/AP-1信号通路诱导COX-2表达和星形胶质细胞活化，突出了其在调节中枢神经系统炎症反应中的潜在作用。

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引用次数: 0

In vitro effects of recombinant human Neuritin on hair cell recovery post-gentamicin injury in SC lineage-tracing models: Involvement of notch and FGFR signaling 重组人神经素对SC谱系追踪模型中庆大霉素损伤后毛细胞恢复的体外影响：Notch和FGFR信号通路的参与

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2025.105935

Haiyan Wang , Xue Zhang , Fei Gui , Xiaopin Sun , Rong Chen , Guanwu Yin , Yu Hong , Jin Huang , Lei Yang

Hair cell (HC) loss, frequently induced by ototoxic agents such as gentamicin, leads to irreversible hearing loss. Because of the restricted regenerative capabilities of the mammalian inner ear, the exploration of therapeutic strategies to restore damaged HCs is critically needed. Recombinant human Neuritin (rhNeuritin), a neurotrophic factor with established roles in promoting cell survival and regeneration across various systems, presents itself as a promising therapeutic candidate for HC repair. In this study, we elucidate the protective effects of rhNeuritin on injured HCs and its capacity to facilitate HC regeneration post-damage. Through the use of cochlear Supporting Cell (SC) lineage-tracing models in neonatal mice, we demonstrate that SC trans-differentiation serves as the origin of HC regeneration following damage. Simultaneously, we uncover that rhNeuritin potentiates the proliferation of SC precursor cells. Mechanistic insights reveal that rhNeuritin-induced cochleae exhibit downregulation of the critical Notch pathway mediator, Hes1, and upregulation of the essential FGFR pathway component Erm, which together may underpin HC regeneration and the proliferation of SC precursors. Notably, rhNeuritin demonstrates significant preservation of HC structural integrity. These findings collectively highlight the therapeutic potential of rhNeuritin in addressing hearing loss resulting from HC damage, thereby opening a new avenue for the restoration of auditory function.

毛细胞（HC）的损失，经常由耳毒性药物如庆大霉素引起，导致不可逆的听力损失。由于哺乳动物内耳的再生能力有限，因此迫切需要探索修复受损hc的治疗策略。重组人神经素（rhNeuritin）是一种神经营养因子，在促进各种系统的细胞存活和再生方面具有重要作用，是一种有前途的HC修复治疗候选药物。在这项研究中，我们阐明了rhNeuritin对受损HC的保护作用及其促进HC损伤后再生的能力。通过在新生小鼠中使用耳蜗支持细胞（SC）谱系追踪模型，我们证明SC反分化是HC损伤后再生的起源。同时，我们发现rhNeuritin增强SC前体细胞的增殖。机制研究表明，鼻神经素诱导耳蜗表现出Notch通路关键介质Hes1的下调和FGFR通路基本组分Erm的上调，这可能共同支持HC再生和SC前体的增殖。值得注意的是，rhNeuritin显示了HC结构完整性的显著保存。这些发现共同强调了rhNeuritin在解决HC损伤导致的听力损失方面的治疗潜力，从而为听觉功能的恢复开辟了新的途径。

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引用次数: 0

VNS facilitates the neurological function recovery after ischemia/reperfusion injury by regulating the A1/A2 polarization of astrocytes through the NMU-NMUR2 pathway VNS 通过 NMU-NMUR2 通路调节星形胶质细胞的 A1/A2 极化，从而促进缺血再灌注损伤后神经功能的恢复。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105918

Xia Jiang , Wendi Yang , Gang Liu , Hao Tang , Renzi Zhang , Lina Zhang , Changqing Li , Sheng Li

Stroke is the second leading cause of death worldwide. Although conventional treatments such as thrombolysis and mechanical thrombectomy are effective, their narrow therapeutic window limits long-term neurological recovery. Previous studies have shown that vagus nerve stimulation (VNS) enhances neurological recovery after ischemia/reperfusion (I/R) injury, and neuromedin U (NMU) has neuroprotective effects. This study used a mouse model of cerebral I/R injury to investigate the potential mechanisms of NMU in VNS-mediated neurological improvement. The study consisted of two parts: first, assessing the dynamic expression of NMU and NMUR2, which peaked on day 14 post-I/R. NMUR2 was primarily localized in astrocytes, suggesting that the NMU-NMUR2 signaling pathway plays an important role in astrocyte regulation. Next, interventions with VNS, NMU, and R–PSOP + VNS were conducted to evaluate the role of this pathway in VNS-mediated recovery. The results showed that VNS significantly upregulated NMU and NMUR2 expression, which was blocked by the NMUR2 antagonist R–PSOP. VNS and NMU treatment increased the proportion of A2 astrocytes, reduced A1 astrocytes, and enhanced the expression of VEGF and BDNF, all of which were also blocked by R–PSOP. These findings indicate that the "VNS-NMU-NMUR2-astrocyte A1/A2 polarization-VEGF/BDNF pathway" plays a crucial role in promoting neurovascular remodeling, axonal and dendritic regeneration, and synaptic plasticity, thereby contributing to functional recovery.

中风是全球第二大死因。虽然传统的治疗方法如溶栓和机械取栓是有效的，但它们狭窄的治疗窗口限制了神经系统的长期恢复。已有研究表明迷走神经刺激（VNS）可促进缺血再灌注（I/R）损伤后神经系统的恢复，神经介质U （NMU）具有神经保护作用。本研究采用脑I/R损伤小鼠模型，探讨NMU在vns介导的神经系统改善中的潜在机制。本研究分为两部分：一是评估NMU和NMUR2的动态表达，NMU和NMUR2在i /R后第14天达到峰值。NMUR2主要定位于星形胶质细胞，提示NMU-NMUR2信号通路在星形胶质细胞调控中起重要作用。接下来，采用VNS、NMU和R-PSOP+VNS进行干预，以评估该途径在VNS介导的恢复中的作用。结果显示，VNS显著上调NMU和NMUR2的表达，而NMUR2的表达被NMUR2拮抗剂R-PSOP阻断。VNS和NMU处理增加了A2星形胶质细胞的比例，减少了A1星形胶质细胞，增加了VEGF和BDNF的表达，这些都被R-PSOP阻断。这些发现表明，“vns - nmu - nmur2 -星形胶质细胞A1/A2极化- vegf /BDNF通路”在促进神经血管重塑、轴突和树突再生、突触可塑性等方面起着至关重要的作用，从而有助于功能恢复。

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引用次数: 0

Hydrogen inhalation exerts anti-seizure effects by preventing oxidative stress and inflammation in the hippocampus in a rat model of kainic acid-induced seizures 在kainic酸诱导的大鼠癫痫模型中，氢吸入通过防止海马氧化应激和炎症发挥抗癫痫作用。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105925

Tzu-Kang Lin , Ming-Shang Pai , Kun-Chieh Yeh , Chi-Feng Hung , Su-Jane Wang

Hydrogen gas (H₂) is an antioxidant with demonstrated neuroprotective efficacy. In this study, we administered H₂ via inhalation to rats to evaluate its effects on seizures induced by kainic acid (KA) injection and the underlying mechanism. The animals were intraperitoneally injected with KA (15 mg/kg) to induce seizures. H₂ was inhaled 2 h once a day for 5 days before KA administration. The seizure activity was evaluated using Racine's convulsion scale and electroencephalography (EEG). Neuronal cell loss, glial cell activation, and the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, CCL2, and CCL3), reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus were assessed. The cerebral blood flow of the rats was also evaluated. The results revealed that KA-treated rats presented increased seizure intensity; increased neuronal loss and astrocyte activation; increased levels of ROS, TNF-α, IL-1β, IL-6, CCL2, and CCL3; and reduced Nrf2 phosphorylation levels. Pretreatment with H₂ inhalation significantly attenuated seizure intensity; prevented neuronal loss; decreased microglial and astrocytic activation; decreased ROS, TNF-α, IL-1β, IL-6, CCL2 and CCL3 levels; and increased Nrf2 levels. Inhalation of H₂ also prevented the KA-induced decrease in cerebral blood flow. These results suggest that pretreatment with H₂ inhalation ameliorates KA-induced seizures and inhibits the inflammatory response and oxidative stress, which protects neurons.

氢气（H2）是一种具有神经保护作用的抗氧化剂。本研究通过大鼠吸入H2，观察其对kainic acid （KA）注射液致癫痫发作的影响及其机制。腹腔注射KA （15mg /kg）诱导癫痫发作。在给药前5天，每天1次吸入H2 2 h。采用拉辛惊厥量表和脑电图（EEG）评估癫痫发作活动。评估海马神经元细胞损失、胶质细胞活化、炎症因子（TNF-α、IL-1β、IL-6、CCL2和CCL3）、活性氧（ROS）和核因子红细胞2相关因子2 （Nrf2）水平。并对大鼠的脑血流量进行了评价。结果显示，ka处理大鼠癫痫发作强度增加；神经元损失和星形胶质细胞活化增加；ROS、TNF-α、IL-1β、IL-6、CCL2、CCL3水平升高；降低Nrf2磷酸化水平。H2吸入预处理显著减弱癫痫发作强度；防止神经元丢失；小胶质细胞和星形胶质细胞活性降低；ROS、TNF-α、IL-1β、IL-6、CCL2、CCL3水平降低；Nrf2水平升高。吸入H2也能阻止ka诱导的脑血流量减少。这些结果表明，H2吸入预处理可以改善ka诱导的癫痫发作，抑制炎症反应和氧化应激，从而保护神经元。

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引用次数: 0

The role of mitochondrial remodeling in neurodegenerative diseases 线粒体重塑在神经退行性疾病中的作用。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105927

Duanqin Guan , Congmin Liang , Dongyan Zheng , Shizhen Liu , Jiankun Luo , Ziwei Cai , He Zhang , Jialong Chen

Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

神经退行性疾病是一类严重威胁人类健康的疾病，如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和肌萎缩侧索硬化症（ALS）等。近年来，人们发现线粒体重塑在神经退行性疾病的发生和发展中起着重要作用。线粒体重塑是指线粒体形态、数量和功能的动态调控过程，通过调节线粒体融合、分裂、清除和生物合成等机制影响神经元细胞功能和存活。线粒体功能障碍是神经退行性疾病发病的重要内在原因。线粒体重构异常参与神经退行性疾病的能量代谢。线粒体功能和形态的病理改变，以及与其他细胞器的相互作用，可影响多巴胺能神经元的能量代谢，参与神经退行性疾病的发生。近年来，PD和AD患者数量逐年增加，采取有效的干预措施，显著降低发病率，提高患者的生活质量，显得尤为重要。越来越多的研究者认为，线粒体重塑及其相关动力学可能从神经元和自我适应周围环境的角度积极影响神经退行性疾病。线粒体重塑主要涉及自身的裂变融合、能量代谢、通道改变、线粒体自噬以及与其他细胞器的相互作用。本文将对线粒体重塑在神经退行性疾病中的作用进行系统总结，以期为进一步研究神经退行性疾病的治疗提供新的思路和策略。

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引用次数: 0

Inhibition of Kv1.1 channels ameliorates Cu(II)-induced microglial activation and cognitive impairment in mice 抑制Kv1.1通道可改善Cu（II）诱导的小鼠小胶质细胞激活和认知障碍。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2025.105936

Wenwen Ni , Jiani Ding , Ping Gong , Xiaofang Tan, Juan Li

Microglia-mediated neuroinflammation plays a critical role in neuronal damage in neurodegenerative disorders such as Alzheimer's disease. Evidence shows that voltage-gated potassium (Kv) channels regulate microglial activation. We previously reported that copper dyshomeostasis causes neuronal injury via activating microglia. This study was designed to explore the role of Kv1.1 channels in copper-evoked microglial neuroinflammation. BV-2 microglial cells were treated with Cu(II). DiBAC4(3) was used to measure membrane potential. Microglial activation and neuronal loss were detected by enzyme-linked immunosorbent assay, Western blotting, and immunostaining. Learning and memory function was assessed with Morris water maze task. Cu(II) caused a hyperpolarized membrane potential in microglial cells, an effect abolished by functional Kv1.1 blockade. Blockade of Kv1.1 and knock-down of Kv1.1 with small interfering RNA repressed Cu(II)-induced microglial production of pro-inflammatory mediators. Also, Kv1.1 inhibition attenuated activation of PI3K/Akt-ERK1/2 signaling pathway and production of mitochondrial reactive oxidative species as well as nuclear factor-κB activation in Cu(II)-stimulated microglia. Moreover, the Cu(II)-caused, microglia-mediated neurotoxicity (indicated by reduced neuronal survival and increased dendritic loss) was attenuated by Kv1.1 knock-down. In an in vivo mouse model, hippocampal injection of Cu(II) caused elevated Kv1.1 mRNA (but not other Kv1 channels) expression and enhanced microglial Kv1.1 immunoreactivity in the hippocampus. Furthermore, blockade of Kv1.1 attenuated Cu(II)-induced microglial activation and neuronal dendritic loss in the hippocampus and learning and memory dysfunction. These findings suggest that inhibition of Kv1.1 ameliorates Cu(II)-induced microglial activation and cognitive impairment. Thus, it might represent a potential molecular target for anti-inflammatory therapy of neurodegenerative disorders.

小胶质细胞介导的神经炎症在阿尔茨海默病等神经退行性疾病的神经元损伤中起着关键作用。有证据表明电压门控钾通道调节小胶质细胞的激活。我们之前报道过铜稳态失调通过激活小胶质细胞导致神经元损伤。本研究旨在探讨Kv1.1通道在铜诱发的小胶质神经炎症中的作用。用Cu（II）处理BV-2小胶质细胞。DiBAC4(3)测定膜电位。采用酶联免疫吸附试验、Western blotting和免疫染色检测小胶质细胞活化和神经元丢失。采用Morris水迷宫任务评估学习记忆功能。Cu（II）在小胶质细胞中引起超极化膜电位，这一效应被功能性Kv1.1阻断所消除。阻断Kv1.1和用小干扰RNA敲低Kv1.1可抑制Cu（II）诱导的促炎介质的小胶质细胞生成。此外，Kv1.1抑制可减弱Cu（II）刺激的小胶质细胞中PI3K/Akt-ERK1/2信号通路的激活、线粒体活性氧化物质的产生以及核因子-κB的激活。此外，Cu（II）引起的小胶质细胞介导的神经毒性（表现为神经元存活减少和树突损失增加）通过Kv1.1敲除而减弱。在小鼠体内模型中，海马注射Cu（II）导致Kv1.1 mRNA表达升高（但不影响其他Kv1通道），并增强海马小胶质细胞Kv1.1免疫反应性。此外，阻断Kv1.1可减轻Cu（II）诱导的海马小胶质细胞激活和神经元树突损失以及学习和记忆功能障碍。这些发现表明，抑制Kv1.1可改善Cu（II）诱导的小胶质细胞激活和认知障碍。因此，它可能是神经退行性疾病抗炎治疗的潜在分子靶点。

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引用次数: 0

HIF-1α downregulates the APP protein after oxygen and glucose deprivation in the APPswe/PSEN1 mouse model of Alzheimer's disease

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105923

Mario Villa-González , Marta García-Juan , Lara Ordóñez-Gutiérrez , María José Pérez-Álvarez , Francisco Wandosell Jurado

The mTORC1 and AMPK signalling pathways are considered key nodes regulating anabolism and catabolism, and they are altered in certain processes of neurodegeneration such as hypoxia associated with ischemic stroke or Alzheimer's disease. The lack of oxygen and/or glucose (oxygen and glucose deprivation-OGD) may affect the equilibrium of the mTORC1/AMPK pathways, perhaps aggravating neurodegeneration. The alteration of these pathways mediated by OGD may be reflected in other alterations, such as the activation of autophagy that could in turn modify the secretion/accumulation of amyloid-β, one of the two histopathological markers of Alzheimer's disease. Accordingly, we set out to analyze whether OGD enhances autophagy and its implication in neuronal amyloidosis. The data obtained reveal that OGD significantly dampens not only neuronal amyloid-β production but also, the total APP protein levels, without affecting BACE-1 levels. We show that this mechanism is independent of cellular proteolysis (autophagy or proteasome) and that it can be partially recovered by inhibiting HIF-1α activity.

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引用次数: 0

Ferritinophagy promotes microglia ferroptosis to aggravate neuroinflammation induced by cerebral ischemia-reperfusion injury via activation of the cGAS-STING signaling pathway 铁蛋白自噬通过激活cGAS-STING信号通路，促进小胶质细胞铁凋亡加重脑缺血再灌注损伤引起的神经炎症。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105920

Haijing Sui , Zhenyu Sun , Chang Liu , Hongjie Xi

Cerebral ischemia-reperfusion injury (CIRI) is a common and serious complication of reperfusion therapy in patients with ischemic stroke (IS). The regulation of microglia-mediated neuroinflammation to control CIRI has garnered considerable attention. The balance of iron metabolism is key to maintaining the physiological functions of microglia. Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy, an important pathway in regulating iron metabolism, is a promising intervention target. However, studies on the impacts of ferritinophagy on microglia-mediated neuroinflammation are lacking. This study aimed to identify potential treatments for CIRI-induced neuroinflammation by focusing on ferritinophagy and the specific mechanisms whereby iron metabolism regulates microglia-mediated neuroinflammation. CIRI induced the activation of ferritinophagy in microglia, characterized by the upregulation of NCOA4, downregulation of Ferritin Heavy Chain 1 (FTH1), and increased intracellular iron levels. This activation contributes to increased ferroptosis, oxidative stress, and the release of inflammatory factors. Silencing NCOA4 or application of the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively suppressed the CIRI-induced damage in vivo and in vitro. While Fer-1 addition did not inhibit the CIRI-activated ferritinophagy, it did partially reverse the alleviation of NCOA4 depletion-induced neuroinflammation, suggesting that ferroptosis is an essential intermediate step in ferritinophagy-induced neuroinflammatory damage. Furthermore, using IS-related transcriptomic data, the cGAS-STING pathway was identified as a crucial mechanism connecting ferritinophagy and ferroptosis. Specific inhibition of the cGAS-STING pathway reduced ferritinophagy-induced ferroptosis and neuroinflammation. In summary, our results indicated that ferritinophagy activates the cGAS-STING signaling pathway, which promotes the inflammatory response and oxidative stress in microglia in a ferroptosis-dependent manner, thereby exacerbating CIRI-induced neuroinflammation. These findings provide theoretical support for the clinical treatment of CIRI.

脑缺血再灌注损伤（CIRI）是缺血性脑卒中（is）患者再灌注治疗常见且严重的并发症。调节小胶质细胞介导的神经炎症以控制CIRI已经引起了相当大的关注。铁代谢的平衡是维持小胶质细胞生理功能的关键。核受体共激活因子4 （Nuclear Receptor Coactivator 4, NCOA4）介导的铁蛋白自噬是调控铁代谢的重要途径，是一个很有前景的干预靶点。然而，关于铁蛋白自噬对小胶质细胞介导的神经炎症的影响的研究尚缺乏。本研究旨在通过关注铁蛋白自噬和铁代谢调节小胶质细胞介导的神经炎症的具体机制，确定ciri诱导的神经炎症的潜在治疗方法。CIRI诱导小胶质细胞的铁蛋白自噬激活，其特征是NCOA4上调，铁蛋白重链1 （FTH1）下调，细胞内铁水平升高。这种激活有助于增加铁下垂、氧化应激和炎症因子的释放。在体内和体外，沉默NCOA4或应用铁致死特异性抑制剂铁抑素-1 （ferr -1）可有效抑制ciri诱导的损伤。虽然添加铁-1不能抑制ciri激活的铁蛋白自噬，但它确实部分逆转了NCOA4消耗诱导的神经炎症的减轻，这表明铁凋亡是铁蛋白自噬诱导的神经炎症损伤的重要中间步骤。此外，利用is相关的转录组学数据，cGAS-STING通路被确定为连接铁蛋白自噬和铁凋亡的关键机制。特异性抑制cGAS-STING通路可减少铁蛋白吞噬诱导的铁下垂和神经炎症。综上所述，我们的研究结果表明，自噬铁蛋白激活cGAS-STING信号通路，以嗜铁依赖的方式促进小胶质细胞的炎症反应和氧化应激，从而加剧ciri诱导的神经炎症。这些发现为CIRI的临床治疗提供了理论支持。

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引用次数: 0

Brain endocannabinoid control of metabolic and non-metabolic feeding behaviors 脑内源性大麻素对代谢性和非代谢性摄食行为的控制。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-01 DOI: 10.1016/j.neuint.2024.105921

Maoxing Zhang , Qingyu Wang , Ying Wang

The central endocannabinoid (eCB) system in brain shows a crucial role in the regulation of feeding behaviors, influencing both metabolic and non-metabolic mechanisms of appetite control, which has been paid much attention. Although there are already many review articles discussing eCB modulation of feeding behaviors, our paper attempts to summarize the recent advancements through synapses, circuits, and network in brain. Our focus is on the dual role of eCB signalling in regulating metabolic energy balance and hedonic reward-related feeding. In the context of metabolic regulation of feeding behaviors, eCBs affect the hypothalamic circuits that balance hunger and satiety through signal integration related to energy status and nutrient availability. Dysregulation of this system can contribute to metabolic disorders such as obesity and anorexia. In non-metabolic feeding, the eCB system influences the hedonic aspects of eating by modulating reward pathways, including the mesolimbic system and the olfactory bulb, critical for motivating food intake and processing sensory cues. This review also explores therapeutic strategies targeting the eCB system, including cannabinoid receptor antagonists and eCB hydrolase enzyme inhibitors, which hold promise for treating conditions associated with appetite dysregulation and eating disorders. By synthesizing recent findings, we aim to highlight the intricate mechanisms through which the eCB system affects feeding behavior and to propose future directions for research and therapeutic intervention in the realm of appetite control and eating disorders.

脑内中枢内源性大麻素（eCB）系统在摄食行为的调控中发挥着重要作用，影响着食欲控制的代谢和非代谢机制，已受到广泛关注。虽然已经有许多综述文章讨论了eCB对摄食行为的调节，但我们的论文试图从突触、电路和大脑网络的角度总结最近的研究进展。我们的重点是在调节代谢能量平衡和享乐奖励相关喂养的eCB信号的双重作用。在摄食行为代谢调节的背景下，eCBs通过与能量状态和营养可用性相关的信号整合影响下丘脑平衡饥饿和饱腹感的回路。该系统的失调会导致代谢紊乱，如肥胖和厌食症。在非代谢性进食中，eCB系统通过调节奖励通路（包括中边缘系统和嗅球）来影响进食的享乐方面，这些通路对刺激食物摄入和处理感官线索至关重要。本综述还探讨了针对eCB系统的治疗策略，包括大麻素受体拮抗剂和eCB水解酶抑制剂，它们有望治疗与食欲失调和饮食失调相关的疾病。通过综合最近的发现，我们旨在强调eCB系统影响摄食行为的复杂机制，并提出食欲控制和饮食失调领域的研究和治疗干预的未来方向。

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引用次数: 0