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Visceral adiposity is associated with iron deposition and myelin loss in the brains of aged mice 内脏脂肪与老龄小鼠大脑中的铁沉积和髓鞘脱落有关。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.neuint.2024.105833

Iron deposition and myelin loss are observed in the brain with aging, and iron accumulation is suggested to be involved in myelin damage. However, the exact mechanism of iron deposition with aging remains unclear. This study was aimed to determine whether expanded visceral adipose tissue contributes to iron deposition and myelin loss by inducing hepcidin in the brains of aged male mice. Compared with young adult mice, levels of hepcidin in the brain, epididymal adipose tissue, and circulation were increased in aged mice, which had expanded visceral adipose tissue with inflammation. An increase in expressions of ferritin, an indicator of intracellular iron status, was accompanied by decreased levels of proteins related to myelin sheath in the brains of aged mice. These age-related changes in the brain were improved by visceral fat removal. In addition, IL-6 level, activation of microglia/macrophages, and nuclear translocation of phosphorylated Smad1/5 (pSmad1/5) inducing hepcidin expression were reduced in the brains of aged mice after visceral fat removal, accompanied by decreases of pSmad1/5- and ferritin-positive microglia/macrophages and mature oligodendrocytes. These findings indicate that visceral adiposity contributes to hepcidin-mediated iron deposition and myelin loss with inflammation in the aged brain. Our results support the importance of preventing visceral adiposity for maintaining brain health in older individuals.

随着年龄的增长,大脑中会出现铁沉积和髓鞘脱落,铁的积累被认为与髓鞘损伤有关。然而,铁沉积随年龄增长的确切机制仍不清楚。本研究旨在通过诱导老龄雄性小鼠大脑中的血红素来确定内脏脂肪组织的扩张是否会导致铁沉积和髓鞘脱落。与年轻成年小鼠相比,内脏脂肪组织扩张并伴有炎症的老年小鼠大脑、附睾脂肪组织和血液循环中的血红素水平均有所升高。铁蛋白是细胞内铁状态的指标,其表达量的增加伴随着老年小鼠大脑中与髓鞘有关的蛋白质水平的降低。去除内脏脂肪后,大脑中这些与年龄有关的变化得到了改善。此外,去除内脏脂肪后,老龄小鼠大脑中的 IL-6 水平、小胶质细胞/巨噬细胞的活化以及诱导 hepcidin 表达的磷酸化 Smad1/5 (pSmad1/5)的核转位均有所降低,同时 pSmad1/5 和铁蛋白阳性的小胶质细胞/巨噬细胞以及成熟的少突胶质细胞也有所减少。这些研究结果表明,内脏脂肪会导致血红素介导的铁沉积和髓鞘脱落,并引发老年脑部炎症。我们的研究结果支持了预防内脏脂肪过多对保持老年人大脑健康的重要性。
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引用次数: 0
Drug delivery based exosomes uptake pathways 基于外泌体摄取途径的药物输送。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.neuint.2024.105835

Most cells secrete a material called extracellular vesicles (EVs), which play a crucial role in cellular communication. Exosomes are one of the most studied types of EVs. Recent research has shown the many functions and substrates of cellular exosomes. Multiple studies have shown the efficacy of exosomes in transporting a wide variety of cargo to their respective target cells. As a result, they are often utilized to transport medicaments to patients. Natural exosomes as well as exosomes modified with other compounds to enhance transport capabilities have been employed. In this article, we take a look at how different types of exosomes and modified exosomes may transport different types of cargo to their respective targets. Exosomes have a lot of potential as drug delivery vehicles for many synthetic compounds, proteins, nucleic acids, and gene repair specialists because they can stay in the body for a long time, are biocompatible, and can carry natural materials. A good way to put specific protein particles into exosomes is still not clear, though, and the exosomes can't be used in many situations yet. The determinants for exosome production, as well as ways for loading certain therapeutic molecules (proteins, nucleic acids, and small compounds), were covered in this paper. Further study and the development of therapeutic exosomes may both benefit from the information collected in this review.

大多数细胞都会分泌一种叫做细胞外囊泡(EVs)的物质,这种物质在细胞通讯中起着至关重要的作用。外泌体是研究最多的 EVs 类型之一。最新研究表明,细胞外泌体具有多种功能和底物。多项研究表明,外泌体能有效地将各种货物运送到各自的靶细胞。因此,外泌体经常被用来向患者运送药物。天然外泌体以及用其他化合物修饰以增强运输能力的外泌体已被采用。在本文中,我们将探讨不同类型的外泌体和修饰外泌体如何将不同类型的货物运输到各自的靶细胞。外泌体作为许多合成化合物、蛋白质、核酸和基因修复专家的药物输送载体具有很大的潜力,因为它们可以在体内停留很长时间,具有生物相容性,而且可以携带天然材料。不过,将特定蛋白质颗粒放入外泌体的好方法还不明确,外泌体还不能用于很多情况。本文介绍了外泌体产生的决定因素以及装载某些治疗分子(蛋白质、核酸和小化合物)的方法。进一步的研究和治疗外泌体的开发都可能受益于本综述收集的信息。
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引用次数: 0
ISRIB ameliorates spatial learning and memory impairment induced by adolescent intermittent ethanol exposure in adult male rats ISRIB 可改善成年雄性大鼠因青少年间歇性接触乙醇而导致的空间学习和记忆损伤。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.neuint.2024.105834

Alcohol exposure in adolescence is considered a major cause of cognitive impairments later in life including spatial learning and memory. Integrated stress response (ISR), a program of conservative translation and transcription, is crucial in synaptic plasticity and memory. Although previous studies have elucidated ISR in different brain areas involved in learning and memory disorders, the impact of ISR on learning and memory following adolescent alcohol exposure remains unclear. Here, we demonstrated that adolescent intermittent ethanol (AIE) exposure caused spatial learning and memory impairment, combined with neuronal damage in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (HIP) in adult rats. Moreover, integrated stress response inhibitor (ISRIB) administration not only improved spatial learning and memory impairment and neuronal damage but also inhibited the endoplasmic reticulum stress (ER) and reversed changes in synaptic proteins. These findings suggested that ISRIB ameliorates AIE exposure-induced spatial learning and memory deficits by improving neural morphology and synaptic function through inhibiting ER stress signaling pathway in the mPFC, NAc and HIP in adulthood. Our findings may enhance comprehension of cognitive function and neuronal effects of adolescent ethanol exposure and ISRIB treatment may be an underlying potential option for addressing alcohol-induced learning and memory deficits.

青少年时期接触酒精被认为是导致日后认知障碍(包括空间学习和记忆)的主要原因。综合应激反应(ISR)是一种保守的翻译和转录程序,在突触可塑性和记忆中至关重要。尽管之前的研究已经阐明了涉及学习和记忆障碍的不同脑区的 ISR,但青少年接触酒精后 ISR 对学习和记忆的影响仍不清楚。在这里,我们证明了青少年间歇性乙醇暴露(AIE)会导致成年大鼠的空间学习和记忆障碍,并合并内侧前额叶皮层(mPFC)、伏隔核(NAc)和海马(HIP)的神经元损伤。此外,服用综合应激反应抑制剂(ISRIB)不仅能改善空间学习和记忆损伤以及神经元损伤,还能抑制内质网应激(ER)并逆转突触蛋白的变化。这些研究结果表明,ISRIB可通过抑制mPFC、NAc和HIP中的ER应激信号通路,改善神经形态和突触功能,从而改善AIE暴露引起的空间学习和记忆缺陷。我们的发现可能会加深对青少年乙醇暴露的认知功能和神经元效应的理解,ISRIB治疗可能是解决酒精诱导的学习和记忆缺陷的潜在选择。
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引用次数: 0
Dopaminergic cAMP signaling in mouse olfactory bulb astrocytes 小鼠嗅球星形胶质细胞中的多巴胺能 cAMP 信号转导
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-10 DOI: 10.1016/j.neuint.2024.105828

Cyclic AMP (cAMP) is an important second messenger in virtually all animal cell types, including astrocytes. In the brain, it modulates energy metabolism, development and synaptic plasticity. Dopamine receptors are G protein-coupled receptors that affect cAMP production by adenylyl cyclases. They are divided into two subgroups, D1-like receptors linked to Gs proteins stimulating cAMP production and D2-like receptors linked to Gi/o proteins inhibiting cAMP production. In the present study, we investigated the effect of dopamine receptor activation on cAMP dynamics in astrocytes of the mouse olfactory bulb, the brain region with the largest population of dopaminergic neurons. Using the genetically encoded cAMP sensor Flamindo2 we visualized changes in the cytosolic cAMP concentration and showed that dopamine application results in a transient increase in cAMP. This cAMP increase could be mimicked by the D1-like receptor agonist A 68930 and was inhibited by the D1-like receptor antagonist SCH 23390, whereas D2-like receptor ligands had no effect on the astrocytic cAMP concentration. Thus, olfactory bulb astrocytes express D1-like receptors that are linked to cAMP production.

环磷酸腺苷(cAMP)是几乎所有动物细胞类型(包括星形胶质细胞)中的重要第二信使。在大脑中,它调节能量代谢、发育和突触可塑性。多巴胺受体是影响腺苷酸环化酶产生 cAMP 的 G 蛋白偶联受体。多巴胺受体分为两类,一类是与Gs蛋白相连的D1类受体,可刺激cAMP的产生;另一类是与Gi/o蛋白相连的D2类受体,可抑制cAMP的产生。在本研究中,我们研究了多巴胺受体激活对小鼠嗅球星形胶质细胞中 cAMP 动态变化的影响,小鼠嗅球是多巴胺能神经元数量最多的脑区。利用基因编码的 cAMP 传感器 Flamindo2,我们对细胞膜 cAMP 浓度的变化进行了可视化分析,结果表明应用多巴胺会导致 cAMP 的短暂增加。D1 样受体激动剂 A 68930 可模拟这种 cAMP 的增加,D1 样受体拮抗剂 SCH 23390 则可抑制这种增加,而 D2 样受体配体对星形胶质细胞的 cAMP 浓度没有影响。因此,嗅球星形胶质细胞表达的D1样受体与cAMP的产生有关。
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引用次数: 0
l-theanine, the unique constituent of tea, improves neuronal survivability by curtailing inflammatory responses in MPTP model of Parkinson's disease 茶叶中的独特成分 L-茶氨酸可通过抑制帕金森病 MPTP 模型中的炎症反应来提高神经元的存活率。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-10 DOI: 10.1016/j.neuint.2024.105830

Discrete components of tea possess multitude of health advantages. Escalating evidence advocate a consequential association between habitual tea consumption and a subsided risk of Parkinson's disease (PD). l-theanine is a non-protein amino acid inherent in tea plants, which exhibits structural resemblance with glutamate, the copious excitatory neurotransmitter in brain. Neuromodulatory effects of l-theanine are evident from its competency in traversing the blood brain barrier, promoting a sense of calmness beyond enervation, and enhancing cognition and attention. Despite the multifarious reports on antioxidant properties of l-theanine and its potential to regulate brain neurotransmitter levels, it is obligatory to understand its exact contribution in ameliorating the pathophysiology of PD. In this study, MPTP-induced mouse model was established and PD-like symptoms were developed in test animals where an increasing dosage of l-theanine (5, 25, 50, 100 and 250 mg/kg) was intraperitoneally administered for 23 days. 50 and 100 mg/kg dosage of l-theanine alleviated motor impairment and specific non-motor symptoms in Parkinsonian mice. The dosage of 100 mg/kg of l-theanine also improved striatal dopamine and serotonin level and tyrosine-hydroxylase positive cell count in the substantia nigra. Most crucial finding of the study is the proficiency of l-theanine to diminish astroglial injury as well as nitric oxide synthesis, which suggests its possible credential to prevent neurodegeneration by virtue of its anti-inflammatory attribute.

茶叶中的不同成分具有多种健康益处。越来越多的证据表明,习惯性饮茶与降低帕金森病(PD)风险之间存在着必然联系。茶氨酸(L-theanine)是茶树中固有的一种非蛋白氨基酸,与谷氨酸(大脑中大量的兴奋性神经递质)结构相似。左旋茶氨酸的神经调节作用体现在它能够穿越血脑屏障,增强镇静感,提高认知能力和注意力。尽管有关左旋茶氨酸的抗氧化特性及其调节脑神经递质水平的潜力的报道层出不穷,但我们仍有必要了解它在改善帕金森病病理生理学方面的确切贡献。本研究建立了 MPTP 诱导的小鼠模型,并在试验动物出现类似帕金森病症状的情况下,连续 23 天腹腔注射 5、25、50、100 和 250 毫克/千克剂量的左旋茶氨酸。50 和 100 毫克/千克剂量的左旋茶氨酸可减轻帕金森病小鼠的运动障碍和特定非运动症状。每公斤 100 毫克的左旋茶氨酸还能改善纹状体多巴胺和血清素水平,以及黑质中酪氨酸羟化酶阳性细胞数量。这项研究最重要的发现是,左旋茶氨酸能够减少星形胶质细胞损伤和一氧化氮合成,这表明它可能通过抗炎特性来防止神经变性。
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引用次数: 0
Capsaicin-insensitivity of TRPV1-R575D mutant located at the lipid-water-interface region can be rescued by either extracellular Ca2+-chelation or cholesterol reduction 位于脂质-水-界面区域的 TRPV1-R575D 突变体对辣椒素的敏感性可通过细胞外 Ca2+ 螯合或降低胆固醇来挽救。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-06 DOI: 10.1016/j.neuint.2024.105826

TRPV1 acts as a unique polymodal ion channel having distinct structure and gating properties. In this context, TRPV1-R575D represents a special mutant located at the inner lipid-water-interface (LWI) region that has less possibility of interaction with membrane cholesterol. In control conditions, this lab-generated mutant of TRPV1 shows no “ligand-sensitivity”, reduced surface expression, reduced localization in the lipid rafts, yet induces high cellular lethality. Notably, the cellular lethality induced by TRPV1-R575D expression can be rescued by adding 5′I-RTX (a specific inhibitor of TRPV1) or by introducing another mutation in the next position, i.e. in TRPV1-R575D/D576R. In this work we characterized TRPV1-R575D and TRPV1-R575D/D576R mutants in different cellular conditions and compared with the TRPV1-WT. We report that the “ligand-insensitivity” of TRPV1-R575D can be rescued in certain conditions, such as by chelation of extracellular Ca2+, or by reduction of the membrane cholesterol. Here we show that Ca2+ plays an important role in the channel gating of TRPV1-WT as well as LWI mutants (TRPV1-R575D, TRPV1-R575D/D576R). However, chelation of intracellular Ca2+ or depletion of ER Ca2+ did not have a significant effect on the TRPV1-R575D. Certain properties related to channel gating of mutant TRPV1-R575D/D576R can be rescued partially or fully in a context -dependent manner. Cholesterol depletion also alters these properties. Our data suggests that lower intracellular basal Ca2+ acts as a pre-requisite for further opening of TRPV1-R575D. These findings enable better understanding of the structure-function relationship of TRPV1 and may be critical in comprehending the channelopathies induced by other homologous thermosensitive TRPVs.

TRPV1 是一种独特的多模式离子通道,具有独特的结构和门控特性。在这种情况下,TRPV1-R575D 代表了一种位于内脂水界面(LWI)区域的特殊突变体,它与膜胆固醇相互作用的可能性较小。在对照条件下,这种实验室产生的 TRPV1 突变体不显示 "配体敏感性",表面表达减少,在脂筏中的定位减少,但却诱导细胞高度致死。值得注意的是,通过添加 5'I-RTX(TRPV1 的特异性抑制剂)或在下一个位置(即 TRPV1-R575D/D576R)引入另一个突变,可以挽救 TRPV1-R575D 表达诱导的细胞致死性。在这项工作中,我们对不同细胞条件下的 TRPV1-R575D 和 TRPV1-R575D/D576R 突变体进行了表征,并与 TRPV1-WT 进行了比较。我们报告说,TRPV1-R575D 的 "配体不敏感性 "在某些条件下可以被挽救,例如通过螯合细胞外 Ca2+ 或降低膜胆固醇。在这里,我们发现 Ca2+ 在 TRPV1-WT 以及 LWI 突变体(TRPV1-R575D、TRPV1-R575D/D576R)的通道门控中起着重要作用。然而,细胞内 Ca2+ 的螯合或 ER Ca2+ 的耗竭对 TRPV1-R575D 没有显著影响。突变体 TRPV1-R575D/D576R 与通道门控有关的某些特性可以通过上下文依赖的方式得到部分或全部挽救。胆固醇耗竭也会改变这些特性。我们的数据表明,较低的细胞内基础 Ca2+ 是 TRPV1-R575D 进一步开放的先决条件。这些发现有助于更好地理解 TRPV1 的结构-功能关系,并可能对理解其他同源热敏 TRPV 诱导的通道病变至关重要。
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引用次数: 0
The autophagy paradox: A new hypothesis in neurodegenerative disorders 自噬悖论:神经退行性疾病的新假说。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-05 DOI: 10.1016/j.neuint.2024.105827

A recent study showed that while autophagy is usually tied to protein and organelle turnover, it can also play dual roles in neurodegenerative diseases. Traditionally, autophagy was seen as protective since it removes damaged proteins and organelles. but new data suggests autophagy can sometimes promote neuron death. and This review tackles autophagy's seemingly contradictory effects in neurodegeneration, or the "autophagy paradox. " It offers a framework for understanding autophagy in neurodegenerative research and the cellular processes involved. In short, our data uncovers a harmful autophagy role in certain situations, conflicting the view that it's always beneficial. We describe the distinct, disease-specific autophagy pathways functioning in various neurodegenerative diseases. Part two concerns potential therapeutic implications of manipulating autophagy and current strategies targeting the autophagic system, suggesting interesting areas for future research into tailored modulators. This could eventually enable activating or controlling specific autophagy pathways and aid in developing more effective treatments. Researchers believe more molecular-level research is needed so patient-tailored autophagy-modulating therapeutics can be developed given this dilemma. Moreover, research must translate faster into effective neurodegenerative disease treatment options. This article aims to provide a wholly new perspective on autophagy's classically described role in these severe diseases, challenging current dogma and opening new therapeutic avenue options.

最近的一项研究表明,虽然自噬通常与蛋白质和细胞器的更替有关,但它在神经退行性疾病中也能发挥双重作用。本综述探讨了自噬在神经退行性疾病中看似矛盾的作用,即 "自噬悖论"。"它为理解神经退行性病变研究中的自噬及其所涉及的细胞过程提供了一个框架。简而言之,我们的数据揭示了自噬在某些情况下的有害作用,这与自噬总是有益的观点相矛盾。我们描述了在各种神经退行性疾病中发挥作用的不同的、针对特定疾病的自噬途径。第二部分涉及操纵自噬的潜在治疗意义和当前针对自噬系统的策略,并提出了未来研究定制调节剂的有趣领域。这最终可以激活或控制特定的自噬途径,帮助开发更有效的治疗方法。研究人员认为,鉴于这种困境,需要开展更多分子水平的研究,以便开发出适合患者的自噬调节疗法。此外,研究必须更快地转化为有效的神经退行性疾病治疗方案。本文旨在从一个全新的视角探讨自噬在这些严重疾病中的经典作用,挑战当前的教条,开辟新的治疗途径选择。
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引用次数: 0
The selective disruption of the JNK2/Syntaxin-1A interaction by JGRi1 protects against NMDA-evoked toxicity in SH-SY5Y cells JGRi1 对 JNK2/SYNTAXIN-1A 相互作用的选择性分离可保护 SH-SY5Y 细胞免受 NMDA 引起的毒性。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-03 DOI: 10.1016/j.neuint.2024.105824

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets.

We previously reported non-conventional intracellular signaling triggered by which, upon activation, promotes the interaction between JNK2 and STX1A which enhances the rate of vesicular secretion. We developed a cell-permeable peptide, named JGRi1, able to disrupt such interaction, thus reducing vesicular secretion. In this work, to selectively study the effect of JGRi1 in a much simpler system, we employed neuroblastoma cells, SH-SY5Y. We found that SH-SY5Y cells express the components of the NMDA receptor-JNK2 axis and that the NMDA stimulus increases the rate of vesicle release. Both JGRi1 and memantine protected SH-SY5Y cells from NMDA toxicity, but only JGRi1 reduced the interaction between JNK2 and STX1A. Both drugs successfully reduced NMDA-induced vesicle release, although, unlike memantine, JGRi1 did not prevent calcium influx. NMDA treatment induced JNK2 expression, but not JNK1 or JNK3, which was prevented by both JGRi1 and memantine, suggesting that JNK2 may be specifically involved in the response to NMDA.

In conclusion, being JGRi1 able to protect cells against NMDA toxicity by interfering with JNK2/STX1A interaction, it could be considered a novel pharmacological tool to counteract excitotoxicity.

N-甲基-D-天冬氨酸(NMDA)受体是钙离子通道受体,专门由谷氨酸激活,允许激活特定的细胞内钙依赖途径。NMDA 受体的异常激活会导致一种被称为兴奋性中毒的病症,在这种病症中,过量的钙流入会诱导细胞凋亡途径。迄今为止,美金刚是唯一获准用于临床实践的 NMDA 受体拮抗剂,因此需要更好地了解 NMDA 级联,以发现新的药理靶点。我们以前曾报道过由其触发的非常规细胞内信号传导,这种信号传导在激活后会促进 JNK2 和 STX1A 之间的相互作用,从而提高囊泡分泌率。我们开发了一种名为 JGRi1 的细胞渗透性多肽,它能破坏这种相互作用,从而减少囊泡分泌。在这项工作中,为了在一个更简单的系统中选择性地研究 JGRi1 的作用,我们采用了神经母细胞瘤细胞 SH-SY5Y。我们发现,SH-SY5Y 细胞表达 NMDA 受体-JNK2 轴的成分,NMDA 刺激会增加囊泡的释放速度。JGRi1和美金刚都能保护SH-SY5Y细胞免受NMDA的毒性,但只有JGRi1能减少JNK2和STX1A之间的相互作用。两种药物都成功地减少了 NMDA 诱导的囊泡释放,但与美金刚不同的是,JGRi1 不能阻止钙离子流入。NMDA 处理会诱导 JNK2 的表达,但不会诱导 JNK1 或 JNK3 的表达,JGRi1 和美金刚均可阻止这种表达,这表明 JNK2 可能专门参与了对 NMDA 的反应。总之,由于 JGRi1 能够通过干扰 JNK2/STX1A 的相互作用来保护细胞免受 NMDA 的毒性,因此它可被视为一种对抗兴奋性毒性的新型药理学工具。
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引用次数: 0
Tumor necrosis factor alpha induces NOX2-dependent reactive oxygen species production in hypothalamic paraventricular nucleus neurons following angiotensin II infusion 输注血管紧张素 II 后,肿瘤坏死因子 alpha 可诱导下丘脑室旁核神经元产生 NOX2 依赖性活性氧。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-02 DOI: 10.1016/j.neuint.2024.105825

There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα′s actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension. Using dual labeling immunoelectron microscopy and dihydroethidium (DHE) microfluorography, we provide structural and functional evidence for interactions between TNFα and NOX2 in the PVN. The TNFα type 1 receptor (TNFR1), the major mediator of TNFα signaling in the PVN, was commonly co-localized with the catalytic gp91phox subunit of NOX2 in postsynaptic sites of PVN neurons. Additionally, there was an increase in dual labeled dendritic profiles following fourteen-day slow-pressor angiotensin II (AngII) infusion. Using DHE microfluorography, it was also shown that TNFα application resulted in a NOX2-dependent increase in ROS in isolated PVN neurons projecting to the spinal cord. Further, TNFα-mediated ROS production was heightened after AngII infusion. The finding that TNFR1 and gp91phox are positioned for rapid interactions, particularly in PVN-spinal cord projection neurons, provides a molecular substrate by which inflammatory signaling and oxidative stress may jointly contribute to AngII hypertension.

有证据表明,肿瘤坏死因子α(TNFα)会影响下丘脑室旁核(PVN)内协调的自律神经过程,然而,TNFα在这一脑区发挥作用的信号机制尚不清楚。在非神经元细胞类型中,TNFα已被证明在典型的NADPH氧化酶(NOX2)介导的活性氧(ROS)产生中发挥了重要作用,众所周知,活性氧分子也与高血压密切相关。然而,人们对 TNFα 在高血压背景下 PVN 中 NOX2 依赖性 ROS 生成中的作用知之甚少。我们利用双标记免疫电子显微镜和双氢乙锭显微荧光成像技术,提供了 TNFα 和 NOX2 在视网膜神经元中相互作用的结构和功能证据。TNFα 1型受体(TNFR1)是PVN中TNFα信号传导的主要介质,它与NOX2的催化gp91phox亚基共同定位在PVN神经元突触后部位。此外,在注射血管紧张素 II(AngII)十四天后,双标记树突轮廓有所增加。使用二氢乙啶(DHE)微荧光成像技术还显示,在向脊髓投射的离体PVN神经元中,TNFα的应用导致了依赖于NOX2的ROS增加。此外,输注 AngII 后,TNFα 介导的 ROS 生成增加。TNFR1和gp91phox定位为快速相互作用,尤其是在PVN-脊髓投射神经元中,这一发现提供了一个分子底物,炎症信号传导和氧化应激可能共同导致AngII高血压。
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引用次数: 0
Diet and Nutraceuticals for treatment and prevention of primary and secondary stroke: Emphasis on nutritional antiplatelet and antithrombotic agents 治疗和预防一级和二级中风的饮食和营养保健品:重点是营养抗血小板和抗血栓药物
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-30 DOI: 10.1016/j.neuint.2024.105823

Ischemic stroke is a devastating disease that causes morbidity and mortality. Malnutrition following ischemic stroke is common in stroke patients. During the rehabilitation, the death rates of stroke patients are significantly increased due to malnutrition. Nutritional supplements such as protein, vitamins, fish, fish oils, moderate wine or alcohol consumption, nuts, minerals, herbal products, food colorants, marine products, fiber, probiotics and Mediterranean diets have improved neurological functions in stroke patients as well as their quality of life. Platelets and their mediators contribute to the development of clots leading to stroke. Ischemic stroke patients are treated with thrombolytics, antiplatelets, and antithrombotic agents. Several systematic reviews, meta-analyses, and clinical trials recommended that consumption of these nutrients and diets mitigated the vascular, peripheral, and central complications associated with ischemic stroke (Fig. 2). Particularly, these nutraceuticals mitigated the platelet adhesion, activation, and aggregation that intended to reduce the risks of primary and secondary stroke. Although these nutraceuticals mitigate platelet dysfunction, there is a greater risk of bleeding if consumed excessively. Moreover, malnutrition must be evaluated and adequate amounts of nutrients must be provided to stroke patients during intensive care units and rehabilitation periods. In this review, we have summarized the importance of diet and nutraceuticals in ameliorating neurological complications and platelet dysfunction with an emphasis on primary and secondary prevention of ischemic stroke.

缺血性中风是一种破坏性疾病,会导致发病率和死亡率。缺血性中风后营养不良在中风患者中很常见。在康复期间,由于营养不良,脑卒中患者的死亡率明显增加。蛋白质、维生素、鱼、鱼油、适量饮用葡萄酒或酒精、坚果、矿物质、草药产品、食品着色剂、海产品、纤维素、益生菌和地中海饮食等营养补充剂可改善中风患者的神经功能及其生活质量。血小板及其介质会导致血栓形成,从而引发中风。缺血性中风患者需要接受溶栓药物、抗血小板药物和抗血栓药物治疗。一些系统综述、荟萃分析和临床试验建议,摄入这些营养素和饮食可减轻与缺血性中风相关的血管、外周和中枢并发症(图 2)。特别是,这些营养保健品可减轻血小板的粘附、活化和聚集,从而降低原发性和继发性中风的风险。虽然这些营养保健品能缓解血小板功能障碍,但如果过量食用,出血的风险也会增加。此外,在重症监护室和康复期间,必须对营养不良进行评估,并为中风患者提供充足的营养。在本综述中,我们总结了饮食和营养保健品在改善神经系统并发症和血小板功能障碍方面的重要性,重点是缺血性脑卒中的一级和二级预防。
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Neurochemistry international
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