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Red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β 红核 mGluR2 而非 mGluR3 通过抑制 TNF-α 和 IL-1β 的表达,在 SNI 诱导的神经病理性疼痛的发展过程中起介导抑制作用。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-22 DOI: 10.1016/j.neuint.2024.105840
Wen-Tao Wang , Fan Feng , Miao-Miao Zhang , Xue Tian , Qing-Qing Yang , Yue-Jia Li , Xiao-Xia Tao , Ya-Li Xu , E Dou , Jun-Yang Wang , Xiao-Yan Zeng

Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than β-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1β in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1β, these effects were reversed by EGLU instead of β-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1β in normal rats, while intrarubral injection of EGLU rather than β-NAAG significantly boosted the expressions of TNF-α and IL-1β. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain.

我们之前的研究已经证实,红核(RN)中Ⅰ群代谢谷氨酸受体(mGluRⅠ)的激活促进了神经病理性疼痛的发生。在此,我们进一步探讨了红核mGluRⅡ(mGluR2和mGluR3)在幸免神经损伤(SNI)诱导的神经病理性疼痛发生中的功能和可能的分子机制。我们的研究结果表明,mGluR2 和 mGluR3 在正常大鼠的 RN 中均呈组成型表达。在神经损伤后 2 周,mGluR2 而不是 mGluR3 的蛋白表达在神经损伤对侧的 RN 中明显减少。在SNI后2周,向神经损伤对侧RN注射mGluR2/3激动剂LY379268可明显减轻SNI诱导的神经病理性疼痛,而mGluR2/3拮抗剂EGLU代替选择性mGluR3拮抗剂β-NAAG可逆转这种效应。在正常大鼠的后爪内注射 LY379268 不会改变对侧后爪的脉搏波速度,而在大鼠的后爪内注射 EGLU 而不是 β-NAAG 会引起明显的机械异感。进一步的研究表明,SNI 后 2 周,RN 中痛觉因子 TNF-α 和 IL-1β 的表达增强。在 SNI 后 2 周,睾丸内注射 LY379268 能显著抑制 TNF-α 和 IL-1β 的过度表达,而 EGLU 代替 β-NAAG 则能逆转这些效应。正常大鼠睾丸内注射 LY379268 不会影响 TNF-α 和 IL-1β 的蛋白表达,而睾丸内注射 EGLU 而非 β-NAAG 则会明显提高 TNF-α 和 IL-1β 的表达。这些研究结果表明,红核mGluR2而非mGluR3通过抑制TNF-α和IL-1β的表达来介导抑制SNI诱导的神经病理性疼痛的发生。
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引用次数: 0
Transthyretin Amyloidosis: Role of oxidative stress and the beneficial implications of antioxidants and nutraceutical supplementation 转甲状腺素淀粉样变性:氧化应激的作用以及抗氧化剂和营养补充剂的有益影响。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.neuint.2024.105837
Fredrick Nwude Eze

Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.

转甲状腺素(ATTR)淀粉样变性病是由部分未折叠/聚集的异常转甲状腺素在细胞外系统性沉积引起的一系列使人衰弱的神经退行性疾病。同型四聚体蛋白 TTR 在血浆中含量丰富,在脑脊液中含量也较少。原生蛋白的限速四聚体解离被认为是形成形态各异的毒性聚集体以及多发性神经病、心肌病、运动和自主神经功能紊乱等临床表现的关键步骤。过去几十年来,越来越多的证据表明,除了 TTR 四聚体结构的不稳定性外,氧化应激也可能在 ATTR 淀粉样变性的发病机制中扮演重要角色。本综述讨论了氧化应激在 TTR 淀粉样变性发生和 TTR 聚集体介导的病理学中的最新影响。此外,还根据最新证据对抗氧化剂和营养保健品在治疗ATTR淀粉样变性中的抗衡作用进行了批判性研究。所揭示的观点可进一步加强目前对ATTR淀粉样变性基础机制的理解,并扩大有效治疗ATTR淀粉样变性的策略范围。
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引用次数: 0
Neuroprotective Effects of Sulforaphane in a rat model of Alzheimer's Disease induced by Aβ (1–42) peptides Aβ (1-42) 肽诱导的阿尔茨海默病大鼠模型中红豆杉素的神经保护作用
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.neuint.2024.105839
Wasi Uzzaman Khan , Mohd Salman , Mubashshir Ali , Haya Majid , M Shahar Yar , Mohd Akhtar , Suhel Parvez , Abul Kalam Najmi

The intricate nature of Alzheimer's disease (AD) has presented significant hurdles in the development of effective interventions. Sulforaphane (SFN) is of interest due to its antioxidative, anti-inflammatory, and neuroprotective properties, which could address various aspects of AD pathology. This study explores the potential of SFN in a rat model of AD induced by Aβ (1–42) peptides. AD symptoms were triggered in rats by injecting Aβ (1–42) peptides directly into their cerebral ventricles. SFN (10 mg/kg and 20 mg/kg), Trigonelline (10 mg/kg), and Pioglitazone (10 mg/kg) were administered in Aβ (1–42) treated animals. Behavioral assessments were performed using the Novel Object Recognition tests. Various biochemical parameters, such as soluble Aβ (1–42), IRS-S312, GSK-3β, TNF-α, acetylcholinesterase, nitrite levels, lipid peroxidation, and reduced glutathione activity, were quantified using ELISA kits and spectrophotometric assays. Histopathological analyses included Hematoxylin and Eosin, Crystal Violet, Congo red, and IRS-1 Immunohistochemistry staining. Quantification was performed to assess neuronal loss and Aβ plaque burden. The novelty of this study lies in its comprehensive evaluation of SFN's impact on multiple AD-related pathways at dual doses. The Novel Object Recognition test revealed that SFN, especially at higher doses, improved memory deficits induced by Aβ (1–42). Biochemically, SFN reduced hippocampal Aβ levels, IRS-S312, GSK-3β, TNF-α, and acetylcholinesterase activity, while increasing glutathione levels, all in a dose-dependent manner. Histopathological analyses further confirmed SFN's protective role against Aβ-induced neuronal damage, amyloidosis, and changes in insulin signaling. These results highlight SFN's potential as a multifaceted therapeutic agent for AD, offering a promising avenue for treatment due to its antioxidative, anti-inflammatory, and neuroprotective properties. The inclusion of combination treatments with Trigonelline and Pioglitazone alongside SFN offers insights into potential synergistic effects, which could pave the way for developing combination therapies for AD.

阿尔茨海默病(AD)的病因错综复杂,给有效干预措施的开发带来了巨大障碍。绿萘素(SFN)因其抗氧化、抗炎和神经保护特性而备受关注,它可以解决阿尔茨海默病病理的各个方面。本研究探讨了SFN在Aβ(1-42)肽诱导的AD大鼠模型中的潜力。向大鼠脑室直接注射Aβ(1-42)肽,诱发大鼠出现AD症状。给Aβ(1-42)治疗动物注射SFN(10毫克/千克和20毫克/千克)、曲戈奈林(10毫克/千克)和吡格列酮(10毫克/千克)。行为评估采用新物体识别测试。使用酶联免疫吸附试剂盒和分光光度法对各种生化指标进行量化,如可溶性 Aβ (1-42)、IRS-S312、GSK-3β、TNF-α、乙酰胆碱酯酶、亚硝酸盐水平、脂质过氧化和还原型谷胱甘肽活性。组织病理学分析包括苏木精和伊红、刚果红和 IRS-1 免疫组织化学染色。对神经元损失和Aβ斑块负担进行量化评估。这项研究的新颖之处在于它以双重剂量全面评估了SFN对多种AD相关通路的影响。新物体识别测试显示,SFN,尤其是高剂量的SFN,可改善Aβ(1-42)诱导的记忆缺陷。在生化方面,SFN能降低海马Aβ水平、IRS-S312、GSK-3β、TNF-α和乙酰胆碱酯酶活性,同时提高谷胱甘肽水平,所有这些均呈剂量依赖性。组织病理学分析进一步证实了 SFN 对 Aβ 诱导的神经元损伤、淀粉样变性和胰岛素信号变化的保护作用。这些结果凸显了SFN作为一种多方面的AD治疗剂的潜力,它的抗氧化、抗炎和神经保护特性为治疗提供了一种前景广阔的途径。在使用SFN的同时使用曲高奈林和吡格列酮进行联合治疗,有助于深入了解潜在的协同效应,从而为开发AD联合疗法铺平道路。
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引用次数: 0
3-Nitrotyrosine shortens axons of non-dopaminergic neurons by inhibiting mitochondrial motility 3-硝基酪氨酸通过抑制线粒体的运动缩短非多巴胺能神经元的轴突。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-16 DOI: 10.1016/j.neuint.2024.105832
Masahiro Hirai , Kohei Suzuki , Yusuke Kassai , Yoshiyuki Konishi

3-Nitrotyrosine (3-NT), a byproduct of oxidative and nitrosative stress, is implicated in age-related neurodegenerative disorders. Current literature suggests that free 3-NT becomes integrated into the carboxy-terminal domain of α-tubulin via the tyrosination/detyrosination cycle. Independently of this integration, 3-NT has been associated with the cell death of dopaminergic neurons. Given the critical role of tyrosination/detyrosination in governing axonal morphology and function, the substitution of tyrosine with 3-NT in this process may potentially disrupt axonal homeostasis, although this aspect remains underexplored. In this study, we examined the impact of 3-NT on the axons of cerebellar granule neurons, which is used as a model for non-dopaminergic neurons. Our observations revealed axonal shortening, which correlated with the incorporation of 3-NT into α-tubulin. Importantly, this axonal effect was observed prior to the onset of cellular death. Furthermore, 3-NT was found to diminish mitochondrial motility within the axon, leading to a subsequent reduction in mitochondrial membrane potential. The suppression of syntaphilin, a protein responsible for anchoring mitochondria to microtubules, restored the mitochondrial motility and axonal elongation that were inhibited by 3-NT. These findings underscore the inhibitory role of 3-NT in axonal elongation by impeding mitochondrial movement, suggesting its potential involvement in axonal dysfunction within non-dopaminergic neurons.

3-硝基酪氨酸(3-NT)是氧化和亚硝基应激的副产物,与年龄相关的神经退行性疾病有关。目前的文献表明,游离的 3-NT 会通过酪氨酸化/去酪氨酸化循环整合到 α-微管蛋白的羧基末端结构域中。与这种整合无关,3-NT 与多巴胺能神经元的细胞死亡有关。鉴于酪氨酸化/去酪氨酸化在支配轴突形态和功能方面的关键作用,在这一过程中用 3-NT 取代酪氨酸可能会破坏轴突的稳态,尽管这方面的研究仍然不足。在本研究中,我们研究了 3-NT 对小脑颗粒神经元轴突的影响,小脑颗粒神经元被用作非多巴胺能神经元的模型。我们的观察结果表明,轴突缩短与3-NT掺入α-微管蛋白有关。重要的是,这种轴突效应是在细胞死亡开始之前观察到的。此外,研究还发现 3-NT 会降低轴突内线粒体的运动性,从而导致线粒体膜电位随之降低。3-NT抑制了线粒体的运动和轴突的伸长,而抑制了负责将线粒体锚定在微管上的蛋白质--合成鞘磷脂,则恢复了线粒体的运动和轴突的伸长。这些发现强调了 3-NT 通过阻碍线粒体运动对轴突伸长的抑制作用,表明它可能参与了非多巴胺能神经元的轴突功能障碍。
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引用次数: 0
Unlocking the potential of low-molecular-weight (Poly)phenol metabolites: Protectors at the blood-brain barrier frontier 释放低分子量(多)酚代谢物的潜力:血脑屏障前沿的保护者。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.neuint.2024.105836
Daniela Marques , Diogo Moura-Louro , Inês P. Silva , Sara Matos , Cláudia Nunes dos Santos , Inês Figueira

Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide.

The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression.

Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB.

In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites’ ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.

神经退行性疾病(NDDs)是一类日益增多的慢性进行性神经系统疾病,最终导致神经细胞衰竭和死亡。尽管经过几十年的努力,这些疾病对个人和社会造成的负担仍然是全球最严重的社会经济问题之一。在 NDDs 中观察到的神经元衰竭是由一系列错综复杂的事件引起的,反映了疾病的复杂性,包括蛋白质聚集、氧化应激、(神经)炎症,甚至血脑屏障(BBB)功能障碍,最终导致患者出现认知和运动症状。由于病理生物学如此复杂,迄今为止,仍没有有效的治疗方法来治疗/控制 NDDs 的进展。幸运的是,由于膳食(多)酚代谢产生的生物可利用性低分子量(LMW)酚类代谢物在减轻多种 NDDs 特征方面具有多靶点潜力,人们对它们的兴趣日益浓厚。即使它们的生物BB渗透性不高,但由于摄入富含(多)酚的膳食,它们在血液中的浓度相对较高,这使它们成为在血管中,特别是在生物BB水平发挥作用的理想候选物质。在这篇综述中,我们将重点介绍最新的研究,这些研究表明 LMW 酚类代谢物具有调节 BBB 平衡的能力,包括改善紧密连接蛋白和粘连蛋白,以及降低体外和体内促炎细胞因子分泌和氧化应激水平的能力。特定的BBB渗透性低分子量酚类代谢物(如简单的酚硫酸盐)已逐渐成为BBB的强力助推剂,这些多效化合物能够改善细胞在氧化和促炎条件下的健康状况。然而,要全面了解低分子量酚类代谢物在预防和治疗非传染性疾病中的作用,充分利用其真正的治疗潜力,还需要进一步的研究。
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引用次数: 0
Monoamine oxidase and neurodegeneration: Mechanisms, inhibitors and natural compounds for therapeutic intervention 单胺氧化酶与神经退行性变:治疗干预的机制、抑制剂和天然化合物。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.neuint.2024.105831
Chayan Banerjee , Debasmita Tripathy , Deepak Kumar , Joy Chakraborty

Mammalian flavoenzyme Monoamine oxidase (MAO) resides on the outer mitochondrial membrane (OMM) and it is involved in the metabolism of different monoamine neurotransmitters in brain. During MAO mediated oxidative deamination of relevant substrates, H2O2 is released as a catalytic by-product, thus serving as a major source of reactive oxygen species (ROS). Under normal conditions, MAO mediated ROS is reported to propel the functioning of mitochondrial electron transport chain and phasic dopamine release. However, due to its localization onto mitochondria, sudden elevation in its enzymatic activity could directly impact the form and function of the organelle. For instance, in the case of Parkinson's disease (PD) patients who are on l-dopa therapy, the enzyme could be a concurrent source of extensive ROS production in the presence of uncontrolled substrate (dopamine) availability, thus further impacting the health of surviving neurons. It is worth mentioning that the expression of the enzyme in different brain compartments increases with age. Moreover, the involvement of MAO in the progression of neurological disorders such as PD, Alzheimer's disease and depression has been extensively studied in recent times. Although the usage of available synthetic MAO inhibitors has been instrumental in managing these conditions, the associated complications have raised significant concerns lately. Natural products have served as a major source of lead molecules in modern-day drug discovery; however, there is still no FDA-approved MAO inhibitor which is derived from natural sources. In this review, we have provided a comprehensive overview of MAO and how the enzyme system is involved in the pathogenesis of different age-associated neuropathologic conditions. We further discussed the applications and drawbacks of the long-term usage of presently available synthetic MAO inhibitors. Additionally, we have highlighted the prospect and worth of natural product derived molecules in addressing MAO associated complications.

哺乳动物黄酶类单胺氧化酶(MAO)位于线粒体外膜(OMM)上,参与大脑中不同单胺神经递质的代谢。在 MAO 介导的相关底物氧化脱氨过程中,会释放出 H2O2 作为催化副产物,从而成为活性氧(ROS)的主要来源。据报道,在正常情况下,MAO 介导的 ROS 可促进线粒体电子传递链的运作和多巴胺的阶段性释放。然而,由于其定位在线粒体上,其酶活性的突然升高会直接影响细胞器的形态和功能。例如,帕金森病(PD)患者在接受 L-DOPA l-多巴治疗时,在底物(多巴胺)供应失控的情况下,该酶可能同时成为大量 ROS 生成的来源,从而进一步影响存活神经元的健康。值得一提的是,该酶在不同脑区的表达量会随着年龄的增长而增加。此外,MAO 与神经系统疾病(如帕金森病、阿尔茨海默病和抑郁症)进展的关系近来也得到了广泛研究。虽然现有的合成 MAO 抑制剂在控制这些疾病方面发挥了重要作用,但相关的并发症近来也引起了人们的极大关注。天然产品是现代药物研发中先导分子的主要来源;然而,目前仍没有一种从天然来源中提取的 MAO 抑制剂获得 FDA 批准。在这篇综述中,我们全面概述了 MAO 以及该酶系统如何参与不同年龄相关神经病理学疾病的发病机制。我们进一步讨论了长期使用现有合成 MAO 抑制剂的应用和缺点。此外,我们还强调了天然产物衍生分子在解决 MAO 相关并发症方面的前景和价值。
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引用次数: 0
Validating the nutraceutical and neuroprotective pharmacodynamics of flavones 验证黄酮类化合物的营养和神经保护药效学。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.neuint.2024.105829
Jeyaram Bharathi Jeyabalan , Suhrud Pathak , Esakkimuthukumar Mariappan , K.P. Mohanakumar , Muralikrishnan Dhanasekaran

Neurodegenerative disorders are generally characterized by progressive neuronal loss and cognitive decline, with underlying mechanisms involving oxidative stress, protein aggregation, neuroinflammation, and synaptic dysfunction. Currently, the available treatment options only improve the symptoms of the disease but do not stop disease progression; neurodegeneration. This underscores the urgent need for novel therapeutic strategies targeting multiple neurodegenerative pathways alongside the conventional therapeutic strategies available.

Emerging evidence demonstrates that flavones a subgroup of flavonoids found abundantly in various dietary sources, have surfaced as promising candidates for neuroprotection due to their multifaceted pharmacological properties. Flavones possess the potency to modulate these pathophysiological processes through their antioxidant, anti-inflammatory, and neurotrophic activities. Additionally, flavones have been shown to interact with various cellular targets, including receptors and enzymes, to confer neuroprotection.

Though there are ample evidence available, the nutraceutical and neuroprotective pharmacodynamics of flavones have not been very well established. Hence, the current review aims to explores the therapeutic potential of flavones as nutraceuticals with neuroprotective effects, focusing on their ability to modulate key pathways implicated in neurodegenerative diseases. The current article also aims to actuate supplementary research into flavones as potential agents for alleviating neurodegeneration and improving patient outcomes in neurodegenerative disorders globally.

神经退行性疾病通常以神经元逐渐丧失和认知能力下降为特征,其潜在机制包括氧化应激、蛋白质聚集、神经炎症和突触功能障碍。目前,现有的治疗方案只能改善疾病症状,却无法阻止疾病的进展和神经退行性变。这突出表明,除了现有的传统治疗策略外,还迫切需要针对多种神经退行性病变途径的新型治疗策略。新的证据表明,黄酮类化合物是黄酮类化合物的一个亚类,广泛存在于各种膳食来源中,由于其多方面的药理特性,黄酮类化合物已成为有希望保护神经的候选药物。黄酮类化合物具有抗氧化、抗炎和神经营养活性,能够调节这些病理生理过程。此外,黄酮类化合物还能与包括受体和酶在内的各种细胞靶点相互作用,从而起到保护神经的作用。虽然已有大量证据,但黄酮的营养保健和神经保护药效学尚未得到很好的证实。因此,本综述旨在探讨黄酮类化合物作为具有神经保护作用的营养保健品的治疗潜力,重点关注其调节神经退行性疾病相关关键通路的能力。本文还旨在推动对黄酮类化合物作为潜在药物的补充研究,以缓解神经退行性疾病,改善全球神经退行性疾病患者的预后。
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引用次数: 0
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
Gyeonghui Jang , Eun-Mi Lee , Hyun-Jung Kim , Yelin Park , Nayun Hanna Bang , Jihee Lee Kang , Eun-Mi Park

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
Moataz Dowaidar

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
Wenge Jia , Chenchen Li , Hongyun Chen , Xinyu Wang , Yuan Liu , Wanbing Shang , Bian Wang , Wenjing Meng , Yaxin Guo , Lijie Zhu , Dan Wang , Danya Zhou , Bin Zhao , Lai Wei

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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Neurochemistry international
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