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Combating Parkinson's disease with plant-derived polyphenols: Targeting oxidative stress and neuroinflammation 用植物多酚对抗帕金森病:针对氧化应激和神经炎症。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-29 DOI: 10.1016/j.neuint.2024.105798
Reem M. Gahtani , Shoaib Shoaib , Umme Hani , R. Jayachithra , Mohammad N. Alomary , Waseem Chauhan , Roshan Jahan , Saba Tufail , Mohammad Azam Ansari

Parkinson's disease (PD) is a devastating neurodegenerative disorder predominantly affecting the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra. Reactive oxygen species (ROS) generation plays a central role in the pathogenesis of PD and other neurodegenerative diseases. An imbalance between cellular antioxidant activity and ROS production leads to oxidative stress, contributing to disease progression. Dopamine metabolism, mitochondrial dysfunction, and neuroinflammation in dopaminergic neurons have been implicated in the pathogenesis of Parkinson's disease. Consequently, there is a pressing need for therapeutic interventions capable of scavenging ROS. Current pharmacological approaches, such as L-dihydroxyphenylalanine (levodopa or L-DOPA) and other drugs, provide symptomatic relief but are limited by severe side effects. Researchers worldwide have been exploring alternative compounds with less toxicity to address the multifaceted challenges associated with Parkinson's disease. In recent years, plant-derived polyphenolic compounds have gained significant attention as potential therapeutic agents. These compounds exhibit neuroprotective effects by targeting pathophysiological responses, including oxidative stress and neuroinflammation, in Parkinson's disease. The objective of this review is to summarize the current understanding of the neuroprotective effects of various polyphenols in Parkinson's disease, focusing on their antioxidant and anti-inflammatory properties, and to discuss their potential as therapeutic candidates. This review highlights the progress made in elucidating the molecular mechanisms of action of these polyphenols, identifying potential therapeutic targets, and optimizing their delivery and bioavailability. Well-designed clinical trials are necessary to establish the efficacy and safety of polyphenol-based interventions in the management of Parkinson's disease.

帕金森病(PD)是一种以黑质多巴胺能神经元缺失为特征的破坏性神经退行性疾病,主要影响老年人。活性氧(ROS)的产生在帕金森病和其他神经退行性疾病的发病机制中起着核心作用。细胞抗氧化活性与 ROS 生成之间的失衡会导致氧化应激,从而导致疾病进展。多巴胺代谢、线粒体功能障碍和多巴胺能神经元的神经炎症与帕金森病的发病机制有关。因此,迫切需要能够清除 ROS 的治疗干预措施。目前的药理学方法,如左旋多巴或左旋多巴酸(L-DOPA)和其他药物,可缓解症状,但受到严重副作用的限制。世界各地的研究人员一直在探索毒性较小的替代化合物,以应对帕金森病带来的多方面挑战。近年来,植物多酚类化合物作为潜在的治疗药物备受关注。这些化合物通过针对帕金森病的病理生理反应,包括氧化应激和神经炎症,表现出神经保护作用。本综述旨在总结目前对各种多酚在帕金森病中的神经保护作用的认识,重点关注它们的抗氧化和抗炎特性,并讨论它们作为候选治疗药物的潜力。本综述强调了在阐明这些多酚的分子作用机制、确定潜在治疗靶点以及优化其输送和生物利用度方面所取得的进展。要确定基于多酚的干预措施在治疗帕金森病方面的疗效和安全性,必须进行精心设计的临床试验。
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引用次数: 0
Naringenin mitigates nanoparticulate-aluminium induced neuronal degeneration in brain cortex and hippocampus through downregulation of oxidative stress and neuroinflammation 柚皮苷通过下调氧化应激和神经炎症缓解纳米微粒铝诱导的脑皮质和海马神经元退行性病变
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-29 DOI: 10.1016/j.neuint.2024.105799
Ravina Rai , Pankaj Lal Kalar , Deepali Jat , Siddhartha Kumar Mishra

Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.

铝的使用和毒性一直是全球关注的问题,尤其是环境和工作场所对纳米颗粒铝(Al-NPs)产品的使用越来越多。由于人体内的常规生物修复过程,铝在环境中会降解成纳米颗粒形式。Al-NPs 的毒性在神经变性的病理生理学中起着关键作用,神经变性的特征是神经纤维缠结和神经斑块的发展,这与阿尔茨海默氏症有关。本研究评估了 Al-NPs 诱导的小鼠神经退行性变以及氧化应激、炎症、DNA 损伤、β 淀粉样蛋白聚集和组织病理学变化引起的行为改变。此外,还评估了柚皮苷(NAR)作为一种有效的神经保护黄酮类化合物对 Al-NPs 诱导的神经退化的预防作用。研究人员合成了 Al-NPs,并使用傅立叶变换红外光谱(FTIR)、X射线衍射(XRD)、TEM和粒度分析仪对其进行了检测。给小鼠口服 Al-NPs(6 毫克/千克体重),然后进行 NAR 治疗(每天 10 毫克/千克体重),共 66 天。通过新物体识别、T迷宫、Y迷宫和莫里斯水迷宫测试测定小鼠的空间工作记忆。我们测量了一氧化氮、蛋白质的高级氧化产物、蛋白质羰基化、脂质过氧化、超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶、还原型谷胱甘肽、氧化型谷胱甘肽和乙酰胆碱酯酶,以及细胞因子分析、免疫组化和 DNA 损伤。Al-NPs 明显降低了小鼠的学习记忆能力,增加了氧化应激,降低了抗氧化酶的活性,增加了 DNA 损伤,改变了细胞因子的水平,并增加了小鼠大脑皮层和海马区的β-淀粉样蛋白聚集。补充 NAR 后,这些神经行为障碍、神经元氧化应激和组织病理学改变明显减轻。总之,Al-NPs 暴露后可能会产生强烈的神经毒性,NAR 可作为治疗和控制神经元变性的潜在预防措施。
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引用次数: 0
Interweaving the Numerical harmonic symmetry principles of the K+ Pore ion channel momentum 交织 K+ 孔离子通道动量的数值谐波对称原理。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-27 DOI: 10.1016/j.neuint.2024.105797
Yuval Ben-Abu

K+ channels exist in all living systems. They allow a selective transition to the K+ ion, which enables the activity of various vital tissues such as muscle cells, neurons, and even bacteria and plants. Despite the mechanism variation in the gating process of K+ channels in different tissues, the selectivity for the K+ ion is preserved and the electrochemical cascade is maintained in these tissues. The electrochemical gradient of the K+ ion is very close to the diffusion rate of K+ ions in bulk water. On the molecular level, how does a K+ ion move across the ion conduction pathway? There are many molecular models that describe and answer this question, however, this is rarely described on the macro level. Here, a physical model can serve as a very good basis for enabling a deeper understanding of the K+ ion for ion transport. Classical physical energy and linear and angular momentum laws can provide a good explanation as to how and what happens to K+ ions when they pass through an ion conduction pathway. This model describes the passage of the ion even before it enters the ion conduction path until the last ion at the end exits. The simulation described here is fascinating and depicts the state of the ion at the farthest end released at almost the same speed as the first ion initially, while all the other ions remain almost at rest. How does this occur? What happens if we change the size or mass of the ion? In this work, I describe this principle and the related problems that could be studied.

K+ 通道存在于所有生命系统中。它们允许向 K+ 离子进行选择性转换,从而使肌肉细胞、神经元、甚至细菌和植物等各种重要组织得以活动。尽管不同组织中 K+ 通道的门控过程存在机理上的差异,但这些组织对 K+ 离子的选择性得以保留,电化学级联得以维持。K+ 离子的电化学梯度与 K+ 离子在大量水中的扩散速率非常接近。在分子水平上,K+ 离子是如何穿过离子传导途径的呢?有许多分子模型可以描述和回答这个问题,但很少有宏观层面的描述。在此,物理模型可以作为一个很好的基础,让我们能够更深入地了解 K+ 离子的离子传输。经典的物理能量、线性和角动量定律可以很好地解释 K+ 离子在通过离子传导途径时是如何以及发生了什么。该模型描述了离子在进入离子传导通路之前直至最后一个离子离开时的经过。这里描述的模拟令人着迷,它描绘了最远端的离子以与最初第一个离子几乎相同的速度释放的状态,而所有其他离子几乎保持静止。这是如何发生的呢?如果我们改变离子的大小或质量,又会发生什么呢?在这项工作中,我将介绍这一原理以及可以研究的相关问题。
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引用次数: 0
Anticonvulsant and anxiolytic-like potential of the essential oil from the Ocimum basilicum Linn leaves and its major constituent estragole on adult zebrafish (Danio rerio) 欧鼠李叶精油及其主要成分雌甾醇对成年斑马鱼(Danio rerio)的抗惊厥和抗焦虑潜力。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-25 DOI: 10.1016/j.neuint.2024.105796
Francisco Lucas A. Batista , Sandra Maria B. de Araújo , Daniela Braga de Sousa , Francisco Bastos C. Sobrinho , Maria Gabriely de Lima Silva , Maria Rayane C. de Oliveira , Roger Henrique S. da Costa , Lindaiane Bezerra Rodrigues , Franciglauber Silva Bezerra , Djane Ventura de Azevedo , Antônio Eufrásio Vieira-Neto , Francisco Ernani A. Magalhães , Irwin Rose Alencar de Menezes

The Ocimum species present active compounds with the potential to develop drugs for treating chronic disease conditions, such as anxiety and seizures. The present study aims to investigate the anticonvulsant and anxiolytic-like effect of the essential oil from O. basilicum Linn (OEFOb) leaves and its major constituent estragole (ES) in vivo on adult zebrafish (aZF) and in silico. The aZF were treated with OEFOb or ES or vehicle and submitted to the tests of toxicity, open-field, anxiety, and convulsion and validated the interactions of the estragole on the involvement of GABAergic and serotonergic receptors by molecular docking assay. The results showed that the oral administration of OEFOb and ES did not have a toxic effect on the aZF and showed anxiolytic-like effects with the involvement of GABAA, 5-HT1, 5-HT2A/2C and 5-HT3A/3B as well on anxiety induced by alcohol withdrawal. The OEFOb and ES showed anticonvulsant potential attenuating the seizures induced by pentylenetetrazole (PTZ) by modulation of the GABAA system. Both anxiolytic and anticonvulsant effects were corroborated by the potential of the interaction of ES by in silico assay. These study samples demonstrate the pharmacological evidence and potential for using these compounds to develop new anxiolytic and anticonvulsant drugs.

欧鼠李属植物的活性化合物具有开发治疗慢性疾病(如焦虑症和癫痫发作)药物的潜力。本研究旨在调查欧芹叶精油(OEFOb)及其主要成分雌甾醇(ES)对成年斑马鱼(aZF)的抗惊厥和抗焦虑作用。用 OEFOb 或 ES 或载体处理成年斑马鱼,并对其进行毒性、开放场、焦虑和惊厥测试,通过分子对接试验验证了雌甾醇与 GABA 能受体和血清素能受体的相互作用。结果表明,口服 OEFOb 和 ES 不会对 aZF 产生毒性作用,并且在 GABAA、5-HT1、5-HT2A/2C 和 5-HT3A/3B 受体的参与下,对酒精戒断引起的焦虑表现出类似抗焦虑的作用。通过调节 GABAA 系统,OEFOb 和 ES 显示出抗惊厥潜力,可减轻戊四唑(PTZ)诱发的癫痫发作。ES 的相互作用潜能也证实了这两种抗焦虑和抗惊厥作用。这些研究样本证明了使用这些化合物开发抗焦虑和抗惊厥新药的药理证据和潜力。
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引用次数: 0
p53 lysine-lactylated modification contributes to lipopolysaccharide-induced proinflammatory activation in BV2 cell under hypoxic conditions 在缺氧条件下,p53 赖氨酸-乳酸修饰有助于脂多糖诱导的 BV2 细胞促炎激活。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-21 DOI: 10.1016/j.neuint.2024.105794
Xuechao Fei , Lu Chen , Jiayue Gao , Xiufang Jiang , Wen Sun , Xiang Cheng , Tong Zhao , Ming Zhao , Lingling Zhu

p53 has diversity functions in regulation of transcription, cell proliferation, cancer metastasis, etc. Recent studies have shown that p53 and nuclear factor-κB (NF-κB) co-regulate proinflammatory responses in macrophages. However, the role of p53 lysine lactylation (p53Kla) in mediating proinflammatory phenotypes in microglia under hypoxic conditions remains unclear. In the current study, we investigated the proinflammatory activation exacerbated by hypoxia and the levels of p53Kla in microglial cells. BV2 cells, an immortalized mouse microglia cell line, were divided into control, lipopolysaccharide (LPS)-induced, hypoxia (Hy), and LPS-Hy groups. The protein expression levels of p53 and p53Kla and the activation of microglia were compared among the four groups. Sodium oxamate and mutant p53 plasmids were transfected into BV2 cells to detect the effect of p53Kla on microglial proinflammatory activation. LPS-Hy stimulation significantly upregulated p53Kla levels in both the nucleus and the cytoplasm of BV2 cells. In contrast, the p53 protein levels were downregulated. LPS-Hy stimulation upregulated phosphorylated p65 protein levels in nuclear and activated the NF-κB pathway in BV2 cells, resulting in increased expression of pro-inflammatory cytokines (iNOS, IL6, IL1β, TNFα), enhanced cell viability, and concomitantly, increased cytotoxicity. In conclusion, p53 lysine-lactylated modification contributes to LPS-induced proinflammatory activation in BV2 cells under hypoxia through NF-κB pathway and inhibition of lactate production may alleviate neuroinflammatory injury.

p53 在调节转录、细胞增殖、癌症转移等方面具有多种功能。最近的研究表明,p53 和核因子-κB(NF-κB)共同调节巨噬细胞的促炎反应。然而,p53赖氨酸乳化(p53Kla)在缺氧条件下介导小胶质细胞促炎表型的作用仍不清楚。在本研究中,我们调查了缺氧加剧的促炎激活和小胶质细胞中的 p53Kla 水平。我们将永生化小鼠小胶质细胞系 BV2 细胞分为对照组、脂多糖(LPS)诱导组、缺氧(Hy)组和 LPS-Hy 组。比较了四组中 p53 和 p53Kla 的蛋白表达水平以及小胶质细胞的活化情况。将草氨酸钠和突变型 p53 质粒转染至 BV2 细胞,检测 p53Kla 对小胶质细胞促炎激活的影响。LPS-Hy刺激显著上调了BV2细胞核和胞质中的p53Kla水平。与此相反,p53 蛋白水平则有所下降。LPS-Hy 刺激上调了 BV2 细胞核中磷酸化 p65 蛋白水平,激活了 NF-κB 通路,导致促炎细胞因子(iNOS、IL6、IL1β、TNFα)表达增加,增强了细胞活力,同时增加了细胞毒性。总之,p53 赖氨酸乳酸化修饰通过 NF-κB 通路促使缺氧条件下 LPS 诱导的 BV2 细胞促炎激活,而抑制乳酸的产生可减轻神经炎性损伤。
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引用次数: 0
Intermittent fasting induced cerebral ischemic tolerance altered gut microbiome and increased levels of short-chain fatty acids to a beneficial phenotype 间歇性禁食诱导的脑缺血耐受性改变了肠道微生物组并增加了短链脂肪酸水平,从而形成了有益的表型。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-20 DOI: 10.1016/j.neuint.2024.105795
Bharath Chelluboina , Tony Cho , Jin-Soo Park , Suresh L. Mehta , Saivenkateshkomal Bathula , Soomin Jeong , Raghu Vemuganti

Preconditioning-induced cerebral ischemic tolerance is known to be a beneficial adaptation to protect the brain in an unavoidable event of stroke. We currently demonstrate that a short bout (6 weeks) of intermittent fasting (IF; 15 h fast/day) induces similar ischemic tolerance to that of a longer bout (12 weeks) in adult C57BL/6 male mice subjected to transient middle cerebral artery occlusion (MCAO). In addition, the 6 weeks IF regimen induced ischemic tolerance irrespective of age (3 months or 24 months) and sex. Mice subjected to transient MCAO following IF showed improved motor function recovery (rotarod and beam walk tests) between days 1 and 14 of reperfusion and smaller infarcts (T2-MRI) on day 1 of reperfusion compared with age/sex matched ad libitum (AL) controls. Diet influences the gut microbiome composition and stroke is known to promote gut bacterial dysbiosis. We presently show that IF promotes a beneficial phenotype of gut microbiome following transient MCAO compared with AL cohort. Furthermore, post-stroke levels of short-chain fatty acids (SCFAs), which are known to be neuroprotective, are higher in the fecal samples of the IF cohort compared with the AL cohort. Thus, our studies indicate the efficacy of IF in protecting the brain after stroke, irrespective of age and sex, probably by altering gut microbiome and SCFA production.

众所周知,预处理诱导的脑缺血耐受性是在不可避免的中风事件中保护大脑的一种有益适应。我们目前证明,在接受短暂性大脑中动脉闭塞(MCAO)的成年 C57BL/6 雄性小鼠中,短时间(6 周)间歇性禁食(IF;15 小时/天)诱导的缺血耐受性与长时间(12 周)诱导的缺血耐受性相似。此外,无论年龄(3 个月或 24 个月)和性别如何,6 周 IF 方案都能诱导缺血耐受。与年龄/性别匹配的自由饮食(AL)对照组相比,接受短暂MCAO后进行IF治疗的小鼠在再灌注第1天和第14天之间的运动功能恢复(转体和横梁行走测试)有所改善,再灌注第1天的梗死(T2-MRI)也有所缩小。饮食会影响肠道微生物组的组成,而中风会导致肠道细菌菌群失调。目前,我们的研究表明,与AL队列相比,IF能促进一过性MCAO后肠道微生物组的有益表型。此外,与 AL 队列相比,中风后 IF 队列粪便样本中具有神经保护作用的短链脂肪酸 (SCFA) 水平更高。因此,我们的研究表明,无论年龄和性别如何,中风后 IF 都能有效保护大脑,这可能是通过改变肠道微生物群和 SCFA 的产生来实现的。
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引用次数: 0
A2AR antagonists triggered the AMPK/m-TOR autophagic pathway to reverse the calcium-dependent cell damage in 6-OHDA induced model of PD 在6-OHDA诱导的帕金森病模型中,A2AR拮抗剂触发了AMPK/m-TOR自噬途径,从而逆转了钙依赖性细胞损伤。
IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-15 DOI: 10.1016/j.neuint.2024.105793
Tuithung Sophronea, Saurabh Agrawal, Namrata Kumari, Jyoti Mishra, Vaishali Walecha, Pratibha Mehta Luthra

Calcium dyshomeostasis, oxidative stress, autophagy and apoptosis are the pathogenesis of selective dopaminergic neuronal loss in Parkinson's disease (PD). Earlier, we reported that A2A R modulates IP3-dependent intracellular Ca2+ signalling via PKA. Moreover, A2A R antagonist has been reported to reduce oxidative stress and apoptosis in PD models, however intracellular Ca2+ ([Ca2+]i) dependent autophagy regulation in the 6-OHDA model of PD has not been explored. In the present study, we investigated the A2A R antagonists mediated neuroprotective effects in 6-OHDA-induced primary midbrain neuronal (PMN) cells and unilateral lesioned rat model of PD. 6-OHDA-induced oxidative stress (ROS and superoxide) and [Ca2+]i was measured using Fluo4AM, DCFDA and DHE dye respectively. Furthermore, autophagy was assessed by Western blot of p-m-TOR/mTOR, p-AMPK/AMPK, LC3I/II, Beclin and β-actin. Apoptosis was measured by Annexin V-APC-PI detection and Western blot of Bcl2, Bax, caspase3 and β-actin. Dopamine levels were measured by Dopamine ELISA kit and Western blot of tyrosine hydroxylase. Our results suggest that 6-OHDA-induced PMN cell death occurred due to the interruption of [Ca2+]i homeostasis, accompanied by activation of autophagy and apoptosis. A2A R antagonists prevented 6-OHDA-induced neuronal cell death by decreasing [Ca2+]i overload and oxidative stress. In addition, we found that A2A R antagonists upregulated mTOR phosphorylation and downregulated AMPK phosphorylation thereby reducing autophagy and apoptosis both in 6-OHDA induced PMN cells and 6-OHDA unilateral lesioned rat model. In conclusion, A2A R antagonists alleviated 6-OHDA toxicity by modulating [Ca2+]i signalling to inhibit autophagy mediated by the AMPK/mTOR pathway.

钙失衡、氧化应激、自噬和细胞凋亡是帕金森病选择性多巴胺神经元缺失的发病机制。早些时候,我们报道了 A2A R 通过 PKA 调节 IP3 依赖性细胞内 Ca2+ 信号。此外,有报道称 A2A R 拮抗剂可减少帕金森病模型中的氧化应激和细胞凋亡,但在 6-OHDA 帕金森病模型中,细胞内 Ca2+ ([Ca2+]i)依赖的自噬调节尚未得到探讨。在本研究中,我们研究了 A2A R 拮抗剂在 6-OHDA 诱导的原发性中脑神经元(PMN)细胞和单侧病变的 PD 大鼠模型中介导的神经保护作用。使用Fluo4AM、DCFDA和DHE染料分别测量了6-OHDA诱导的氧化应激(ROS和超氧化物)和[Ca2+]i。此外,还通过对p-m-TOR/mTOR、p-AMPK/AMPK、LC3I/II、Beclin和β-actin进行Western印迹来评估自噬。细胞凋亡通过 Annexin V-APC-PI 检测和 Bcl2、Bax、caspase3 和 β-actin 的 Western 印迹进行测定。多巴胺水平通过多巴胺ELISA试剂盒和酪氨酸羟化酶Western印迹检测。我们的研究结果表明,6-OHDA诱导的PMN细胞死亡是由于[Ca2+]i平衡被破坏,同时伴有自噬和细胞凋亡的激活。A2A R拮抗剂通过降低[Ca2+]i过载和氧化应激防止了6-OHDA诱导的神经元细胞死亡。此外,我们还发现,在 6-OHDA 诱导的 PMN 细胞和 6-OHDA 单侧病变大鼠模型中,A2A R 拮抗剂可上调 mTOR 磷酸化,下调 AMPK 磷酸化,从而减少自噬和细胞凋亡。总之,A2A R拮抗剂通过调节[Ca2+]i信号来抑制AMPK/mTOR通路介导的自噬,从而减轻了6-OHDA的毒性。
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引用次数: 0
Exposure to lipid mixture induces intracellular lipid droplet formation and impairs mitochondrial functions in astrocytes 暴露于脂质混合物会诱导细胞内脂滴的形成,并损害星形胶质细胞线粒体的功能。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1016/j.neuint.2024.105792
Yi-Chen Li, Jing-Ting Fu, Shun-Fen Tzeng

Astrocytes, the predominant glial cells in the central nervous system (CNS), play diverse roles including metabolic support for neurons, provision of neurotrophic factors, facilitation of synaptic neurotransmitter uptake, regulation of ion balance, and involvement in synaptic formation. The accumulation of lipids has been noted in various neurological conditions, yet the response of astrocytes to lipid-rich environments remains unclear. In this study, primary astrocytes isolated from the neonatal rat cortex were exposed to a lipid mixture (LM) comprising cholesterol and various fatty acids to explore their reaction. Our results showed that astrocyte viability remained unchanged following 24 h of 5% or 10% LM treatment. However, exposure to LM for 96 h resulted in reduced cell viability. In addition, LM treatment led to the accumulation of lipid droplets (LDs) in astrocytes, with LD size increasing over prolonged exposure periods. Following 24 h of LM treatment and then 48 h in fresh medium, a significant reduction in intracellular LD size was observed in cultures treated with 5% LM, while no change occurred in cultures exposed to 10% LM. Yet, exposure to 10% LM for 24 h significantly increased the expression of the cholesterol efflux regulatory protein/ATP-binding cassette transporter (ABCA1) gene, responsible for intracellular cholesterol efflux, resulting in reduced cholesterol content within astrocytes. Moreover, LM exposure led to decreased mitochondrial membrane potential (MMP) and increased levels of mature apoptosis-inducing factor (AIF). The smaller LDs were observed to co-localize with microtubule-associated protein 1A/1 B light chain 3 B (LC3) and lysosomal-associated membrane protein-1 (LAMP-1) in LM-treated astrocytes, coinciding with lysosomal acidification. These results indicate that the continuous buildup of LDs in astrocytes residing in lipid-enriched environments may be attributed to disruptions caused by LM in mitochondrial and lysosomal functions. Such disruptions could potentially impede the supportive role of astrocytes in neuronal function.

星形胶质细胞是中枢神经系统(CNS)中最主要的胶质细胞,发挥着多种作用,包括为神经元提供代谢支持、提供神经营养因子、促进突触神经递质摄取、调节离子平衡以及参与突触形成。在各种神经系统疾病中都发现了脂质的积累,但星形胶质细胞对富脂质环境的反应仍不清楚。本研究将从新生大鼠皮层中分离出的原代星形胶质细胞暴露于由胆固醇和各种脂肪酸组成的脂质混合物(LM)中,以探究它们的反应。结果表明,5% 或 10% LM 处理 24 小时后,星形胶质细胞的活力保持不变。然而,暴露于 LM 96 小时后,细胞活力会降低。此外,LM 处理会导致脂滴(LDs)在星形胶质细胞中积累,随着暴露时间的延长,LDs 的大小也会增加。经过 24 小时的 LM 处理,然后在新鲜培养基中培养 48 小时后,在用 5% LM 处理的培养物中观察到细胞内 LD 大小显著减少,而暴露于 10% LM 的培养物中则没有变化。然而,暴露于 10%的 LM 24 小时后,负责细胞内胆固醇外流的胆固醇外流调节蛋白/ATP 结合盒转运体(ABCA1)基因的表达明显增加,导致星形胶质细胞内胆固醇含量减少。此外,暴露于 LM 会导致线粒体膜电位(MMP)降低和成熟的凋亡诱导因子(AIF)水平升高。在经 LM 处理的星形胶质细胞中,观察到较小的 LD 与微管相关蛋白 1A/1B 轻链 3B(LC3)和溶酶体相关膜蛋白-1(LAMP-1)共定位,这与溶酶体酸化相吻合。这些结果表明,居住在富脂环境中的星形胶质细胞中 LD 的持续积累可能是由于 LM 破坏了线粒体和溶酶体的功能。这种干扰可能会阻碍星形胶质细胞在神经元功能中发挥支持作用。
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引用次数: 0
Thiazolium salt mimics the non-coenzyme effects of vitamin B1 in rat synaptosomes 噻唑盐在大鼠突触体中模拟维生素 B1 的非辅酶效应
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1016/j.neuint.2024.105791
Yu.M. Parkhomenko , A.I. Vovk , Z.S. Protasova , S. Yu Pylypchuk , S.A. Chorny , O.S. Pavlova , O.A. Mejenska , L.I. Chehovska , S.P. Stepanenko

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2–14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogues of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.

长期研究证实,神经退行性病变的发生与缺乏维生素 B1(硫胺素)之间存在因果关系。然而,人们对硫胺素具有高度神经刺激活性的生化机制尚不完全清楚。同时,越来越多的证据表明,维生素 B1 除了具有辅酶功能外,还可能具有对神经元特别重要的非辅酶活性。为了弄清维生素 B1 对神经元的影响哪些是由于其辅酶功能,哪些是由于其非辅酶活性,我们对硫胺素及其衍生物--3-癸氧羰基甲基-5-(2-羟乙基)-4-甲基-1,3-噻唑氯化物(DMHT)--对突触体中某些过程的影响进行了比较研究。实验证明,DMHT 能够有效地与硫胺素竞争,与突触体质膜上的硫胺素结合位点结合,并作为底物参与硫胺素焦磷激酶反应。在用大鼠脑突触体进行的实验中,证实了 DMHT 和硫胺素对丙酮酸脱氢酶复合物(PDC)的活性以及放射性标记的 [2-14C]丙酮酸掺入乙酰胆碱的单向作用。硫胺素和 DMHT 对乙酰胆碱合成调节作用的观察结果表明,这两种化合物在细胞中与硫胺素代谢酶相互作用,通过影响复合体的调节酶,使其磷酸化并对 PDC 活性产生抑制/激活作用(浓度依赖性)。在硫胺素和 DMHT 的结构类似物存在的情况下,如果噻唑鎓循环的第 5 位没有 2- 羟乙基取代基,则不会观察到这种效应。DMHT 对质膜 Ca-ATP 酶的影响与硫胺相似。同时,DMHT 对神经母细胞瘤细胞具有很高的细胞抑制活性。
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引用次数: 0
Curcumin as a potential therapeutic agent for treating neurodegenerative diseases 姜黄素是一种治疗神经退行性疾病的潜在药物。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-07 DOI: 10.1016/j.neuint.2024.105790
Valeria Perales-Salinas , Sushmitha S. Purushotham , Yossi Buskila

Neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function, posing a tremendous burden on health systems worldwide. Although the underlying pathological mechanisms for various neurodegenerative diseases are still unclear, a common pathological hallmark is the abundance of neuroinflammatory processes, which affect both disease onset and progression. In this review, we explore the pathways and role of neuroinflammation in various neurodegenerative diseases and further assess the potential use of curcumin, a natural spice with antioxidant and anti-inflammatory properties that has been extensively used worldwide as a traditional medicine and potential therapeutic agent. Following the examination of preclinical and clinical studies that assessed curcumin as a potential therapeutic agent, we highlight the bioavailability of curcumin in the body and discuss both the challenges and benefits of using curcumin as a therapeutic compound for treating neurodegeneration. Although elucidating the involvement of curcumin in aging and neurodegeneration has great potential for developing future CNS-related therapeutic targets, further research is required to elucidate the mechanisms by which Curcumin affects brain physiology, especially BBB integrity, under both physiological and disease conditions.

神经退行性疾病的特征是神经元结构和功能的逐渐丧失,给全球卫生系统造成了巨大负担。尽管各种神经退行性疾病的潜在病理机制尚不清楚,但一个共同的病理特征是神经炎症过程的大量存在,这对疾病的发生和发展都有影响。姜黄素是一种具有抗氧化和抗炎特性的天然香料,在全世界被广泛用作传统药物和潜在的治疗药物。在对姜黄素作为一种潜在治疗剂的临床前和临床研究进行审查之后,我们强调了姜黄素在体内的生物利用度,并讨论了将姜黄素作为一种治疗化合物用于治疗神经变性的挑战和益处。虽然阐明姜黄素在衰老和神经退行性变中的作用对于开发未来中枢神经系统相关治疗靶点具有巨大潜力,但还需要进一步研究,以阐明姜黄素在生理和疾病条件下影响大脑生理,特别是影响 BBB 完整性的机制。
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引用次数: 0
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