Molecular and Cellular Neuroscience最新文献_第2页

Decoding aging through nitrogen containing compounds: A nutrigenomic insight 通过含氮化合物解码衰老：营养基因组学见解

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-11-13 DOI: 10.1016/j.mcn.2025.104055

Spandana Rajendra Kopalli , Nitu L. Wankhede , Sushruta Koppula , Brijesh Taksande , Aman B. Upaganlawar , Arifullah Mohammed , Milind Umekar , Mayur B. Kale

Nitrogen compounds are increasingly recognized as key modulators in nutrigenomics, with profound implications for understanding and influencing the aging process. Traditionally central to human nutrition, these compounds are now understood to play critical roles in regulating gene expression, cellular signalling, and metabolic pathways that are essential for maintaining health during aging. Nitrogen-containing molecules, such as amino acids, polyamines, and nitric oxide, contribute to vital processes including protein synthesis, mitochondrial function, and oxidative stress management. These mechanisms are crucial for cellular homeostasis but become increasingly vulnerable to disruption during aging, leading to tissue degeneration and heightened susceptibility to age-related diseases. Disruptions in nitrogen metabolism can impair proteostasis, mitochondrial bioenergetics, and antioxidant defences, accelerating cellular decline. Recent research has expanded our understanding of how nitrogen compounds interact with nutrient-sensing pathways such as mTOR and AMPK, as well as epigenetic regulators that influence DNA repair, autophagy, and inflammation. These findings highlight the therapeutic potential of optimizing nitrogen metabolism to enhance health span and mitigate the effects of aging. The emerging field of nitrogen nutrigenomics offers promising opportunities for developing targeted nutritional strategies aimed at improving quality of life and delaying age-related decline. By integrating historical perspectives with contemporary discoveries, this review underscores the complex interplay between nitrogen compounds and aging while inspiring future research into innovative interventions that harness their benefits for longevity and well-being. Ultimately, optimizing nitrogen metabolism could pave the way for new approaches to extending health span and addressing age-related health challenges.

氮化合物越来越被认为是营养基因组学中的关键调节剂，对理解和影响衰老过程具有深远的意义。传统上，这些化合物是人类营养的核心，现在人们了解到，这些化合物在调节基因表达、细胞信号传导和代谢途径方面发挥着关键作用，这些途径对于在衰老过程中保持健康至关重要。含氮分子，如氨基酸、多胺和一氧化氮，有助于蛋白质合成、线粒体功能和氧化应激管理等重要过程。这些机制对细胞稳态至关重要，但在衰老过程中越来越容易受到破坏，导致组织变性和对年龄相关疾病的易感性增加。氮代谢的中断会损害蛋白质平衡、线粒体生物能量学和抗氧化防御，加速细胞衰退。最近的研究扩大了我们对氮化合物如何与营养感应途径（如mTOR和AMPK）以及影响DNA修复、自噬和炎症的表观遗传调节因子相互作用的理解。这些发现突出了优化氮代谢以延长健康寿命和减轻衰老影响的治疗潜力。新兴的氮营养基因组学领域为制定有针对性的营养策略提供了有希望的机会，旨在提高生活质量和延缓与年龄相关的衰退。通过将历史观点与当代发现相结合，本综述强调了氮化合物与衰老之间复杂的相互作用，同时启发了未来对利用氮化合物对长寿和健康有益的创新干预措施的研究。最终，优化氮代谢可以为延长健康寿命和解决与年龄相关的健康挑战的新方法铺平道路。

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引用次数: 0

The role of polarization dynamics in macrophages and microglia on the inflammatory microenvironment of spinal cord injury 巨噬细胞和小胶质细胞极化动力学在脊髓损伤炎症微环境中的作用。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-11-06 DOI: 10.1016/j.mcn.2025.104054

Yue Hu, Jun Gao

Spinal cord injury (SCI) triggers complex pathological processes—including neuroinflammation, glial scar formation, and impaired neuronal regeneration—that hinder recovery. Macrophages and microglia centrally regulate these processes through dynamic polarization states across a spectrum of pro−/anti-inflammatory phenotypes. While single-cell technologies reveal glial and immune heterogeneity and interactions in the SCI microenvironment, translating these insights into immunomodulatory therapies remains challenging. This review therefore examines mechanisms driving macrophage/microglia polarization in the microenvironment of SCI, focusing on their therapeutic targeting potential.

脊髓损伤（SCI）引发复杂的病理过程，包括神经炎症、神经胶质瘢痕形成和神经元再生受损，这些都会阻碍康复。巨噬细胞和小胶质细胞通过动态极化状态集中调节这些过程。虽然单细胞技术揭示了脊髓损伤微环境中神经胶质和免疫的异质性和相互作用，但将这些见解转化为免疫调节疗法仍然具有挑战性。因此，本综述探讨了在脊髓损伤微环境中驱动巨噬细胞/小胶质细胞极化的机制，重点研究了它们的治疗靶向潜力。

引用次数: 0

Glymphatic impairment in Moyamoya disease 烟雾病的淋巴损害。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-11-04 DOI: 10.1016/j.mcn.2025.104053

Yao Chen , Xichang Liu

Moyamoya disease (MMD) is a chronic disease characterized by the progressive narrowing of the terminal internal carotid artery, accompanied by abnormal angiogenesis at the base of the skull and defective formation of the vascular network, with a complex clinical picture and a risk of cognitive impairment and dementia in addition to ischemic and hemorrhagic events. The glymphatic system is a cerebrospinal fluid and interstitial fluid drainage pathway that acts throughout the brain to remove metabolic wastes from the brain parenchyma. Clinical studies have found that cognitive decline in patients with MMD is linked to metabolite accumulation and reduced diffusion tensor image analysis along the perivascular space (DTI-ALPS), highlighting the potential impact of glymphatic system impairment. This dysfunction may stem from a combination of chronic hypoperfusion, systemic microstructural damage and inflammatory response, and is an important link to further deterioration of vascular cognitive function. This article discusses the recent findings on glymphatic system disorders in MMD, with the objective of providing new approaches to the disease.

烟雾病（Moyamoya disease， MMD）是一种慢性疾病，以颈内动脉终末进行性狭窄为特征，伴有颅底血管生成异常和血管网络形成缺陷，临床表现复杂，除了缺血性和出血事件外，还存在认知障碍和痴呆的风险。淋巴系统是脑脊液和间质液的引流途径，作用于整个大脑，从脑实质中清除代谢废物。临床研究发现，烟雾病患者的认知能力下降与代谢物积累和沿血管周围间隙弥散张量图像分析（DTI-ALPS）减少有关，突出了淋巴系统损伤的潜在影响。这种功能障碍可能源于慢性灌注不足、全身微结构损伤和炎症反应的共同作用，是血管认知功能进一步恶化的重要环节。本文讨论了烟雾病中淋巴系统疾病的最新发现，目的是提供新的治疗方法。

引用次数: 0

Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation 利用粪便微生物群移植弥合阿尔茨海默病管理方面的差距。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-11-01 DOI: 10.1016/j.mcn.2025.104052

Bushra Bashir , Monica Gulati , Sukriti Vishwas , Md Sadique Hussain , Gaurav Gupta , Puneet Kumar , Poonam Negi , Neeraj Mittal , Kamal Dua , Sachin Kumar Singh

Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.

阿尔茨海默病（Alzheimer's disease， AD）是一种严重损害人类健康的神经退行性疾病，给个人、家庭和社会造成了巨大的负担。AD的特点是病理蛋白的积累和神经胶质细胞活性失调。其他标志性特征包括氧化应激、神经炎症、自噬受损、细胞衰老、线粒体功能障碍、表观遗传改变、神经发生减少、血脑屏障通透性增加和与年龄不适应的肠道生态失调。有重要证据表明，肠道微生物群影响阿尔茨海默病的发生和进展。因此，调节肠道菌群已被确定为阿尔茨海默病临床管理的新方法，并且越来越多的人致力于寻找预防和治疗阿尔茨海默病的新方法。本文将讨论肠道微生物群在AD发病机制中的作用，并考虑补充粪便微生物群提取物（FME）的可能性，通常称为粪便微生物群移植（FMT）。它既是一种预防方法，也是一种治疗方法。FMT治疗的前提是抗炎作用、β淀粉样蛋白修饰、突触可塑性改善、短链脂肪酸和组蛋白乙酰化是阿尔茨海默病增强背后的原理。本综述也将概述FMT和AD之间的联系。它进一步检查和评估FMT对支持AD发展的基于衰老的机制的影响。它还提供了关于FMT应用于AD的近期临床和临床前证据的广泛描述。

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引用次数: 0

The LINC00094/miR-19a-3p signalling regulates glycolysis and mediates cold induced traumatic brain injury LINC00094/miR-19a-3p信号调节糖酵解并介导冷诱导的创伤性脑损伤。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-10-10 DOI: 10.1016/j.mcn.2025.104050

Divya Mishra , Rashi Saxena , Deepak , Rekha Yadav , Durga Prasad Mishra

Cold induced traumatic brain injury (Ci-TBI), is a lethal and highly debilitating neurodegenerative condition with limited therapeutic options. Metabolic perturbations like deregulated glycolysis is perceived as a hallmark of TBIs including Ci-TBIs. Elucidation of the underlying mechanisms regulating Ci-TBI are essential devising effective therapeutic strategies. In the present study, induction of Ci-TBI in-vitro and in a mice model down regulated the long noncoding RNA LINC00094. Our mechanistic studies revealed that LINC00094 targeted and inhibited miR-19a-3p both in the neuronal culture based in vitro model of Ci-TBI vitro and a Ci-TBI mice model in vivo. The elevated expression of miR-19a-3p further targeted and inhibited the adiponectin receptor 2 (AdipoR2) and repressed glycolysis, glucose uptake and lactate production. Collectively, our results elucidated the molecular cascade and underscored the significance of the LINC00094/miR-19a-3p signalling in regulation of glycolysis mediating Ci-TBI. These novel findings indicate that LINC00094 and miR-19a-3p could be of prognostic and diagnostic value as potential biomarkers of Ci-TBI progression.

冷致创伤性脑损伤（Ci-TBI）是一种致命且高度衰弱的神经退行性疾病，治疗选择有限。代谢紊乱如糖酵解失调被认为是包括ci - tbi在内的tbi的标志。阐明调节Ci-TBI的潜在机制是制定有效治疗策略的必要条件。在本研究中，体外和小鼠模型诱导Ci-TBI下调长链非编码RNA LINC00094。我们的机制研究表明，LINC00094在体外培养的Ci-TBI模型和体内Ci-TBI小鼠模型中都能靶向并抑制miR-19a-3p。miR-19a-3p的表达升高进一步靶向并抑制脂联素受体2 (AdipoR2)，抑制糖酵解、葡萄糖摄取和乳酸生成。总的来说，我们的结果阐明了分子级联，并强调了LINC00094/miR-19a-3p信号传导在糖酵解介导的Ci-TBI调控中的重要性。这些新发现表明，LINC00094和miR-19a-3p可能作为Ci-TBI进展的潜在生物标志物具有预后和诊断价值。

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引用次数: 0

AstroGreen transgenic mouse illuminates the trafficking of astrocyte-derived extracellular vesicles AstroGreen转基因小鼠阐明了星形胶质细胞衍生的细胞外囊泡的运输。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-10-08 DOI: 10.1016/j.mcn.2025.104051

Lisa Nieland , Edwina Abou Haidar , David Rufino-Ramos , Shilpa Prabhakar , Youssef Samaha , Koen Breyne , Francis K. Fordjour , Saumya Das , Marike L.D. Broekman , Stephen Gould , Xandra O. Breakefield , Erik R. Abels

Astrocytes interact with neighboring cells by releasing extracellular vesicles (EVs). Tools to study astrocyte EV-mediated communication with other brain cells in vivo are essential. In this study, we crossed the Exomap1 transgenic mouse expressing Cre-activated human-specific CD81 (HsCD81) fused to the fluorescent protein mNeonGreen (HsCD81mNG), to a transgenic mouse expressing Cre under the astrocyte-expressing GFAP promoter resulting in Exomap1::Gfap-Cre mice, referred to here as AstroGreen. We characterized HsCD81mNG-expressing astrocytes and shedded EVs loaded with HsCD81mNG and Cre, both in vitro and in mouse brains. Using this model, we show that HsCD81mNG can be used to track EV content, production, and functional Cre transfer in vitro and in the brain, allowing evaluation of the interaction of astrocytes with neighboring cells mediated by EVs. We anticipate that this model will improve our understanding of astrocytes transferring EVs within their surroundings during normal physiological processes and in the context of neuropathological conditions.

星形胶质细胞通过释放细胞外囊泡（EVs）与邻近细胞相互作用。在体内研究星形胶质细胞ev介导的与其他脑细胞的通讯工具是必不可少的。在本研究中，我们将表达crea激活的人类特异性CD81 （HsCD81）与荧光蛋白mNeonGreen （HsCD81mNG）融合的Exomap1转基因小鼠与在星形胶质细胞表达GFAP启动子下表达Cre的转基因小鼠杂交，得到Exomap1:: GFAP -Cre小鼠，这里简称AstroGreen。我们在体外和小鼠脑内对表达HsCD81mNG的星形胶质细胞和装载HsCD81mNG和Cre的脱落的EVs进行了表征。通过该模型，我们发现HsCD81mNG可用于在体外和脑内跟踪EV含量、产生和功能Cre转移，从而评估EV介导的星形胶质细胞与邻近细胞的相互作用。我们预计该模型将提高我们对星形胶质细胞在正常生理过程和神经病理条件下在其周围环境中转移ev的理解。

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引用次数: 0

Exosome-based therapeutic approach for spinal cord injury: A review 基于外泌体的脊髓损伤治疗方法综述。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-09-25 DOI: 10.1016/j.mcn.2025.104048

Shuai Bai , Rong Rong Qiang , Rui Yang Liu , De Jie Kang , Yan Ling Yang

Spinal cord injury (SCI) is a devastating neurological condition associated with high rates of disability and mortality, placing substantial burdens on patients, families, and healthcare systems. Current treatment strategies, including surgical decompression, pharmacological intervention, and rehabilitation, offer only limited functional recovery. Exosomes, extracellular vesicles with a double-membrane structure, range in diameter from 30 to 150 nm and play a key role in intercellular communication by transporting proteins, lipids, and nucleic acids. Recent studies have highlighted their potential as natural nanocarriers for the treatment of neurodegenerative disorders. Due to their low immunogenicity and multifunctional reparative properties, exosomes have shown considerable efficacy in promoting neurological recovery following SCI. They exert therapeutic effects through multiple mechanisms, including modulation of the inflammatory response, promoting axonal regeneration and angiogenesis, and inhibiting apoptosis. This review summarizes the pathophysiological mechanisms underlying SCI and elucidates the therapeutic roles of exosomes and exosomal microRNAs (exo-miR) in SCI repair. Furthermore, it discusses current challenges and prospects for the clinical translation of exosome-based therapies, aiming to provide valuable insights for future research and clinical applications.

脊髓损伤（SCI）是一种具有高致残率和高死亡率的破坏性神经系统疾病，给患者、家庭和医疗保健系统带来了沉重的负担。目前的治疗策略，包括手术减压、药物干预和康复，只能提供有限的功能恢复。外泌体是具有双膜结构的细胞外囊泡，直径从30到150 nm （nm）不等，通过运输蛋白质、脂质和核酸在细胞间通讯中起关键作用。最近的研究强调了它们作为治疗神经退行性疾病的天然纳米载体的潜力。由于其低免疫原性和多功能修复特性，外泌体在促进脊髓损伤后神经恢复方面显示出相当大的功效。它们通过多种机制发挥治疗作用，包括调节炎症反应、促进轴突再生和血管生成、抑制细胞凋亡。本文综述了脊髓损伤的病理生理机制，并阐明了外泌体和外泌体microRNAs （exo-miR）在脊髓损伤修复中的治疗作用。此外，本文还讨论了目前基于外泌体疗法的临床翻译面临的挑战和前景，旨在为未来的研究和临床应用提供有价值的见解。

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引用次数: 0

Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine 二甲胺四环素和n -乙酰半胱氨酸可预防小鼠单一闭合性头部损伤后的慢性功能缺陷。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-09-23 DOI: 10.1016/j.mcn.2025.104049

Siobhán C. Lawless , Craig Kelley , Elena Nikulina , Ufaq Tahir , Ashmeet Kaur , Juan Marcos Alarcon , Peter J. Bergold

Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.

创伤性脑损伤（TBI）可产生慢性肢体协调和步态缺陷，这些缺陷与持续的白质损伤有关。在啮齿动物TBI模型中，慢性运动缺陷可能被衰老或运动补偿所掩盖。此外，TBI没有治疗方法。小鼠闭合性脑损伤（CHI）模型产生弥漫性慢性白质损伤，可能是慢性白质功能障碍和运动缺陷的基础。诱发复合动作电位（CAP）评估损伤后3 ~ 180天的胼胝体功能。CHI急剧降低总CAP振幅，在90 DPI时恢复，并在180 DPI时进一步增加。损伤后12 h （MN12）开始给药二甲胺四环素和n -乙酰半胱氨酸可阻断总CAP振幅变化。受伤小鼠和假小鼠在梁式行走中行走的时间和足部故障数量相似。DeepLabCut™无标记肢体跟踪提供肢体位置，用于开发新的分析方法来评估梁行走和简单/复杂车轮。姿态分析综合了梁行走过程中足部故障的持续时间和程度。受伤小鼠在90 DPI时出现定位缺陷，在180 DPI时恶化，表明慢性和进行性下降。MN12治疗可阻断慢性退位缺陷。速度通常评估简单/复杂车轮的性能。新的肢体协调实验表明，在180 DPI时，受伤小鼠的协调能力下降，与总CAP振幅增加显著相关。MN12可缓解慢性胼胝体功能障碍和运动缺陷，提示其对TBI有较强的治疗效果。DeepLabCut™肢体跟踪显示慢性缺陷和运动补偿未见标准结果。

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引用次数: 0

Covalent inhibitors in Parkinson's disease: Molecular targeting strategies for neuroprotective intervention 帕金森病的共价抑制剂：神经保护干预的分子靶向策略。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-09-09 DOI: 10.1016/j.mcn.2025.104037

Devadharuna Mohan , Raghul Venkatesan , Amarjith Thiyyar Kandy , Santhoshkumar Muthu , Saravanan Jayaram , Rajinikanth Baskaran , Palanisamy Pethappachetty , Divakar Selvaraj

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by dopaminergic neuronal loss, protein aggregation, and neuroinflammation. Current symptomatic therapies have not demonstrated disease-modifying effects. Covalent inhibitors represent a promising multifactorial therapeutic approach due to their ability to form irreversible and specific bonds with target proteins. This narrative review incorporates recent experimental and computational findings on emerging covalent inhibitors that target key molecular mechanisms implicated in PD. This includes α-synuclein aggregation, LRRK2 kinase hyperactivity, monoamine oxidase B (MAO-B) dysfunction, glutathione S-transferase Pi 1 (GSTP1)-mediated oxidative stress, and modulation of the Nrf2 signaling pathway. We discuss structure-guided drug design strategies, warhead chemistry, and unique inhibition modalities that contribute to improved pharmacological profiles and neuroprotective potential. In addition to classical covalent inhibition, the review explores emerging targeted covalent degrader strategies that expand therapeutic possibilities by promoting selective protein degradation rather than mere functional suppression. Furthermore, recent preclinical advances and clinical translation challenges are evaluated, positioning covalent approaches as leading candidates for targeted and sustained PD interventions. Lastly, we address developmental obstacles, such as enhancing selectivity and blood-brain barrier penetration while minimizing off-target effects, highlighting the role of activity-based protein profiling, covalent PROTACs, and bifunctional covalent degraders as next-generation strategies to optimize therapeutic efficacy in PD treatment.

帕金森病（PD）是一种复杂的神经退行性疾病，以多巴胺能神经元丧失、蛋白质聚集和神经炎症为特征。目前的对症治疗尚未显示出改善疾病的效果。共价抑制剂由于其与靶蛋白形成不可逆和特异性键的能力，代表了一种有前途的多因子治疗方法。这篇叙述性的综述结合了最近的实验和计算发现，新出现的共价抑制剂的目标涉及PD的关键分子机制。这包括α-突触核蛋白聚集、LRRK2激酶高活性、单胺氧化酶B （MAO-B）功能障碍、谷胱甘肽s -转移酶Pi 1 （GSTP1）介导的氧化应激和Nrf2信号通路的调节。我们讨论了结构导向的药物设计策略，弹头化学和独特的抑制模式，有助于改善药理学概况和神经保护潜力。除了经典的共价抑制外，该综述还探讨了新兴的靶向共价降解策略，通过促进选择性蛋白质降解而不仅仅是功能抑制来扩大治疗可能性。此外，评估了最近的临床前进展和临床翻译挑战，将共价方法定位为靶向和持续PD干预的主要候选方法。最后，我们解决了发育障碍，如增强选择性和血脑屏障穿透，同时最大限度地减少脱靶效应，强调了基于活性的蛋白质谱分析，共价PROTACs和双功能共价降解物作为优化PD治疗效果的下一代策略的作用。

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引用次数: 0

Genetic modifiers of epilepsy: A narrative review 癫痫的遗传修饰因子：一个叙述性的回顾。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-09-05 DOI: 10.1016/j.mcn.2025.104038

Saliha Rizvi , Syed Tasleem Raza , Farzana Mahdi

Epilepsy is a neurological disorder that shows strong genetic control on the timing and onset of symptoms and drug response variability. Some epilepsy syndromes have clear monogenic mutations but genes with control on the phenotype and severity of the disorder and drug sensitivity are present in the whole genetic profile. Genetic modifiers are not the cause of epilepsy but control significant networks such as synaptic plasticity and ion channels and neurodevelopment and neuroinflammation and therefore the reason why two individuals with the same primary mutations have different clinical courses. The review comprehensively examines the genetics of epilepsy to outline standard and minority genetic determinants and to distinguish between single-genetic and poly-genetic causes. It examines genetic modifiers and the mechanism by which they act and the control they exert on drug resistance and seizure risk and development of epilepsy and cognitive and behavioral problems. Alongside it explains how GWAS data with the help of epigenetics to identify significant modifying genes with control on neurotransmission and the immune response and metabolic pathways and ion channel regulation such as SCN1A and KCNQ2. The major functional mechanisms of genetic modifiers and the control they exert on network excitability and the control on the blood-brain barrier and neurodevelopmental pathways has been emphasized and explained in specific sections. The final section in this overview discusses the future possibility with precision medicine through genetic modifier-directed treatments and new drug development strategies and will develop tailored epilepsy treatment strategies.

癫痫是一种神经系统疾病，对症状的时间和发作以及药物反应变异性有很强的遗传控制。一些癫痫综合征有明显的单基因突变，但控制表型、疾病严重程度和药物敏感性的基因存在于整个遗传谱中。遗传修饰因子不是癫痫的病因，但控制着突触可塑性、离子通道、神经发育和神经炎症等重要网络，因此，具有相同原发性突变的两个个体有不同的临床病程。这篇综述全面检查了癫痫的遗传学，概述了标准和少数遗传决定因素，并区分了单遗传和多遗传原因。它审查基因修饰物及其作用机制，以及它们对耐药性、癫痫发作风险和癫痫发展以及认知和行为问题的控制。此外，它还解释了GWAS数据如何在表观遗传学的帮助下识别具有控制神经传递和免疫反应以及代谢途径和离子通道调节的重要修饰基因，如SCN1A和KCNQ2。遗传修饰因子的主要功能机制及其对神经网络兴奋性、血脑屏障和神经发育途径的控制已在特定章节中得到强调和解释。本综述的最后一部分讨论了未来通过基因修饰导向治疗和新药开发策略的精准医学的可能性，并将制定量身定制的癫痫治疗策略。

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引用次数: 0