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Targeting Oxidative Stress in Neurodegenerative Disorders: A Novel Role for PCSK9 Inhibition? 针对神经退行性疾病中的氧化应激:抑制 PCSK9 的新作用?
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1021/acschemneuro.4c00299
Lauren M Park, Pal Pacher, Falk W Lohoff

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.

Proprotein convertase subtilisin/kexin type 9(PCSK9)是一种通过溶酶体低密度脂蛋白受体(LDLR)降解调节胆固醇水平的蛋白质,最近被认为与神经元氧化应激和年龄相关性心血管功能障碍的产生有关。由于氧化应激和血管功能障碍的增加与衰老和各种神经退行性疾病的病理过程有关,因此靶向 PCSK9 可能会为解决这些问题提供一种很有前景的治疗途径。虽然 PCSK9 促成脑血管和神经元氧化应激的确切机制仍然难以捉摸,但临床前研究强调了与 PCSK9 抑制有关的神经保护作用。这种抑制有望减少氧化应激、减轻神经炎症和缓解神经病理变化,从而凸显了这种方法在治疗神经退行性疾病方面的潜力。
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引用次数: 0
Healthy Plasma Exosomes Exert Potential Neuroprotective Effects against Methylmalonic Acid-Induced Hippocampal Neuron Injury. 健康血浆外泌体对甲基丙二酸诱导的海马神经元损伤具有潜在的神经保护作用
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1021/acschemneuro.4c00224
Wei Zhou, Huizhong Li, Jinxiu Song, Feng Suo, Maosheng Gu, Suhua Qi

Exosomes have shown good potential for alleviating neurological deficits and delaying memory deterioration, but the neuroprotective effects of exosomes remain unknown. Methylmalonic acidemia is a metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) in various tissues that inhibits neuronal survival and function, leading to accelerated neurological deterioration. Effective therapies to mitigate these symptoms are lacking. The purpose of this study was to explore the neuroprotective effects of plasma exosomes on cells and a mouse model of MMA-induced injury. We evaluated the ability of plasma exosomes to reduce the neuronal apoptosis, cross the blood-brain barrier, and affect various parameters related to neuronal function. MMA promoted cell apoptosis, disrupted the metabolic balance, and altered the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), and synaptophysin-1 (Syp-1), and these changes may be involved in MMA-induced neuronal apoptosis. Additionally, plasma exosomes normalized learning and memory and protected against MMA-induced neuronal apoptosis. Our findings indicate that neurological deficits are linked to the pathogenesis of methylmalonic acidemia, and healthy plasma exosomes may exert neuroprotective and therapeutic effects by altering the expression of exosomal microRNAs, facilitating neuronal functional recovery in the context of this inherited metabolic disease. Intravenous plasma-derived exosome treatment may be a novel clinical therapeutic strategy for methylmalonic acidemia.

外泌体在缓解神经功能缺损和延缓记忆衰退方面显示出良好的潜力,但外泌体的神经保护作用仍然未知。甲基丙二酸血症是一种代谢性疾病,其特点是甲基丙二酸(MMA)在各种组织中积累,抑制神经元的存活和功能,导致神经功能加速衰退。目前尚缺乏缓解这些症状的有效疗法。本研究的目的是探索血浆外泌体对细胞和 MMA 诱导损伤的小鼠模型的神经保护作用。我们评估了血浆外泌体减少神经元凋亡、穿过血脑屏障以及影响与神经元功能相关的各种参数的能力。MMA促进了细胞凋亡,破坏了代谢平衡,改变了B细胞淋巴瘤-2(Bcl-2)、Bcl2相关X(Bax)和突触素-1(Syp-1)的表达,这些变化可能与MMA诱导的神经元凋亡有关。此外,血浆外泌体还能使学习和记忆正常化,并防止 MMA 诱导的神经元凋亡。我们的研究结果表明,神经功能缺陷与甲基丙二酸血症的发病机制有关,而健康的血浆外泌体可能会通过改变外泌体microRNA的表达来发挥神经保护和治疗作用,从而促进这种遗传性代谢疾病的神经元功能恢复。静脉注射血浆外泌体治疗可能是治疗甲基丙二酸血症的一种新型临床治疗策略。
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引用次数: 0
Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein-Protein Interactions in a Yeast Two-Hybrid System. Rexinoids 在酵母双杂交系统中诱导人胶质母细胞瘤细胞的差异基因表达和蛋白质-蛋白质相互作用。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.1021/acschemneuro.4c00286
Jennifer F Hackney, Jennifer E Broatch, Rita A Dallal, Christian Brotherson, Sarah Livingston, Zhela Sabir, Sabeeha Mushtaq Reshi, Samantha R Faltermeier Petras, Sanchita Mallick, Michael T Applegate, Nicholas J Mellor, Kristina Buss, Joy M Blain, Carl E Wagner, Peter W Jurutka, Pamela A Marshall

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

雷克西诺德是一种能与雷克西诺德 X 受体(RXR)结合以调节基因表达的化合物,已被提议作为治疗阿尔茨海默病的一类新疗法。尽管这类化合物在结构上相似,与 RXR 的结合亲和力也相当,但不同的类风湿因子会产生不同的下游效应。RXR 可以同源二聚体和异源二聚体,这些蛋白-蛋白相互作用和随后的转录激活潜力会导致不同的基因表达,这取决于 RXR 二聚体伙伴、招募的其他辅助因子以及上调或下调的下游转录因子。我们的分析表明,具有相似 RXR EC50 值的雷希诺类药物在不同基因表达方面会有明显差异。Rexinoid的结合可能会导致RXR构象的不同,从而通过调节RXR相互作用蛋白引起下游基因表达的重大改变。酵母双杂交分析 RXR 诱饵与两个 RXR 相互作用伙伴的结合情况表明,雷克西诺德会促使 RXR 与不同的蛋白伙伴发生不同的结合。对类木犀的理化分析表明,类木犀分子的聚类与其基因表达模式相似。因此,具有相似 RXR 结合亲和力的类雷公藤毒素通过刺激 RXR 及其同源和异源伙伴的额外结合模式,在这些分子的理化特性的驱动下,驱动不同的基因表达。
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引用次数: 0
Interplay between Copper, Phosphatidylserine, and α-Synuclein Suggests a Link between Copper Homeostasis and Synaptic Vesicle Cycling. 铜、磷脂酰丝氨酸和α-突触核蛋白之间的相互作用表明铜平衡与突触小泡循环之间存在联系
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-16 DOI: 10.1021/acschemneuro.4c00280
Xiangyu Teng, Ewelina Stefaniak, Keith R Willison, Liming Ying

Copper homeostasis is critical to the functioning of the brain, and its breakdown is linked with many brain diseases. Copper is also known to interact with the negatively charged lipid, phosphatidylserine (PS), as well as α-synuclein, an aggregation-prone protein enriched in the synapse, which plays a role in synaptic vesicle docking and fusion. However, the interplay between copper, PS lipid, and α-synuclein is not known. Herein, we report a detailed and predominantly kinetic study of the interactions among these three components pertinent to copper homeostasis and neurotransmission. We found that synaptic vesicle-mimicking small unilamellar vesicles (SUVs) can sequester any excess free Cu2+ within milliseconds, and bound Cu2+ on SUVs can be reduced to Cu+ by GSH at a nearly constant rate under physiological conditions. Moreover, we revealed that SUV-bound Cu2+ does not affect the binding between wild-type α-synuclein and SUVs but affect that between N-terminal acetylated α-synuclein and SUVs. In contrast, Cu2+ can effectively displace both types of α-synuclein from the vesicles. Our results suggest that synaptic vesicles may mediate copper transfer in the brain, while copper could participate in synaptic vesicle docking to the plasma membrane via its regulation of the interaction between α-synuclein and synaptic vesicle.

铜的平衡对大脑的功能至关重要,铜的失衡与许多脑部疾病有关。铜还与带负电荷的脂质磷脂酰丝氨酸(PS)以及α-突触核蛋白相互作用,α-突触核蛋白是一种富含在突触中的易聚集蛋白,在突触小泡对接和融合中发挥作用。然而,铜、PS 脂质和α-突触核蛋白之间的相互作用尚不清楚。在此,我们报告了对这三种与铜平衡和神经传递有关的成分之间相互作用的详细和主要动力学研究。我们发现,在生理条件下,模拟突触小泡的单层小泡(SUVs)能在几毫秒内封存任何多余的游离 Cu2+,SUVs 上的结合 Cu2+ 能以几乎恒定的速度被 GSH 还原成 Cu+。此外,我们发现 SUV 结合的 Cu2+ 不会影响野生型 α-synuclein 与 SUV 之间的结合,但会影响 N 端乙酰化的 α-synuclein 与 SUV 之间的结合。相反,Cu2+ 能有效地将两种类型的α-突触核蛋白从囊泡中置换出来。我们的研究结果表明,突触小泡可能在大脑中介导铜的转移,而铜可能通过调节α-突触核蛋白与突触小泡之间的相互作用参与突触小泡与质膜的对接。
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引用次数: 0
Correction to "Substrate Selection Criteria in Regulated Intramembrane Proteolysis". 更正 "调节膜内蛋白水解过程中的底物选择标准"。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1021/acschemneuro.4c00406
Celine Moser, Nadja Guschtschin-Schmidt, Mara Silber, Julia Flum, Claudia Muhle-Goll
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引用次数: 0
Why Is Arginine the Only Amino Acid That Inhibits Polyglutamine Monomers from Taking on Toxic Conformations? 为什么精氨酸是唯一能抑制聚谷氨酰胺单体形成有毒形态的氨基酸?
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1021/acschemneuro.4c00276
Shoichi Tanimoto, Hisashi Okumura

Polyglutamine (polyQ) diseases are devastating neurodegenerative disorders characterized by abnormal expansion of glutamine repeats within specific proteins. The aggregation of polyQ proteins is a critical pathological hallmark of these diseases. Arginine was identified as a promising inhibitory compound because it prevents polyQ-protein monomers from forming intra- and intermolecular β-sheet structures and hinders polyQ proteins from aggregating to form oligomers. Such an aggregation inhibitory effect was not observed in other amino acids. However, the underlying molecular mechanism of the aggregation inhibition and the factors that differentiate arginine from other amino acids, in terms of the inhibition of the polyQ-protein aggregation, remain poorly understood. Here, we performed replica-permutation molecular dynamics simulations to elucidate the molecular mechanism by which arginine inhibits the formation of the intramolecular β-sheet structure of a polyQ monomer. We found that the intramolecular β-sheet structure with more than four β-bridges of the polyQ monomer with arginine is more unstable than without any ligand and with lysine. We also found that arginine has 1.6-2.1 times more contact with polyQ than lysine. In addition, we revealed that arginine forms more hydrogen bonds with the main chain of the polyQ monomer than lysine. More hydrogen bonds formed between arginine and polyQ inhibit polyQ from forming the long intramolecular β-sheet structure. It is known that intramolecular β-sheet structure enhances intermolecular β-sheet structure between proteins. These effects are thought to be the reason for the inhibition of polyQ aggregation. This study provides insights into the molecular events underlying arginine's inhibition of polyQ-protein aggregation.

多谷氨酰胺(polyQ)疾病是一种破坏性神经退行性疾病,其特征是特定蛋白质中谷氨酰胺重复序列的异常扩展。多聚 Q 蛋白的聚集是这些疾病的一个重要病理特征。精氨酸被认为是一种很有前景的抑制化合物,因为它能阻止多 Q 蛋白单体形成分子内和分子间的β片状结构,并阻碍多 Q 蛋白聚集形成寡聚体。在其他氨基酸中没有观察到这种聚集抑制作用。然而,人们对抑制聚合的分子机制以及精氨酸在抑制多 Q 蛋白聚合方面有别于其他氨基酸的因素仍然知之甚少。在此,我们进行了复制跃迁分子动力学模拟,以阐明精氨酸抑制聚 Q 单体分子内 β 片层结构形成的分子机制。我们发现,与不含任何配体和含赖氨酸的聚 Q 单体相比,含精氨酸的聚 Q 单体的分子内β-片状结构(具有四个以上的β桥)更不稳定。我们还发现,精氨酸与 polyQ 的接触是赖氨酸的 1.6-2.1 倍。此外,我们还发现精氨酸与聚 Q 单体主链形成的氢键比赖氨酸多。精氨酸与 polyQ 之间形成的氢键越多,就越能抑制 polyQ 形成分子内的长β-片状结构。众所周知,分子内 β 片层结构会增强蛋白质之间的分子间 β 片层结构。这些效应被认为是抑制 polyQ 聚集的原因。本研究深入探讨了精氨酸抑制多 Q 蛋白聚集的分子事件。
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引用次数: 0
Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer's-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function. 探索苯磷硫胺在散发性阿尔茨海默病大鼠模型中的治疗潜力:洞察胰岛素信号转导和认知功能
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1021/acschemneuro.4c00113
Camila A E F Cardinali, Yandara A Martins, Ruan C M Moraes, Andressa P Costa, Mayke B Alencar, Ariel M Silber, Andrea S Torrão

Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.

阿尔茨海默病(AD)是一种复杂的神经退行性病变过程,由于大脑中葡萄糖代谢和胰岛素信号通路的改变,它也被认为是一种代谢性疾病,与糖尿病有相似之处。本研究旨在探讨维生素 B1 类似物苯磷硫胺(BFT)在通过脑室内注射链脲佐菌素(STZ)诱导的零星阿尔茨海默氏症样疾病模型的神经退行性过程早期阶段的治疗效果。连续 7 天补充 150 毫克/千克的 BFT 可逆转 STZ 对啮齿动物短期和长期记忆造成的认知障碍。我们将这些作用归因于 BFT 能够调节海马中的葡萄糖转运体 1 型和 3 型(GLUT1 和 GLUT3)、抑制海马中 GSK3 的活性、调节海马和内视网膜皮层中的胰岛素信号转导,以及减少海马中细胞凋亡通路(BAX)的激活。因此,BFT有望成为治疗与AD相似病症的初步干预措施。
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引用次数: 0
Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents. 芬太尼支架的结构-活性关系:鉴定作为潜在阿片类药物过量逆转剂的拮抗剂。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-12 DOI: 10.1021/acschemneuro.4c00203
Jessica P Anand, Sierra C Moore, Emma E Dixon, Carmelita M Perrien Naccarato, Joshua L West, Lennon J Delong, Emily Burgess, Jack J Twarozynski, John R Traynor

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

在美国,与阿片类药物过量相关的死亡人数几乎占所有吸毒过量死亡人数的一半,每年造成的可预防死亡人数比车祸还多。芬太尼是一种强效μ阿片受体(MOR)激动剂,其类似物(芬太尼类药物)越来越多地出现在非法药物样本中,无论是主要滥用药物是阿片类还是非阿片类。芬太尼在非法药物市场的流行被认为是 2016 年以来阿片类药物相关过量死亡人数增加的主要驱动因素。事实上,芬太尼及其类似物涉及 70% 以上的阿片类药物相关过量。在目前的治疗模式下,标准的阿片类药物过量抢救疗法纳洛酮往往不足以逆转芬太尼类激动剂导致的阿片类药物过量。然而,许多芬太尼类激动剂的药理作用尚不清楚。此外,在芬太尼系列化合物中,有可能会发现拮抗剂作为阿片类药物过量逆转剂可能优于纳洛酮。在本报告中,我们探究了 70 种芬太尼类药物的药理学,确定了在体外表现为 MOR 拮抗剂的化合物,并证明了其中一种化合物可逆转芬太尼诱导的小鼠呼吸抑制。这些化合物可为开发逆转阿片类药物过量的有效药物提供线索。
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引用次数: 0
Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration. 多谷氨酰胺(PolyQ)疾病:导航神经退行性疾病。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-12 DOI: 10.1021/acschemneuro.4c00184
Rumiana Tenchov, Janet M Sasso, Qiongqiong Angela Zhou

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.

多聚谷氨酰胺(polyQ)疾病是一组遗传性神经退行性疾病,由胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复序列扩增引起,编码的蛋白质具有异常扩增的多聚谷氨酰胺束。目前已发现的多聚 Q 疾病共有九种,包括亨廷顿氏病、六种脊髓小脑性共济失调、齿颚苍白肌萎缩症(DRPLA)以及脊髓和球部肌萎缩症(SBMA)。这类疾病中的每一种都被认为是罕见的,但多 Q 疾病却构成了单基因神经退行性疾病中最大的一个群体。虽然多 Q 疾病的每个亚型都有自己的致病基因,但几乎所有多 Q 疾病都与某些病理分子属性有关,包括蛋白质聚集、蛋白水解裂解、神经元功能障碍、转录失调、自噬功能障碍和线粒体功能障碍。虽然多聚酶疾病的动物模型有助于了解其发病机理并获得改变疾病的疗法,但这些疾病既无法治愈,也无法预防,只能对症治疗。在本文中,我们分析了 CAS 内容库中的数据,总结了多 Q 族疾病的研究进展。我们研究了该领域的论文发表情况,以深入了解当前的知识进步和发展。我们回顾了讨论最多的概念,并评估了应对这些疾病的策略。最后,我们考察了针对多 Q 族疾病的产品的临床应用及其开发管线。本综述旨在概述当前有关多 Q 族疾病的知识的演变情况,概述面临的挑战,并评估发展机遇,以进一步努力防治这些疾病。
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引用次数: 0
Machine Learned Classification of Ligand Intrinsic Activities at Human μ-Opioid Receptor. 人μ-阿片受体配体内在活性的机器学习分类。
IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1021/acschemneuro.4c00212
Myongin Oh, Maximilian Shen, Ruibin Liu, Lidiya Stavitskaya, Jana Shen

Opioids are small-molecule agonists of μ-opioid receptor (μOR), while reversal agents such as naloxone are antagonists of μOR. Here, we developed machine learning (ML) models to classify the intrinsic activities of ligands at the human μOR based on the SMILES strings and two-dimensional molecular descriptors. We first manually curated a database of 983 small molecules with measured Emax values at the human μOR. Analysis of the chemical space allowed identification of dominant scaffolds and structurally similar agonists and antagonists. Decision tree models and directed message passing neural networks (MPNNs) were then trained to classify agonistic and antagonistic ligands. The hold-out test AUCs (areas under the receiver operator curves) of the extra-tree (ET) and MPNN models are 91.5 ± 3.9% and 91.8 ± 4.4%, respectively. To overcome the challenge of a small data set, a student-teacher learning method called tritraining with disagreement was tested using an unlabeled data set comprised of 15,816 ligands of human, mouse, and rat μOR, κOR, and δOR. We found that the tritraining scheme was able to increase the hold-out AUC of MPNN models to as high as 95.7%. Our work demonstrates the feasibility of developing ML models to accurately predict the intrinsic activities of μOR ligands, even with limited data. We envisage potential applications of these models in evaluating uncharacterized substances for public safety risks and discovering new therapeutic agents to counteract opioid overdoses.

阿片类药物是μ-阿片受体(μOR)的小分子激动剂,而纳洛酮等逆转剂则是μOR的拮抗剂。在此,我们开发了机器学习(ML)模型,根据 SMILES 字符串和二维分子描述符对配体在人类 μOR 上的内在活性进行分类。首先,我们以人工方式建立了一个包含 983 种小分子的数据库,这些小分子在人类 μOR 上的最大测量值。通过对化学空间的分析,我们确定了优势支架以及结构相似的激动剂和拮抗剂。然后对决策树模型和有向信息传递神经网络(MPNN)进行训练,以对激动剂和拮抗剂配体进行分类。决策树模型(ET)和有向信息传递神经网络(MPNN)模型的保留测试 AUC(接收器运算曲线下面积)分别为 91.5 ± 3.9% 和 91.8 ± 4.4%。为了克服小数据集带来的挑战,我们使用一个由 15,816 个人类、小鼠和大鼠 μOR、κOR 和 δOR 配体组成的无标记数据集测试了一种称为 "带分歧三训练 "的学生-教师学习方法。我们发现,三训练方案能够将 MPNN 模型的保持率 AUC 提高到 95.7%。我们的工作证明了开发 ML 模型的可行性,即使数据有限,也能准确预测 μOR 配体的内在活性。我们设想这些模型有可能应用于评估未定性物质的公共安全风险,以及发现对抗阿片类药物过量的新治疗药物。
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ACS Chemical Neuroscience
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