Ávila Daiana Silva, Pereira Camila Milagres Macedo, Bezerra Iverson Conrado, Viçozzi Gabriel Pedroso, Rosini Silva Alex Aparecido, da Silva Artur José, Padilha Heloísa Aiolfi, Cordeiro Emilly de Souza, Silva Aline Castro, Cardoso de Oliveira Danilo, do Nascimento Katarine Gabriely Aurista, de SantanaCavalcante Julianne, Silva Clarice Beatriz Gonçalves, da Silva Roberto Afonso, Bianchini Matheus Chimelo, de Lima Filho José Luiz, Porcari Andreia M, Gubert Priscila
Graduate Program in Biochemistry, Federal University of Pampa (UNIPAMPA), Uruguaiana 96460-000, Brazil.
Graduate Program in Biological Sciences, Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria 97105-900, Brazil.
ACS Omega. 2025 Jul 17;10(29):31313-31330. doi: 10.1021/acsomega.4c10748. eCollection 2025 Jul 29.
Autism spectrum disorder (ASD) is a developmental and neurological condition that impacts an individual's behavior, communication, social interaction, and learning abilities. This disease is complex and involves different mechanisms, and therefore, modeling is a major challenge. Some features can be reproduced in different animal models to investigate therapeutic approaches. Here, we proposed a new simple model to induce development delay by using the nematode and dithiothreitol (DTT) as a chemical agent. In order to investigate a complementary treatment, a commercial supplement and its isolated components (vit. B12, B1, B6, and B9), curcumin, and palmitoylethanolamide (PEA) were used to revert the oxidative stress, development impairments, and metabolomic changes caused by DTT. Furthermore, computational tools predicted pharmacokinetic properties (SwissADME) and possible pathways (enrichment analysis) linked to ASD, an important neurodevelopmental disorder. The supplement and its components (curcumin, PEA, vit. B12, B6, and B9) partially alleviated the delay in larval progression and completely recovered the GABAergic neurodevelopmental impairments (supplement, curcumin, vit. B6, B9, and B12) caused by DDT. Vitamin B9, B12, and supplement partially protected mortality against the oxidative stressor Paraquat. Curcumin, vit. B1, B6, and supplement showed potential protection against coexposure to DTT by reducing DAF-16 migration to the nucleus compared to DTT. Vitamins B1, B9, and B12 coexposure to DTT positively modulated SOD-3 expression. Amino acids, carnitines, and lipids revealed by LC-MS analysis enabled group differentiation and pathway analysis, indicating potential signaling molecules. In silico analysis predicted that these components may interact with pathways linked to ASD pathogenesis such as immunomodulation, synaptic pruning, and complex behavior regulation. Our data indicate that DTT is a good chemical model to induce developmental disorders and that the supplement, with all its components associated, is a promising therapy to be investigated in ASD.
自闭症谱系障碍（ASD）是一种发育性神经疾病，会影响个体的行为、沟通、社交互动和学习能力。这种疾病很复杂，涉及不同的机制，因此，建立模型是一项重大挑战。一些特征可以在不同的动物模型中重现，以研究治疗方法。在这里，我们提出了一种新的简单模型，通过使用线虫和二硫苏糖醇（DTT）作为化学试剂来诱导发育迟缓。为了研究一种补充治疗方法，我们使用了一种商业补充剂及其分离成分（维生素B12、B1、B6和B9）、姜黄素和棕榈酰乙醇胺（PEA）来逆转由DTT引起的氧化应激、发育障碍和代谢组学变化。此外，计算工具预测了与重要神经发育障碍ASD相关的药代动力学特性（SwissADME）和可能的途径（富集分析）。该补充剂及其成分（姜黄素、PEA、维生素B12、B6和B9）部分缓解了幼虫发育进程的延迟，并完全恢复了由DDT引起的GABA能神经发育障碍（补充剂、姜黄素、维生素B6、B9和B12）。维生素B9、B12和补充剂部分保护了免受氧化应激剂百草枯的致死作用。与DTT相比，姜黄素、维生素B1、B6和补充剂通过减少DAF-16向细胞核的迁移，显示出对共同暴露于DTT的潜在保护作用。维生素B1、B9和B12与DTT共同暴露可正向调节SOD-3的表达。液相色谱-质谱分析揭示的氨基酸、肉碱和脂质能够进行组间区分和途径分析，表明存在潜在的信号分子。计算机模拟分析预测，这些成分可能与ASD发病机制相关的途径相互作用，如免疫调节、突触修剪和复杂行为调节。我们的数据表明，DTT是诱导发育障碍的良好化学模型，并且该补充剂及其所有相关成分是一种有前景的可在ASD中进行研究的治疗方法。
