Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
Toxicol Appl Pharmacol. 2023 Feb 15;461:116399. doi: 10.1016/j.taap.2023.116399. Epub 2023 Jan 27.
Development of targeted therapeutics to alleviate gastrointestinal (GI) inflammation and its debilitating consequences are required. In this context, the trace aminergic system may link together sex, diet and inflammation. Utilising a zebrafish larval model of GI inflammation, the current study aimed to investigate mechanisms by which excess amounts of trace amines (TAs) may influence GI health. In addition, we probed the potential role of 17β-estradiol (E2) and its receptors, given the known female-predominance of many GI disorders. To assess GI functionality and integrity, live imaging techniques (neutral red staining) and post-mortem immunofluorescent staining of tight junction proteins (occludin and ZO-1) were analyzed respectively. In addition, behavioural assays, as an indication of overall wellbeing, as well as whole body HO and prostaglandin E2 assays were performed to inform on oxidative and inflammatory status. Excess β-phenethylamine (PEA), tryptamine (TRP) and ρ-tyramine (TYR) resulted in adverse GI and systemic effects. In this regard, clear beneficial effects of E2 to modulate the effects of PEA, TRP and TYR was evident. Moreover, agmatine displayed potential protective effects on GI epithelium and whole body oxidative status, however, potential to induce systemic inflammation suggests the importance of dosage and administration optimisation. Taken together, TYR seems like the most prominent TA to have damaging GI effects, feasibly exacerbating GI inflammation. In this context, the relative lack of E2 may provide mechanistic insights into the reported female-predominance of GI disorders. Moreover, an effective therapeutic in this context may be required to maintain GI TA load despite fluctuating E2 levels.
需要开发靶向治疗药物来缓解胃肠道 (GI) 炎症及其不良后果。在这种情况下，痕量胺能系统可能将性别、饮食和炎症联系在一起。本研究利用斑马鱼幼虫 GI 炎症模型，旨在研究痕量胺 (TA) 过量可能影响 GI 健康的机制。此外，鉴于许多 GI 疾病女性居多，我们还探讨了 17β-雌二醇 (E2) 及其受体的潜在作用。为了评估 GI 的功能和完整性，分别使用活细胞成像技术（中性红染色）和紧密连接蛋白（occludin 和 ZO-1）的死后免疫荧光染色进行分析。此外，还进行了行为测定，作为整体健康状况的指示，以及全身 HO 和前列腺素 E2 测定，以了解氧化和炎症状态。过量的 β-苯乙胺 (PEA)、色胺 (TRP) 和 ρ-酪胺 (TYR) 导致胃肠道和全身不良影响。在这方面，E2 明显有益于调节 PEA、TRP 和 TYR 的作用。此外，胍丁胺对 GI 上皮和全身氧化状态具有潜在的保护作用，但可能诱导全身炎症表明需要优化剂量和给药。总的来说，TYR 似乎是对胃肠道有破坏性影响的最主要的 TA，可能会加剧胃肠道炎症。在这种情况下，E2 的相对缺乏可能为报道的 GI 疾病女性居多提供机制上的见解。此外，在这种情况下，可能需要有效的治疗方法来维持 GI TA 负荷，尽管 E2 水平波动。
