Disner Geonildo Rodrigo, Fernandes Thales Alves de Melo, Nishiyama-Jr Milton Yutaka, Lima Carla, Wincent Emma, Lopes-Ferreira Monica
Immunoregulation Unit, Laboratory of Applied Toxinology (CeTICS/FAPESP), Butantan Institute, São Paulo 05585-000, Brazil.
Unit of System Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
Pharmaceuticals (Basel). 2024 Aug 31;17(9):1155. doi: 10.3390/ph17091155.
Aryl Hydrocarbon Receptor (AHR) signaling is crucial for regulating the biotransformation of xenobiotics and physiological processes like inflammation and immunity. Meanwhile, Peptide (P), a promising anti-inflammatory candidate from toadfish venom, demonstrates therapeutic effects through immunomodulation. However, its influence on AHR signaling remains unexplored. This study aimed to elucidate P's molecular mechanisms on the AHR-cytochrome P450, family 1 (CYP1) pathway upon injury-induced inflammation in wild-type (WT) and -knockdown (KD) zebrafish larvae through transcriptomic analysis and reporters. P, while unable to directly activate AHR, potentiated AHR activation by the high-affinity ligand 6-Formylindolo [3,2-b]carbazole (FICZ), implying a role as a CYP1A inhibitor, confirmed by in vitro studies. This interplay suggests P's ability to modulate the AHR-CYP1 complex, prompting investigations into its influence on biotransformation pathways and injury-induced inflammation. Here, the inflammation model alone resulted in a significant response on the transcriptome, with most differentially expressed genes (DEGs) being upregulated across the groups. -KD resulted in an overall greater number of DEGs, as did treatment with the higher dose of P in both WT and KD embryos. Genes related to oxidative stress and inflammatory response were the most apparent under inflamed conditions for both WT and KD groups, e.g., , , and . P, specifically, induces the expression of , , , and . Overall, this study suggests an interplay between P and the AHR-CYP1 pathway, stressing the inflammatory modulation through AHR-dependent mechanisms. Altogether, these results may offer new avenues in novel therapeutic strategies, such as based on natural bioactive molecules, harnessing AHR modulation for targeted and sustained drug effects in inflammatory conditions.
芳烃受体（AHR）信号传导对于调节外源性物质的生物转化以及炎症和免疫等生理过程至关重要。同时，肽（P）是一种来自蟾鱼毒液的有前景的抗炎候选物，通过免疫调节发挥治疗作用。然而，其对AHR信号传导的影响仍未得到探索。本研究旨在通过转录组分析和报告基因阐明P在野生型（WT）和敲低（KD）斑马鱼幼虫损伤诱导的炎症中对AHR-细胞色素P450 1家族（CYP1）途径的分子机制。P虽然不能直接激活AHR，但能增强高亲和力配体6-甲酰基吲哚并[3,2-b]咔唑（FICZ）对AHR的激活作用，这意味着它作为一种CYP1A抑制剂，体外研究证实了这一点。这种相互作用表明P有调节AHR-CYP1复合物的能力，促使人们研究其对生物转化途径和损伤诱导炎症的影响。在这里，单独的炎症模型导致转录组有显著反应，大多数差异表达基因（DEG）在各组中上调。KD导致DEG的总数总体上更多，WT和KD胚胎中较高剂量的P处理也是如此。在WT和KD组的炎症条件下，与氧化应激和炎症反应相关的基因最为明显，例如 、 和 。具体而言，P诱导 、 、 和 的表达。总体而言，本研究表明P与AHR-CYP1途径之间存在相互作用，强调通过AHR依赖性机制进行炎症调节。总之，这些结果可能为新的治疗策略提供新途径，例如基于天然生物活性分子，利用AHR调节在炎症条件下实现靶向和持续的药物作用。
