Effects of Strigolactones on NLRP3 Activation, Nitrosative Stress, and Antioxidant Mox Phenotype: In Vitro and In Silico Evidence

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2024-02-19 DOI:10.1021/acsbiomedchemau.3c00063
Gizem Antika, Zeynep Özlem Cinar, Serhat Dönmez, Esma Seçen, Mehmet Özbil, Cristina Prandi and Tugba Boyunegmez Tumer*, 
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Abstract

Phytohormones have significant roles in redox metabolism, inflammatory responses, and cellular survival mechanisms within the microenvironment of the mammalian brain. Herein, we identified the mammalian molecular targets of three representative strigolactone (SL) analogues structurally derived from apocarotenoids and the functional equivalent of plant hormones. All tested SL analogues have an inhibitory effect on NLRP3 inflammasome-mediated IL-1β release in murine microglial cells. However, IND and EGO10 became prominent among them due to their high potency at low micromolar doses. All SL analogues dose-dependently suppressed the release and expression of proinflammatory factors. For EGO10 and IND, IC50 values for iNOS-associated NO secretion were as low as 1.72 and 1.02 μM, respectively. In silico analyses revealed that (S)-EGO10 interacted with iNOS, NLRP3, and Keap1 ligands with the highest binding affinities among all stereoisomeric SL analogues. Although all compounds were effective in microglial Mox phenotype polarization, 4-Br-debranone exhibited a differential pattern for upregulating Nrf2-driven downstream enzymes.

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三苯甲内酯对 NLRP3 活化、亚硝基应激和抗氧化莫克斯表型的影响:体外和硅学证据
植物激素在哺乳动物大脑微环境的氧化还原代谢、炎症反应和细胞存活机制中发挥着重要作用。在这里,我们确定了三种具有代表性的芪内酯(SL)类似物的哺乳动物分子靶标,这些类似物在结构上源自类胡萝卜素,在功能上等同于植物激素。所有测试的SL类似物都对小鼠微神经胶质细胞中NLRP3炎性体介导的IL-1β释放有抑制作用。然而,IND和EGO10因其在低微摩尔剂量下的高效力而成为其中的佼佼者。所有 SL 类似物都能剂量依赖性地抑制促炎因子的释放和表达。对于 EGO10 和 IND,iNOS 相关 NO 分泌的 IC50 值分别低至 1.72 和 1.02 μM。硅学分析表明,在所有立体异构体 SL 类似物中,(S)-EGO10 与 iNOS、NLRP3 和 Keap1 配体的结合亲和力最高。虽然所有化合物都对小胶质细胞 Mox 表型极化有效,但 4-Br-debranone 在上调 Nrf2 驱动的下游酶方面表现出不同的模式。
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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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