Heckmann Mara, Karlsberger Lea, Blank-Landeshammer Bernhard, Klanert Gerald, Sadova Nadiia, Stadlbauer Verena, Sandner Georg, Gramatte Theresa, Kasis Simone, Weghuber Julian
Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Stelzhamerstraße 23, 4600, Wels, Austria.
FFoQSI GmbH-Austrian Competence Centre for Feed and Food Quality, Safety and Innovation, Technopark 1D, Tulln, 3430, Austria.
Redox Biol. 2025 Jun 14;85:103731. doi: 10.1016/j.redox.2025.103731.
Tormentic acid (TA), a plant-derived pentacyclic triterpene, exhibits antioxidant and anti-inflammatory potential, yet the pharmacological effects of its 3-O-trans-p-coumaroyl ester (trans-TACE) remain underexplored. This study investigates how hydroxycinnamoyl esterification influences the biological activity of pentacyclic triterpenes by comparing TA and trans-TACE in cellular and in vivo stress models. We assessed their ability to mitigate oxidative stress by evaluating the inhibition of ROS and NO molecules. Pro-inflammatory cytokine production in LPS-stimulated THP-1 macrophages was analyzed through cytokine arrays and multiplex immunoassays, while NF-κB activation was examined in both TLR4-dependent and -independent models using HEK-Blue reporter cells. Uptake efficiencies into Caco-2 enterocytes were measured via LC-MS. The in vivo relevance of these findings was assessed using C. elegans as a model for oxidative and inflammatory stress response. Results showed that trans-TACE significantly reduced cellular ROS and NO levels compared to TA. Protein analyses of LPS-stimulated THP-1 macrophages indicated that trans-TACE significantly decreased pro-inflammatory cytokines involved in NF-κB signaling (e.g., TNFα, IL-8, CCL2, CXCL5 and CXCL11). Trans-TACE also inhibited NF-κB activation in both TLR4-dependent and -independent models. In C. elegans, both TA and trans-TACE downregulated several stress-induced genes, with trans-TACE exhibiting broader effects by additionally targeting daf-16 and gst-4 gene expression. Moreover, we revealed key differences in bioactivities between the trans and cis isoform of TACE, underscoring the importance of considering the structural properties of geometric isomers in therapeutic assessments. Overall, this study suggests that esterification significantly enhances the biological activity of pentacyclic triterpenes and points towards new possibilities for developing effective natural anti-inflammatory therapies.
tormentic酸（TA）是一种植物来源的五环三萜，具有抗氧化和抗炎潜力，但其3 - O - 反式对香豆酰酯（反式TACE）的药理作用仍未得到充分研究。本研究通过在细胞和体内应激模型中比较TA和反式TACE，探讨羟基肉桂酰酯化如何影响五环三萜的生物活性。我们通过评估对ROS和NO分子的抑制作用来评估它们减轻氧化应激的能力。通过细胞因子阵列和多重免疫测定分析LPS刺激的THP - 1巨噬细胞中促炎细胞因子的产生，同时使用HEK - Blue报告细胞在TLR4依赖性和非依赖性模型中检测NF - κB激活。通过LC - MS测量进入Caco - 2肠细胞的摄取效率。使用秀丽隐杆线虫作为氧化和炎症应激反应模型评估这些发现的体内相关性。结果表明，与TA相比，反式TACE显著降低了细胞ROS和NO水平。对LPS刺激的THP - 1巨噬细胞的蛋白质分析表明，反式TACE显著降低了参与NF - κB信号传导的促炎细胞因子（例如TNFα、IL - 8、CCL2、CXCL5和CXCL11）。反式TACE在TLR4依赖性和非依赖性模型中也抑制了NF - κB激活。在秀丽隐杆线虫中，TA和反式TACE均下调了几个应激诱导基因，反式TACE通过额外靶向daf - 16和gst - 4基因表达表现出更广泛的作用。此外，我们揭示了TACE反式和顺式异构体之间生物活性的关键差异，强调了在治疗评估中考虑几何异构体结构特性的重要性。总体而言，本研究表明酯化显著增强了五环三萜的生物活性，并为开发有效的天然抗炎疗法指出了新的可能性。
