2,4′-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation,ACS Pharmacology & Translational Science

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2,4′-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2024-04-27 , DOI: 10.1021/acsptsci.4c00003
Mirissa Hewage Dumindu Kavinda ₁ , Yung Hyun Choi ₂ , Chang-Hee Kang ₃ , Mi-Hwa Lee ₃ , Gi-Young Kim ₁

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The biochemical properties of 2,4′-dihydroxybenzophenone (DHP) have not been extensively studied. Therefore, this study aimed to investigate whether DHP could alleviate inflammatory responses induced by lipopolysaccharide (LPS) and endotoxemia. The results indicated that DHP effectively reduced mortality and morphological abnormalities, restored heart rate, and mitigated macrophage and neutrophil recruitment to inflammatory sites in LPS-microinjected zebrafish larvae. Additionally, the expression of pro-inflammatory mediators, including inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12), was significantly reduced in the presence of DHP. In RAW 264.7 macrophages, DHP inhibited the LPS-induced inflammatory response by downregulating pro-inflammatory mediators and decreasing the expression of myeloid differentiation primary response 88 (MyD88), phosphorylation of IL-1 receptor-associated protein kinase-4 (p-IRAK4), and nuclear factor-κB (NF-κB). Molecular docking analysis demonstrated that DHP occupies the hydrophobic pocket of myeloid differentiation factor 2 (MD2) and blocks the dimerization of Toll-like receptor 4 (TLR4). A molecular dynamics simulation confirmed that DHP stably bound to the hydrophobic pocket of MD2. Furthermore, the DHP treatment inhibited mitochondrial reactive oxygen species (mtROS) production during the LPS-induced inflammatory response in both RAW 264.7 macrophages and zebrafish larvae, which was accompanied by stabilizing mitochondrial membrane potential. In conclusion, our study highlights the therapeutic potential of DHP in alleviating LPS-induced inflammation and endotoxemia. The findings suggest that DHP exerts its anti-inflammatory effects by inhibiting the TLR4/MD2 signaling pathway and reducing the level of mtROS production. These results contribute to a better understanding of the biochemical properties of DHP and support its further exploration as a potential therapeutic agent for inflammatory conditions and endotoxemia.

中文翻译：

2,4'-二羟基二苯甲酮：一种有前途的抗炎剂，靶向 Toll 样受体 4/骨髓分化因子 2 介导的脂多糖诱导的全身炎症过程中线粒体活性氧的产生

2,4'-二羟基二苯甲酮 (DHP) 的生化性质尚未得到广泛研究。因此，本研究旨在探讨DHP是否可以减轻脂多糖（LPS）和内毒素血症引起的炎症反应。结果表明，DHP 有效降低了 LPS 显微注射的斑马鱼幼虫的死亡率和形态异常，恢复了心率，并减轻了巨噬细胞和中性粒细胞向炎症部位的募集。此外，在 DHP 存在下，促炎介质的表达显着降低，包括诱导型一氧化氮合酶 (iNOS)、肿瘤坏死因子-α (TNF-α) 和白细胞介素 12 (IL-12)。在 RAW 264.7 巨噬细胞中，DHP 通过下调促炎介质并降低骨髓分化初级反应 88 (MyD88) 的表达、IL-1 受体相关蛋白激酶 4 (p-IRAK4) 的磷酸化来抑制 LPS 诱导的炎症反应。和核因子-κB (NF-κB)。分子对接分析表明，DHP 占据骨髓分化因子 2 (MD2) 的疏水口袋，并阻断 Toll 样受体 4 (TLR4) 的二聚化。分子动力学模拟证实 DHP 稳定地结合到 MD2 的疏水口袋上。此外，DHP 处理可抑制 RAW 264.7 巨噬细胞和斑马鱼幼虫 LPS 诱导的炎症反应期间线粒体活性氧 (mtROS) 的产生，同时稳定线粒体膜电位。总之，我们的研究强调了 DHP 在减轻 LPS 诱导的炎症和内毒素血症方面的治疗潜力。研究结果表明，DHP 通过抑制 TLR4/MD2 信号通路和降低 mtROS 产生水平来发挥抗炎作用。这些结果有助于更好地了解 DHP 的生化特性，并支持进一步探索其作为炎症性疾病和内毒素血症的潜在治疗剂。

更新日期：2024-04-27

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