Modified Suberoylanilide Hydroxamic Acid Reduced Drug-Associated Immune Cell Death and Organ Damage under Lipopolysaccharide Inflammatory Challenge.
Modified Suberoylanilide Hydroxamic Acid Reduced Drug-Associated Immune Cell Death and Organ Damage under Lipopolysaccharide Inflammatory Challenge.
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修饰的辛二酰苯胺异羟肟酸可减少脂多糖炎症挑战下药物相关的免疫细胞死亡和器官损伤。
DOI：
10.1021/acsptsci.2c00119
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发表时间：
2022
影响因子：
--
通讯作者：
Pearson,RyanM
中科院分区：
文献类型：
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作者：
Truong,Nhu;Goodis,ChristopherC;Cottingham,AndreaL;Shaw,JacobR;Fletcher,Steven;Pearson,RyanM
组蛋白去乙酰化酶抑制剂（HDACi）用于治疗炎症性疾病时可诱导有效的抗炎反应。亚甲基苯胺羟肟酸（SAHA）是一种泛hdaci，可降低脓毒症中的促炎细胞因子水平并减轻细胞因子风暴；然而，其对免疫细胞的毒性限制了其作为败血症治疗药物的使用。在这里，我们开发了一种对SAHA的修饰，通过对帽基羟基甲基化来生成SAHA- oh。我们发现，与SAHA相比，SAHA- oh提供了有利的毒性改善。在脂多糖（LPS）诱导的内毒素血症小鼠模型中，SAHA-OH可显著减少原代巨噬细胞凋亡和脾B细胞死亡，并减轻器官损伤。此外，通过体外和体内lps诱导的促炎细胞因子分泌减少，SAHA- oh保留了与SAHA相似的抗炎反应。根据ic50值测定，这些影响归因于HDAC1、2、3、8的选择性降低和HDAC6对SAHA-OH的选择性增加。我们的研究结果支持SAHA-OH调节急性促炎反应的潜力，同时减轻saha相关的药物毒性，用于治疗炎症相关疾病和病症。
Histone deacetylase inhibitors (HDACi) induce potent anti-inflammatory responses when used to treat inflammatory diseases. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, decreases pro-inflammatory cytokine levels and attenuates cytokine storm in sepsis; however, its toxicity profile toward immune cells has limited its use as a sepsis therapeutic. Here, we developed a modification to SAHA bypara-hydroxymethylating the capping group to generate SAHA-OH. We discovered that SAHA-OH provides a favorable improvement to the toxicity profile compared to SAHA. SAHA-OH significantly reduced primary macrophage apoptosis and splenic B cell death as well as mitigated organ damage using a lipopolysaccharide (LPS)-induced endotoxemia mouse model. Furthermore, SAHA-OH retained anti-inflammatory responses similar to SAHA as measured by reductions in LPS-induced proinflammatory cytokine secretions in vitro and in vivo. These effects were attributed to a decreased selectivity of HDAC1, 2, 3, 8 and an increased selectivity for HDAC6 for SAHA-OH as determined by IC50values. Our results support the potential for SAHA-OH to modulate acute proinflammatory responses while mitigating SAHA-associated drug toxicity for use in the treatment of inflammation-associated diseases and conditions.