一种新型 IIa 类组蛋白去乙酰化酶抑制剂可减轻胶原蛋白诱发的关节炎。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-09-02 DOI:10.1111/bph.17306
Eunice K. Poon, Ligong Liu, Kai-Chen Wu, Junxian Lim, Matthew J. Sweet, Rink-Jan Lohman, Abishek Iyer, David P. Fairlie
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引用次数: 0

摘要

背景和目的:大多数组蛋白去乙酰化酶(HDACs)抑制剂都没有选择性,而且具有细胞毒性。有些抑制剂在疾病模型中具有抗炎活性,但细胞毒性阻碍了其在非致命性疾病中的长期应用。对 IIa 类 HDAC 具有选择性的抑制剂的细胞毒性要小得多,可用于慢性炎症性疾病的治疗:实验方法:LL87 是一种新型 HDAC 抑制剂,本实验对其 HDAC 酶选择性进行了研究。实验方法:LL87 是一种新型 HDAC 抑制剂,本文研究了它对 HDAC 酶的选择性,还研究了它在巨噬细胞中的细胞毒性和对脂多糖(LPS)刺激的细胞因子分泌的抑制作用。在胶原蛋白诱导的大鼠关节炎模型中,研究了 LL87 对 Dark Agouti 大鼠关节炎症的影响。组织学、免疫组化、微型计算机断层扫描和分子分析显示了关节炎发展和抗炎功效的特征:主要结果:LL87 对 IIa 类 HDAC 酶的抑制作用明显强于 I 类或 IIb 类 HDAC 酶。在巨噬细胞中,LL87 没有细胞毒性,并能减少 LPS 诱导的促炎细胞因子分泌和 IL6 诱导的 IIa 类 HDAC 活性。在大鼠身上,LL87 可减轻爪肿和关节炎的临床症状,减少胶原蛋白流失和踝关节的组织学损伤。LL87 可减少免疫细胞,尤其是促炎巨噬细胞和破骨细胞向滑膜关节的浸润,并显著降低促炎细胞因子和组织降解蛋白酶的表达:一种新型 IIa 类 HDAC 抑制剂具有不同于现有疗法的抗炎和抗关节炎特性。在慢性大鼠关节炎模型中,它能有效减少巨噬细胞浸润和关节炎症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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A novel inhibitor of class IIa histone deacetylases attenuates collagen-induced arthritis

Background and Purpose

Most inhibitors of histone deacetylases (HDACs) are not selective and are cytotoxic. Some have anti-inflammatory activity in disease models, but cytotoxicity prevents long-term uses in non-fatal diseases. Inhibitors selective for class IIa HDACs are much less cytotoxic and may have applications in management of chronic inflammatory diseases.

Experimental Approach

LL87 is a novel HDAC inhibitor examined here for HDAC enzyme selectivity. It was also investigated in macrophages for cytotoxicity and for inhibition of lipopolysaccharide (LPS)-stimulated cytokine secretion. In a rat model of collagen-induced arthritis, LL87 was investigated for effects on joint inflammation in Dark Agouti rats. Histological, immunohistochemical, micro-computed tomography and molecular analyses characterise developing arthritis and anti-inflammatory efficacy.

Key Results

LL87 was significantly more inhibitory against class IIa than class I or IIb HDAC enzymes. In macrophages, LL87 was not cytotoxic and reduced both LPS-induced secretion of pro-inflammatory cytokines, and IL6-induced class IIa HDAC activity. In rats, LL87 attenuated paw swelling and clinical signs of arthritis, reducing collagen loss and histological damage in ankle joints. LL87 decreased immune cell infiltration, especially pro-inflammatory macrophages and osteoclasts, into synovial joints and significantly reduced expression of pro-inflammatory cytokines and tissue-degrading proteases.

Conclusion and Implications

A novel inhibitor of class IIa HDACs has been shown to have an anti-inflammatory and anti-arthritic profile distinct from current therapies. It is efficacious in reducing macrophage infiltration and joint inflammation in a chronic model of rat arthritis.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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