Sappanone A: A natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the heartwood of Caesalpinia sappan L.,Journal of Ethnopharmacology

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Sappanone A: A natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the heartwood of Caesalpinia sappan L.
Journal of Ethnopharmacology ( IF 4.8 ) Pub Date : 2022-12-16 , DOI: 10.1016/j.jep.2022.116020
You-Zhi Wang ₁ , Yu-Long Wang ₁ , Hao-Jie Che ₁ , Yi-He Jia ₁ , Hui-Fang Wang ₁ , Lin-Fei Zuo ₁ , Kan Yang ₂ , Ting-Ting Li ₃ , Jin-Xin Wang ₁

Affiliation

Ethnopharmacological relevance

Sumu (Lignum sappan), the dry heartwood of Caesalpinia sappan L., is a traditional Chinese medicine used as an analgesic and anti-inflammatory agent.

Aim of the study

The study aspired to discover natural phosphodiesterase 4 (PDE4) inhibitors with dual anti-inflammatory and antioxidant activities from Sumu for the treatment of chronic obstructive pulmonary disease (COPD).

Materials and methods

To accurately and efficiently identify natural PDE4 inhibitors from Sumu, molecular docking and molecular dynamics (MD) analysis methods were used for structure-based virtual screening of a self-built database of primary polyphenols in Sumu. According to the previous studies of Sumu and the free radical scavenging mechanism of polyphenols, the reported antioxidant components from Sumu and the potential antioxidants with the antioxidant pharmacophore of catechol and π-conjugated moieties were selected from the potential PDE4 inhibitors predicted by docking. Sappanone A, a potential PDE4 inhibitor with antioxidant activity from Sumu, was selected, calculated and synthesized to evaluate its dual anti-inflammatory and antioxidant functions in vitro and in vivo studies. Herein sappanone A was assayed for its inhibitory effects against PDE4 enzyme activity, tumor necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe²⁺ in mouse lung homogenate; sappanone A was also assayed for its abilities of radical (DPPH) scavenging, reducing Fe³⁺ and complexing Fe²⁺ in vitro. Additionally, LPS-induced acute lung injury (ALI) in mice was used to evaluate its anti-inflammatory activity as a PDE4 inhibitor in vivo, and the levels of TNF-α and total protein in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung were assayed.

Results

The present study predicted and validated that sappanone A was a promising PDE4 inhibitor from Sumu with dual anti-inflammation and antioxidant activities from Sumu. In vitro, sappanone A remarkably inhibited PDE4 enzyme activity and reduced TNF-α production induced by LPS in RAW264.7 macrophages and MDA production induced by Fe²⁺ in mouse lung homogenate. Meanwhile, it showed outstanding abilities of scavenging DPPH radicals, reducing Fe³⁺ and complexing Fe²⁺. In vivo, sappanone A (25 mg/kg and 50 mg/kg, i.p., twice daily for 7 days) distinctly prevented LPS-induced ALI in mice by reducing the levels of TNF-α and total protein in BALF and MPO activity in the lung.

Conclusion

Sappanone A is a natural PDE4 inhibitor with dual anti-inflammatory and antioxidant activities from the traditional Chinese medicine Sumu, which may be a promising therapeutic agent to prevent the vicious cycle of COPD inflammation and oxidative stress.

中文翻译：

Sappanone A：一种天然 PDE4 抑制剂，具有双重抗炎和抗氧化活性，来自苏木实木的心材。

民族药理学相关性

苏木 ( Lignum sappan ) 是苏木实木的干燥心材，是一种用作镇痛和抗炎剂的中药。

研究目的

该研究旨在从苏木中发现具有双重抗炎和抗氧化活性的天然磷酸二酯酶 4 (PDE4) 抑制剂，用于治疗慢性阻塞性肺疾病 (COPD)。

材料和方法

为了准确高效地鉴定苏木中的天然PDE4抑制剂，采用分子对接和分子动力学（MD）分析方法，对自建的苏木初级多酚数据库进行了基于结构的虚拟筛选。根据前人对苏木的研究以及多酚类物质的自由基清除机制，从对接预测的潜在PDE4抑制剂中筛选出已报道的苏木抗氧化成分和具有邻苯二酚抗氧化药效团和π-共轭基团的潜在抗氧化剂。Sappanone A 是一种来自苏木的具有抗氧化活性的潜在 PDE4 抑制剂，被选择、计算和合成，以评估其在体外和体内研究中的双重抗炎和抗氧化功能。小鼠肺匀浆^{2+ ；}还测定了 sappanone A在体外清除自由基 (DPPH)、还原 Fe ³⁺和络合 Fe ^{2+的能力。}此外，LPS 诱导的小鼠急性肺损伤 (ALI) 用于评估其作为 PDE4 抑制剂的体内抗炎活性，以及支气管肺泡灌洗液 (BALF) 和髓过氧化物酶 (MPO) 中 TNF-α 和总蛋白的水平) 测定肺中的活性。

结果

本研究预测并验证了苏木酮 A 是一种很有前途的苏木 PDE4 抑制剂，具有来自苏木的双重抗炎和抗氧化活性。在体外，sappanone A 显着抑制 PDE4 酶活性，减少 RAW264.7 巨噬细胞中 LPS 诱导的 TNF-α 产生和小鼠肺匀浆中Fe ^{2+诱导的 MDA 产生。}同时，它表现出优异的清除DPPH自由基、还原Fe ³⁺和络合Fe ²⁺的能力。在体内，sappanone A（25 mg/kg 和 50 mg/kg，ip，每天两次，连续 7 天）通过降低 BALF 中的 TNF-α 和总蛋白水平以及肺。