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Cycloarta-23-ene-3beta,25-diol a pentacyclic steroid from Euphorbia spinidens, as COX inhibitor with molecular docking, and in vivo study of its analgesic and anti-inflammatory activities in male swiss mice and wistar rats.
ProstaglandIns & Other Lipid Mediators ( IF 2.9 ) Pub Date : 2020-07-04 , DOI: 10.1016/j.prostaglandins.2020.106473
Valiollah Hajhashemi 1 , Mustafa Ghanadian 2 , Abbasali Palizaban 3 , Karim Mahnam 4 , Hamed Eshaghi 5 , Bahareh Gheisari 3 , Hojjat Sadeghi-Aliabadi 6
Affiliation  

Background and aims

Euphorbia is a large genus of flowering plants. In Iran, some plants of this family have been used in the treatment of inflammatory disorders and also to relieve back pain. Euphorbia spinidens is a rich source of Cycloarta-23-ene-3beta,25-diol. Cycloartane structures are the starting material for the synthesis of plant steroids, and the aim of this study is to demonstrate COX inhibitory activity, molecular docking and in vivo approach of anti-inflammatory activity of cycloartane compound isolated from Euphorbia spinidens.

Material and Methods: Plant material was extracted with acetone-chloroform and submitted to column chromatography for fractionation. Based on preliminary 1H-NMR spectra, cycloartane fraction was selected and purified by repeated recycle HPLC system. The structure and purity of compound were determined by 1H and 13C-NMR, HPTLC, and mass spectra. Inhibitory activities of the tested compounds on COX-1 and COX-2 were evaluated by a colorimetric COX (ovine) inhibitor screening method. Vero cells were used to assess the toxicity against the normal cells, and calculate the selectivity index. COX inhibitory activity results were evaluated and confirmed by molecular docking experiments. In the in vivo approach, analgesic activity was assessed by acetic acid-induced abdominal writhing and formalin tests. Croton oil-induced ear edema in mice and carrageenan-induced rat paw edema in rats were used to evaluate anti-inflammatory activity. Pain tests were carried out on male Swiss mice (25–35 g). Male Wistar rats (160–200 g) were used for the carrageenan test.

Results

Cycloart-23-ene-3β,25-diol showedin vitro cyclooxygenase 1 and 2 inhibitory activities with more selectivity for COX-2. Molecular docking by predicting binding energies in COX protein receptors confirmed in vitro COX inhibitory results, and determined the best position for ligand in COX receptors along with its residue interactions in receptor pockets, which must be considered for designing of their inhibitors. In the in vivo studies, cycloartane inhibited significantly acetic acid-induced abdominal contractions and formalin-induced licking behavior at a dose of 200 mg/kg. The same dose reduced croton oil ear edema in mice and carrageenan-induced paw edema in rats.

Conclusion

Therefore, according to these findings, cycloart-23-ene-3beta,25-diol showed promising analgesic and anti-inflammatory effects with low toxicity against normal cells and can be suggested as a template lead for designing anti-inflammatory compounds with good selectivity index, and potency for COX-2 inhibitory activity.



中文翻译:

Cycloarta-23-ene-3beta,25-diol 一种来自大戟属植物的五环类固醇,作为具有分子对接的 COX 抑制剂,以及其在瑞士雄性小鼠和 wistar 大鼠中的镇痛和抗炎活性的体内研究。

背景和目标

大戟属是一大类开花植物。在伊朗,该科的一些植物已被用于治疗炎症性疾病和缓解背痛。大戟是 Cycloarta-23-ene-3beta,25-diol 的丰富来源。环磷酰胺结构是合成植物类固醇的起始材料,本研究的目的是证明从大戟属植物中分离的环磷酰胺化合物的COX 抑制活性、分子对接和抗炎活性的体内方法。

材料和方法:植物材料用丙酮-氯仿提取,并进行柱色谱分离。根据初步的1 H-NMR 谱,通过重复循环 HPLC 系统选择和纯化环磷灰石馏分。化合物的结构和纯度通过1 H 和13 C-NMR、HPTLC 和质谱确定。通过比色 COX(绵羊)抑制剂筛选方法评估测试化合物对 COX-1 和 COX-2 的抑制活性。Vero细胞用于评估对正常细胞的毒性,并计算选择性指数。通过分子对接实验评估和证实了 COX 抑制活性结果。在体内在该方法中,镇痛活性通过乙酸诱导的腹部扭体和福尔马林试验进行评估。使用巴豆油引起的小鼠耳水肿和角叉菜胶引起的大鼠爪水肿来评估抗炎活性。对雄性瑞士小鼠(25-35 克)进行了疼痛测试。雄性 Wistar 大鼠(160-200 克)用于角叉菜胶测试。

结果

Cycloart-23-ene-3β,25-diol在体外表现出环氧合酶 1 和 2 抑制活性,对 COX-2 具有更高的选择性。通过预测COX蛋白受体结合能的分子对接证实了体外COX抑制结果,并确定了COX受体中配体的最佳位置及其在受体口袋中的残基相互作用,这是设计它们的抑制剂时必须考虑的。在体内研究中,环阿坦在 200 mg/kg 的剂量下显着抑制了醋酸诱导的腹部收缩和福尔马林诱导的舔舐行为。相同剂量可减少小鼠巴豆油耳水肿和大鼠角叉菜胶引起的爪水肿。

结论

因此,根据这些发现,cycloart-23-ene-3beta,25-diol 显示出有前景的镇痛和抗炎作用,对正常细胞的毒性低,可以作为设计具有良好选择性指数的抗炎化合物的模板。和 COX-2 抑制活性的效力。

更新日期:2020-07-17
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