含硒化合物已成为用于氧化还原基和炎性疾病的有希望的治疗方法。本研究旨在研究一种名为二苄基[二硒二(丙烷-3-1二基)]二氨基甲酸酯(DD)的新型二硒酸盐的体外和体内抗炎活性。DD与HOCl反应(k=9.2×107M-1s-1),如谷胱甘肽(k=1.2x108M-1s-1),产生硒和硒酸衍生物,它还减少了活化的人嗜中性粒细胞(IC50=4.6μM)和纯化的髓过氧化物酶(MPO)(IC50=3.8μM)的HOCl形成。然而,酪氨酸,MPO-I和MPO-II底物,在DD存在下没有恢复HOCl的形成。DD抑制dHL-60细胞中的氧化爆发,直到25µM持续48小时都没有毒性。接下来,腹膜内给药25、50和75mg/kgDD可降低总白细胞,中性粒细胞趋化性,和炎症标志物(MPO活性,脂质过氧化,白蛋白渗出,亚硝酸盐,TNF-α,IL-1β,CXCL1/KC,和CXCL2/MIP-2)对角叉菜胶诱导的腹膜炎的小鼠模型。同样,50mg/kgDD(i.p.)在5h内减少角叉菜胶诱导的爪水肿。对爪组织的组织学和免疫组织化学分析显示中性粒细胞计数减少,水肿面积,MPO,羰基化,和硝化蛋白染色。此外,DD处理在体外降低了fMLP诱导的人嗜中性粒细胞的趋化性(IC50=3.7μM),没有毒性。最后,DD在使用小鼠的单剂量模型中没有毒性(50mg/kg,i.p.)超过15天,并在卤虫盐藻生物测定中(50至2000µM),证实了硅毒理学研究的结果。总之,这些结果表明,DD主要通过减少中性粒细胞迁移和MPO介导的氧化爆发造成的损伤来减轻角叉菜胶诱导的炎症.
Selenium-containing compounds have emerged as promising treatment for redox-based and inflammatory diseases. This study aimed to investigate the in vitro and in vivo anti-inflammatory activity of a novel diselenide named as dibenzyl[diselanediyIbis(propane-3-1diyl)] dicarbamate (DD). DD reacted with HOCl (k = 9.2 x 107 M-1s-1), like glutathione (k = 1.2 x 108 M-1s-1), yielding seleninic and selenonic acid derivatives, and it also decreased HOCl formation by activated human neutrophils (IC50=4.6 μM) and purified myeloperoxidase (MPO) (IC50=3.8 μM). However, tyrosine, MPO-I and MPO-II substrates, did not restore HOCl formation in presence of DD. DD inhibited the oxidative burst in dHL-60 cells with no toxicity up to 25 µM for 48h. Next, an intraperitoneal administration of 25, 50, and 75 mg/kg DD decreased total leukocyte, neutrophil chemotaxis, and inflammation markers (MPO activity, lipid peroxidation, albumin exudation, nitrite, TNF-α, IL-1β, CXCL1/KC, and CXCL2/MIP-2) on a murine model of carrageenan-induced peritonitis. Likewise, 50 mg/kg DD (i.p.) decreased carrageenan-induced paw edema over 5h. Histological and immunohistochemistry analyses of the paw tissue showed decreased neutrophil count, edema area, and MPO, carbonylated, and nitrated protein staining. Furthermore, DD treatment decreased the fMLP-induced chemotaxis of human neutrophils (IC50=3.7 μM) in vitro with no toxicity. Lastly, DD presented no toxicity in a single-dose model using mice (50 mg/kg, i.p.) over 15 days and in Artemia salina bioassay (50 to 2000 µM), corroborating findings from in silico toxicological study. Altogether, these results demonstrate that DD attenuates carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting damage from MPO-mediated oxidative burst.