虽然目前可用于治疗查加斯病的两种药物,苯并硝唑和硝呋替莫,已经证明在疾病的急性期是有效的,60-90天的治疗导致高毒性和不必要的副作用,介绍,此外,在疾病的慢性期疗效低。出于这个原因,需要更有效的新疗法。在这方面,我们最近表明Epac-Rap1b途径的抑制抑制了cAMP介导的克氏锥虫对宿主细胞的侵袭。有趣的是,据描述,vitexin,一种保护缺血再灌注损伤的天然黄酮,通过抑制Epac和Rap1蛋白的表达起作用。Vitexin可以在Crataegusspp属植物中找到。,传统上被称为山楂,考虑到它们作为心脏保护剂的大量记录,它们非常感兴趣。用Crataegusoxyacantha提取物预处理细胞产生的克氏锥虫侵袭水平与市售Epac1特异性抑制剂观察到的水平相当。ESI-09.此外,提取物处理的细胞显示Rap1b的活化降低,这表明提取物的作用是通过抑制cAMP-Epac-Rap1信号通路介导的。使用HPLC-HRMS2,我们可以确认牡蛎素的存在,和其他可以作为Epac/Rap1b抑制剂的黄酮,在C.oxyacantha的提取物中。最重要的是,当细胞用C.oxyacantha提取物与Nifurtimox一起处理时,观察到入侵的调制增加。
Although the two drugs currently available for the treatment of Chagas disease, Benznidazole and Nifurtimox, have proven to be effective in the acute phase of the disease, the 60-90-day treatment leads to high toxicity and unwanted side effects, presenting, in addition, a low efficacy in the chronic phase of the disease. For this reason, new therapies that are more effective are needed. In this regard, we have recently shown that the inhibition of the Epac-Rap1b pathway suppressed the cAMP-mediated host cell invasion by Trypanosoma cruzi. Interestingly, it has been described that vitexin, a natural flavone that protects against ischemia-reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genus Crataegus spp., traditionally known as hawthorn, which are of great interest considering their highly documented use as cardio-protectors. Pre-treating cells with an extract of Crataegus oxyacantha produced levels of T. cruzi invasion comparable to the ones observed for the commercially available Epac1-specific inhibitor, ESI-09. In addition, extract-treated cells exhibited a decrease in the activation of Rap1b, suggesting that the effects of the extract would be mediated by the inhibition of the cAMP-Epac-Rap1 signaling pathway. Using HPLC-HRMS2, we could confirm the presence of vitexin, and other flavones that could act as inhibitors of Epac/Rap1b, in the extracts of C. oxyacantha. Most significantly, when cells were treated with the extract of C. oxyacantha in conjunction with Nifurtimox, an increased modulation of invasion was observed.