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Antileishmanial drugs activate inflammatory signaling pathways via toll-like receptors (docking approach) from Leishmania amazonensis-infected macrophages.
International Immunopharmacology ( IF 4.8 ) Pub Date : 2020-05-26 , DOI: 10.1016/j.intimp.2020.106640
João Rafael Valentim-Silva 1 , Sharon Rose Aragão Macedo 2 , Neuza Biguinati de Barros 3 , Amália Dos Santos Ferreira 4 , João Hermínio Martins da Silva 5 , Larissa Deadame de Figueiredo Nicolete 6 , Roberto Nicolete 7
Affiliation  

The activation of proinflammatory cellular processes and signals such as those linked to NF-kB in macrophages are involved in the control of infection by Leishmania ssp. However, little is known about the influence of the drugs used in the treatment on the host cellular inflammatory signaling pathways. This study aimed to evaluate the effects of different drugs used in the treatment of leishmaniasis on inflammatory profile related to Toll-like receptors (TLRs) from L. amazonensis-infected macrophages. J774 macrophage-like cells were infected with the promastigote forms (5:1) and 24 hs incubated with Amphotericin B (AmB), Glucantime® (GLU) or Pentamidine (Pent). The following inflammatory pathways were evaluated: NF-κB p65, NF-κB p65 phosphorylated (Ser536), stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) phosphorylated (Thr183/Tyr185), p38 mitogen activated protein kinase (MAPK p38) phosphorylated (Thr180/Tyr182), signal transducer and activator of transcription-3 (Stat3) phosphorylated (Tyr705) and inhibitor kappa B-α (IκB-α) phosphorylated (Ser32). In silico tests were performed to evaluate the molecular affinity between TLRs and antileishmanial drugs. Molecular docking showed that affinities varied significantly among the binders evaluated. The lowest affinity (-8.6 Kcal/Mol) was calculated for AmB in complex with TLR4. Pent showed higher values for TLR1, TLR2 and TLR3, while for TLR4 the affinity value was lower (5.5 Kcal/Mol). The values obtained for GLU were the highest for the set of binders tested. From the infected macrophages, treatments inhibited NF-kB p65 for GLU (65.44%), for Pent (46.43%) and for AmB (54.07%) compared to untreated infected macrophages. The activation of the signaling pathway of NF-kB, SAPK/JNK and IκB-α caused by AmB and Pent may potentiate the microbicidal mechanisms of the infected macrophages.



中文翻译:

抗利什曼病药物通过来自亚马逊利什曼原虫感染的巨噬细胞的toll样受体(对接途径)激活炎症信号通路。

促炎性细胞过程和信号(例如与巨噬细胞中与NF-kB连锁的那些信号)的激活与利什曼原虫ssp感染的控制有关。然而,关于用于治疗的药物对宿主细胞炎性信号通路的影响知之甚少。这项研究旨在评估用于治疗利什曼病的不同药物对与亚马逊L. Toll样受体(TLR)有关的炎症反应的影响被感染的巨噬细胞。将J774巨噬细胞样细胞用前鞭毛体形式(5:1)感染,并与两性霉素B(AmB),(GLU)或喷他idine(Pent)孵育24小时。评价了以下炎症途径:NF-κBp65,NF-κBp65磷酸化(Ser536),应激激活的蛋白激酶/ c-Jun NH(2)-末端激酶(SAPK / JNK)磷酸化(Thr183 / Tyr185),p38丝裂原活化蛋白激酶(MAPK p38)磷酸化(Thr180 / Tyr182),信号转导和转录激活因子3(Stat3)磷酸化(Tyr705)和抑制剂kappaB-α(IκB-α)磷酸化(Ser32)。电脑进行了测试以评估TLR和抗衰老药物之间的分子亲和力。分子对接表明,所评估的粘合剂之间的亲和力差异很大。计算了与TLR4复合的AmB的最低亲和力(-8.6 Kcal / Mol)。Pent显示TLR1,TLR2和TLR3的值较高,而TLR4的亲和力值较低(5.5 Kcal / Mol)。对于GLU所获得的值是测试的一组粘合剂中最高的。与未处理的感染巨噬细胞相比,从感染的巨噬细胞中,治疗抑制了GLU(65.44%),Pent(46.43%)和AmB(54.07%)的NF-kB p65。由AmB和Pent引起的NF-kB,SAPK / JNK和IκB-α信号通路的激活可能增强了被感染巨噬细胞的杀微生物机制。

更新日期:2020-05-26
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