Zafirlukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Reduces the Effect of Advanced Glycation End-Products in Rat Renal Mesangial Cells In Vitro

Abstract

Departmental sources Background: Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1). Advanced glycation end-products (AGEs) are formed by the glycation of lipids and proteins in hyperglycemia, including diabetes mellitus. Zafirlukast has not previously been studied in diabetic nephropathy. This study aimed to investigate the effects of zafirlukast on rat renal mesangial cells cultured with AGEs in vitro. Material/Methods: Mesangial cells were cultured in AGEs (0, 20, 50, 100 μg/ml), and with AGEs (100 μg/ml) and zafirlukast (2.5 μm, 5 μm, and 100 μm). An enzyme-linked immunoassay (ELISA) was used to measure the levels of tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), IL-6, and monocyte chemoattractant protein-1 (MCP-1). Reactive oxygen species (ROS) were assessed by intracellular fluorescence measurement of 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and detection kits were used to measure malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD). Cell apoptosis was assessed by flow cytometry, and Western blot was used to measure protein levels. Results: In mesangial cells cultured with AGEs, markers of inflammation, oxidative stress, and apoptosis and levels of CysLTR1 increased, and these effects were reduced by zafirlukast in a dose-dependent manner. The effects of zafirlukast as a CysLTR1 antagonist protected mesangial cells from the effects of AGE in vitro. Conclusions: Zafirlukast, a CysLTR1 antagonist, reduced the levels of inflammatory cytokines, markers of oxidative stress, and cell apoptosis induced by AGE in mesangial cells in a dose-dependent way. Future in vivo studies are needed to investigate the potential role for zafirlukast in models of diabetic nephropathy.

A large-scale computational screen identifies strong potential inhibitors for disrupting SARS-CoV-2 S-protein and human ACE2 interaction

“…Although the exact mechanism of action of Velpatasvir has not yet been completely determined, it has been reported to bind to domain I of the NS5A protein, inhibiting the activity of the NS5A protein, which results in the disruption of the viral RNA replication complex, blockage of viral HCV RNA production and inhibition of viral replication (Asselah et al, 2018;Bonaventura et al, 2016;Heo & Deeks, 2018). Zafirlukast and pranlukast, both being leukotriene receptor antagonists used for treating chronic asthma (Adkins & Brogden, 1998;Hur et al, 2018;Keam et al, 2003;Yan et al, 2019), had docking score of À8.71 kcal/mol and À8.61 kcal/mol. These molecules blocked 11 hACE2 binding sites of S-protein (Figures 2(B,C) and 4(D,E)).…”