In silico and in vivo studies of Astragalus glycyphylloides saponin(s) with relevance to metabolic syndrome modulation. (August 2019)

• Record Type: Journal Article
• Authors: Al Sharif, Merilin; Vitcheva, Vessela; Simeonova, Rumyana; Krasteva, Ilina; Manov, Vasil; Alov, Petko; Popov, Georgi; Shkondrov, Aleksandar; Pajeva, Ilza
• Is Part Of: Food and chemical toxicology. Volume 130(2019)
• Page Start: 317
• Page End: 325
• Publication Date: 2019-08
• Subjects: Metabolic syndrome -- Saponins -- Metabolites -- PPARγ -- Pharmacophore-based docking -- Diabetic spontaneously hypertensive rats; BM Binding mode -- CAT Catalase -- DTNB 2, 2-Dinitro-5, 5-dithiodibenzoic acid -- GSH Reduced glutathione -- HB Hydrogen bond -- MDA Malonedialdehyde -- MoA Mode of action -- NADPH Beta–nicotinamide adenine dinucleotide 2′-phosphate -- PDB Protein data bank -- PLIFs Protein-ligand interaction fingerprints -- PPARγ Peroxisome proliferator-activated receptor gamma -- PSM Purified saponins' mixture -- ROS Reactive oxygen species -- SHR Spontaneously hypertensive rats -- SEM Standard error of measurement -- SOD Superoxide dismutase -- STZ Streptozotocin -- TBA 2-Thiobarbituric acid -- T2D Type 2 diabetes; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2019.05.032
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Triterpenoids are well known modulators of metabolic syndrome. One of the suggested modes of action (MoAs) involves peroxisome proliferator-activated receptor gamma (PPARγ) binding. In this study we aimed to: (i) evaluate in silico potential metabolites and PPARγ-mediated MoA of the sapogenin of the main saponin present in a purified saponins' mixture (PSM) from Astragalus glycyphylloides ; (ii) estimate in silico and in vivo PSM's toxicity; and (iii) investigate in vivo antihyperglycaemic, hypolipidaemic, antioxidant and hepatoprotective effects of PSM. Metabolites and toxicity were predicted using Meteor and Derek Nexus expert systems (Lhasa Limited) and PPARγ binding was investigated using the software MOE (CCG Inc.). PSM's acute oral toxicity was evaluated in mice and the pharmacological effects were assessed in streptozotocin-induced diabetic spontaneously hypertensive rats (SHRs). Liver histopathology was studied as well. PPARγ weak partial agonism was predicted in silico for 24 probable/plausible Phase I metabolites which docking poses were clustered in 12 different binding modes with characteristic protein-ligand interactions. PSM's beneficial effects on the levels of blood glucose, triglycerides, and total cholesterol, on oxidative stress markers and liver histology in diabetic SHRs were comparable to those of the PPARγ ligand pioglitazone. PSM's safety profile was confirmed in silico and in vivo . Graphical abstract: Image 1 Highlights: Phase I metabolites of the main sapogenin in purified saponin's mixture (PSM) from Astragalus glycyphylloides were predicted. PPARγ weak partial agonism was predicted for 24 metabolites of the main PSM sapogenin (oleanolic acid). PSM safety was confirmed by in silico predictions of toxicity and in vivo acute oral toxicity assessment. Type 2 diabetes was induced in spontaneously hypertensive rats (SHRs) by treatment with streptozotocin-nicotineamide. Antihyperglycaemic, hypolipidaemic, antioxidant and hepatoprotective effects of PSM were observed in diabetic SHRs.