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

Al Sharif, Merilin, Vitcheva, Vessela, Simeonova, Rumyana, Krasteva, Ilina, Manov, Vasil, Alov, Petko, Popov, Georgi, Shkondrov, Aleksandar, Pajeva, Ilza
Food and chemical toxicology 2019 v.130 pp. 317-325
Astragalus, acute oral toxicity, animal disease models, antioxidants, blood glucose, cholesterol, expert systems, hepatoprotective effect, histology, histopathology, hypertension, in vivo studies, ligands, liver, mechanism of action, metabolic syndrome, metabolites, mice, oxidative stress, peroxisome proliferator-activated receptor gamma, rats, saponins, toxicology, triacylglycerols, triterpenoids
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.