Antilipolytic and hypotriglyceridemic effects of dietary Salvia triloba Lf (Lamiaceae) in experimental rats

Purpose: Pancreatic triacylglycerol lipase (PL) is a noteworthy pharmacological target for the management of dyslipidemia, and diabetes and obesity. This study was aimed to evaluate the modulatory effects of Salvia triloba L.f. (Lamiaceae) leaves methanol extract (ME) on a high fat diet (HFD)-induced hypertriglyceridemia in rats, with complementary in vitro evaluation of sage PL-inhibitory potential.Methods: Pre-induction of HFD hypertriglyceridemia sage leaves ME (750 mg/kg) was orally supplemented (via gastric intubation) to overnight fasting rats (n = 5). Potential plant modulation of PL was also quantified in vitro by a colorimetric assay (n = 3). For comparison, the effect of Orlistat was similarly evaluated as reference standard.Results: Compared to Orlistat, supplementation of S. triloba at a dose of 750 mg/kg b.wt significantly reversed the HFD-induced postprandial hypertriglyceridemia in experimental overnight fasting rats (p < 0.001 vs. HFD rats). Dietary sage caused 66.4 % reduction in plasma triglycerides. Compared to Orlistat which exerted antilipolytic activity, with half-maximal inhibitory concentration (IC50) of 0.114 ± 0.004 μg/mL), sage inhibited PL activity in vitro in a dose-dependent manner IC50 of 100.80 ± 9.07 μg/mL)Conclusion: Sage has dual hypotriglyceridemic and antilipolytic properties which indicate that it can potentially be used to suppress body weight gain.Keywords: Pancreatic lipase, Salvia triloba, Sage, Methanol extract, Hypertriglyceridemia, Orlista

Pancreatic lipase inhibitory activity of selected pharmaceutical agents

Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT

Exploring the Active Center of the LSD1/CoREST Complex by Molecular Dynamics Simulation Utilizing Its Co-crystallized Co-factor Tetrahydrofolate as a Probe

Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and it uses tetrahydrofolate as a co-factor to accept CH₂ from the demethylation process. In this study, the co-crystallized co-factor tetrahydrofolate was utilized to determine possible binding regions in the active center of the LSD1/CoREST complex. Also, the flexibility of the complex has been investigated by molecular dynamics simulation and subsequent analysis by clustering and principal component analysis. This research supported other studies and showed that LSD1/CoREST complex exists in two main conformational structures: open and closed. Furthermore, this study showed that tetrahydrofolate stably binds to the LSD1/CoREST complex, in its open conformation, at its entrance. It then binds to the core of the complex, inducing the closed conformation. Furthermore, the interactions of tetrahydrofolate to these two binding regions and the corresponding binding mode of tetrahydrofolate were investigated to be used in structure-based drug design