Extracts of selected Lamiaceae species as promising antidiabetics: Chemical profiling, in vitro and in silico approach combined with dynamical modeling
Graphical Abstract
Introduction
Diabetes is a common metabolic disorder, manifested by increased blood glucose levels – hyperglycemia and impaired metabolism of carbohydrates, proteins, and lipids (Behradmanesh et al., 2013). It occurs as a type 1 (an autoimmune disease characterized by insufficient endogenous insulin secretion by pancreatic β-cells) or type 2 diabetes (DT2), which involves insulin resistance and abnormal insulin secretion or action (up to 95 % of reported cases of diabetes) (Chinsembu, 2019, Lima et al., 2006). According to the World Health Organization, 180 million people worldwide are currently diagnosed with diabetes mellitus – DT2 (Javid et al., 2021), designating this metabolic disorder as one of the most challenging public health issues both nowadays and in the upcoming times.
Therapeutic strategies in the treatment of DT2 are predominantly based on the inhibition of α-glucosidase, which is the enzyme that catalyzes the final step of carbohydrate digestion in the intestine. This inhibition leads to delayed digestion and absorption of carbohydrates, thus suppressing postprandial hyperglycemia as one of the earliest metabolic abnormalities occurring in diabetes mellitus (Wang et al., 2015). Therefore, the inhibition of α-glucosidase can be considered a reliable approach for the treatment of carbohydrate intake disorders, such as diabetes and obesity (Chinsembu, 2019, Mahdi et al., 2020, Sales et al., 2012, Tundis et al., 2010). One of the widely used inhibitors of α-glucosidase is acarbose (a pseudotetra-saccharide produced by Actinoplanes sp. in the fermentation process), which slows down oligosaccharide-degradation and glucose-uptake in the small intestine (Sales et al., 2012, Tundis et al., 2010, Wang et al., 2021). However, higher doses can cause various side effects, such as hypoglycemia, liver dysfunction, lactic acidosis, bloating, and diarrhea. These side effects are also characteristic of many other DT2 commercial drugs (metformin, sulfonylureas, etc.) (Bodmer et al., 2008). Consequently, a plethora of investigations is now focusing on discovering safer alternatives for DT2 control, where plant extracts arise as fruitful sources of new therapeutics (Barbosa et al., 2013, Jacob and Narendhirakannan, 2019, Tundis et al., 2010).
Lamiaceae represents one of the largest families of flowering plants, comprising 236 genera and approximately 7200 species (Esra et al., 2011, Raja, 2012). A number of these plants and corresponding secondary metabolites are highly appreciated in food, agricultural, cosmetic, as well as in pharmacological industries (Trivellini et al., 2016). Bearing that in mind, miscellaneous in vitro and in vivo studies have already shown considerable antidiabetic effects of different Lamiaceae species (Afolayan and Sunmonu, 2010, Casanova et al., 2014, Castellano et al., 2013, Jadhav and Puchchakayala, 2012, Mnonopi et al., 2012, Wu et al., 2014), which can be attributed to the inherent abundance of biologically active compounds. Among these, phenolic compounds are the ones most frequently identified and analyzed. Phytochemicals such as phenolic acids, flavonoids, triterpenoids, and others have been continuously used in the management of metabolic disorders – diabetes mellitus and its complications (Bahadoran et al., 2013, Menezes et al., 2017). The underlying mechanisms of these phytoconstituents’ antidiabetic effects include the inhibition of the α-glucosidase activity, hypoglycemic activity, oxygen radical scavenging activity, modulation of lipid status, stimulation of insulin secretion and activation, while some of the secondary metabolites found in these plants also increase insulin and glucose transporter gene expression levels in INS-1 (insulin-secreting cell line 1) cells.
The present study aimed to investigate the antidiabetic potential of 18 Lamiaceae representatives cultivated in Serbia on yeast α-glucosidase and further translate obtained experimental data into predicted human α-glucosidase inhibition, by combining an in silico approach with dynamical modeling. Lamiaceae extracts (70 % methanol, 70 % ethanol, and water) were obtained by classical maceration and chemically characterized via Liquid Chromatography-Mass Spectrometry (LC-MS). Extracts were subjected to in vitro determination of yeast α-glucosidase inhibitory potential and the most potent extract was further explored to reveal the mode of enzyme inhibition. Based on the kinetic results, docking simulations were performed on both yeast and human α-glucosidase to examine the binding mode and energies of the secondary metabolites identified in the extracts. Finally, the dynamical model, which successfully describes the binding of secondary metabolites to yeast α-glucosidase and its inhibition, has been constructed. The proposed model was applied to predict the inhibitory potential of the explored Lamiaceae extract onto the human α-glucosidase, providing a significant advance in the discovery of compounds with antidiabetic potential in humans.
Section snippets
Chemicals and reagents
All used reagents and standards were of analytical grade. Acarbose, acetonitrile, apigenin, apigetrin, astragalin, caffeic acid, chlorogenic acid, cirsimaritin, eriodictyol, ferulic acid, formic acid, gentisic acid, hispidulin, isoquercetin, kaempferol, luteolin, naringenin, naringin, p-coumaric acid, p-hydroxybenzoic acid, potassium dihydrogen phosphate, protocatechuic acid, quercitrin, p-nitrophenyl-α-D-glucoside (pNPG) rosmarinic acid, rutin, salvianolic acid A, sinapic acid, sodium
Chemical characterization
Investigated plant species, extraction conditions, as well as secondary metabolites found in the extracts of selected Lamiaceae representatives are shown in Fig. 1. To determine the secondary metabolites of the selected Lamiaceae representatives, LC-MS chromatography has been applied (SI, Excel file, sheet named LC-MS parameters). According to the results presented in SI (Excel file, sheet named LC-MS characterization) – 14 flavonoids, 10 phenolic acids, and one phenolic aldehyde were
Discussion
Representatives of the Lamiaceae family with corresponding secondary metabolites have long been studied both in vitro and in vivo for antidiabetic potential; however, extracts of these plants are less intensively studied compared with corresponding essential oils. Therefore, in the present study, plant extracts of the selected Lamiaceae representatives were chemically characterized by LC-MS (profiling of secondary metabolites) and further subjected to in vitro determination of α-glucosidase
Conclusions
The results from the present study demonstrate a significant α-glucosidase inhibitory potential of different Lamiaceae species extracts. The LC-MS analysis of investigated species revealed 25 secondary metabolites previously reported as potent antidiabetic agents. The established antidiabetic activity was more thoroughly examined by a kinetic study, where a mixed type of the yeast α-glucosidase inhibition was inferred for one of the most potent extracts (Aq-extract of M. piperita). Most of the
Funding
This work was supported by the Grant of the Ministry of Education, Science and Technological Development of the Republic of Serbia [Contract numbers: 451-03-68/2022-14/200178; 451-03-9/2021-14/200007].
CRediT authorship contribution statement
Mariana Oalđe Pavlović: Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Tanja Lunić: Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization. Stefan Graovac: Formal analysis, Writing – original draft, Writing – review & editing. Marija Mandić: Investigation, Writing – review & editing. Jelena Repac: Investigation, Writing – review & editing. Uroš Gašić: Investigation, Writing – review & editing. Biljana Božić
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to dedicate this paper to Prof. Sonja Duletić-Laušević who suddenly passed away. We are very grateful for all our collaborations.
The authors would like to thank Prof. Petar Marin for manuscript reading and useful suggestions.
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These authors contributed equally to this study.