PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L.
Graphical abstract
Introduction
The use of traditional herbs for the treatment and management of chronic diseases is still a mainstay in developing countries. Among all the chronic diseases, the application of traditional medicine for diabetes mellitus (DM) is the most representative [1]. DM is a metabolic and chronic disease characterized by high blood sugar levels. It can be broadly categorized into diabetes mellitus type I (T1DM), diabetes mellitus type II (T2DM), gestational diabetes and diabetes of other etiology. T2DM accounts for about 90–95% of all cases of diabetes [2], [3], [4], [5], [6]. Therefore, there have been various studies to identify the T2DM mechanisms through which plant drugs bring about diabetic inhibition activities, such as the mechanisms of α-amylase inhibitors, α-glucosidase inhibitors, protein tyrosine phosphatase 1B (PTP1B) inhibitors, and dipeptidyl peptidase-4 (DPP-IV) inhibitors [7]. Recently, PTP1B inhibition was reported as a promising target for the treatment of T2DM [8]. PTP1B has been implicated in the negative regulation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) within the insulin-stimulated signal transduction pathway. Thus, pharmacological agents that inhibit PTP1B activity have the potential to augment and prolong insulin action for the treatment of T2DM [9], [10], [11]. Nowadays, α-glucosidase inhibitors are widely used in the treatment of T2DM [12], [13]. The diabetic inhibitor agents used clinically, namely acarbose, voglibose, and miglitol, inhibit α-glucosidase competitively in the brush border of the small intestine, and consequently delay the hydrolysis of carbohydrates (starch and disaccharides), alleviating postprandial hyperglycemia [14], [15], [16]. DPP-IV inhibitors were recently introduced as some of the newest diabetes drugs [17]. The DPP-IV enzyme is responsible for the rapid degradation of incretins, such as glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 secreted by intestinal L cells helps control blood sugar levels since it has important physiological functions, such as the stimulation of insulin secretion, inhibition of glucagon release, and delayed gastric emptying. Hence, inhibition of DPP-IV leads to the potentiation of endogenous GLP-1 and GIP, which have clearly established roles in glucose-dependent insulin secretion [18], [19], [20], [21].
Smilax china L., a member of the Smilacaceae family, is distributed widely in tropical and temperate parts of the world, especially in East Asia [22]. It is a perennial, slightly woody climber with paired tendrils for climbing. The tuber of Smilax china L. is commonly used in traditional medicines for the treatment of furunculosis, tumors, and inflammation [23]. Pharmacological research has been reported indicating that the tuber of S. china L. possesses anti-inflammatory, anti-cancer, anti-microbial, and anti-tyrosinase activities [24], [25]. However, all of the published studies were focused on the tuber of S. china L. There are only a few reports of experiments using the leaves of S. china L. Flavonoids, such as rutin, kaempferin, and kaempferitrin have been isolated from the leaves of S. china L [26], but there is no report on anti-diabetic activity by the chemical constituents isolated from the leaves of this plant [27], [28]. The aim of this study was to isolate the compounds from the leaves of this plant and to investigate their inhibitory effects on DPP-IV, PTP1B, and α-glucosidase enzyme activities.
Section snippets
Plant materials
The leaves of S. china L. were collected in September 2012 from Cho-lye mountain in Daegu, Republic of Korea. These materials were confirmed taxonomically by Professor Byung Sun Min, College of Pharmacy, Catholic University of Daegu, Korea. A voucher specimen, No. 201209, has been deposited at the College of Pharmacy, Catholic University of Daegu, Korea.
Instruments and reagents
Melting points were determined on a Yanaco micro melting point apparatus. Optical rotations were measured on a JASCO DIP-370 digital
Phytochemical investigation
In this study, the leaves of S. china L. were extracted with 70% EtOH, and the concentrated extract was partitioned in succession with n-hexane, methylene chloride, ethyl acetate, and n-butanol. From the ethyl acetate fraction, a new biflavonoid, 4′-methoxy-5,7-dihydroxyflavone-(3-O-7″)-4‴,5″,7″-trihydroxyflavone (11), and a new isoflavone glucoside, 5,7-dihydroxy-4'-methoxyisoflavone-2′-O-β-d-glucopyranoside (14), along with 14 known compounds were isolated and characterized. The known
Conclusion
In conclusion, the inhibitory activities of the isolated compounds against DPP-IV, PTP1B, and α-glucosidase enzymes indicate that the leaves of S. china L. may have beneficial effects in the treatment of diabetes. However, further work will be necessary to definitively determine if the activity is sufficient to warrant evaluation of the compounds for clinical applications.
Conflict of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Acknowledgements
The authors are grateful to S. H. Kim and collaborators at the Korea Basic Science Institute (Daegu) for measuring the mass spectra.
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