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Inhibitory Effects Against Α-Glucosidase and Α-Amylase of The Li et al. Chemistry Central Journal (2018) 12:82 https://doi.org/10.1186/s13065-018-0445-y RESEARCH ARTICLE Open Access Inhibitory efects against α‑glucosidase and α‑amylase of the favonoids‑rich extract from Scutellaria baicalensis shoots and interpretation of structure–activity relationship of its eight favonoids by a refned assign‑score method Ke Li, Fan Yao, Qiang Xue, Hang Fan, Lingguang Yang, Xiang Li, Liwei Sun and Yujun Liu* Abstract A favonoids-rich extract of Scutellaria baicalensis shoots and its eight high content favonoids were investigated for their inhibitory efects against α-glucosidase and α-amylase. Results show that abilities of the extract in inhibiting the two enzymes were obviously higher than those of acarbose. Moreover, inhibitory abilities of all the eight individual favonoids against the two enzymes show exactly a same order (i.e., apigenin > baicalein > scutellarin > chrysin > api- genin-7-O-glucuronide > baicalin > chrysin-7-O-glucuronide > isocarthamidin-7-O-glucuronide), and their structure– activity relationship could be well-interpretated by the refned assign-score method. Furthermore, based on the inhibitory abilities and their contents in the extract, it was found that the eight favonoids made predominant contri- butions, among which baicalein and scutellarin played roles as preliminary contributors, to overall inhibitory efects of the extract against the two enzymes. Beyond these, contributions of the eight favonoids to the overall enzyme inhibitory activity were compared with those to the overall antioxidant activity characterized in our recent study, and it could be inferred that within the basic favonoid structure the hydroxyl on C-4′ of ring B was more efective than that on C-6 of ring A in enzyme inhibitory activities while they behaved inversely in antioxidant activities; scutellarin and apigenin contributed more to the overall enzyme inhibitory activity, and baicalin and scutellarin, to the overall antioxidant activity of the extract; and favonoids of the extract, apart from directly inhibiting enzymes, might also be conducive to curing type 2 diabetes via scavenging various free radicals caused by increased oxidative stresses. Keywords: Scutellaria baicalensis shoots, Flavonoids, α-Glucosidase, α-Amylase, Structure–activity relationship, Refned assign-score method *Correspondence: [email protected] National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Biotechnology, Beijing Forestry University, Qinghuadonglu No. 35, Haidian District, Beijing 100083, China © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. Chemistry Central Journal (2018) 12:82 Page 2 of 11 Introduction attempts have been made in establishing a structure– Diabetes is a chronic disease caused by defciency in and activity relationship for a single type of efects such as insensitivity to insulin [1], usually resulting in postpran- antioxidant activities by the assign-score method [20]. dial hyperglycemia and various diabetic complications Similar approaches should also be accordingly conducted [2]. In 2013, 382 million individuals worldwide are living on other biological activities of favonoids, such as their with diabetes, 90% of them were afected by non-insulin- hydrolytic enzyme inhibitory efects against α-amylase dependent (type 2) diabetes, and the number is expected and α-glucosidase, in that establishment of structure– to rise to 592 million by 2035 [3, 4]. Diabetes has become activity relationships of many such individual types of a major cause of death in people younger than 60 years, efects must be helpful to fully clarify the comprehensive and death caused by diabetes accounts for nearly 9% of structure–activity relationship of favonoids. And this the total global deaths [5]. Tus, it is urgent to explore will certainly have some reference signifcance for estab- efective therapeutic methods for diabetes and diabetic lishing structure–activity relationship of other groups of complications. bioactive compounds. A promising approach for management of diabetes, Scutellaria baicalensis in the family Labiatae, a peren- particularly type 2 diabetes, is to decrease postpran- nial herb long listed in the Chinese Pharmacopoeia under dial hyperglycemia by inhibiting carbohydrate hydro- the name “Huang Qin” in Chinese, is well-known for its lyzing enzymes in gastrointestinal tract [6]. α-Amylase root as medicine in East Asian countries [21]. Recently, is involved in degrading long chain of starch and pharmacological studies found that S. baicalensis shoot α-glucosidase breaks down oligosaccharides and disac- could also deliver a wide variety of benefcial therapeu- charides [7]. Inhibitors of these enzymes slow down car- tic efects, such as cardiovascular protection, hepato- bohydrate digestion thus prolong overall digestion time, protection, neuroprotection, anti-bacterial activity, causing a reduction in glucose absorption and conse- improvement of memory defcits, and anti-tumor activ- quently blunting postprandial plasma glucose [8]. ity [22–24], indicating that it might be at least a good Currently there are several antidiabetic drugs such candidate of potential supplement for developing func- as acarbose that act by inhibiting α-amylase and tional foods. Our previous study [20] identifed ffteen α-glucosidase. Acarbose is an oligosaccharide of micro- favonoids from the shoot of S. baicalensis, and eight bial origin (Actinoplanes) that potently inhibits in vitro high content favonoids, including baicalin, baicalein, and in vivo such brush-border enzymes as glucoamylase, scutellarin, apigenin, chrysin, apigenin-7-O-glucuron- dextrinase, maltase and sucrase as well as the pancreatic ide, chrysin-7-O-glucuronide, and isocarthamidin-7-O- α-amylase [9]. Due to the presence of an intramolecular glucuronide, were determined as main contributors to nitrogen, acarbose attaches to the carbohydrate binding its antioxidant activities. Nevertheless, there are still site of α-glucosidase enzyme with an afnity exceeding no reports on anti-diabetic activities of the S. baicalen- that of the normal substrate by a factor of 10 4–105. Te sis shoot, let alone the contributions of individual com- enzymatic reaction stops because the C–N linkage in pounds to these activities. the acarviosine unit of acarbose cannot be cleaved [10]. Te objective of this study was to evaluate potentials While efcient in attenuating the rise in blood glucose, of the favonoids-rich extract, especially the contribution continuous uses of acarbose and other similar drugs are of the eight high content favonoids, from S. baicalensis often associated with undesirable efects [11]. It is for this shoot as inhibitors against α-glucosidase and α-amylase, reason that there is a need for natural α-glucosidase and and to establish a structure–activity relationship for the α-amylase inhibitors that would possess no adverse or eight favonoids using the assign-score method, so as to unwanted side efects. Traditional medicines have long providing base-line data of this valuable natural source employed herbal extracts as inhibitory agents against for development of functional foods. α-glucosidase and α-amylase [12] that, typically rich in polyphenolics, may own the potential in controlling post- Materials and methods prandial hyperglycemia via their high antioxidant and/or Chemicals enzymatic inhibitory efects [13, 14]. Eight authentic standards (i.e., baicalin, baicalein, scutel- Flavonoids are a peculiar group of polyphenols ubiq- larin, apigenin, chrysin, apigenin-7-O-glucuronide, uitously distributed in plant kingdom and important chrysin-7-O-glucuronide, and isocarthamidin-7-O-glu- functional compositions of human diets. Daily intake curonide) were purchased from Institute for Control of of favonoids ranges between 50 and 800 mg/capita, Pharmaceutical and Biological Products (Beijing, China), depending mainly on consumptions of vegetables and/ acarbose, yeast α-glucosidase from Saccharomyces cerevi- or fruits [15, 16]. Studies have suggested that favonoids siae, porcine pancreatic α-amylase, and p-nitrophenyl-α- exhibit conspicuous biological activities [17–19], and glucopyranoside (pNPG) were from Sigma-Aldrich Co. Li et al. Chemistry Central Journal (2018) 12:82 Page 3 of 11 Determinations of α‑glucosidase inhibitory efect (St. Louis, MO, USA), and they were all stored at − 20 °C before using. All solvents (analytical grade) were bought α-Glucosidase inhibitory efect was assayed as reported from Beijing Chemical Factory, and purifed water was by Zhang et al. [26]. Briefy, 10 μL α-glucosidase from a mili-Q system (Millipore, Billerica, MA). (1 unit/mL) was mixed with 60 μL phosphate bufer (0.1 mM, pH 6.8) and 100 μL sample (extract or each of the eight favonoids) or acarbose (0, 0.5, 1.0, 1.5, and Plant materials and extraction of favonoids 2.0 mg/mL) in corresponding well of a 96-well plate Shoots of annual S. baicalensis were collected in Great and the mixture was incubated
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