Dataset Information

Isolation of Chalcomoracin as a Potential α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism.

ABSTRACT: Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of Morus alba) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels-Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gastrointestinal side effects. In this study, chalcomoracin was effectively isolated from mulberry leaves, and its α-glucosidase inhibition was studied via enzymatic kinetics, isothermal titration (ITC) and molecular docking. The results showed that chalcomoracin inhibited α-glucosidase through both competitive and non-competitive manners, and its inhibitory activity was stronger than that of 1-doxymycin (1-DNJ) but slightly weaker than that of acarbose. ITC analysis revealed that the combination of chalcomoracin and α-glucosidase was an entropy-driven spontaneous reaction, and the molecular docking results also verified this conclusion. During the binding process, chalcomoracin went into the "pocket" of α-glucosidase via hydrophobic interactions, and it is linked with residues Val544, Asp95, Ala93, Gly119, Arg275 and Pro287 by hydrogen bonds. This study provided a potential compound for the prevention and treatment of diabetes and a theoretical basis for the discovery of novel candidates for α-glycosidase inhibitors.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9504037 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Isolation of Chalcomoracin as a Potential α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism.

Liu Yang Y Zhou Xue X Zhou Dan D Jian Yongxing Y Jia Jingfu J Ge Fahuan F

Molecules (Basel, Switzerland) 20220906 18

Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of <i>Morus alba</i>) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels-Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gast ...[more]

PMID: 36144478

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Project description:Mulberry (Morus alba L.) leaves have long been considered beneficial in traditional Chinese medicine to treat infectious and internal diseases. Recently studies have discovered that the mulberry leaf's total flavonoids (MLF) display excellent hypoglycemia properties. However, the active ingredients and their molecular mechanisms are still uncharacterized. In this study, we explored the hypoglycemic effects of MLF and mulberry leaf polysaccharides (MLP) on ob/ob mice, an animal model of type 2 diabetes mellitus (T2DM), compared with Ramulus Mori (Sangzhi) alkaloid (RMA). Network pharmacology was employed to identify the potential available targets and active compounds of MLF and RMA against hyperglycemia. Molecular docking, an insulin-resistant cell model and qPCR were employed to verify the antidiabetic activity of the critical compounds and the gene expression profiles of the top molecular targets. Here, the results showed that MLF and MLP improved glucose uptake in insulin-resistant hepatocytes. MLF, MLP and RMA alleviated insulin resistance and glucose intolerance in ob/ob mice. Unlike MLF and MLP, RMA administration did not influence the accumulation of intrahepatic lipids. Network pharmacology analysis revealed that morusin, kuwanon C and morusyunnansin L are the main active compounds of MLF and that they amend insulin resistance and glycemia via the PI3K- Akt signaling pathway, lipid and atherosclerosis pathways, and the AGE-RAGE signaling pathway. Moreover, 1-deoxynojirimycin (DNJ), fagomine (FA), and N-methyl-1-deoxynojirimycin are the primary active ingredients of RMA and target carbohydrate metabolism and regulate alpha-glucosidase activity to produce a potent anti-diabetic effect. The molecular docking results indicated that morusin, kuwanon C and morusyunnansin L are the critical bioactive compounds of MLF. They had high affinities with the key targets adenosine A1 receptor (ADORA1), AKT serine/threonine kinase 1 (AKT1), peroxisome proliferator-activated receptor gamma (PPARγ), and glycogen synthase kinase 3 beta (GSK3β), which play crucial roles in the MLF-mediated glucose-lowering effect. Additionally, morusin plays a role in amending insulin resistance of hepatocytes by repressing the expression of the ADORA1 and PPARG genes. Our results shed light on the mechanism behind the glucose-lowering effects of MLF, suggesting that morusin, kuwanon C, and morusyunnansin L might be promising drug leads for the management of T2DM.

Project description:BackgroundThe discovery of bioactive compounds in traditional Chinese medicine (TCM) has become an important field in TCM modernization. Ligand fishing is a suitable method for discovery of bioactive compounds in complex mixtures such as TCM with high selectivity. Because of unique advantage of low cost and convenience, paper-based microdevices can be good carriers for enzyme immobilized ligand fishing.MethodsAs an important enzyme for glucose metabolism, α-glucosidase was immobilized on polycaprolactone-chitosan-modified paper to prepare the microdevice with unique microfluid structure generated by 3D printing technology, which can be easily applied to screen active compounds in herbal extracts. The preparation conditions of the paper microarray were optimized. The activity of immobilized α-glucosidase was verified by colorimetric reactions which can be easily monitored by cellphone. The paper microarray with α-glucosidase immobilized was used to screen active compounds in the water extracts of mulberry leaves and lotus leaves.ResultsSeveral key parameters including Na2CO3 solution concentration, Na2CO3 solution volume, glutaraldehyde concentration, crosslinking time of glutaraldehyde and time of α-glucosidase immobilization were optimized. The proposed paper-based microarray was successfully applied in screening active compounds in two herbal extracts. Four compounds including chlorogenic acid, quercetin-3-O-glucuronide, isoquercetin, and quercetin were identified as α-glucosidase inhibitors. The compounds with significant non-specific adsorption caused by chitosan, such as isoquercitrin, astragalin, quercetin, were also found to be active compounds.ConclusionsAn enzyme immobilized paper microarray was designed and fabricated in this work. Polycaprolactone and chitosan were used to modify filter paper to prepare paper microarrays. Parameters of paper device preparation were optimized. Our findings suggested that 3D-printing paper-based microarrays can be a simple and low-cost approach for discovery of active compounds of TCM.

Project description:ObjectiveMulberry (Morus spp.) fruits and leaves have been proven to possess nutraceutical properties. Due to its fast and easy growing characteristics, mulberry fruits (MF) and leaves (ML) potentially emerge as a great source of functional foods. This study aims to enhance bioactivities (antioxidant, anti-inflammation, and hypoglycemic activity) of MF and ML via submerged fermentation using bacteria (Lactobacillus plantarum TAR 4), yeast (Baker's yeast and red yeast) and fungi (Tempeh and Tapai starter).MethodsIn this study, 25% (mass to volume ratio) of MF and ML were fermented (48 h) with 1% (mass to volume ratio) of different microbial cultures, respectively. Effects of different fermentations on MF and ML were determined based on the changes of total phenolics (TPC), flavonoids (TFC), anthocyanins, total sugar, DPPH activity, ferric reducing antioxidant power (FRAP), albumin denaturation inhibition activity (ADI), anti-lipoxygenase activity and α-amylase inhibition activity (AI).ResultsGenerally, ML had higher AI than MF. However, MF exhibited higher DPPH, FRAP and anti-lipoxygenase activity than ML. After all forms of fermentation, DPPH and AI activity of MF and ML were increased significantly (P < 0.05). However, the effects of fermentation on TPC, FRAP, ADI and anti-lipoxygenase activity of MF were in contrast with ML. TPC, FRAP and anti-lipoxygenase activity of ML were enhanced, but reduced in MF after fermentation. Although the effects exerted by different microorganisms in MF and ML fermentation were different, the bioactivities of MF and ML were generally improved after fermentation. Fermentation by Tempeh starter enhanced TPC (by 2-fold), FRAP (by 2.3-fold), AI (at 10% increment) and anti-lipoxygenase activity (by 5-fold) of ML, whereas Tapai fermentation effectively enhanced the DPPH (at 17% increment) and ADI (by 2-fold) activity of MF.ConclusionFindings of this study provide an insight into the future process design of MF and ML processing into novel functional foods.

Dataset Information

Isolation of Chalcomoracin as a Potential α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism.

Publications

Isolation of Chalcomoracin as a Potential α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism.

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