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Influence of Degree of Polymerization of Low-Molecular-Weight Chitosan Oligosaccharides on the α-Glucosidase Inhibition.

ABSTRACT: Chitosan oligosaccharide (COS) is a bioactive compound derived from marine by-products. COS consumption has been demonstrated to lower the risk of diabetes. However, there are limited data on the inhibitory effect of low-molecular-weight COSs with different degrees of polymerization (DP) on α-glucosidase. This study investigates the α-glucosidase inhibitory activity of two low-molecular-weight COSs, i.e., S-TU-COS with DP2-4 and L-TU-COS with DP2-5, both of which have different molecular weight distributions. The inhibition constants of the inhibitors binding to free enzymes (Ki) and an enzyme-substrate complex (Kii) were investigated to elucidate the inhibitory mechanism of COSs with different chain lengths. The kinetic inhibition model of S-TU-COS showed non-completive inhibition results which are close to the uncompetitive inhibition results with Ki and Kii values of 3.34 mM and 2.94 mM, respectively. In contrast, L-TU-COS showed uncompetitive inhibition with a Kii value of 5.84 mM. With this behavior, the IC50 values of S-TU-COS and L-TU-COS decreased from 12.54 to 11.84 mM and 20.42 to 17.75 mM, respectively, with an increasing substrate concentration from 0.075 to 0.3 mM. This suggests that S-TU-COS is a more potent inhibitor, and the different DP of COS may cause significantly different inhibition (p < 0.05) on the α-glucosidase activity. This research may provide new insights into the production of a COS with a suitable profile for antidiabetic activity.

SUBMITTER: Khaisaat S

PROVIDER: S-EPMC9740910 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Influence of Degree of Polymerization of Low-Molecular-Weight Chitosan Oligosaccharides on the α-Glucosidase Inhibition.

Khaisaat Supharada S Chancharoensin Saovanee S Wipatanawin Angkana A Suphantharika Manop M Payongsri Panwajee P

Molecules (Basel, Switzerland) 20221122 23

Chitosan oligosaccharide (COS) is a bioactive compound derived from marine by-products. COS consumption has been demonstrated to lower the risk of diabetes. However, there are limited data on the inhibitory effect of low-molecular-weight COSs with different degrees of polymerization (DP) on α-glucosidase. This study investigates the α-glucosidase inhibitory activity of two low-molecular-weight COSs, i.e., S-TU-COS with DP2−4 and L-TU-COS with DP2−5, both of which have different molecular weight ...[more]

PMID: 36500221

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Project description:BackgroundSuccessful non-viral gene delivery currently requires compromises to achieve useful transfection levels while minimizing toxicity. Despite high molecular weight (MW) branched polyethylenimine (bPEI) is considered the gold standard polymeric transfectant, it suffers from high cytotoxicity. Inversely, its low MW counterpart is less toxic and effective in transfection. Moreover, chitosan is a highly biocompatible and biodegradable polymer but characterized by very low transfection efficiency. In this scenario, a straightforward approach widely exploited to develop effective transfectants relies on the synthesis of chitosan-graft-low MW bPEIs (Chi-g-bPEI(x)) but, despite the vast amount of work that has been done in developing promising polymeric assemblies, the possible influence of the degree of grafting on the overall behavior of copolymers for gene delivery has been largely overlooked.Methodology/principal findingsWith the aim of providing a comprehensive evaluation of the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of copolymeric vectors, we have synthesized seven Chi-g-bPEI(x) derivatives with a variable amount of bPEI grafts (minimum: 0.6%; maximum: 8.8%). Along the Chi-g-bPEI(x) series, the higher the degree of grafting, the greater the ζ-potential and the cytotoxicity of the resulting polyplexes. Most important, in all cell lines tested the intermediate degree of grafting of 2.7% conferred low cytotoxicity and higher transfection efficiency compared to other Chi-g-bPEI(x) copolymers. We emphasize that, in transfection experiments carried out in primary articular chondrocytes, Chi-g-bPEI(2.7%) was as effective as and less cytotoxic than the gold standard 25 kDa bPEI.Conclusions/significanceThis work underlines for the first time the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of Chi-g-bPEI(x) copolymers. Crucially, we have demonstrated that, along the copolymer series, the fine tuning of the degree of grafting directly affected the overall charge of polyplexes and, altogether, had a direct effect on cytotoxicity.

Project description:BackgroundCellodextrin phosphorylase (CdP; EC 2.4.1.49) catalyzes the iterative β-1,4-glycosylation of cellobiose using α-D-glucose 1-phosphate as the donor substrate. Cello-oligosaccharides (COS) with a degree of polymerization (DP) of up to 6 are soluble while those of larger DP self-assemble into solid cellulose material. The soluble COS have attracted considerable attention for their use as dietary fibers that offer a selective prebiotic function. An efficient synthesis of soluble COS requires good control over the DP of the products formed. A mathematical model of the iterative enzymatic glycosylation would be important to facilitate target-oriented process development.ResultsA detailed time-course analysis of the formation of COS products from cellobiose (25 mM, 50 mM) and α-D-glucose 1-phosphate (10-100 mM) was performed using the CdP from Clostridium cellulosi. A mechanism-based, Michaelis-Menten type mathematical model was developed to describe the kinetics of the iterative enzymatic glycosylation of cellobiose. The mechanistic model was combined with an empirical description of the DP-dependent self-assembly of the COS into insoluble cellulose. The hybrid model thus obtained was used for kinetic parameter determination from time-course fits performed with constraints derived from initial rate data. The fitted hybrid model provided excellent description of the experimental dynamics of the COS in the DP range 3-6 and also accounted for the insoluble product formation. The hybrid model was suitable to disentangle the complex relationship between the process conditions used (i.e., substrate concentration, donor/acceptor ratio, reaction time) and the reaction output obtained (i.e., yield and composition of soluble COS). Model application to a window-of-operation analysis for the synthesis of soluble COS was demonstrated on the example of a COS mixture enriched in DP 4.ConclusionsThe hybrid model of CdP-catalyzed iterative glycosylation is an important engineering tool to study and optimize the biocatalytic synthesis of soluble COS. The kinetic modeling approach used here can be of a general interest to be applied to other iteratively catalyzed enzymatic reactions of synthetic importance.

Project description:Diabetes mellitus is a chronic disease that is becoming a serious global health problem. Diabetes has been considered to be one of the major risks of cataract and retinopathy. Synthetic and natural product inhibitors of carbohydrate degrading enzymes are able to reduce type 2 diabetes and its complications. For a long time, potatoes have been portrayed as unhealthy for diabetic patients by some nutritionist due to their high starch content. However, purple and red potato cultivars have received considerable attention from consumers because they have high levels of polyphenolic compounds that have potent antioxidant activities. In this study, we screened the total phenolics (TP) and total anthocyanins (TA) and analyzed the phenolic and anthocyanin compounds in selected potato cultivars and advanced selections with distinct flesh colors (purple, red, yellow and white). Purple and red potato cultivars had higher levels of TP and TA than tubers with other flesh colors. Chlorogenic acid is the predominant phenolic acid, and major anthocyanin is composed of the derivatives of petunidin, peonidin, malvidin and pelargonidin. We tested the potential inhibitory effect of potato extracts on the activities of α-amylase and α-glucosidase, which were targeted to develop antidiabetic therapeutic agents. We also measured inhibitory effect of potato extracts on aldose reductase (AR) which is a key enzyme that has been a major drug target for the development of therapies to treat diabetic complications. Purple flesh tubers extract showed the most effective inhibition of α-amylase, α-glucosidase, and aldose reductase with IC50 values 25, 42, and 32 μg/ml, respectively. Kinetic studies showed that anthocyanins are noncompetitive inhibitors of these enzymes, whereas phenolic acids behaved as mixed inhibitors for α-amylase and α-glucosidase and noncompetitive inhibitors for AR. This study supports the development of a positive and healthful image of potatoes, which is an important issue for consumers.

Dataset Information

Influence of Degree of Polymerization of Low-Molecular-Weight Chitosan Oligosaccharides on the α-Glucosidase Inhibition.

Publications

Influence of Degree of Polymerization of Low-Molecular-Weight Chitosan Oligosaccharides on the α-Glucosidase Inhibition.

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