Natural phenolic compounds potentiate hypoglycemia via inhibition of Dipeptidyl peptidase IV

Abstract Dipeptidyl peptidase IV (DPP IV) is a surface glycoprotein that can degrade glucagon like pepetide-1 (GLP-1) by decreasing blood sugar. Herbal medicines for diabetic therapy are widely used with acceptable efficacy but unsatisfied in advances. DPP IV was chosen as a template to employ molecular docking via Discovery Studio to search for natural phenolic compounds whether they have the inhibitory function of DPP IV. Then, docking candidates were validated and further performed signal pathway via Caco-2, C2C12, and AR42J cells. Lastly, a diet-induced diabetes in mice were applied to examine the efficacy and toxicity of hit natural phenolic products in long-term use (in vivo). After screening, curcumin, syringic acid, and resveratrol were found in high affinity with DPP IV enzymes. In enzymatic tests, curcumin and resveratrol showed potential inhibition of DPP IV. In vitro assays, curcumin inhibited of DPP IV activity in Caco-2 cells and ERK phosphorylation in C2C12 cells. Additionally, curcumin attenuated blood sugar in S961-treated C57BL/6 mice and in diet-induced diabetic ICR mice and long-term regulate HbA1c in diabetic mice. Curcumin targeted to DPP IV for reducing blood glucose, it possesses potential and alternative substitution of synthetic clinical drugs for the medication of diabetes.

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Identification and characterisation of peptides from a boarfish (Capros aper) protein hydrolysate displaying in vitro dipeptidyl peptidase-IV (DPP-IV) inhibitory and insulinotropic activity

Food Research International ◽

10.1016/j.foodres.2020.108989 ◽

2020 ◽

Vol 131 ◽

pp. 108989 ◽

Cited By ~ 6

Author(s):

Pádraigín A. Harnedy-Rothwell ◽

Chris M. McLaughlin ◽

Martina B. O'Keeffe ◽

Aurélien V. Le Gouic ◽

Philip J. Allsopp ◽

...

Keyword(s):

Protein Hydrolysate ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Dpp Iv

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Bioprocessing of common pulses changed seed microstructures, and improved dipeptidyl peptidase-IV and α-glucosidase inhibitory activities

Scientific Reports ◽

10.1038/s41598-019-51547-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Elisa Di Stefano ◽

Apollinaire Tsopmo ◽

Teresa Oliviero ◽

Vincenzo Fogliano ◽

Chibuike C. Udenigwe

Keyword(s):

Phenolic Compounds ◽

Protein Digestibility ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Dpp Iv ◽

Glucosidase Inhibitors ◽

Yellow Peas ◽

Faba Beans ◽

Inhibitory Activities ◽

Green Lentils

Abstract Type 2 diabetes mellitus (T2DM) is a leading cause of death globally. T2DM patients experience glucose intolerance, and inhibitors of dipeptidyl peptidase IV (DPP-IV) and α-glucosidase are used as drugs for T2DM management. DPP-IV and α-glucosidase inhibitors are also naturally contained in foods, but their potency can be affected by the food matrix and processing methods. In this study, germination and solid-state fermentation (SSF) were used to alter pulse seed microstructures, to convert compounds into more bioactive forms, and to improve their bioaccessibility. Germination substantially modified the seed microstructure, protein digestibility, contents and profiles of phenolic compounds in all the pulses. It also increased DPP-IV and α-glucosidase inhibitory activities in chickpeas, faba beans and yellow peas. Compared to germination, SSF with Lactobacillus plantarum changed the content and the profile of phenolic compounds mainly in yellow peas and green lentils because of greater disruption of the seed cell wall. In the same pulses, heat treatment and SSF of flour increased DPP-IV and α-glucosidase inhibitory activities. The results of this study suggest that germination and SSF with L. plantarum are effective and simple methods for modulating phenolic and protein profiles of common pulses and improve the action on DPP-IV and α-glucosidase.

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Berry and Citrus Phenolic Compounds Inhibit Dipeptidyl Peptidase IV: Implications in Diabetes Management

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/479505 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 45

Author(s):

Junfeng Fan ◽

Michelle H. Johnson ◽

Mary Ann Lila ◽

Gad Yousef ◽

Elvira Gonzalez de Mejia

Keyword(s):

Phenolic Compounds ◽

Computational Modeling ◽

Active Sites ◽

Fruits And Vegetables ◽

Diabetes Management ◽

Binding Mode ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Dpp Iv ◽

Regulatory Effects

Beneficial health effects of fruits and vegetables in the diet have been attributed to their high flavonoid content. Dipeptidyl peptidase IV (DPP-IV) is a serine aminopeptidase that is a novel target for type 2 diabetes therapy due to its incretin hormone regulatory effects. In this study, well-characterized anthocyanins (ANC) isolated from berry wine blends and twenty-seven other phenolic compounds commonly present in citrus, berry, grape, and soybean, were individually investigated for their inhibitory effects on DPP-IV by using a luminescence assay and computational modeling. ANC from blueberry-blackberry wine blends strongly inhibited DPP-IV activity (IC50, 0.07 ± 0.02 to >300 μM). Of the twenty-seven phenolics tested, the most potent DPP-IV inhibitors were resveratrol (IC50, 0.6 ± 0.4 nM), luteolin (0.12 ± 0.01 μM), apigenin (0.14 ± 0.02 μM), and flavone (0.17 ± 0.01 μM), with IC50values lower than diprotin A (4.21 ± 2.01 μM), a reference standard inhibitory compound. Analyses of computational modeling showed that resveratrol and flavone were competitive inhibitors which could dock directly into all three active sites of DPP-IV, while luteolin and apigenin docked in a noncompetitive manner. Hydrogen bonding was the main binding mode of all tested phenolic compounds with DPP-IV. These results indicate that flavonoids, particularly luteolin, apigenin, and flavone, and the stilbenoid resveratrol can act as naturally occurring DPP-IV inhibitors.

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Dipeptidyl-Peptidase IV Converts Intact B-Type Natriuretic Peptide into Its des-SerPro Form

Clinical Chemistry ◽

10.1373/clinchem.2005.057638 ◽

2006 ◽

Vol 52 (1) ◽

pp. 82-87 ◽

Cited By ~ 145

Author(s):

Inger Brandt ◽

Anne-Marie Lambeir ◽

Jean-Marie Ketelslegers ◽

Marc Vanderheyden ◽

Simon Scharpé ◽

...

Keyword(s):

Natriuretic Peptide ◽

Ex Vivo ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Amino Terminal ◽

Dpp Iv

Abstract Background: Analysis of plasma B-type natriuretic peptide (BNP) has suggested the in vivo formation of a truncated form, BNP (3–32), also called des-SerPro-BNP. The objectives of this study were to investigate (a) whether BNP and other natriuretic peptides are truncated by dipeptidyl-peptidase IV (DPP IV/CD26; EC 3.4.14.5) and (b) whether this truncation affects the susceptibility to cleavage by neutral endopeptidase (NEP; EC 3.4.24.11). Methods: Human BNP (1–32), A-type natriuretic peptide 1–28 (ANP 1–28), and related peptides were incubated with purified DPP IV and with human plasma. In addition, BNP (1–32), BNP (3–32), and ANP (1–28) were subjected to hydrolysis by NEP. Cleavage products were analyzed by mass spectrometry. Results: BNP (1–32) was cleaved by purified DPP IV with a specificity constant of 0.37 × 106 L · mol−1 · s−1. The DPP IV activity in EDTA-plasma was able to truncate BNP (1–32) ex vivo. Addition of Vildagliptin, a specific DPP IV inhibitor, prevented this truncation in a concentration-dependent manner. Under in vitro circumstances in which ANP was hydrolyzed extensively, BNP (1–32) and BNP (3–32) were very resistant to NEP-mediated cleavage. Conclusions: DPP IV cleaves BNP (1–32) with an efficiency higher than or comparable to several known in vivo substrates of the enzyme. Even after loss of the amino-terminal dipeptide, BNP remains highly resistant to cleavage by NEP.

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Quinoa (Chenopodium quinoa Willd.) protein hydrolysates with in vitro dipeptidyl peptidase IV (DPP-IV) inhibitory and antioxidant properties

Journal of Cereal Science ◽

10.1016/j.jcs.2015.07.004 ◽

2015 ◽

Vol 65 ◽

pp. 112-118 ◽

Cited By ~ 59

Author(s):

Alice B. Nongonierma ◽

Solène Le Maux ◽

Cécile Dubrulle ◽

Chloé Barre ◽

Richard J. FitzGerald

Keyword(s):

Antioxidant Properties ◽

Chenopodium Quinoa ◽

Dipeptidyl Peptidase ◽

Protein Hydrolysates ◽

Dipeptidyl Peptidase Iv ◽

Dpp Iv

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Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78β into a most efficient monocyte attractant and CCR1 agonist

Blood ◽

10.1182/blood.v96.5.1674 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1674-1680 ◽

Cited By ~ 110

Author(s):

Paul Proost ◽

Patricia Menten ◽

Sofie Struyf ◽

Evemie Schutyser ◽

Ingrid De Meester ◽

...

Keyword(s):

Mononuclear Cells ◽

Specific Activity ◽

High Capacity ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Surface Glycoprotein ◽

Peripheral Blood Mononuclear ◽

Dpp Iv ◽

Stromal Cell Derived Factor ◽

Hiv 1

Abstract Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell–derived factor-1 (SDF-1) are NH2-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH2-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein–1β (MIP-1β) and the related chemokine, LD78α (ie, one of the MIP-1α isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78β, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus–1 (HIV-1) infection, into LD78β(3-70). Naturally truncated LD78β(3-70), but not truncated MIP-1β, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78β(3-70) had increased chemotactic activity in comparison to intact LD78β. With a minimal effective concentration of 30 pmol/L, LD78β(3-70) became the most efficient monocyte chemoattractant. LD78β(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78β(3-70) was 30-fold more potent than intact LD78β. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78β. CD26/DPP IV–cleaved LD78β(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti–HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions.

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Generation of Dipeptidyl Peptidase-IV-Inhibiting Peptides fromβ-Lactoglobulin Secreted byLactococcus lactis

BioMed Research International ◽

10.1155/2014/393598 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Suguru Shigemori ◽

Kazushi Oshiro ◽

Pengfei Wang ◽

Yoshinari Yamamoto ◽

Yeqin Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Expression System ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Delivery Vehicle ◽

Dpp Iv

Previous studies showed that hydrolysates ofβ-lactoglobulin (BLG) prepared using gastrointestinal proteases strongly inhibit dipeptidyl peptidase-IV (DPP-IV) activityin vitro. In this study, we developed a BLG-secretingLactococcus lactisstrain as a delivery vehicle andin situexpression system. Interestingly, trypsin-digested recombinant BLG fromL. lactisinhibited DPP-IV activity, suggesting that BLG-secretingL. lactismay be useful in the treatment of type 2 diabetes mellitus.

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A Novel Dipeptidyl Peptidase IV Inhibitory Tea Peptide Improves Pancreatic β-Cell Function and Reduces α-Cell Proliferation in Streptozotocin-Induced Diabetic Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20020322 ◽

2019 ◽

Vol 20 (2) ◽

pp. 322 ◽

Cited By ~ 3

Author(s):

Yating Lu ◽

Peng Lu ◽

Yu Wang ◽

Xiaodong Fang ◽

Jianming Wu ◽

...

Keyword(s):

Mass Spectrometry ◽

Type 2 Diabetes ◽

Inhibitory Activity ◽

Black Tea ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Inhibitory Peptides ◽

Dpp Iv

Dipeptidyl peptidase IV (DPP-IV) inhibitors occupy a growing place in the drugs used for the management of type 2 diabetes. Recently, food components, including food-derived bioactive peptides, have been suggested as sources of DPP-IV inhibitors without side effects. Chinese black tea is a traditional health beverage, and it was used for finding DPP-IV inhibitory peptides in this study. The ultra-filtrated fractions isolated from the aqueous extracts of black tea revealed DPP-IV inhibitory activity in vitro. Four peptides under 1 kDa were identified by SDS-PAGE and LC-MS/MS (Liquid Chromatography-Mass Spectrometry-Mass Spectrometry) from the ultra-filtrate. The peptide II (sequence: AGFAGDDAPR), with a molecular mass of 976 Da, showed the greatest DPP-IV inhibitory activity (in vitro) among the four peptides. After administration of peptide II (400 mg/day) for 57 days to streptozotocin (STZ)-induced hyperglycemic mice, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increased from 9.85 ± 1.96 pmol/L to 19.22 ± 6.79 pmol/L, and the insulin level was increased 4.3-fold compared to that in STZ control mice. Immunohistochemistry revealed the improved function of pancreatic beta-cells and suppressed proliferation of pancreatic alpha-cells. This study provides new insight into the use of black tea as a potential resource of food-derived DPP-IV inhibitory peptides for the management of type 2 diabetes.

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Quercetin and Coumarin Inhibit Dipeptidyl Peptidase-IV and Exhibits Antioxidant Properties: In Silico, In Vitro, Ex Vivo

Biomolecules ◽

10.3390/biom10020207 ◽

2020 ◽

Vol 10 (2) ◽

pp. 207 ◽

Cited By ~ 6

Author(s):

Anand-Krishna Singh ◽

Pankaj Kumar Patel ◽

Komal Choudhary ◽

Jaya Joshi ◽

Dhananjay Yadav ◽

...

Keyword(s):

Oxidative Stress ◽

In Silico ◽

Ex Vivo ◽

Antioxidant Properties ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Food Ingredients ◽

Dpp Iv ◽

In Silico Studies

Quercetin and coumarin, two naturally occurring phytochemicals of plant origin, are known to regulate hyperglycemia and oxidative stress. The present study was designed to evaluate the inhibitory activity of quercetin and coumarin on dipeptidyl peptidase-IV (DPP-IV) and their antioxidant potential. DPP-IV inhibition assays were performed, and evaluated IC50 values of diprotin A, quercetin, coumarin, and sitagliptin were found to be 0.653, 4.02, 54.83, and 5.49 nmol/mL, respectively. Furthermore, in silico studies such as the drug-likeliness and docking efficiency of quercetin and coumarin to the DPP-IV protein were performed; the ex vivo antiperoxidative potential of quercetin and coumarin were also evaluated. The results of the present study showed that the DPP-IV inhibitory potential of quercetin was slightly higher than that of sitagliptin. Virtual docking revealed the tight binding of quercetin with DPP-IV protein. Quercetin and coumarin reduced oxidative stress in vitro and ex vivo systems. We report for the first time that both compounds inhibited the DPP-IV along with antioxidant activity and thus may be use as function food ingredients in the prevention of diabetes.

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