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

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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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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4-Hydroxyderricin Isolated from the Sap of Angelica keiskei Koidzumi: Evaluation of Its Inhibitory Activity towards Dipeptidyl Peptidase-IV

Scientia Pharmaceutica ◽

10.3390/scipharm87040030 ◽

2019 ◽

Vol 87 (4) ◽

pp. 30

Author(s):

Diah Lia Aulifa ◽

I Ketut Adnyana ◽

Jutti Levita ◽

Sukrasno Sukrasno

Keyword(s):

In Silico ◽

In Vitro Study ◽

Gradient Elution ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Inhibition Constant ◽

Hydroxyl Group ◽

Dpp Iv ◽

Angelica Keiskei

Angelica keiskei sap is used as a blood-sugar reducer in Indonesia, however its molecular mechanism has not yet been explored. 4-hydroxyderricin (4-HD) is one of the major components extracted from A. keiskei sap. The aim of this work was to isolate 4-HD from the sap of A. keiskei planted in Lombok, Indonesia, and to study in silico and in vitro mechanisms against dipeptidyl peptidase-IV (DPP-IV). The dried sap was submitted to liquid–liquid extraction using solvents with different polarity. Further purification processing was conducted using gradient elution column chromatography. The isolated compound was a yellowish powder, m/z 339.2215 [M + H]+, which was confirmed as 4-HD. Sitagliptin, a DPP-IV inhibitor, was employed as the positive control for both the in silico and in vitro studies. It was indicated that 4-HD interacts with Glu206 and Phe357, important amino acid residues in the DPP-IV binding pocket. These interactions are similar to that of sitagliptin. The affinity of 4-HD (inhibition constant (Ki) = 3.99 μM) to DPP-IV is lower than that of sitagliptin (inhibition constant (Ki) = 0.17 μM). Furthermore, in vitro study showed that 4-HD inhibits DPP-IV (IC50 = 81.44 μM) weaker than for sitagliptin (IC50 = 0.87 μM). We concluded that 4- HD might have potential in inhibiting DPP-IV. However, by considering the polar interaction of sitagliptin with DPP-IV, a further structure modification of 4-HD, e.g., by introducing a polar moiety such as a hydroxyl group, might be needed to obtain stronger activity as a DPP-IV inhibitor.

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Application of a Combined Peptidomics and In Silico Approach for the Identification of Novel Dipeptidyl Peptidase-IV-Inhibitory Peptides in In Vitro Digested Pinto Bean Protein Extract

Current Issues in Molecular Biology ◽

10.3390/cimb44010011 ◽

2021 ◽

Vol 44 (1) ◽

pp. 139-151

Author(s):

Serena Martini ◽

Alice Cattivelli ◽

Angela Conte ◽

Davide Tagliazucchi

Keyword(s):

In Silico ◽

Integrated Approach ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Protein Extract ◽

Dpp Iv ◽

Pinto Bean ◽

Starting Point ◽

Bean Protein

The conventional approach in bioactive peptides discovery, which includes extensive bioassay-guided fractionation and purification processes, is tedious, time-consuming and not always successful. The recently developed bioinformatics-driven in silico approach is rapid and cost-effective; however, it lacks an actual physiological significance. In this study a new integrated peptidomics and in silico method, which combines the advantages of the conventional and in silico approaches by using the pool of peptides identified in a food hydrolysate as the starting point for subsequent application of selected bioinformatics tools, has been developed. Pinto bean protein extract was in vitro digested and peptides were identified by peptidomics. The pool of obtained peptides was screened by in silico analysis and structure–activity relationship modelling. Three peptides (SIPR, SAPI and FVPH) were selected as potential inhibitors of the dipeptidyl-peptidase-IV (DPP-IV) enzyme by this integrated approach. In vitro bioactivity assay showed that all three peptides were able to inhibit DPP-IV with the tetra-peptide SAPI showing the highest activity (IC50 = 57.7 μmol/L). Indeed, a new possible characteristic of peptides (i.e., the presence of an S residue at the N-terminus) able to inhibit DPP-IV was proposed.

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Antioxidative and anti-proliferative potential of Curculigo orchioides Gaertn in oxidative stress induced cytotoxicity: In vitro, ex vivo and in silico studies

Food and Chemical Toxicology ◽

10.1016/j.fct.2018.03.013 ◽

2018 ◽

Vol 115 ◽

pp. 244-259 ◽

Cited By ~ 8

Author(s):

Iram Iqbal Hejazi ◽

Rashmin Khanam ◽

Syed Hassan Mehdi ◽

Abdul Roouf Bhat ◽

M.Moshahid Alam Rizvi ◽

...

Keyword(s):

Oxidative Stress ◽

In Silico ◽

Ex Vivo ◽

Proliferative Potential ◽

Curculigo Orchioides ◽

In Silico Studies

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Gliptins vs. Milk-derived Dipeptidyl-Peptidase IV Inhibiting Biopeptides: Physicochemical Characterization and Pharmacokinetic Profiling

Revista Vitae ◽

10.17533/udea.vitae.v28n3a346531 ◽

2021 ◽

Vol 28 (3) ◽

Author(s):

Jorge Andrés Barrero ◽

Fabio Cabrera ◽

Claudia Marcela Cruz

Keyword(s):

Physicochemical Properties ◽

In Silico ◽

Physicochemical Characterization ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Dpp Iv ◽

Synthetic Accessibility ◽

Enhanced Solubility ◽

Significant Difference

Background: Milk-derived biopeptides have reported in vitro dipeptidyl-peptidase IV (DPP-IV) inhibition, suggesting a glycemic-regulatory effect in Type 2 Diabetes Mellitus (T2DM). Nonetheless, the therapeutic application of these nutraceuticals is limited by the scarcity of knowledge regarding their pharmacokinetic profile. Objective: This study aimed to characterize and assess the pharmacokinetics of milk-derived biopeptides. Through an in silico comparative analysis with gliptins, we expected to identify enhanced properties in food-hydrolysates and suitable DPP-IV inhibiting peptides as candidates for T2DM therapy. Methods: A comparison between gliptins and biopeptides was conducted based on in silico evaluation of drug-likeness, physicochemical properties, pharmacokinetics, and synthetic accessibility. Suitable target proteins for gastrointestinal-absorbable biopeptides were determined as well. Data collection was performed on SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes, and BIOPEP-UWM platforms. Statistical analysis was carried out using a one-way ANOVA test. Results: Drug-likeness compliance showed no significant difference between gliptins and biopeptides (p>0.05) in three out of nine assessed rules, though gastrointestinal-absorbable biopeptides exhibited no significant difference with gliptins in five drug-likeness guidelines. The physicochemical evaluation revealed a significant difference (p<0.05) between both groups, with peptides exhibiting enhanced solubility, flexibility, and polarity. Nine out of thirty-six assessed biopeptides reported being likely gastrointestinal-absorbable molecules, from which six displayed ≥30% predicted bioavailability, two reported CYP450 interactions, and all were determined to be blood confined. Biopeptides showed a slightly lower clearance than gliptins yet counteracted by a significantly lower half-life. Moreover, synthetic accessibility scores indicated higher synthetic ease for biopeptides. In addition, absorbable bioactive peptides reported a considerable binding affinity to DPP-IV and Calpain-I. Conclusions: Compared to gliptins, gastrointestinal-absorbable biopeptides exhibit superior physicochemical properties (higher solubility, flexibility, and polarity), lesser CYP450 interactions, higher synthetic ease, and some reported an important affinity for DPP-IV and Calpain-I. Only a small fraction of milk-derived biopeptides are suitable drug-like compounds and feasible candidates for T2DM therapy; yet, testing their therapeutic potency remains subject to further studies.

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In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190305131425 ◽

2019 ◽

Vol 19 (8) ◽

pp. 633-644 ◽

Cited By ~ 1

Author(s):

Komal Kalani ◽

Sarfaraz Alam ◽

Vinita Chaturvedi ◽

Shyam Singh ◽

Feroz Khan ◽

...

Keyword(s):

Bone Marrow ◽

In Silico ◽

Ex Vivo ◽

Virulent Strain ◽

Infection Model ◽

Mouse Bone Marrow ◽

Significant Activity ◽

Macrophage Infection ◽

In Silico Studies

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

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10-gingerol induces oxidative stress through HTR1A in cumulus cells: in-vitro and in-silico studies

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2019-0042 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Kiptiyah Kiptiyah ◽

Widodo Widodo ◽

Gatot Ciptadi ◽

Aulanni’am Aulanni’Am ◽

Mohammad A. Widodo ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Culture ◽

Superoxide Dismutase ◽

In Silico ◽

Cumulus Cell ◽

Cumulus Cells ◽

Sod Activity ◽

In Silico Studies ◽

Incubation Periods

AbstractBackgroundWe investigated whether 10-gingerol is able to induce oxidative stress in cumulus cells.MethodsFor the in-vitro research, we used a cumulus cell culture in M199, containing 10-gingerol in various concentrations (0, 12, 16, and 20 µM), and detected oxidative stress through superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentrations, with incubation periods of 24, 48, 72, and 96 h. The obtained results were confirmed by in-silico studies.ResultsThe in-vitro data revealed that SOD activity and MDA concentration increased with increasing incubation periods: SOD activity at 0 µM (1.39 ± 0.24i), 12 µM (16.42 ± 0.35ab), 16 µM (17.28 ± 0.55ab), 20 µM (17.81 ± 0.12a), with a contribution of 71.1%. MDA concentration at 0 µM (17.82 ± 1.39 l), 12 µM (72.99 ± 0.31c), 16 µM (79.77 ± 4.19b), 20 µM (85.07 ± 2.57a), with a contribution of 73.1%. Based on this, the in-silico data uncovered that 10˗gingerol induces oxidative stress in cumulus cells by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.Conclusions10-gingerol induces oxidative stress in cumulus cells through enhancing SOD activity and MDA concentration by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.

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