Potential Antidiabetic Compounds Research Articles

Studi In Silico Senyawa Kimia Zingiber Montanum J.König sebagai Antidiabetes terhadap Reseptor α-Glukosidase

Diabetes Mellitus (DM) is a metabolic disorder resulting from the impaired secretion of insulin, glucagon, and other hormones, leading to elevated blood sugar levels. Bangle (Zingiber montanum) is recognized for its potent antidiabetic compounds. This study sought to evaluate the potential and interaction of chemical compounds from bangle on the α-glucosidase receptor as an antidiabetic using molecular docking studies. The molecular docking analyses were conducted using Autodock Vina software and Biovia Discovery Studio Visualizer for 2D and 3D visualization. Fifteen chemical compounds from the bangle plant were subjected to molecular docking studies against the α-glucosidase receptor, with the comparative ligand acarbose. Results indicated that acarbose demonstrated a bond energy (ΔGbind) of -6.9 cal/mol. Conversely, six test compounds, including cassumunarin A (-7.7 kcal/mol), cassumunarin B (-7.5 kcal/mol), cassumunarin C (-8.0 kcal/mol), cassumunin A (-7.0 kcal/mol), cassumunin C (-7.0 kcal/mol), and banglenol A (-6.9 kcal/mol), exhibited lower binding energy than acarbose, signifying a more stable bond conformation and a stronger effect. These compounds formed hydrogen bonds with the amino acids Asp327, Asp203, Arg526, and Asp542, hydrophobic bonds with Tyr299, Thr406, and Phe575, and electrostatic bonds with Asp327, Asp203, Met444, and Asp542. In conclusion, this research indicates that several chemical compounds from the rhizome of bangle have the potential to interact with the α-glucosidase receptor as antidiabetic agents.

Alkaloids Isolated from Vepris glandulosa with Antidiabetic Properties: An In Vitro and In Silico Analysis.

Diabetes is a major global health issue and as current treatments fail, the search for new antidiabetic drugs is crucial. This investigation, focusing on identifying potential antidiabetic compounds from the endangered plant species Vepris glandulosa, led to the isolation of two known alkaloids, choisyine acetate (1) and choisyine (2). The study established the in vitro inhibitory activities and in silico molecular interaction of the two alkaloids with α-amylase based on IC50 values, Linewaever-Burk/Dixon plot kinetic analyses and Molecular docking, respectively. The α-amylase inhibition assay revealed noncompetitive inhibition for both compounds with IC50 and Ki values of 4.74±0.17 and 4.75 mM for compound 1, and 11.29±0.44 and 12.37 mM for compound 2, respectively. In comparison, the standard drug acarbose displayed a competitive mode of inhibition, with IC50 and Ki values of 11.99±0.02 and 12.68 mM, respectively. The binding affinities with α-amylase were -6.42 and -6.07 kcal/mol for compounds 1 and 2, respectively relative to acarbose -8.03 Kcal/mol. Moreover, these two compounds' predicted physicochemical and ADMET properties justified their potential as lead compounds for drug discovery. These compounds demonstrated remarkable inhibition potential comparable to the standard drug, highlighting their potential as viable alternatives in managing diabetes.

Profiling of Potential Anti-Diabetic Active Compounds in White Tea: An Integrated Study of Polyphenol-Targeted Metabolomics, Network Pharmacology, and Computer Simulation.

Diabetes remains a critical global public health challenge, posing a growing threat to human health and well-being. White tea is a lightly fermented tea and one of the six traditional tea categories in China. Owing to its rich content of bioactive compounds such as catechins and alkaloids, it has demonstrated potential anti-diabetic properties. However, its precise bioactive components, mechanisms of action, and relevant molecular targets require further investigation. In this study, an integrated approach combining polyphenol-targeted metabolomics, in vitro antioxidant assays, α-glucosidase inhibition tests, network pharmacology analysis, GEO database exploration, molecular docking, and molecular dynamics simulations was employed to identify the potential anti-diabetic compounds, targets, and mechanisms of white tea. The findings revealed that white tea is particularly abundant in 10 bioactive compounds, including epigallocatechin gallate, epicatechin gallate, and catechin, all of which exhibit significant anti-diabetic potential. These compounds were found to exert their effects by interacting with core molecular targets, namely cathepsin V (CTSV) and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and engaging in pathways related to signal transduction, apoptosis, and immune responses. This study establishes a strong theoretical basis for advancing white tea research and underscores new opportunities for applying natural products in diabetes therapy.

Extraction, characterization, antioxidant, and antidiabetic activities of ethanolic extracts from the split gill mushroom (Schizophyllum commune)

Split gill mushroom (Schizophyllum commune) is among the known functional foods for the antitumor and immunomodulatory activities. However, its antidiabetic activity has not been well characterized. Thus, this study aims to characterize ethanolic extracts and investigate the antidiabetic mechanism of the extracts from the split gill mushroom. We utilized both dried and fresh split gill mushrooms as sources for ethanol extractions. We find that the extracts have differential carbohydrate, protein, total phenolic, and total flavonoid compositions, and antioxidant activities. The fresh mushroom extract 1 (FME1) is the best stimulator of glucose uptake in the C2C12 myotubes. Furthermore, FME1 dose-dependently activates glucose uptake in 3T3-L1 adipocytes, possibly by promoting the phosphorylation of the α-subunit of the AMP-activated protein kinase (AMPK) complex. This sample also enhance lipid accumulation in 3T3-L1 adipocytes. Additionally, the ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHLC-ESI-QTOF/MS) reveals many potential antidiabetic compounds in the sample. In conclusion, we illustrated the antioxidant and antidiabetic mechanism of an ethanolic extract from fresh split gill mushrooms and identified potential antidiabetic components in the extract, demonstrating the antidiabetic potential of S. commune.

Identification of Betulinic Acid and Trimethoxyellagic Acid as the Antidiabetic Compounds in Anogeissus leiocarpus Stem Bark Purified Extract

Objectives: The study aimed to identify the antidiabetic compounds purified from stem bark of Anogeissus leiocarpus and propose the mechanisms of action. Design: Anogeissus leiocarpus stem bark was purified through ethyl acetate and n-hexane with minor exceptions. For very clear separation, cold acetone was added to trigger the precipitation. The precipitate was dissolved with a mixture of DCM:methanol (9:1), adsorbed it to silica gel (5 g), evaporated to free flowing powder and fractionated it over silica gel (50 g) to realize 40 fractions. The gummy fractions were ignored. The light brown powder which possessed antidiabetic effect was selected for Nuclear Magnetic Resonance for structural elucidation. Nuclear Magnetic Resonance (NMR) and Determination of Structure of Purified Compound: After column chromatography and TLC processes, along with the cold acetone, to the point of crystallization, the purified compounds, the light brown powder, were presented to NMR (Bruker Avance III, Spectrometer frequency 400 MHz; solvents DMSO-do, CDCl3, Acetone-d6. Institute of Chemistry, Strathclyde University Glasgow UK.) for determination of compound structures and analyses. Results: The NMR spectra and analyses revealed the existence of Betulinic acid and Trimethoxyellagic acid. Conclusion: We show that Betulinic acid and Trimethoxyellagic acid are potent antidiabetic compounds in the stem bark extract of A. leiocarpus. Keywords: Anogeissus leiocarpus, Betulinic Acid, Trimethoxyellagic Acid, Antidiabetic agent

Antidiabetic Properties of Caffeoylmalic Acid, a Bioactive Natural Compound Isolated from Urtica dioica

The uncontrolled hyperglycemia that characterizes diabetes mellitus (DM) causes several complications in the organism. DM is among the major causes of deaths, and the limited efficacy of current treatments push the search for novel drug candidates, also among natural compounds.We focused our attention on caffeoylmalic acid, a phenolic derivative extracted from Urtica dioica, a plant investigated for its potential against type 2 DM. This compound was tested for its antidiabetic activity in vitro through a glucose uptake assay, in vivo in a mouse DM model and through molecular docking towards α-amylase and α-glucosidase. The effects on glucose blood level, liver enzymes, insulin and creatinine levels as well as on lipid and blood parameters, considered biochemical markers of diabetes, were also evaluated. The results showed an antidiabetic activity in vitro and in vivo, as the compound stimulates glucose absorbtion and reduces blood glucose levels. Moreover, it ameliorates lipid profile, liver and blood parameters, with moderate effect on insulin secretion.Taken together, these findings pave the way for the compounds from this class of caffeoylmalic acid as potential antidiabetic compounds.

Identification of potential DPP-4 inhibitors from Bryophyllum pinnatum by in-silico analysis

Background: An estimated 463 million people already live with diabetes and that figure is set to rise to over 700 million by 2045, as per the International Diabetes Federation (IDF). The current form of treatment for Type-2 DM can be done with sulfonylureas, meglitinides, metformin, thiazolidinediones, incretin mimetics: Glucagon-like peptide 1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), and amylin analogues (Pramlintide). Bryophyllum pinnatum (Lam.) Oken (B. pinnatum) belongs to the plant family crassulaceae used in traditional medicine in Asia. GLP-1 and Glucose-dependant Insulinotropic Polypeptide (GIP), both play a similar role in stimulating insulin secretion and are inactivated by dipeptidyl peptidase-4 (serine protease dipeptidyl peptidase-4) enzymes. Aims: To identify the potential anti-diabetic active compounds of Bryophyllum pinnatum against DPP-4 enzyme using in-silico methods. Methods and Material: The phytochemicals associated with Bryophyllum pinnatum were retrieved from ChEBI and canonical SMILES retrieved, followed by searching for its molecular properties and druglikeness using MolSoft LLC, toxicity test using ADVERPred, Swiss Target Prediction for predicting the DPP-4 inhibitors, molecular docking using Schrodinger software suite. Results: The in-silico study identified two phytochemicals from fourteen that have been predicted for DPP-4 inhibition potential against Type-2 DM. In CH2CL2 and CH3OH solvent compounds 3,5-dihydroxybenzoic acid (-5.623 kcal/mol) and 3,4-didehydro-N4-deethylbrinzolamide (-4.91 kcal/mol) displayed the highest docking scores against human DPP-4 (5Y7K). Conclusions: The above-mentioned compounds revealed no side effects. The in-silico results strongly favour the beneficial use of phytochemicals from Bryophyllum pinnatum as a probable herb that can be used for adjuvant therapy. Further in-vitro and in-vivo tests are needed for confirmation.

Design, synthesis of new 2,4-thiazolidinediones: In-silico, in-vivo anti-diabetic and anti-inflammatory evaluation

In this study, a series of nine novel heterocyclic compounds were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione or rhodanine ring-system. Comprehensive physicochemical and spectral analyses, including FTIR, Mass, 1H NMR and 13C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their potential in various therapeutic domains. In-vivo anti-diabetic activity was assessed diabetes induced wistar rats, anti-inflammatory effects were gauged using the carrageenan and formalin induced rat paw edema model. Additionally, the in-vitro PPAR-γ modulatory activity, glucose uptake by using Saccharomyces cerevisiae and rat hemidiaphragm and cyclooxygenase inhibitory activity along with scavenge free radicals was tested by FRAP and DPPH method. According to the potential binding patterns of the most potent anti-diabetic compounds, namely 7a and 13a with the active sites of target PPAR-γ (PDB ID: 5U5L), was obtained through molecular docking using Schrodinger’s Glide model. Among the tested compounds, the compound 13a demonstrated significant antidiabetic activity with reduction in blood glucose levels (108.5 ± 2.171 mg/dL), comparable to the effect of pioglitazone (101.66 ± 0.95 mg/dL), similarly anti-inflammatory activity at fourth hour paw volume 93.6% and thickness at 3.99 ± 0.076 mm, respectively closer to that of standard drug diclofenac sodium (91.2% and 4.7 ± 0.057 mm) in carrageenan-induced paw edema in rat. The compound 13a displayed promising COX-2 inhibitory activity (IC50 = 7.82 μM) and DPPH antioxidant activity showcasing its multifaceted therapeutic potential. This study not only presents multi-targeting approach and highlights the significant potential compounds as a lead molecule for further therapeutic development.

In Vitro Antioxidant and Antidiabetic properties of leaves aqueous extract of Sonchus maritimus

One of the most serious health issues facing worldwide today is diabetes mellitus. Although they have inevitable adverse effects, conventional antidiabetic medications are effective. However, plants might also provide an alternate source of anti-diabetic chemicals. This study was focused on determining the antioxidant activities of the leaves aqueous extract of Sonchus maritimus using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity and ferric reducing ability assay power (FRAP), as well as its antidiabetic activities, which were performed using different protocols, including alpha-amylase inhibitory properties, glucose uptake by yeast cell’s ability, and glucose adsorption capacity. It was noted that S. maritimum extract exhibited moderate activities to scavenge the free radical DPPH and to reduce ferric iron to ferrous iron compared to standard (ascorbic acid). However, the aqueous extract of S. maritimus showed better alpha-amylase inhibitory activity compared to acarbose. It also showed good adsorption strength for binding to glucose molecules. Moreover, the extract showed excellent improvement in glucose uptake by yeast cells at different glucose concentrations in the medium compared to metformin. In conclusion, the aqueous extract of S. maritimus leaves is a promising source of potential antidiabetic compounds that can help prevent diabetes complications and alleviate associated oxidative stress.

Computational analysis of potential drug-like compounds from Solanum torvum - A promising phytotherapeutics approach for the treatment of diabetes

Diabetes mellitus (DM) is a global pandemic that is characterized by high blood glucose levels. Conventional treatments have limitations, leading to the search for natural alternatives. This study focused on Solanum torvum (STV), a medicinal plant, to identify potential anti-diabetic compounds using molecular docking and molecular dynamics simulations. We focused on identifying natural inhibitors of two key enzymes involved in glucose metabolism: α-amylase (1HNY) and α-glucosidase (4J5T). In our preliminary docking study, rutin showed the highest binding affinity (−11.58 kcal/mol) to α-amylase, followed by chlorogenin (−7.58 kcal/mol) and myricetin (−5.82 kcal/mol). For α-glucosidase, rutin had the highest binding affinity (−11.78 kcal/mol), followed by chlorogenin (−7.11 kcal/mol) and fisetin (−6.44 kcal/mol). Hence, chlorogenin and rutin were selected for further analysis and compared with acarbose, an FDA-approved antidiabetic drug. Comparative docking revealed that chlorogenin had the highest binding affinity of (−9.9 kcal/mol) > rutin (−8.7 kcal/mol) and > acarbose (−7.7 kcal/mol) for α-amylase. While docking with α-glucosidase, chlorogenin again had the highest binding affinity of (−9.8 kcal/mol) > compared to rutin (−9.5 kcal/mol) and acarbose (−7.9 kcal/mol). Molecular dynamics (MD) simulations were conducted to assess their stability. We simulated 100 nanoseconds (ns) trajectories to analyze their stability on various parameters, including RMSD, RMSF, RG, SASA, H-bond analysis, PCA, FEL, and MM-PBSA on the six docked proteins. In conclusion, our study suggests that chlorogenin and rutin derived from STV may be effective natural therapeutic agents for diabetes management because of their strong binding affinities for the α-amylase and α-glucosidase enzymes. Communicated by Ramaswamy H. Sarma

Potential Antidiabetic Compounds from Anogeissus leiocarpus: Molecular Docking, Molecular Dynamic Simulation, and ADMET Studies

This study aimed to evaluate the antidiabetic potential of compounds from Anogeissus leiocarpus in silico and the potential of the compounds as antidiabetic drug candidates. Molecular docking (MD), molecular dynamics simulation (MDS), and ADMET were carried out in silico to evaluate the compounds' antidiabetic potential and drug candidacy. The MDS revealed the least BA (-8.7 kcal/mol) was exhibited by compound X (palmitic acid) with Glucagon-like Peptide-1 Receptor (GLP1), while the highest BA (-5.8 kcal/mol) was demonstrated by I (1,2,4-benzetriol) with dipeptidyl peptidase IV (DPP-4) among the best interactions. The MDS result showed good docked complexes' flexibility, deformability, and stability with low eigenvalues ranging from 8.52 × 10-5 to 1.30 × 10-4. All the compounds had a bioavailability score of 0.55 except VI (0.85), while the synthetic ability showed a good score of ≤3.01. Eight compounds were predicted to be soluble, with two poorly soluble. Additionally, all the compounds had high gastrointestinal absorption, with the majority being blood-brain barrier permeant, while skin permeation value was between -2.55 and -7.48 cm/s. Furthermore, none of the compounds were either permeability glycoprotein (P-gp) substrate or CYP2C19 and CYP2C9 inhibitors, though some were CYP1A2, CYP2D6, and CYP3A4 inhibitors. Moreover, the toxicity study showed moderate to non-toxicity results with toxicity classes between 3 and 5. Conclusively, the compounds from A. leiocarpus showed good binding interactions, which are the protein targets of antidiabetic therapy and potentially good candidates for antidiabetic drug development.

Chemical composition and biological activities of the extracts of Peperomia pellucida fractions

Background: Peperomia pellucida is a medicinal and vegetable plant used worldwide, representing a multi-purpose vegetable with applications in the pharmaceutical, food and cosmetic industries. Objective: This study evaluated the antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic potential of fractional extracts from P. pellucida plant derived from Can Tho City, Vietnam. Methods: Four fractional extracts were prepared using different polarity solvents (hexane, dichloromethane, ethyl acetate) and used to determine the best extract for each biological property. The fractions’ total alkaloid, phenolic, and flavonoid content were observed. The four extracts were evaluated for their potential bioactivities: antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic. Results: Correspond with the hexane, dichloromethane, ethyl acetate, and aqueous fractions, the total content of alkaloids was determined to be 255 ± 23.8; 157 ± 14.0; 219 ± 6.55; 221 ± 6.23 (mg AE/g extract), the total phenolic content was 112 ± 3.34; 141 ± 1.77; 234 ± 29.5; 123 ± 5.04 (mg GAE/g extract), whereas the total content of flavonoids was 423 ± 22.6; 169 ± 6.30; 1839 ± 18.8; 173 ± 22.6 (mg QE/g extract), respectively. The ethyl acetate fraction gave the best efficiency in DPPH, ABTS, iron reduction, and TAC methods (IC50 = 334 ± 2.10 µg/mL; 51.4 ± 0.41 µg/mL; 79.1 ± 0.40 µg/mL; and 83.0 ± 0.17 µg/mL, respectively). Antibacterial activity was investigated on 5 strains of Bacillus cereus, Escherichia coli, Staphylococcus aureus, Salmonella typhimunum, Pseudomonas aeruginosa; the results showed that the extracts were resistant to 5 strains of bacteria, especially best resistant in 2 fractions of ethyl acetate and aqueous. The minimum inhibitory concentration (MIC) value ranged from 0.5 to 32 mg/mL, while the minimum bactericidal concentration (MBC) value ranged from 16 to 64 mg/mL. The best anti-inflammatory activity was ethyl acetate with an IC50 value of 216.7 ± 7.2 µg/mL, close to that of Diclofenac at 205.4 ± 0.5. The antidiabetic activity was investigated based on the ability to inhibit α-amylase and α-glucosidase enzymes. The results showed that the best α-amylase inhibitors were hexane and dichloromethane (IC50 = 208.83 ± 2.41 and 191.60 ± 1.27 µg/mL, respectively), roughly equal to the acarbose (155.68 ± 2.59 µg/mL). The best α-glucosidase inhibitory fraction was ethyl acetate (IC50 of 157.04 ± 0.23 µg/mL), close to that of acarbose (116.45 ± 0.21 µg/mL). Conclusion: Fractional extracts from P. pellucida distributed in gardens of Can Tho City, Vietnam, contain potential antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic bioactive compounds.

Metabolite profiling and biochemical investigation of the antidiabetic potential of Loranthus pulverulentus Wall n-butanol fraction in diabetic animal models

Ethnopharmacological relevanceGlobally, 537 million individuals are estimated to have diabetes. The traditional use of herbs for ameliorating diabetes symptoms is a common practice in Pakistan and use of Loranthus pulverulentus Wall (L. pulverulentus) by local people in Azad Jammu and Kashmir has been reported. Aim of the studyIn the present study, the antidiabetic potential of standardized n-butanol fraction of leaves of L. pulverulentus Wall, which is a parasite of Dalbergia sisso Roxb was assessed in both alloxan (ALX) and streptozotocin (STZ) diabetic animal models. Materials and methodsChemical characterization of BF was performed using HPLC, GCMS and UHPLC-MS. The effect of the fraction (250 mg/kg) on insulin, plasma free fatty acids, L-lactate, pyruvate, MDA, HbA1c and glycogen levels in ALX and STZ animal models was determined. Liver and renal profiles were analyzed in the STZ model. Toxicological studies were performed by hemolytic, Ames mutagenicity, DNA protection, and thrombolytic assays. Histopathological analysis of the pancreas, liver, and kidney was performed. ResultsBF demonstrated highly significant (p < 0.001) antidiabetic potential in both diabetic models. BF significantly (p < 0.05) improved OGTT results in alloxanized diabetic mice and blocked the absorption of glucose from the gut. A significant (p < 0.001) increase in insulin levels and glycogen content in liver tissue and a decrease in plasma FFA, MDA, HbA1c, L-lactate, and pyruvate levels in STZ-diabetic mice were recorded. GC-MS and chromatographic analysis showed the presence of catechin, eugenol, longifolene, caryophyllene, Ar-tumerone and Geranyl-alpha-terpinene. Various metabolites with antidiabetic potential, including 4-hydroxycinnamyl alcohol 4-D-glucoside, zingerone glucoside, trans-trismethoxy resveratrol-d4, epigallocatechin 3-O-cinnamate, and β-glucogallin, were identified using UHPLC-MS. Animals treated with BF showed marked improvements in cellular structures of the pancreas, liver and kidneys. This fraction is non-mutagenic and protects the DNA. ConclusionThe experimental fraction contained potential antidiabetic bioactive compounds responsible for alleviating diabetes-associated biochemical dysregulation. The fraction increased insulin levels and enhanced glycogen storage in muscles and the liver. It blocked glucose absorption from the intestine and substantially decreased HbA1c, lactate, pyruvate, free fatty acids, lipid, liver and kidney damage. Therefore, the use of BF for the treatment of type-2 diabetes may be beneficial.

Repurposing phytochemicals of Citrullus colocynthis against maltase-glucoamylase using molecular docking, MMGBSA, MD simulation and linear regression to identify potential anti-diabetic compounds

Diabetes is a common lifestyle disorder found in populations of different age groups. Maltase-glucoamylase catalyses the release of the glucose molecule in the final enzymatic reaction of starch digestion; therefore, inhibition of maltase-glucoamylase is one of the approaches in the development of therapeutics for diabetes. Citrullus colocynthis is commonly recommended in Ayurveda for the treatment of diabetes. The current study applied a structure-based drug design approach to repurpose the phytochemicals of Citrullus colocynthis to identify potential inhibitors for maltase-glucoamylase. 70 phytochemicals of Citrullus colocynthis were screened against maltase-glucoamylase and top 5 molecules 8-p-hydroxybenzylisovitexin, isoorientin, cucurbitacin B, cucurbitacin E, and cucurbitacin I with significant binding energy of −10 kcal/mol, −9.9 kcal/mol, −9.6 kcal/mol, −9.2 kcal/mol, and −7.7 kcal/mol were identified. Furthermore, MMGBSA, pharmacokinetics properties and toxicity prediction were performed on the five identified molecules and top 3 molecules were selected for molecular dynamics (MD) simulation. It was observed from the structural flexibility and dynamic behaviour of the systems that conformational changes were noticed in the complexes as compared to its native state, which suggests that the 3 molecules, namely 8-p-hydroxybenzylisovitexin, isoorientin, and cucurbitacin I of Citrullus colocynthis may act as inhibitors for maltase-glucoamylase. Communicated by Ramaswamy H. Sarma

Discovery of anthraquinones as DPP-IV inhibitors: Structure-activity relationships and inhibitory mechanism

Dipeptidyl peptidase IV (DPP-IV) is an integrated type II transmembrane protein that reduces endogenous insulin contents and increases plasma glucose levels by hydrolyzing glucagon-like peptide-1 (GLP-1). Inhibition of DPP-IV regulates and maintains glucose homeostasis, making it an attractive drug target for the treatment of diabetes II. Natural compounds have tremendous potential to regulate glucose metabolism. In this study, we examined the DPP-IV inhibitory activity of a series of natural anthraquinones and synthetic structural analogues on DPP-IV using fluorescence-based biochemical assays. The inhibitory efficiency differed among anthraquinone compounds with different structures. Alizarin (7), aloe emodin (11), emodin (13) emerged the outstanding inhibitory potential for DPP-IV with IC50 values lower than 5 μM. To clarifying the inhibitory mechanism, inhibitory kinetics were performed, which showed that alizarin red S (8) and 13 were effective non-competitive inhibitors of DPP-IV, while alizarin complexone (9), rhein (12), and anthraquinone-2-carboxylic acid (23) were mixed inhibitors. Emodin was determined as inhibitor with the strongest DPP-IV-binding affinity determined via molecular docking. Structure-activity relationship (SAR) demonstrated that hydroxyl group at C-1 and C-8 sites and hydroxyl, hydroxymethyl or carboxyl group at the C-2 or C-3 site were very essential for DPP-IV inhibition, replacement of hydroxyl group with amino group at C-1 could led to an increase of the inhibitory potential. Further fluorescence imaging showed that both compounds 7 and 13 significantly inhibited DPP-IV activity in RTPEC cells. Overall, the results indicated that anthraquinones would be a natural functional ingredient for inhibiting DPP-IV and provided new ideas for searching and developing potential antidiabetic compounds.

In Vitro and In Vivo Antidiabetic, α-Glucosidase Inhibition and Antibacterial Activities of Three Brown Algae, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a Red Alga, Palisada perforata from the Persian Gulf.

In recent decades, algae have attracted worldwide attention for their great biological activities, such as antidiabetic and antibacterial properties. We measured antibacterial and α-glucosidase inhibition potential of methanol and 80% methanol extracts of three brown algae species, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a red alga, Palisada perforata, from the Persian Gulf coasts. Antibacterial activity of the algal extracts was assessed by broth dilution method against three gram-negative and -positive bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa; Staphylococcus epidermidis, Staphylococcus aureus, and Bacillus subtilis, respectively. Furthermore, the yeast's α-glucosidase inhibition of the algal extracts was measured via colorimetric assay. In addition, we investigated the beneficial effect of 80% MeOH extract of S. boveanum on the blood glucose levels in streptozotocin-induced diabetic rats. The MeOH extract of S. boveanum was the best antibacterial extract with MIC = 2.5 mg/mL against all bacterial strains except for E. coli. The MeOH and 80% MeOH extracts of P. myrica and P. antillarum inhibited α-glucosidase at most with IC50 values of 12.70 ± 1.88 µg/mL and 13.06 ± 4.44 µg/mL, respectively. The oral gavage of S. boveanum extract in streptozotocin- (STZ-) induced diabetic rats resulted in decreasing their postprandial blood glucose levels. The algae and acarbose decreased blood glucose levels after sucrose administration in 60 minutes, compared to the non-drug-treated animals, with p values of 0.03 and 0.007, respectively. Overall, due to the in vitro and in vivo antidiabetic potential of S. boveanum, we suggest the alga as a new source for the isolation and identification of potential antidiabetic and antibacterial compounds.

Identification, Screening, and Comprehensive Evaluation of Novel DPP-IV Inhibitory Peptides from the Tilapia Skin Gelatin Hydrolysate Produced Using Ginger Protease.

Inhibition of dipeptidyl peptidase-IV (DPP-IV) is an effective therapy for treating type II diabetes (T2D) that has been widely applied in clinical practice. We aimed to evaluate the DPP-IV inhibitory properties of ginger protease hydrolysate (GPH) and propose a comprehensive approach to screen and evaluate DPP-IV inhibitors. We evaluated the in vitro inhibitory properties of fish skin gelatin hydrolysates produced by five proteases, namely, neutral protease, alkaline protease, bromelain, papain, and ginger protease, toward DPP-IV. We screened the most potent DPP-IV inhibitory peptide (DIP) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with in silico analysis. Next, surface plasmon resonance (SPR) technology was innovatively introduced to explore the interactions between DPP-IV and DIP, as well as the IC50. Furthermore, we performed oral administration of DIP in rats to study its in vivo absorption. GPH displayed the highest degree of hydrolysis (20.37%) and DPP-IV inhibitory activity (65.18%). A total of 292 peptides from the GPH were identified using LC-MS/MS combined with de novo sequencing. Gly-Pro-Hyp-Gly-Pro-Pro-Gly-Pro-Gly-Pro (GPXGPPGPGP) was identified as the most potent DPP-IV inhibitory peptide after in silico screening (Peptide Ranker and molecular docking). Then, the in vitro study revealed that GPXGPPGPGP had a high inhibitory effect on DPP-IV (IC50: 1012.3 ± 23.3 μM) and exhibited fast kinetics with rapid binding and dissociation with DPP-IV. In vivo analysis indicated that GPXGPPGPGP was not absorbed intact but partially, in the form of dipeptides and tripeptides. Overall, the results suggested that GPH would be a natural functional food for treating T2D and provided new ideas for searching and evaluating potential antidiabetic compounds. The obtained GPXGPPGPGP can be structurally optimized for in-depth evaluation in animal and cellular experiments.

Inhibitory Potential of Six Brown Algae from the Persian Gulf on α-Glucosidase and In Vivo Antidiabetic Effect of Sirophysalis Trinodis.

Background: Brown algae have gained worldwide attention due to their significant biological activities, such as antidiabetic properties. In the present study, the antidiabetic properties of six brown algae from the Persian Gulf were investigated.Methods: An experimental study was conducted from 2017 to 2019 to examine the inhibitory effects of six brown algae against the α-glucosidase activity. Methanol (MeOH) and 80% MeOH extracts of Colpomenia sinuosa, Sargassum acinaciforme, Iyengaria stellata, Sirophysalis trinodis, and two accessions of Polycladia myrica were analyzed. The effect of 80% MeOH extracts of Sirophysalis trinodis on blood glucose levels in streptozotocin-induced diabetic rats was evaluated. Chemical constituents of brown algae were analyzed using thin-layer chromatography and liquid chromatography-mass spectrometry techniques. Data were analyzed using SPSS software, and P<0.05 was considered statistically significant.Results: The 80% MeOH extracts of Iyengaria stellata (IC50=0.33±0.15 μg/mL) and Colpomenia sinuosa (IC50=3.50±0.75 μg/mL) as well as the MeOH extracts of Colpomenia sinuosa (IC50=3.31±0.44 μg/mL) exhibited stronger inhibitory effect on α-glucosidase than the acarbose (IC50=160.15±27.52 μg/mL, P<0.001). The 80% MeOH extracts of Sirophysalis trinodis reduced postprandial blood glucose levels in diabetic rats compared to the control group (P=0.037). Fucoxanthin was characterized as the major antidiabetic agent in most of the algal extracts.Conclusion: Sirophysalis trinodis is recommended as a novel source for isolation and identification of potential antidiabetic compounds due to its high in vivo and in vitro antidiabetic effects.

Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy.

E. humifusa Willd, a monoecious annual plant, native to Eastern Asia, has been traditionally attributed to the treatment and prevention of miscellaneous diseases, including diabetes mellitus and its associated complications. Earlier studies have supported this species’ pharmacological efficacies including its antibacterial, antidiabetic, and anti-inflammatory properties. Even so, the underlying bioactive components with their mechanisms of action associated with its antidiabetic and anti-inflammatory effects remain elusive. The preamble in vitro assessments of the crude extract and its different fractions revealed that the n-butanol fraction (EHNB) exhibited the best activity, which was subsequently subjected to a rapid screening of candidate ligands through bio-affinity ultrafiltration with the two enzyme targets: α-glucosidase (α-Glu) and cycloxygenase-2 (COX-2) combined with UPLC/QTOF-MS. As a result, 7 compounds were identified from EHNB, among them, vitexin and astragalin were screened out as the most active ligand compounds. Vitexin showed great specific binding (SB) affinity values of 1.26 toward α-Glu and 1.32 toward COX-2, while astragalin showed 1.32 and 1.36, respectively. The docking simulation results exhibited strong interactions of vitexin and astragalin with the key residues of the enzyme targets, suggesting their possible mechanisms of action. The in vitro antidiabetic validation revealed noticeable half-maximal inhibitory effects (IC50) of 36.38 ± 3.06 µM for vitexin and 42.47 ± 4.13 µM for astragalin, much better than that of the positive drug acarbose (109.54 ± 14.23 µM). Similarly, these two compounds showed the inhibitory activity against COX-2 with the half-maximal inhibitory effects (IC50) at 27.91 ± 1.74 µM and 49.05 ± 1.49 µM, respectively. Therefore, these two flavonoid compounds (vitexin and astragalin) were speculated as potential antidiabetic and anti-inflammatory compounds from E. humifusa. Taken together, the integrated strategy applied to E. humifusa led to the fast identification of two potential double-acting flavonoids and enlightened its antidiabetic and anti-inflammatory uses. Besides these findings, the integrated strategy in this study could also be used to facilitate the rapid discovery and development of active candidates from other traditional herbal medicines against multi-drug targets and to aid in revealing their mechanisms of action for their traditional uses.

Improving Regulation of Polymeric Proanthocyanidins and Tea Polyphenols against Postprandial Hyperglycemia via Acid-Catalyzed Transformation.

A novel protocol was established to synthesize novel α-glucosidase inhibitors (prodelphinidin B gallates) from proanthocyanidins from Chinese bayberry leaves (BLPs) and epigallocatechin gallate (EGCG) via acid-catalyzed transformation, which had improved regulation against postprandial hyperglycemia. Their structural-activity relationship was clarified by enzymatic kinetics, multispectroscopic method, molecular docking analysis, and sucrose loading test. ProDB MG and DG were noncompetitive inhibitors of α-glucosidase with IC50 values of 7.82 and 7.52 μg/mL, respectively. They bound with α-glucosidase spontaneously through van der Waals force and hydrogen bonding interaction, inducing the change of spatial conformation and secondary structure of α-glucosidase. Molecular docking studies suggested that proDB MG and DG attached to another one nonactive pocket with strong affinity. ProDB DG exerted significant improvement of postprandial hyperglycemia in a dose-dependent manner. Hence, proDB MG and DG, potential antidiabetic compounds, alleviate postprandial hyperglycemia by inhibiting α-glucosidase.