Integration of network and experimental pharmacology to decipher the antidiabetic action of Duranta repens L / 中西医结合学报

OBJECTIVE@#Duranta repens is reported to contain a wide array of secondary metabolites, including α-amylase and α-glucosidase inhibitors, and - has potent antioxidant activity. The present study evaluated the network pharmacology of D. repens (whole plant) with targets related to diabetes mellitus and assessed its outcome by evaluating the effects of the hydroalcoholic extract of D. repens in streptozotocin-nicotinamide-induced diabetes mellitus in rats.@*METHODS@#Phytoconstituents of D. repens were retrieved from an open-source database and published literature, and their targets were predicted for diabetes mellitus using BindingDB and the therapeutic target database. Protein-protein interaction was predicted using STRING, and pathways involved in diabetes mellitus were identified using the Kyoto Encyclopedia of Genes and Genomes pathway browser. Druglikeness, ADMET profile (absorption, distribution, metabolism, excretion and toxicity) and cytotoxicity of compounds modulating proteins involved in diabetes were predicted using MolSoft, admetSAR2.0 and CLC-Pred, respectively. The interaction network among phytoconstituents, proteins and pathways was constructed using Cytoscape, and the docking study was performed using AutoDock4.0. The hydroalcoholic extract of D. repens was evaluated using streptozotocin-nicotinamide-induced diabetes mellitus animal model for 28 d, followed by an oral glucose tolerance test. At the end of the study, biochemical parameters like glycogen content, hepatic enzymes, antioxidant biomarkers and lipid profiles were quantified. Further, the liver and pancreas were collected for a histopathology study.@*RESULTS@#Thirty-six different secondary metabolites from D. repens were identified to regulate thirty-one targets involved in diabetes mellitus, in which protein-tyrosine phosphatase 1B (PTP1B) was primarily targeted. Enrichment analysis of modulated proteins identified 12 different pathways in diabetic pathogenesis in which the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway was chiefly regulated. The docking study found that durantanin I possessed the highest binding affinity (-8.9 kcal/mol) with PTP1B. Similarly, ADMET profiling showed that the majority of bioactive constituents from D. repens had higher human intestinal absorptivity and minimal cytotoxicity to normal cell lines, than tumor cell lines. Further, an in vivo animal study reflected the efficacy of the hydroalcoholic extract of D. repens to lower the elevated blood glucose level by stimulating insulin secretion, maintaining pancreatic β cell mass, regulating glycolysis/gluconeogenesis and enhancing the glucose uptake in skeletal muscles.@*CONCLUSION@#The present study reflected the probable network interaction of bioactive constituents from D. repens, their targets and modulated pathways, which identified the prime regulation of the PI3K-Akt signaling pathway and PTP1B protein. Modulation of PTP1B protein and PI3K-Akt signaling pathway could contribute to enhancing glucose uptake, insulin production and glycolysis and decreasing gluconeogenesis in diabetes, which was evaluated via the experimental study.

In vitro and in silico anti-oxidant, cytotoxicity and biological activities of Ficus benghalensis and Duranta repens / 中草药·英文版

Objective: To report in vitro anti-oxidant activity and cytotoxicity of hydroalcoholic extract of Ficus benghalensis (bark) and Duranta repens (whole plant), and present the probable biological spectrum of major anti-oxidants from both plants. Methods: The coarse powder of both plants was first extracted with 70% ethanol (maceration) followed by 99% ethanol (Soxhlet-extraction). Anti-oxidant activity of the extracts was evaluated using DPPH, H2O2, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), NO scavenging assay, total antioxidant capacity, cupric reducing antioxidant capacity (CUPRAC), and metal chelating assay. Cytotoxicity of both extracts was evaluated using MTT assay in both tumor and normal cell lines i.e. Chinese hamster ovary cells (CHO) and A549 cells. Biological activity of individual anti-oxidants from both medicinal plants was identified using prediction of activity spectra for substances and a docking study was performed by using autodock4.0. Results: Hydroalcoholic extract of F. benghalensis and D. repens showed the highest free radical scavenging (ABTS) and chelating capacity respectively. Both extracts showed minimum cytotoxicity in normal cell lines compared to tumor cell lines. Computer imitation hits reflected the multiple biological activities agreeing with the folk use and some scientific reports. Further, we found the binding affinity of predicted anti-oxidant compounds with multiple protein molecules involved in oxidative stress. Conclusion: The present study reports the probable anti-oxidant mechanism for two folk agents and also presents probable pharmacological activities via computer simulations.

Gene set enrichment analysis of alpha-glucosidase inhibitors from Ficus benghalensis

Objective: To identify alpha-glucosidase inhibitors from Ficus benghalensis and analyze gene set enrichment of regulated protein molecules. Methods: The phytoconstituents of Ficus benghalensis were queried for inhibitors of alpha-glucosidase, also identified as aldose reductase inhibitors. Druglikeness score, absorption, distribution, metabolism, excretion and toxicity profile, biological spectrum, and gene expression were predicated for each compound. Docking study was performed to predict the binding affinity with alpha-glucosidase and aldose reductase and compared with clinically proven molecules. Kyoto Encyclopedia of Genes and Genomes pathway analysis was performed for the regulated genes to identify the modulated pathways. Results: Apigenin, 3,4',5,7-tetrahydroxy-3'-methoxyflavone, and kaempferol were identified as inhibitors of alpha-glucosidase and aldose reductase. Kaempferol was predicted to possess the highest binding affinity with both targets. The p53 signaling pathway was predicted to modulate the majority of protein molecules in diabetes mellitus. All the alpha-glucosidase inhibitors were also predicted as membrane integrity agonist and anti-mutagenic compounds. Conclusions: The current study indicates alpha-glucosidase inhibitors from Ficus benghalensis can act as aldose reductase inhibitors after absorption from the intestinal tract. Furthermore, these phytoconstituents are involved in the regulation of numerous protein molecules and pathways. Hence, the anti-diabetic efficacies of these compounds are due to their action on multiple protein molecules and synergistic effects which should be confirmed by future investigations.