Insulin sensitization by Feronia elephantum in fructose-induced hyperinsulinemic rats: Insights from computational and experimental pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Feronia elephantum corr. (synonym: Feronia limonia, Murraya odorata, Schinus Limonia, or Limonia acidissima; common names: Bela, Kath, Billin, and Kavitha), belonging to the family Rutaceae has been known for clinical conditions such as pruritus, diarrhea, impotence, dysentery, heart diseases, and is also used as a liver tonic. However, the effect of the fruit pulp of F. elephantum on insulin resistance has yet not been reported. AIM OF THE STUDY: The present study aimed to assess the effect of hydroalcoholic extract/fraction of F. elephantum fruit pulp on fasting blood glucose, oral glucose tolerance test, and glucose uptake in fructose-induced insulin-resistant rats and predict the gene-set enrichment of lead hits of F. elephantum with targets related to insulin resistance. MATERIAL AND METHODS: System biology tools were used to predict the best category of fraction and propose a possible mechanism. Docking was carried out with adiponectin and its receptor (hub genes). Further, fructose supplementation was used for the induction of insulin resistance. Later, three doses of extract (400, 200, and 100 mg/kg) and a flavonoid-rich fraction (63 mg/kg) were used for treatment along with metformin as standard. The physical parameters like body weight, food intake, and water intake were measured along with oral glucose tolerance test, insulin tolerance test, glycogen content in skeletal muscles and liver, glucose uptake by rat hemidiaphragm, lipid profiles, anti-oxidant biomarkers, and histology of the liver and adipose tissue. RESULTS: Network pharmacology reflected the potency of F. elephantum to regulate adiponectin which may promote the reversal of insulin resistance and inhibit α-amylase and α-glucosidase. Vitexin was predicted to modulate the most genes associated with diabetes mellitus. Further, F. elephantum ameliorated the exogenous glucose clearance, promoted insulin sensitivity, reduced oxidative stress, and improved glucose and lipid metabolism. HPLC profiling revealed the presence of apigenin and quercetin in the extract for the first time. CONCLUSION: The fruit pulp of F. elephantum reverses insulin resistance by an increase in glucose uptake and a decrease in gluconeogenesis which may be due to the regulation of multiple proteins via multiple bio-actives.

Gene set enrichment analysis of PPAR-γ regulators from Murraya odorata Blanco.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPAR-γ) is reported to regulate insulin sensitivity and progression of Type 2 diabetes mellitus (T2DM). Hence the present study is aimed to identify PPAR-γ regulators from Murraya odorata Blanco and predict their role to manage T2DM. METHODS: Multiple in-silico tools and databases like SwissTargetPrediction, ADVERPred, PubChem, and MolSoft, were used to retrieve the information related to bioactives, targets, druglikeness character, and probable side effects as applicable. Similarly, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to identify the regulated pathways. Further, the bioactives-protein-pathways network interaction was constructed using Cytoscape. Finally, molecular docking was performed using Autodock4. RESULTS: Twenty-five bioactives were shortlisted in which six were predicted as PPAR-γ modulators. Among them, stigmasterol was predicted to possess the best binding affinity towards PPAR-γ and possessed no side effects. Similarly, n-hexadecanoic acid was predicted to modulate the highest number of proteins, and protein CD14 was targeted by the highest number of bioactives. Further, the PI3K-Akt pathway was predicted as the maximum modulated genes. CONCLUSIONS: The anti-diabetic property of the Murraya odorata Blanco of fruit pulp may be due to the presence of n-hexadecanoic acid and stigmasterol; may also involve in the regulation of the PI3K-Akt pathway which needs further investigated by in-vitro and in-vivo protocols.

Identification of PTP1B regulators from Cymbopogon citratus and its enrichment analysis for diabetes mellitus.

PTP1B is identified as the insulin signaling pathway downregulator; involved in pancreatic ß-cell apoptosis. Further, it associates in regulating multiple pathways in diabetes mellitus; kindled us to identify the binding affinity of bioactives from Cymbopogon citratus by targeting PTP1B and identify the probably associated with it; further identifying the probable pathways involved in diabetes mellitus. In this regard, ChEBI database was used to retrieve bio-actives from C. citrates and 3D structures for the same were obtained from the PubChem database. The energy of bioactives was minimized and converted into ligand and the docking was carried using autodock 4.0 against PTP1B. Further, multiple characters of bio-actives like drug-likeness score, ADMET profile, probable adverse effects, and boiled egg model for bioavailability were also studied. Swertiajaponin was predicted for the highest drug-likeness score i.e. 0.26. However, swertiajaponin was predicted with the highest probable side effect of nephrotoxicity with pharmacological activity of 0.478. Similarly, swertiajaponin was predicted for the highest binding affinity with PTP1B with the binding energy of - 8.3 kcal/mol. Likewise, KEGG identified 80 pathways associated with PTP1B modulation in which 7 pathways were involved in diabetes mellitus in which FoxO signaling pathway was predicted to have the least false discovery rate by modulating 7 genes. Swertiajaponin could act as the potent inhibitor of PTP1B; scored highest druglikeness score but possessed minimum GIT absorptivity; further, PTP1B was identified to be linked with multiple pathways that are concerned with diabetes mellitus.

Synthesis and anti-inflammatory evaluation of methylene bridged benzofuranyl imidazo[2,1-b][1,3,4]thiadiazoles.

A series of 6-substituted and 5,6-disubstituted 2-(6-methyl-benzofuran-3-ylmethyl)-imidazo[2,1-b][1,3,4]thiadiazoles have been synthesized. The new compounds have been tested for their in vivo analgesic, anti-inflammatory activities. Qualitative SAR studies indicate that the chloro substitution in the imidazole ring and introduction of formyl group at C-5 position of the imidazole ring increased the anti-inflammatory and analgesic activity. All the newly synthesized compounds have been characterized by spectral data and ORTEP diagram of one of the intermediates 6-(4-chlorophenyl)-2-(6-methyl-benzofuran-3-ylmethyl)-5-morpholin-4-ylmethyl imidazo[2,1-b][1,3,4]thiadiazole is reported herein.