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.

Identification of α-amylase inhibitors from flavonoid fraction of Feronia elephantum and its integration with in-silico studies.

Postprandial hyperglycemia is associated with an increase in blood glucose levels after a meal, which is further associated with various risk factors like cardiovascular diseases. α-amylase is a digestive enzyme and secreted by the salivary glands and pancreas, which helps to catalyze the hydrolysis of the internal α-1,4-glycosidic linkages in starch breaking them into smaller units. Hence, the present study is aimed to identify flavonoids from the fruit pulp of Feronia elephantum as α-amylase inhibitors via in-silico and in-vitro protocols. In-silico tools like ADVERPred, PubChem, MolSoft, Discovery studio 2019, and Autodock 4.0 were used to predict the information related to phytoconstituents, drug-likeness character, and probable side effects. In-vitro α-amylase inhibitory activity was performed with five different concentrations of flavonoid fraction of hydroalcoholic extract of the fruit pulp of Feronia elephantum using 1% starch solution and DNS reagent. Four flavonoids were identified from 25 bio-actives present in the fruit pulp of Feronia elephantum. Three bio-actives were predicted to possess a positive drug-likeness score, from which 5,4-dihydroxy3-3(3-methyl-but2-enyl)3,5,6-trimethoxy-flavone-7-O-ß-d-Glucopyranoside was predicted to possess the highest drug-likeness score of 0.70. Vitexin and 5,4-dihydroxy3-3(3-methyl-but2-enyl)3,5,6-trimethoxy-flavone-7-O-ß-d-Glucopyranoside were predicted to possess nephrotoxicity as an adverse effect. The percent inhibition of α-amylase by a flavonoid-rich fraction at 100 µg/ml was found to be 45.95% as compared to standard acarbose with 74.79% inhibition at 100 µg/ml. Further, docking studies predicted that vitexin possessed the highest binding affinity (binding energy - 7.98 kcal/mol) as compared to standard acarbose with binding energy - 5.24 kcal/mol. There were no significant side effects predicted, in-vitro α-amylase inhibitory activity of the flavonoid-rich fraction may be due to the presence of vitexin, predicted via in-silico molecular docking; further, which needs to be further validated via in-vivo protocols.

In vitro antioxidant and cytotoxic activities of essential oil of Feronia elephantum Correa.

OBJECTIVE: To analyse the chemical composition and evaluation of antioxidant, cytotoxic and DNA fragmentation activities of essential oil of Feronia elephantum Correa. METHODS: Chemical composition analysis of hydrodistilled essential oil was determined by gas chromatography-mass spectrometry and in vitro antioxidant activity of oil was determined by DPPH free radical, hydroxyly radical scavenging, metal chelating and prevention of deoxyribose degradation. Cytotoxicity and DNA fragmentation activities against breast cancer cells (MCF-7) were also analyzed. RESULTS: Gas chromatography-mass spectrometry analysis revealed the presence of 24 compounds with caryophyllene oxide (62.29%) as major compound. A considerable antioxidant, cyotoxic and DNA fragmentation activities of oils was observed. CONCLUSIONS: The result of this study clearly indicates oil could be useful for food preservation and preparation.

Protective effect of aqueous extract of Feronia elephantum correa leaves on thioacetamide induced liver necrosis in diabetic rats.

OBJECTIVE: To evalueate hepatoprotective effects Feronia elephantum (F. elephantum) correa against thioacetamide (TA) induced liver necrosis in diabetic rats. METHODS: Male wistar rats were made diabetic with alloxan (160 mg/kg) on day 0 of the study. They were intoxicated with hepatotoxicant (thioacetamide, 300 mg/kg, ip) on day 9 of study to produce liver necrosis. Effects of 7 day daily once administration (day 2 to day 9) of EF (400 and 800 mg/kg, po) were evaluated on necorosis of liver in terms of mortality, liver volume, liver weight, serum aspartate aminotransferase (AST) and serum alanine transaminase (ALT), and histopathology of liver sections (for signs of necorosis and inflammation) on day-9 of the study. Separate groups of rats with treated only with alloxan (DA control), thioacetamide (TA control) and both (TA+DA control) were maintained. RESULTS: FE significantly lowered the mortality rate and showed improvement in liver function parameters in TA-induced diabetic rats without change in liver weight, volume and serum glucose levels. CONCLUSIONS: FE showed promising activity against TA-induced liver necorsis in diabetic rats and so might be useful for prevention of liver complications in DM.