Cuminum cyminum, a commonly used spice, is known to have anti-diabetic action. The present study aims towards the isolation of bioactive components from C. cyminum and the evaluation of their insulin secretagogue potential with the probable mechanism and β-cell protective action. The anti-diabetic activity was detected in the petroleum ether (pet ether) fraction of the C. cyminum distillate and studied through in vivo and in vitro experiments. Bioactive components were identified through GC-MS, Fourier transform infrared spectroscopy and NMR analysis. The isolated components were evaluated for their insulin secretagogue action using rat pancreatic islets. Further, the probable mechanism of stimulation of islets was evaluated through in vitro studies using diazoxide, nifedipine and 3-isobutyl-1-methylxanthine. β-Cell protection was evaluated using the (1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan) (MTT) assay, the alkaline comet assay and nitrite production. The administration of the pet ether fraction for 45 d to streptozotocin-induced diabetic rats revealed an improved lipid profile. Cuminaldehyde and cuminol were identified as potent insulinotrophic components. Cuminaldehyde and cuminol (25 μg/ml) showed 3·34- and 3·85-fold increased insulin secretion, respectively, than the 11·8 mm-glucose control. The insulinotrophic action of both components was glucose-dependent and due to the closure of the ATP-sensitive K (K⁺-ATP) channel and the increase in intracellular Ca²⁺ concentration. An inhibitor of insulin secretion with potent β-cell protective action was also isolated from the same pet ether fraction. In conclusion, C. cyminum was able to lower blood glucose without causing hypoglycaemia or β-cell burn out. Hence, the commonly used spice, C. cyminum, has the potential to be used as a novel insulinotrophic therapy for prolonged treatment of diabetes.
Inhibition of protein glycation is known to ameliorate secondary complications in diabetes. In the present study antiglycative properties of limonene, a natural product, were evaluated using BSA as a model protein. AMG (aminoguanidine) was used as a positive control. Measurement of total AGEs (Advanced Glycation End-products) and specific AGEs revealed that limonene could inhibit protein glycation to the extent of 56.3% and 75.1% respectively at 50 μM concentration as against 54.4% and 82.2% by AMG at 1 mM. Congo red binding and CD (Circular Dichroism) analysis revealed inhibition of α-helix to β-sheet transition wherein 18.5% β-sheet structures were observed in glycated BSA (bovine serum albumin) as against 4.9% with limonene. Glycation of protein in the presence of urea was enhanced by 18%, while in the presence of limonene it was reduced by 23% revealing the stabilizing effect of limonene. Electrophoretic mobility was similar to the normal control and a zeta potential value of -12.1 mV as against -15.1 mV in diabetic control was observed. Inhibition of glycation in limonene treated samples was confirmed through LC-MS analysis wherein AGEs such as pentosidine, CML (N(ε)-(carboxymethyl)lysine), CEL (N(ε)-(carboxyethyl)lysine), MOLD (methylglyoxal-lysine dimer) and imidazolone observed in glycated samples were absent in limonene treated samples. PatchDock studies revealed that limonene could bind to the major glycation sites IB, IIA and IIB sub domains and AMG to the IIIA sub domain. Thus limonene is a potent protein glycation inhibitor that prevents protein glycation through a novel mechanism of stabilization of protein structure through hydrophobic interactions.
Rheum emodi is used as a culinary plant across the world and finds an eminent role in the Ayurvedic and traditional Chinese systems of medicine. The plant is known to principally contain 1,8-dihydroxyanthraquinones (DHAQs) like rhein, aloe emodin, emodin, chrysophanol and physcion that possess diverse pharmacological and therapeutic actions. The present work deals with developing a platform technology for isolation of these DHAQs and evaluating their anti-diabetic potential. Herein, we report the anti-hyperglycemic activity and alpha glucosidase (AG) inhibitory actions of five isolated DHAQs from R. emodi. All the five isolated DHAQs showed good anti-hyperglycemic activity with aloe emodin exhibiting maximum lowering of blood glucose in an oral glucose tolerance test. However, on evaluation of the AG inhibitory potential of the DHAQs only emodin exhibited potent intestinal AG inhibition (93 ± 2.16%) with an IC50 notably lower than acarbose. Subsequent kinetic studies indicated a mixed type of inhibition for emodin. In vivo studies using oral maltose load showed almost total inhibition for emodin when compared to acarbose. Molecular docking studies revealed the presence of an allosteric topographically distinct 'quinone binding site' and showed that interaction with Ser 74 occurs exclusively with emodin, which is vital for AG inhibition. The net benefit from the glucose lowering effect and mixed type inhibition by emodin would enable the administration of a small dosage that is safe and non-toxic in the case of prolonged use in treating diabetes.
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