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- 2019| BioMed CentralBackground: Insulin resistance is a hallmark of type 2 diabetes mellitus (T2DM) and the underlying cause of various metabolic changes observed in type 2 diabetic patients. This study investigated the molecular basis of the anti-hyperglycemic activity of the lanosteryl triterpene (RA-3), from Protorhus longifolia stem bark, in hyperlipidemic and streptozotocin (STZ)-induced T2DM in rats. Methods: The high-fat diet fed (HFD) and STZ-induced T2DM in rat model was used to evaluate the anti-hyperglycemic activity of RA-3. The hyperlipidemic rats received a single intraperitoneal injection of STZ (35 mg/kg body weight) to induce T2DM. The experimental animals received a daily oral single dose of RA-3 (100 mg/kg body) for a period of 28 days, whiles the control group received distilled water only. The animals were euthanized, and skeletal muscle was collected for protein (IRS-1, AKT, GSK and GLUT 4) expression analysis. Western blot confirmed expression of the proteins. Results: Treatment of the diabetic animals with the RA-3 showed marked reduction in fasting plasma glucose levels in comparison to the untreated diabetic group animals. A significant decrease in p-GSK-3β and p-AKT expression was observed, whereas the expression of IRS-1ser307 were increased when compared to the diabetic control group. This effect was ablated upon treatment with RA-3 and this was concomitant to an observed increase in GLUT 4 expression. Conclusions: The results obtained in the present study strongly suggested that the anti-hyperglycemic effect of RA-3 could partly be associated with its ability to improve cellular glucose uptake in muscle tissue from T2DM.
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- Nephropathy continues to be a major single contributor to high rate of morbidity and mortality worldwide. Despite the availability of the current kidney management strategies, incidences of nephropathy continue to rise with many patients progressing to end stage renal disease, which is associated with high rate of morbidity and mortality. The need to search for new effective lead molecules against nephropathy cannot be over emphasized. This study evaluated nephroprotective potential of a lanosteryl triterpene (RA-3) from stem bark of Protorhus longifolia. The nephroprotective effect of RA-3 was evaluated in three different animal models namely: adenine and gentamicin-induced nephropathy, myocardial infarction induced nephropathy, and diabetes induced nephropathy. Sprague Dawley rats (of either sex) were used in all the experimental models for evaluation of the nephroprotective effect of RA-3. In the gentamicin and adenine-induced nephropathy, the rats were orally administered (intragastric) with adenine (150 mg/kg) and injected intraperitoneally with gentamicin (40 mg/kg) daily for 14 days to induce nephropath/. The experimental groups were orally administered with RA-3 at 50 and 100 mg/kg body weight, respectively. The animals in the untreated group received a carrier solvent (2% Tween 20) while the positive control group animals were treated with allopurinol (10 mg/kg). Normal group rats received equivalent volume of water only. The rats received their respective treatments for a further 14 days. Similar experimental set ups were used to evaluate the nephroprotective effect of RA-3 against the secondary causes of nephropathy. In the myocardial infarction and diabetes induced nephropathy, the rats were injected with isoproterenol (85 mg/kg) and streptozotocin (60 mg/kg) to induced myocardial infarction and diabetes, respectively. In these experiments, the rats also received a daily single oral dose of RA-3 for 14 days. Vitamin E (60 mg/kg) and metformin (100 mg/kg) were used as positive controls, respectively. At the end of the experimental periods, all the rats were sacrificed. Thereafter, blood and kidney samples were collected and analysed for some oxidative stress biomarkers such as malondialdehyde (MDA), xanthine oxidase (XOD) and interleukin-6 (IL-6), antioxidant status, some renal dysfunction biomarkers serum creatinine (Ser), angiotensin converting enzyme (ACE) and blood urea nitrogen (BUN) and histomorphological changes. Varying ranges of elevated levels of renal dysfunction biomarkers were observed in the untreated groups of the three animal models. The concentrations ranged 1.4-23 mg/dl, 12-48 mg/dl, 0.30-0.61 mg/dl and 67-101 U/L for BUN, Ser, UA and ACE, respectively. However, treatment of the animals with RA-3, especially at 100 mg/kg, effectively lowered these parameters in all the three animal models, respectively: 4 4. 70 mg/dl (BUN), 8.25-13 mg/dl (Ser), 67-75 U/L (ACE), and 0.11-0.16 mg/dl (UA). A relatively higher antioxidant status along with lower serum levels of IL-6 and XOD in the RA-3 treated groups was observed when compared to the untreated group. Furthermore, improved cell membrane structure of the kidneys, especially in the adenine and gentamicin experimental model was also observed in rats treated with RA-3 when compared to the untreated groups. These results suggest that the lanosteryl triterpene (RA-3) has nephroprotective potential.
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