Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent.

Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by ß-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger's anticancer activity despite sub-therapeutic levels of free GPs in the plasma.

In vivo assessment of antidiabetic and antioxidative activity of natural phytochemical isolated from fruit-pulp of Eugenia jambolana in streptozotocin-induced diabetic rats.

OBJECTIVES: Eugenia jambolana (E. jambolana) is well known for its antidiabetic potential. The aim of the present study was to investigate the antidiabetic and antioxidative effect of an active compound (FIIc) isolated from fruit-pulp of E. jambolana in streptozotocin (45 mg/kg body weight)-induced diabetic rats. METHODS: FIIc was isolated from the crude aqueous extract of fruit-pulp by ion-exchange column chromatography and high-performance column chromatography. Detailed UV, NMR, and IR spectra suggested that FIIc is α-hydroxy succinamic acid. FIIc was orally administered to diabetic rats at a dose of 10, 15, and 20 mg/kg body weight (mg/kg bwt.) to determine its effective dose. Thereafter, effective dose was administered to 8 weeks to determine its antidiabetic and antioxidative activity by estimation of glycemic index, lipid profile, key enzymes of carbohydrate metabolism, and oxidative stress parameters. RESULTS: Administration of 15 mg/kg dose daily for 8 weeks led to significant (P < 0.001) fall in fasting blood glucose. Treatment with FIIc (15 mg/kg bwt.) showed significant improvement (P < 0.001) in all the biochemical parameters. DISCUSSION: The results demonstrate that FIIc possesses significant antidiabetic and antioxidative activity.

Antiatherosclerotic Potential of Active Principle Isolated from Eugenia jambolana in Streptozotocin-Induced Diabetic Rats.

The aim of the present study was to investigate the antiatherosclerotic effect of active principle (FIIc) isolated from aqueous fruit pulp extract of Eugenia jambolana. Crude aqueous extract of E. jambolana was subjected to purification using chromatographic techniques which yielded purified active compound (FIIc). Purity of FIIc was tested by HPLC. Phytochemical investigation of FIIc by NMR, IR, and UV spectra showed that the purified compound is α-hydroxy succinamic acid. The streptozotocin- (STZ-) induced diabetic rats were fed atherosclerotic (Ath) diet containing 1.5 mL olive oil containing 8 mg (3, 20,000 IU) vitamin D(2) and 40 mg cholesterol for 5 consecutive days. The STZ-induced diabetic rats receiving Ath diet were orally administered FIIc at doses of 10, 15, and 20 mg/kg, and results were compared with reference drug, that is, glibenclamide (600 µg/mg) and healthy control. 30-day treatment with FIIc resulted in significant (P < .001) improvement in blood glucose, serum lipid profile, apolipoproteins (Apo A(1) and apoB(100)), and endothelial dysfunction parameters. Histomorphological studies also confirmed biochemical findings. Our results showed that FIIc has protective effect on hyperglycemia-induced atherosclerosis.

Protective effect of Morus rubra L. leaf extract on diet-induced atherosclerosis in diabetic rats.

The antiatherosclerotic effect of aqueous leaves extract of Morus rubra was studied in streptozotocin-induced diabetic rats fed with atherosclerotic (Ath) diet [1.5 ml olive oil containing 8 mg (3, 20,000 IU) vitamin D2 and 40 mg cholesterol] for 5 consecutive days. A short-term toxicity assessment was also conducted in healthy rats to examine toxic effects of the extract. Oral administration of extract to diabetic rats (100, 200 and 400 mg/kg body weight per day for a period of 30 days) produced significant (p<0.001) fall in fasting blood glucose (FBG) in a dose-dependent manner. Treatment with the extract (400 mg/kg) showed significant (p<0.001) improvement in body weight and serum lipid profile i.e., total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol, when compared with diabetic control. Endothelial dysfunction parameters (sVCAM-1, Fibrinogen, total NO levels and oxidized LDL), apolipoprotein A and apolipoprotein B were significantly (p<0.001) reversed to near normal, following treatment with the extract. Thus, our study shows that aqueous leaf extract of Morus rubra (400 mg/kg) significantly improves the homeostasis of glucose and fat and possesses significant anti-atherosclerotic activity.

Attenuation of renal dysfunction by anti-hyperglycemic compound isolated from fruit pulp of Eugenia jambolana in streptozotocin-induced diabetic rats.

The renal protective effect of an active principle isolated from the aqueous extract of fruit pulp of Eugenia jambolana was investigated in streptozotocin (45 mg/kg body weight)-induced severely diabetic rats (FBG > or = 300 mg/dl). For isolation of active principle, crude aqueous extract of E. jambolana fruit pulp was subjected to purification by ion-exchange column chromatography, which yielded a partially purified compound (FII), which on further purification by rechromatography gave a purified active compound (FIIc). Purity of FIIc was confirmed by high pressure liquid chromatography. Detailed UV, NMR, IR spectra suggested that FIIc is a small aliphatic organic compound having molecular formula C4H7O4N. Oral administration of FIIc to diabetic rats (10, 15 and 20 mg/kg body weight per day for a period of 60 days) produced significant (P<0.001) fall in fasting blood glucose (FBG) in a dose-dependent manner. Treatment with FIIc (15 mg/kg body wt.) showed significant (P<0.001) improvement in body weight, blood urea, plasma creatinine levels, urinary volume, urinary sugar and microalbuminuria. Renal hypertrophy, assessed as the ratio of the weight of the two kidneys to total body weight was also significantly (P<0.05) improved after treatment with FIIc. The above results suggest that FIIc possesses significant nephroprotective activity.