Korean red ginseng extract enhances paclitaxel distribution to mammary tumors and its oral bioavailability by P-glycoprotein inhibition.

1. Drug efflux by P-glycoprotein (P-gp) is a common resistance mechanism of breast cancer cells to paclitaxel, the primary chemotherapy in breast cancer. As a means of overcoming the drug resistance-mediated failure of paclitaxel chemotherapy, the potential of Korean red ginseng extract (KRG) as an adjuvant chemotherapy has been reported only in in vitro. Therefore, we assessed whether KRG alters P-gp mediated paclitaxel efflux, and therefore paclitaxel efficacy in in vitro and vivo models. 2. KRG inhibited P-gp protein expression and transcellular efflux of paclitaxel in MDCK-mdr1 cells, but KRG was not a substrate of P-gp ATPase. In female rats with mammary tumor, the combination of paclitaxel with KRG showed the greater reduction of tumor volumes, lower P-gp protein expression and higher paclitaxel distribution in tumors, and greater oral bioavailability of paclitaxel than paclitaxel alone. 3. From these results, KRG increased systemic circulation of oral paclitaxel and its distribution to tumors via P-gp inhibition in rats and under the current study conditions.

Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway.

Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-κB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway.

Mangosteen Extract Attenuates the Metabolic Disorders of High-Fat-Fed Mice by Activating AMPK.

This study investigated the effects of mangosteen on metabolic syndromes in high-fat (HF) diet-fed mice and the underlying mechanisms related to adipogenesis. Mangosteen-supplemented mice gained significantly less body weight, compared with the HF group. The levels were markedly elevated in HF mice for serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, glucose, triglyceride, total cholesterol, low-density lipoprotein (LDL) cholesterol, and free fatty acid; whereas these levels were significantly lower in the 200 mg/kg of the mangosteen extract-treated group. The mangosteen extract did not modify high-density lipoprotein (HDL)-cholesterol, however, LDL-cholesterol was lower and HDL/LDL ratio was higher (9.4 vs. 3.7 in HF group). Furthermore, 200 mg/kg of mangosteen treatment activated the hepatic AMP-activated protein kinase and Sirtuin 1 in an in vivo system. Thus, the results of this study suggest that mangosteen extract exerts antiobesity effects by regulating energy metabolism and hepatic lipid homeostasis.

α-Mangostin Regulates Hepatic Steatosis and Obesity through SirT1-AMPK and PPARγ Pathways in High-Fat Diet-Induced Obese Mice.

Previous studies have shown that α-mangostin (α-MG) suppresses intracellular fat accumulation and stimulation of lipolysis in in vitro systems. Together with the relatively high distribution of α-MG in liver and fat, these observations made it possible to propose a plausible hypothesis that an α-MG supplement may regulate hepatic steatosis and obesity. An α-MG supplement (50 mg/kg) reduced the body weight gain (13.8%) and epidymal and retroperitoneal fat mass accumulation (15.0 and 11.3%, respectively), as well as the biochemical serum profiles such as cholesterol [TC (26.9%), LDL-C (39.1%), and HDL-C (15.3%)], glucose (30.2%), triglyceride (29.7%), and fatty acid (30.3%) levels in high-fat fed mice compared with the high-fat diet-treated group, indicating that α-MG may regulate lipid metabolism. In addition, an α-MG supplement up-regulated hepatic AMPK, SirT1, and PPARγ levels compared with the high-fat diet states, suggesting that α-MG regulates hepatic steatosis and obesity through the SirT1-AMPK and PPARγ pathways in high-fat diet-induced obese mice.

Pharmacokinetics of isoliquiritigenin and its metabolites in rats: low bioavailability is primarily due to the hepatic and intestinal metabolism.

Isoliquiritigenin, a chalcone found in licorice has shown a variety of biological activities including antioxidative, anti-inflammatory, estrogenic, chemopreventive and antitumor effects. Thus, pharmacokinetics of isoliquiritigenin and its metabolites [liquiritigenin, glucuronidated isoliquiritigenin (M1), and glucuronidated liquiritigenin (M2)] after intravenous and oral administration of isoliquiritigenin was evaluated in rats. The pharmacokinetics of isoliquiritigenin, liquiritigenin, M1, and M2 showed no dose dependence after both intravenous and oral administration of isoliquiritigenin. Although approximately 92.0 % of the oral isoliquiritigenin was absorbed, the extent of the absolute bioavailability value was only 11.8 % of the oral dose. The low absolute bioavailability value of isoliquiritigenin might be due to the considerable metabolism of isoliquiritigenin in the small intestine and liver. This was supported by the facts that the ratios of AUC(M1)/AUC(isoLQ) and AUC(M2)/AUC(isoLQ) were high (over 0.25), isoliquiritigenin disappeared, and M1 and M2 were formed mainly in S9 fractions of the liver and small intestine. The affinities of liquiritigenin, isoliquiritigenin, M1, and M2 were high in the liver, small intestine, large intestine, and/or kidney.