ABSTRACT
Objective: Curcumol is one of the major active ingredients isolated from the traditional Chinese medicine Curcumae Rhizoma and is reported to exhibit various bioactivities, such as anti-tumor and anti-liver fibrosis effects. However, studies of curcumol pharmacokinetics and tissue distribution are currently lacking. This study aims to characterize the pharmacokinetics, tissue distribution, and protein binding rate of curcumol. Methods: Pharmacokinetics properties of curcumol were investigated afte doses of 10, 40, and 80 mg/kg of curcumol for rats and a single dose of 2.0 mg/kg curcumol was given to rats via intravenous administration to investigate bioavailability. Tissue distribution was investigated after a single dose of 40 mg/kg of orally administered curcumol. Plasma protein binding of curcumol was studied in vitro via the rapid equilibrium dialysis system. Bound and unbound curcumol in rat plasma were analyzed to calculate the plasma protein binding rate. A UHPLC-MS/MS method was developed and validated to determine curcumol in rat plasma and tissues and applied to study the pharmacokinetics, tissue distribution, and plasma protein binding in rats. Results: After oral administration of 10, 40, and 80 mg/kg curcumol, results indicated a rapid absorption and quick elimination of curcumol in rats. The bioavailability ranging from 9.2% to 13.1% was calculated based on the area under the curves (AUC) of oral and intravenous administration of curcumol. During tissue distribution, most organs observed a maximum concentration of curcumol within 0.5-1.0 h. A high accumulation of curcumol was found in the small intestine, colon, liver, and kidney. Moreover, high protein binding rates ranging from 85.6% to 93.4% of curcumol were observed in rat plasma. Conclusion: This study characterized the pharmacokinetics, tissue distribution, and protein binding rates of curcumol in rats for the first time, which can provide a solid foundation for research into the mechanisms of curcumol's biological function and clinical application.
ABSTRACT
Hypoxia is associated with resistance to chemotherapy in a number of human cancer types; particularly in hepatocellular carcinoma (HCC), which is a highly vascularized tumor. To develop a potential combination therapy strategy that is capable of overcoming the hypoxiainduced insensitivity to chemotherapy, the HCC cell SMMC7721 was employed to investigate the hypoxiainduced chemoresistance to etoposide. Increased levels of hypoxiainducible factor1α (HIF1α) and vascular endothelial growth factor (VEGF) were observed when SMMC7721 cells were exposed to hypoxia, and exposure of tumor cells to hypoxia impaired etoposideinduced DNA damage, as indicated by the failure of upregulation of γHA2X. Etoposideinduced apoptosis and cell cycle arrest of SMMC7721 was also impaired in hypoxia. However, cotreatment with antiVEGF significantly restored etoposideinduced cell apoptosis and cell cycle arrest, as indicated by the elimination of Bcell lymphoma 2 (Bcl2), procaspase 3, cyclin B1 and Cdc2. Furthermore, antiVEGF eliminated phosphorylation of AKT, ERK and IκBα resulting from hypoxia, suggesting the involvement of VEGF in the activation of the survival pathways. In conclusion, the present study suggests a significant role of VEGF in the chemoresistance of etoposide in hypoxia. A rational chemotherapy should be developed based on a combination of etoposide and antiVEGF.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/metabolism , Drug Resistance, Neoplasm , Etoposide/pharmacology , Hypoxia/metabolism , Liver Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism , Cell Cycle Checkpoints/drug effects , Cell Hypoxia/drug effects , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , NF-kappa B/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
The aim of this study was to explore myocardial protection of early extracorporeal membrane oxygenation (ECMO) support for acute myocardial infarction with cardiogenic shock in pigs. 24 male pigs (34.6 ± 1.3 kg) were randomly divided into three groups-control group, drug therapy group, and ECMO group. Myocardial infarction model was created in drug therapy group and ECMO group by ligating coronary artery. When cardiogenic shock occurred, drugs were given in drug therapy group and ECMO began to work in ECMO group. The pigs were killed 24 h after cardiogenic shock. Compared with in drug therapy group, left ventricular end-diastolic pressure in ECMO group decreased significantly 6 h after ligation (P < 0.05). At the end of the experiments, LV - dp/dt among three groups was significantly different, drug therapy group < ECMO group < control group. There was no difference in LV + dp/dt between drug therapy group and ECMO group. Compared with drug group, myocardial infarct size of ECMO group did not reduce significantly, but myocardial enzyme and troponin-I decreased significantly. Compared with drug therapy, ECMO improves left ventricular diastolic function, and may improve systolic function. ECMO cannot reduce myocardial infarct size without revascularization, but may have positive effects on ischemic areas by avoiding further injuring.