Prior reports have suggested that piperine enhances curcumin anti-carcinogenesis. We tested the hypothesis that piperine increases the intracellular concentrations of curcumin by improving intracellular uptake or reducing curcumin efflux or metabolism in breast cells. We incubated SUM149, MCF10A, primary normal human breast cells, ALDH+, and ALDH-CD44+24- SUM149 cells with curcumin with or without piperine at concentrations 1 uM to 15 uM for time periods of 15 minutes to 24 hours. We assayed cell viability by MTT assay and proliferation by primary mammosphere assay. Curcumin and its metabolites were assayed using liquid chromatography mass spectroscopy. Curcumin, but not piperine, showed significantly higher effects on the viability of breast cancer SUM149 cells than in non-tumorigenic MCF10A cells. Curcumin + piperine synergistically reduced viability of SUM149 cells but had a concentration dependent effect upon MCF10A cell viability. Cellular uptake of curcumin in SUM149 is significantly higher, while the efflux in SUM149 is significantly lower than in MCF10A, which correlated with cell viability. Piperine did not alter curcumin cellular uptake, efflux, or metabolism in any of the cell models. The observed synergism of piperine+curcumin in reducing breast stem cell self renewal is likely due to independent anti-carcinogenesis effects rather than any effects upon intracellular curcumin concentrations.

Background: Cholestasis is a condition in which there is impairment of bile flow from the liver to the small bowel. It is a common complication of bacterial infection and sepsis. Treatment is usually directed towards the eradication of bacterial infection and consequences of sepsis. Ursodeoxycholic acid (UDCA) has been under investigation as a possible therapeutic option for the treatments of sepsis-associated cholestasis.Methods: Sixty male albino rats (weighing 100–150g) were subjected to daily doses of UDCA (100 mg/kg, p.o.) for 10 days before or after lipopolysaccharides (LPS) induction of cholestasis. Then, the following liver enzyme activity was assessed: plasma aspartate transferase (AST), plasma alkaline transferase (ALT), plasma alkaline phosphatase (ALP), total bilirubin (TBIL). Hepatocyte apoptosis and immunomodulatory activity were assessed by flow cytometric analysis. Plasma pro-inflammatory cytokines (TNF-, IL-1 and IL-4) were measured by ELISA. Liver histology changes were assessed by hematoxylin and eosin (H&E) staining.Results: Our results showed that LPS-induced cholestasis resulted in a significant rise in the TBIL and liver enzymes including GGT, ALP, AST, and hepatocytes death. UDCA improves serum liver chemistries and halts bile acid cytotoxicity when it was used either as a treatment or prevention, compared to the LPS group. Moreover, UDCA has immunomodulatory properties: the effect of UDCA on the percentage of natural killer (NK) cells did not change in either the treatment or prevention group when compared to LPS induced cholestasis. However, significant decrease in the CD3 has been found in the treatment group as compared to the LPS group, and an unexpected increase in the prevention group compared to the LPS treated group. UDCA failed to ameliorate the increase in plasma TNF-α concentration in the treatment group. On the other hand, UDCA caused reduction in plasma TNF-α in the prevention group. We also found significant reduction in the liver tissue apoptosis in the UDCA treated groups. Conclusion: Prophylactic treatment and treatment with UDCA appear to exert a beneficial effect against the damaging effect of hydrophobic bile acids by LPS-induced secretary failure. This involved multiple mechanisms of action.