Omega-3 fatty acids ameliorate doxorubicin-induced cardiorenal toxicity: In-vivo regulation of oxidative stress, apoptosis and renal Nox4, and in-vitro preservation of the cytotoxic efficacy.

This study examines the protective effects of omega-3 fatty acids (OMG), a frequently used nutritional therapy in cancer patients, against doxorubicin (DOX)-induced acute cardiorenal toxicity in rats, and evaluates the cytotoxic activity of DOX when used with OMG against breast cancer cell line. Five groups of rats were treated for 4 consecutive weeks with vehicle (groups I & II), or OMG (25, 50 or 100 mg/kg/day, po; groups III, IV & V, respectively). After twenty-four hours, the last four groups were injected with DOX (200 mg/kg, ip). In DOX-treated rats, the altered ECG, serum cardiac and renal function biomarkers, and histopathological features indicated the induction of cardiorenal toxicity. Increased oxidative and apoptotic markers in both organs was observed, with elevated renal contents of NADPH-oxidase-4 (Nox4) and renin. OMG pretreatment improved those DOX-induced impairments in a dose-dependent manner, and showed antioxidant and antiapoptotic effects with regulation of renal Nox4 expression. The in-vitro study showed preservation of the cytotoxic activity of DOX on MCF7 cell line in the presence of OMG. The data suggests OMG for protection against acute DOX-induced cardiorenal damage without affecting the latter antitumor activity. It proposes regulation of oxidative stress, Nox4 activity and apoptosis as contributing protective mechanisms.

Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer cells.

Sphingolipids are critical regulators of tumor microenvironments and play an important role in estrogen-dependent cancers. Estrogen and estrogen metabolites were found to be involved in prostate cancer. Fingolimod (FTY720) is a sphingokinase-1 (SphK1) inhibitor with anticancer properties against various tumor cell types. Herein, we investigated the interference of FTY720 with the cross talk between sphingolipid metabolism and estrogen metabolism within prostate cancer cells. FTY720 showed cytotoxic antiproliferative effects against androgen-dependent and -independent prostate cancer cells with IC50 ranging from 3.0 ±â€¯0.3 to 6.8 ±â€¯1.7 µM. Exposure of prostate cancer cells to FTY720 resulted in a dramatic decrease in the concentration of estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone compared to control cells. However, FTY720 significantly increased the concentration of 2-methoxyestrone and 2-methoxyestradiol within prostate cancer cells. This was mirrored by significant downregulating of the expression of estrogen and catechol estrogen-synthesizing enzymes (CYP19, CYP1A1 and CYP1B1) within prostate cancer cells. On the other hand, FTY720 significantly upregulated the expression of catechol estrogen-detoxifying enzyme (COMT). Additionally, FTY720 abolished estrogen-stimulated expression of ERα and basal expression of ERß within prostate cancer cells. Furthermore, FTY720 suppressed the expression of the ER-downstream regulated genes, CXCR4 and cyclin D1. Reciprocally, it was found that estradiol and catechol estrogens significantly induced the expression of SphK1 while methoxylated catechol estrogen suppressed its expression within prostate cancer cells in a dose-dependent manner. Current research has highlighted the hazardous influence of the estrogenic component to prostate cancer. We found that fingolimod (FTY720) could modulate the estrogenic micromilieu and interrupt its cross talk with sphingolipid metabolism.

Hepatoprotective effects of Astragalus kahiricus root extract against ethanol-induced liver apoptosis in rats.

The hepatoprotective activity of the ethanol extract of Astragalus kahiricus (Fabaceae) roots against ethanol-induced liver apoptosis was evaluated and it showed very promising hepatoprotective actions through different mechanisms. The extract counteracted the ethanol-induced liver enzymes leakage and glutathione depletion. In addition, it demonstrated anti-apoptotic effects against caspase-3 activation and DNA fragmentation that were confirmed by liver histopathological examination. Moreover, the phytochemical study of this extract led to the isolation of four cycloartane-type triterpenes identified as astrasieversianin II (1), astramembrannin II (2), astrasieversianin XIV (3), and cycloastragenol (4). The structures of these isolates were established by HRESI-MS and 1D and 2D NMR experiments. The antimicrobial, antimalarial, and cytotoxic activities of the isolates were further evaluated, but none of them showed any activity.