Trabectedin (Yondelis, ET-743) is a marine-derived tetrahydroisoquinoline alkaloid. It is originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and currently produced synthetically. Trabectedin is active against a variety of tumor cell lines growing in culture. The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs). Cluster of differentiation (CD) 133+high/CD44+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry. We studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs. DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 h and the growth inhibition rates were examined using the sphere-forming assay. Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death. Concentration-dependent effects of trabectedin on the cell cycle were also evaluated. The cells were exposed to the different doses of trabectedin for 24, 48 and 72 h to evaluate the effect of trabectedin on the number and diameter of spheroids. According to the results, trabectedin induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose-dependent manner. Cell cycle analyses revealed that trabectedin induces dose-dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments. Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs. Furthermore, we have found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU-145 and PC-3 CSCs. Our results showed that trabectedin inhibits cellular proliferation and accelerates apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer.

Background/aim: Diclofenac sodium (DS) can cross the placental barrier and affect the fetus, and its consumption during pregnancy may cause developmental malformation of embryos. This study investigates the effect of prenatally applied DS on the quantitative morphology of the adult rat heart.Materials and methods: Pregnant rats were divided into three groups (control, sham, and test). The rats in the test group were injected with DS; the control group received physiological saline (1 mL; 1 mg/kg, i.m.) from the 5th to the 20th day of pregnancy; and the rats in the sham group were not injected at all. At the 20th postnatal week, all the offspring were euthanized under deep anesthesia and tissue samples were obtained by perfusion fixation. After routine histological procedures, the paraffin sections were stained with hematoxylin and eosin and examined stereologically and histologically. Results:The volume of the cardiac ventricle wall of each offspring rat was estimated using Cavalieri's principle. The volume of the ventricle walls of the test group was found to be significantly less than that of the controls. Conclusion:Further studies are required to determine how DS has this effect, by reducing the number of myocytes and decreasing the size of these cells affecting the connective tissue.

Torsion/detorsion (T/D) induces testicular damages in both germinal epithelial and interstitial tissues. Ginkgo biloba extract (GbE) exerts antioxidant and free radical scavenger. We investigated the effect of GbE on testicular tissues, Leydig and sperm cells in rats injured with T/D. Twenty-eight Wistar albino rats were randomly assigned into four groups (Control, GbE, Treatment: T/D+GbE, T/D). T/D performed to the rats in torsion, treatment received GbE (50 mg/kg) 1 hr before T/D, GbE group received only GbE (50 mg/kg) and control was defined as sham group. After T/D, the testes along with epididymis were removed and processed. LH-R expression, apoptosis, sperm morphology and histopathological damage scores were determined for each group. Testicular T/D caused significant increases in apoptosis and sperm morphology anomaly, and a significant decrease in Johnsen's testicular biopsy scores, LH-R expression of Leydig cell and normal sperm cell count. GbE ameliorated testicular histopathology and caused significant increases in LH-R expression, normal sperm cell count in the treated and particularly GbE group. Consequently, GbE may prevent testicular injury and enhance Leydig and sperm cell activity following both T/D and normal situation owing to its antioxidant, anti-apoptotic, free radical scavenger and anti-inflammatory effects.

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Background: Hepatic ischemia/reperfusion injury is a major problem that can exacerbate complications, particularly in liver transplantations. Objectives: This study aimed to investigate the cellular mechanisms of ischemia/reperfusion injury and hepatoprotection by curcumin. Methods: Wistar albino rats were divided into four groups as Control, Sham, I/R, and Cur+I/R. Hepatic ischemia/reperfusion was induced in I/R and Cur+I/R animals, the latter of which was also given 50 mg/kg/day of curcumin for 14 days. Liver aminotransferases and the transcription regulators of inflammation (RelA, IκB, PPAR-α, PPAR-γ, CREB1) were examined along with the histological examination. Results: Hepatic ischemia/reperfusion was found to disrupt hepatic microstructure and downregulate PPAR-α, PPAR-γ, and CREB1 transcripts. Curcumin supplementation in hepatic ischemia/reperfusion recovered the structural organization and promoted the hepatocyte regeneration while increasing expressions of PPARs and CREB1. RelA and IκB were found unaltered, possibly due to the crosstalk between targeted transcripts by ischemia/reperfusion and curcumin. Conclusions: In sum, PPAR-α/γ and CREB1 were involved in hepatic ischemia/reperfusion and, moreover, were detected to be stimulated by curcumin. Microstructural improvement, together with curcumin supplementation, was found to provide a route to hepatoprotection through PPAR and CREB pathways.