No abstract

No abstract

Neuroblastoma is a childhood malignancy that accounts for approximately 15% of childhood cancer deaths. Only 20–35% of children with metastatic neuroblastoma survive with standard therapy. Identification of more effective therapies is essential to improving the outcome of children with high-stage disease. Sphingadienes (SD) are growth-inhibitory sphingolipids found in natural sources including soy. They exhibit chemopreventive activity in mouse models of colon cancer, where they mediate cytotoxicity by inhibiting key pro-carcinogenic signaling pathways. In this study, the effect of SD on neuroblastoma was analyzed. Low micromolar concentrations of SD were cytotoxic to transformed and primary neuroblastoma cells independently of N-Myc amplification status. SD induced both caspase-dependent apoptosis and autophagy in neuroblastoma cells. However, only inhibition of caspase-dependent apoptosis protected neuroblastoma cells from SD-mediated cytotoxicity. SD also inhibited AKT activation in neuroblastoma cells as shown by reduced phosphorylated AKT levels. Pre-treatment with insulin attenuated SD-mediated cytotoxicity in vitro. SD-loaded nanoparticles (NP) administered parenterally to immunodeficient mice carrying neuroblastoma xenografts resulted in cytotoxic levels of SD in the circulation and significantly reduced tumor growth compared to vehicle-treated controls. Analysis of tumor extracts demonstrated reduced AKT activation in tumors of mice treated with SD-NP compared to controls treated with empty NP. Our findings indicate SD are novel potential chemotherapeutic agents that promote neuroblastoma cell death and reduce tumorigenicity in vivo.

No abstract

No abstract

The effect of zinc supplementation on Taenia crassiceps murine cysticercosis was studied in susceptible BALB/cAnN mice. Female offspring of mice supplemented with high zinc throughout gestation and lactation were intraperitoneally infected with T. crassiceps cysticerci. Offspring from nonsupplemented mothers were used as controls. Significantly fewer parasites were recovered from zinc-supplemented mice (Zsm) 30 days after infection. Increased resistance was not related to the IgG antibody response. At early stages of infection, T cells from Zsm proliferated to T. crassiceps antigens, whereas cells from control mice did not respond. Infection caused in both groups a decrease in CD3+ cell percentages, which was more pronounced in the controls, and paralleled by a decrease in CD8+ cells; CD3+ and CD8+ percentages returned to normal levels at later stages of infection. In contrast, the CD4+ subpopulation only decreased in control mice. Intracellular cytokine determinations indicate that zinc supplementation favored a stronger and persistent type-1 T cell response in cysticerci-infected mice, which probably participates in the observed increased resistance.

Oral treatment of zinc modulates cytokine secretion during the gestation, lactation, and weaning periods. We used a experimental mice model of zinc supplementation during the perinatal stages to study the effects of this ion over the production of interleukin IL-1a, 2 IL-12, and tumor necrosis factor-alpha by peritoneal macrophages. In addition, we determined the gene expression of these cytokines. Zinc (500 mg/L) was orally administered to mice from gestation to lactation (6-week treatment, Zn+) and weaning (9-week treatment). The serum cytokines IL-1a and IL-12 were assayed in the offspring at 21 and 42 days after birth. Our results showed a significant (P < 0.01) increase in cytokine production in the Zn+ animals at the end of the lactation stage. There was a tendency for the IL-1 concentration to decrease at postweaning; nevertheless, IL-12 concentrations were increased in mice at 42 days of age (P < 0.001). The production of IL-1a, IL-12, and tumor necrosis factor-alpha in the macrophages supernatants in vitro followed the same tendencies (P < 0.001). Molecular analysis showed an increase of mRNA synthesis in all cases, from 4-fold to 6-fold, in the cytokines analyzed. Our results suggest that the increase in the proinflammatory cytokines as a result of zinc administration may potentiate Th1 cells response, which could lead to the increase of cytokine production in deficient newborns. J. Trace Elem.

Severe maternal zinc deficiency has a devastating effect on pregnancy outcome. Studies of humans and experimental animals show that maternal zinc deficiency can cause infertility, prolonged labor, intrauterine growth retardation, teratogenesis, severe immunological deficiencies, or fetal death. The additional need for zinc during pregnancy can be met by an increase in zinc intake. An increase in zinc supplements, when excessive, can cause a decrease in copper. Therefore, it is important to determine the zinc and copper concentrations in embryonic tissue in experimental models and their relationship with embryo number and viability. BALB/c mice were divided into groups according to zinc oral supplementation and gestational age. Phagocytosis was assessed in peritoneal macrophages from dams. The zinc and copper concentrations were obtained by inductively coupled plasma-optical emission spectrometry. Zn and Cu data concentrations in all the analyzed samples were above the detection limits. No spectral interferences were found in both elements. Zinc concentrations show a tendency to increase in embryos (14 gestational days and 21 gestational days) supplemented with zinc. Copper concentrations showed a noticeable tendency to diminish (36% and 27%, respectively) in the same period. In contrast, in placenta Zn values were increased by 30% and Cu values were decreased by 26%. We suggest a pivotal role of the placenta metabolism with its homeostatic mechanisms, in these findings. An important increment appeared in the +Zn embryo number (40%) relative to control (-Zn) embryos at 21 d gestational age. Embryo mortality was at 6% in +Zn embryos and at 20% in -Zn embryos. We consider these findings, both in the number and in the viability of +Zn embryos, outstanding.