Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrP(C)) triggers a large number of trophic effects in the nervous system. We found that both PrP(C) and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrP(C) and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrP(C) binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrP(C) binding site (HOP230-245) abrogates this effect. PrP(C) knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrP(C)-HOP engagement is a promising approach for GBM therapy.

Previous studies in a variety of vertebrates show stressed animals to exhibit acute increases in glucocorticoid levels, with consequences for immune modulation. Chronically elevated glucocorticoid levels are mostly associated with immunosuppression. However, there is still a paucity of knowledge regarding the amphibian physiological reaction to short- and long-term stress conditions, including glucocorticoid effects on the immune response. In order to better clarify the relationship between glucocorticoids and immune response, newly captured Brazilian toads (Rhinella icterica) (1 week in captivity) were subjected to a daily transdermal application (TA), of corticosterone or vehicle, for 30 consecutive days. Measures were made on the first day (acute stressor) and last day (chronic stressor), at timepoints 1, 6, and 12 hr post TA. A number of variables were analyzed: corticosterone plasma levels (CORT); neutrophil/lymphocyte ratio (N:L); testosterone plasma levels (T); innate immune response, as indicated by bacterial killing ability (BKA); and whole blood phagocytosis. The corticosterone TA only simulated hormonal changes associated with the acute stress response, even after 30 consecutive days of the treatment, with the increased CORT in response after corticosterone TA being evident only 1 hr postapplication and not thereafter. The general responses to corticosterone TA included increased CORT and N:L at first day of the treatment, and increased CORT and phagocytosis on the last day of the treatment. A decrease in T and BKA associated with the time in captivity was also evident, suggesting that captivity may be a chronic stressor for these toads.

Aims: Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS),which mimics infections by Gram-negative bacteria, induced autistic-like behavior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism.We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia.Materials and methods:We evaluated the effects of LPS and zinc on female reproductive performance. Communication,which is impaired in autism,was tested in pups by ultrasonic vocalizations. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an autism important biomarker.Key findings: Prenatal LPS exposure reduced offspring number and treatment with zinc prevented this reduction.Moreover, pups that were prenatally exposed to LPS spent longer periods without calling their mothers, and posttreatment with zinc prevented this impairment induced by LPS to the same levels as controls. Prenatal LPS also increased BDNF levels in adult offspring, and posttreatment with zinc reduced the elevation of BDNF to the same levels as controls.Significance: BDNF hyperactivity was also found in several studies of autistic patients. Together with our previous studies, our model of prenatal LPS induced autistic-like behavioral, brain, and immune disturbances. This suggests that it is a valid rat model of autism. Prenatal zinc prevented reproductive, communication, and BDNF impairments.The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway.