Association between endocrinological, immunological and psychosocial variables in psoriasis patients.

BACKGROUND: There is limited data concerning the relationship between psychosocial problems of psoriasis patients and the function of their hypothalamic-pituitary-adrenal (HPA) axis and immunologic markers. This study aimed to determine serum levels of basal cortisol and adrenocorticotropic hormone (ACTH) and circulating levels of various cytokines and chemokines and their association with psychological measures in psoriasis patients. METHODS: Serum concentrations of endocrinological and immunological variables were quantified, and psychiatric questionnaires were completed. RESULTS: In psoriasis patients, serum levels of ACTH, TNF-a, IL-6, IL-23, CCL-17, CCL-27, CCL-20 and CXCL-9, current psychiatric symptoms and childhood neglect scores were all higher than in controls. In addition, in psoriasis patients, physical neglect scores were related to lower basal cortisol, whereas recent stressful life events were related to higher IL-6, IL-23 and CCL-20 levels. CONCLUSIONS: The exposure to stressful life events in childhood and just before a flare-up of psoriasis may be related to altered function of the HPA axis and an immune dysregulation in psoriasis.

Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.

The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats.

Involvement of FKHRL1 in melanoma cell survival and death.

Melanoma is a highly aggressive tumour characterized by a strong resistance to apoptotic stimuli that give rise to a selective advantage for tumour progression and metastasis formation. Therefore, it is of paramount importance to better understand the mechanisms involved in this resistance to apoptosis. In this report, we focused our attention on FKHRL1, a member of the forkhead family of transcription factors, which controls expression of genes involved in cell cycle progression and apoptosis. In melanoma cells, we show that IGF1, which exerts pro-survival properties, induces the phosphorylation and nuclear exclusion of FKHRL1 in a PI3K/AKT-dependent pathway. Moreover, we observe that over-expression of a non-phosphorylable mutant of FKHRL1 (FKHRL1-TM), constitutively localized to the nucleus, promotes apoptotic cell death of melanoma cells. Finally, we find that FKHRL1-TM decreases the expression of survivin, a member of the inhibitor of apoptosis protein and that survivin re-expression partially rescues the deleterious effects of FKHRL1. Taken together, these findings reveal, in melanoma cells, that endogenous FKHRL1 is a downstream target of the PI3K/AKT pathway and suggest that the phosphorylation of this transcription factor may be involved in the pro-survival effects of growth factors such as IGF1. On the other hand, forced nuclear localization of FKHRL1 decreases melanoma cell growth and may serve as a therapeutic strategy against melanoma.