Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25-(OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25-(OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25-(OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production.
Objectives Epigenetics refers to the heritable, but reversible regulation of various biological functions. Changes in DNA methylation and chromatin structure derived from histone modifications are involved in the brain development, pathogenesis and pharmacotherapy of brain disorders.
Key findings Evidence suggests that epigenetic modulations play key roles in psychiatric diseases such as schizophrenia and bipolar disorder. The analysis of epigenetic aberrations in the mechanisms of psychoactive drugs helps to determine dysfunctional genes and pathways in the brain, to predict side effects of drugs on human genome and identify new pharmaceutical targets for treatment of psychiatric diseases.
Summary Although numerous studies have concentrated on epigenetics of psychosis, the epigenetic studies of antipsychotics are limited. Here we present epigenetic mechanisms of various psychoactive drugs and review the current literature on psychiatric epigenomics. Furthermore, we discuss various epigenetic modulations in the pharmacology and toxicology of typical and atypical antipsychotics, methionine, lithium and valproic acid.
Alcohol abuse is often associated with disrupted circadian rhythms and sleep, and the link seems to be bidirectional. In addition, it has been shown that exposure to constant illumination may increase lipid peroxidation in tissues. In this study, we investigated the effects of circadian rhythm disruption (CRD) and chronic alcohol intake (A) alone and in combination (CRD+A), on the oxidative stress in total rat brain homogenate. Our results demonstrated that lipid peroxidation was increased in the brain samples of all experimental animals compared with the control ones. The oxidative stress levels increased in the order: C
Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis.
Risperidone is the most widely used drug for treatment of irritability and aggression of children with autism. However, its effects on some cognitive parameters are not well understood. The present study was undertaken to assess the effects of risperidone on learning and memory parameters in shuttle-box test of rats in experimental model of autism. Our results demonstrated that administration of risperidone had beneficial effects on learning and memory of rats with experimental autism. Our data suggest the potential role of risperidone in modulating brain development, behavior and cognition in individuals with autistic features.
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