Topic
Pregnenolone
About: Pregnenolone is a research topic. Over the lifetime, 3539 publications have been published within this topic receiving 126444 citations. The topic is also known as: (3b)-3-hydroxy-Pregn-5-en-20-one & 3-Hydroxypregn-5-en-20-one.
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TL;DR: Using genetic ablation of an intermediate filament protein in mice, results suggest that vimentin is involved in the movement of cholesterol from its storage in lipid droplets to mitochondria for steroidogenesis.
Abstract: In steroidogenic tissues, cholesterol must be transported to the inner mitochondrial membrane to be converted to pregnenolone as the first step of steroidogenesis. Whereas steroidogenic acute regulatory protein has been shown to be responsible for the transport of cholesterol from the outer to the inner mitochondrial membrane, the process of how cholesterol moves to mitochondria from the cytoplasm is not clearly defined. The involvement of the cytoskeleton has been suggested; however, no specific mechanism has been confirmed. In this paper, using genetic ablation of an intermediate filament protein in mice, we present data demonstrating a marked defect in adrenal and ovarian steroidogenesis in the absence of vimentin. Cosyntropin-stimulated corticosterone production is decreased 35 and 50% in male and female Vimentin null (Vim(-/-)) mice, respectively, whereas progesterone production is decreased 70% in female Vim(-/-) mice after pregnant mare's serum gonadotropin and human chorionic gonadotropin stimulation, but no abnormalities in human chorionic gonadotropin-stimulated testosterone production is observed in male Vim(-/-) mice. These defects in steroid production are also seen in isolated adrenal and granulosa cells in vitro. Further studies show a defect in the movement of cholesterol from the cytosol to mitochondria in Vim(-/-) cells. Because the mobilization of cholesterol from lipid droplets and its transport to mitochondria is a preferred pathway for the initiation of steroid production in the adrenal and ovary but not the testis and vimentin is a droplet-associated protein, our results suggest that vimentin is involved in the movement of cholesterol from its storage in lipid droplets to mitochondria for steroidogenesis.
64 citations
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TL;DR: The present paper will review the molecular and biochemical features concerning the sigma(1) receptor and focus on the recent studies examining the impact of the neuro(active)steroid/sigma( 1) receptor interaction on the antidepressant activity of sigma (1) receptors agonists in the context of neurodegenerative diseases.
Abstract: The sigma(1) receptor is a 223 amino acid protein sharing no homology with other mammalian protein. It is an intracellular protein present on the endoplasmic reticulum membrane, which can translocates to other organelles and plasma membranes after activation. Activation of the sigma(1) receptor results in modulation of calcium mobilization from inositol trisphosphate receptor-gated intracellular pools and, at the plasma membrane, in modulation of several neurotransmitter responses. Behaviorally, sigma(1) receptors are involved in learning and memory, response to stress and depression, psychostimulant-induced sensitization, vulnerability to addiction and pain perception. Numerous synthetic compounds bind to sigma(1) receptor, playing the role of activator/agonist or blocker/antagonist, and these include benzomorphans, neuroleptics, antidepressants, cocaine, peptides related to neuropeptide Y or calcitonin gene-related peptide. It is also the case of neuro(active)steroids, i. e., circulating neuroactive steroids and neurosteroids synthesized de novo by the brain, which appear as the most important endogenous modulators of sigma(1) receptor. Pregnenolone and dehydroepiandrosterone act as sigma(1) receptor agonists and progesterone is a potent antagonist. The present paper will review the molecular and biochemical features concerning the sigma(1) receptor and focus on the recent studies examining the impact of the neuro(active)steroid/sigma(1) receptor interaction on the antidepressant activity of sigma(1) receptor agonists in the context of neurodegenerative diseases.
64 citations
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TL;DR: This review will highlight the possible therapeutic uses of PREG that point towards the development of pregnenolone-like molecules and the possible functional role of PREg with an outline of the modulation of PREGs levels in animal and in human research.
64 citations
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TL;DR: Although interferon (IFN) decreases the expression of P450IIIA2, it may not down regulate theexpression of other steroid-inducible P 450IIIA proteins, which may help predict possible drug interactions in patients receiving IFN.
Abstract: The aim of this study was to clarify the mechanism by which cytochrome P450 (P450)-mediated catalytic activity is decreased following interferon (IFN) administration. Microsomal steroid hydroxylation was assessed to test the hypothesis that IFN selectively decreases the activities of individual P450 isozymes in male rats. Thus, recombinant rat IFN gamma (r-rat IFN gamma) treatment produced 40% and 17% reductions in androst-4-ene-3,17-dione (androstenedione) 6 beta- and 16 beta-hydroxylation, respectively. Androstenedione 16 alpha- and 7 alpha-hydroxylation were unaltered following r-rat IFN gamma treatment. Similar changes in the androstenedione hydroxylation pathways were observed following administration of naturally derived rat IFN alpha/beta. Microsomal levels of P450IIIA2, the male-specific constitutive steroid 6 beta-hydroxylase, were lower after administration of r-rat IFN gamma (42% of control fractions). Furthermore, hepatic P450IIIA2 mRNA was found to be decreased to a similar extent by r-rat IFN gamma. These findings suggest that IFN selectively decreases the content of this isozyme by a mechanism involving altered mRNA regulation. Sex steroids were unlikely to have mediated the decrease in P450IIIA2 levels since serum estradiol and testosterone levels were unchanged by r-rat IFN gamma. In order to determine whether IFN alters the expression of P450IIIA1, a steroid-inducible member of the P450IIIA gene subfamily which is not expressed in untreated rat liver, adult female rats (which lack P450IIIA2) were coadministered pregnenolone 16 alpha-carbonitrile and r-rat IFN gamma. However, IFN failed to impair the induction of androstenedione 6 beta-hydroxylation produced by pregnenolone 16 alpha-carbonitrile. These findings suggest that although IFN decreases the expression of P450IIIA2, it may not down regulate the expression of other steroid-inducible P450IIIA proteins. In view of the existence of human P450IIIA orthologs which catalyze the metabolism of several important therapeutic agents, the findings of this study may help predict possible drug interactions in patients receiving IFN.
64 citations
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TL;DR: The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma, non-small cell lung cancer and CNS cancer were studied and some of tested compounds were found to exhibit much higher inhibitory effects towards the three tumor cell Lines than the reference drug, doxorubicin.
64 citations