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Anat Biegon - One of the best experts on this subject based on the ideXlab platform.
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Aromatase and neuroinflammation in rat focal brain ischemia
The Journal of Steroid Biochemistry and Molecular Biology, 2017Co-Authors: Yu H. Zhong, Joel A. Kovoor, Wei X. Zhang, Dennis W Choi, Jasbeer Dhawan, John Sullivan, Anat BiegonAbstract:Abstract Accumulating evidence suggests that expression of Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is transiently upregulated in rat stroke models. It was further suggested that increased Aromatase expression is linked to neuroinflammation and that it is neuroprotective in females. Our goal was to investigate Aromatase upregulation in male rats subjected to experimental stroke in relationship to neuroinflammation, infarct and response to treatment with different putative neuroprotective agents. Intact male rats were subjected to transient (90 min) middle cerebral artery occlusion (MCAO) and administered selfotel (N-methyl- d -aspartic acid (NMDA) receptor competitive antagonist), TPEN (a zinc chelator), a combination of the two drugs or vehicle, injected immediately after reperfusion. Animals were killed 14 days after MCAO and consecutive brain sections used to measure Aromatase expression, cerebral infarct volume and neuroinflammation. Quantitative immunohistochemistry (IHC) demonstrated increased brain Aromatase expression in the peri-infarct area relative to contralesional area, which was partially abrogated by neuroprotective agents. There was no correlation between Aromatase expression in the peri-infarct zone and infarct volume, which was reduced by neuroprotective agents. Microglial activation, measured by quantitative autoradiography, was positively correlated with infarct and inversely correlated with Aromatase expression in the peri-infarct zone. Our findings indicate that focal ischemia upregulates brain Aromatase in the male rat brain at 14 days post surgery, which is within the time frame documented in females. However, the lack of negative correlation between Aromatase expression and infarct volume and lack of positive correlation between microgliosis and Aromatase do not support a major role for Aromatase as a mediator of neuroprotection or a causal relationship between microglial activation and increased Aromatase expression in male focal ischemia.
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In vivo visualization of Aromatase in animals and humans.
Frontiers in neuroendocrinology, 2015Co-Authors: Anat BiegonAbstract:Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of Aromatase can be performed using positron emission tomography (PET) with radiolabeled Aromatase inhibitors such as [(11)C]vorozole. PET studies in rats, monkeys and healthy human subjects demonstrate widespread but heterogeneous Aromatase availability in brain and body, which appears to be regulated in a species, sex and region-specific manner. Thus, Aromatase availability is high in brain amygdala and in ovaries of all species examined to date, with males demonstrating higher levels than females in all comparable organs. However, the highest concentrations of Aromatase in the human brain are found in specific nuclei of the thalamus while the highest levels in rats and monkeys are found in the amygdala. Regional brain Aromatase availability is increased by androgens and inhibited by nicotine. Future studies may improve diagnosis and treatment in brain disorders and cancers overexpressing Aromatase.
Yoshitaka Nagahama - One of the best experts on this subject based on the ideXlab platform.
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two types of Aromatase with different encoding genes tissue distribution and developmental expression in nile tilapia oreochromis niloticus
General and Comparative Endocrinology, 2005Co-Authors: Xiaotian Chang, Thoru Kobayashi, B Senthilkumaran, Hiroko Kobayashikajura, Cheni Chery Sudhakumari, Yoshitaka NagahamaAbstract:We isolated a novel type of Aromatase cDNA from a Nile tilapia (Oreochromis niloticus) ovary cDNA library. Because this Aromatase is phylogenetically related to brain Aromatase (CYP19b) of goldfish, zebrafish and sea bass, we named it tilapia CYP19b (tCYP19b). tCYP19b encodes a protein that is predicted to consist of 495 residues and have 63.8% homology with the Aromatase (tCYP19a) we previously isolated from the same source. In vitro transient transfection of cultured COS7 cells demonstrated that tCYP19b codes a functional protein to catalyze estrogen production from an androgen substrate. RT-PCR and Northern hybridization analysis showed that tCYP19b was expressed at a high level in the brain and at a low level in a wide variety of other tissues, whereas tCYP19a was mainly present in the ovary and its level significantly increased during the vitellogenic stage. RT-PCR also detected tCYP19b expression in brain and gonad tissues of both female and male tilapia during sex differentiation, but tCYP19a was only found in the ovary of the fry at that period. These results suggest that tCYP19a plays a key role in sex differentiation and ovarian development. We also isolated genes of two tilapia Aromatases. Based on the location of the transcription initiation site, we predicted that there is one promoter for tCYP19a and three promoters for tCYP19b. Although the two Aromatase isoforms have similar gene structures in the coding region, we found that the binding regions of SF-1/Ad4 BP region, WT1-KTS and SRY, which are sex-determining factors in mammals, are present in the 5′ flank region of tCYP19a but not tCYP19b. A similar situation is present in promoters of zebrafish and goldfish Aromatase isoforms. This data indicates that CYP19a plays a decisive role in sex differentiation of those species. The unique presence of the ERE motif in the tCYP19b promoter and the high expression of tCYP19b in the brain support that CYP19b is mainly involved in estrogen-mediated neural estrogen synthesis.
François Brion - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of rainbow trout (Oncorhynchus mykiss) P450 Aromatase activities in brain and ovarian microsomes by various environmental substances
Comparative Biochemistry and Physiology - Part C: Toxicology and Pharmacology, 2006Co-Authors: Nathalie Hinfray, Jean-marc Porcher, François BrionAbstract:Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on Aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal Aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal Aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian Aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian Aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high uM range depending on the substance: steroidal and non steroidal inhibitors of Aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal Aromatase assay is suitable for evaluating potential Aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish.
Serdar E Bulun - One of the best experts on this subject based on the ideXlab platform.
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jund and junb integrate prostaglandin e2 activation of breast cancer associated proximal Aromatase promoters
Molecular Endocrinology, 2011Co-Authors: Dong Chen, Scott Reierstad, Feng Fang, Serdar E BulunAbstract:Aromatase is the key enzyme in estrogen biosynthesis. Normal breast adipose tissue expresses low levels of Aromatase via the distal promoter I.4. Breast adipose tissue surrounding a tumor exhibits excessive Aromatase expression controlled by proximal Aromatase promoters I.3/II, leading to high local levels of estrogen and breast cancer progression. Prostaglandin E2 (PGE2) secreted by malignant breast epithelial cells activates breast cancer-associated Aromatase promoters I.3/II, but silences promoter I.4, in cultured human breast adipose fibroblasts (BAF). The c-Jun N-terminal kinase 1 and p38α mitogen activated protein kinases are necessary for PGE2 activation of Aromatase promoters I.3/II; thus, we examined the roles of downstream targets, c-Jun, JunB, JunD, and activating transcription factor 2, in PGE2-mediated regulation of Aromatase expression in BAF. PGE2 induced JunB and JunD protein expression through protein kinase A and protein kinase C, respectively. JunB or JunD knockdown by small interfering RNA markedly reduced PGE2-induced total Aromatase mRNA level and enzyme activity via promoters I.3/II. JunB knockdown also abrogated JunD expression. JunB stimulated, whereas JunD inhibited, Aromatase promoter I.4 activity. Activating transcription factor 2 knockdown did not affect promoter-specific or total Aromatase mRNA levels. c-Jun knockdown increased promoter I.4-specific and PGE2-induced promoters I.3/II-specific Aromatase mRNA levels, leading to enhanced PGE2-induced total Aromatase mRNA level and enzyme activity. JunD, c-Jun, and JunB bound to a CRE(−211/−199) essential for PGE2 induction of Aromatase promoters I.3/II. Taken together, JunD and c-Jun repress Aromatase promoter I.4. JunD mediates, whereas c-Jun modulates, PGE2 activation of Aromatase promoters I.3/II via CRE(−211/−199). JunB also activates Aromatase promoters I.3/II by maintaining JunD expression. Targeting JunD may abolish Aromatase expression selectively in breast cancer tissue.
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regulation of Aromatase expression in estrogen responsive breast and uterine disease from bench to treatment
Pharmacological Reviews, 2005Co-Authors: Serdar E Bulun, Zhihong Lin, Gonca Imir, Sanober Amin, Masashi Demura, Bertan Yilmaz, Regina Matsunaga Martin, Hiroki Utsunomiya, Steven Thung, Bilgin GuratesAbstract:A single gene encodes the key enzyme for estrogen biosynthesis termed Aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and Aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express Aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress Aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control Aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for Aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase Aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent Aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the Aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of Aromatase in many tissues.
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Aromatase in endometriosis and uterine leiomyomata.
The Journal of Steroid Biochemistry and Molecular Biology, 2005Co-Authors: Serdar E Bulun, Gonca Imir, Hiroki Utsunomiya, Steven Thung, Bilgin Gurates, Mitsutoshi Tamura, Zhihong LinAbstract:Endometrial tissue from uterine disease-free women does not exhibit Aromatase activity. In contrast, Aromatase enzyme activity and mRNA levels are readily detectable in endometriosis. PGE2 stimulates both Aromatase expression and activity in endometriotic stromal cells via promoter II region of the Aromatase gene. This results in local production of estradiol, which induces PGE2 formation and establishes a positive feedback cycle. This mechanism seems to contribute to continuous production of estradiol and PGE2. Aromatase mRNA levels and enzyme activity are also present in uterine leiomyomata that are estrogen-dependent benign tumors of the myometrium. Successful treatment of endometriosis and uterine leiomyomata using Aromatase inhibitors by recent pilot trials underscores the clinical significance of these molecular studies.
David J Penman - One of the best experts on this subject based on the ideXlab platform.
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cloning of brain Aromatase gene and expression of brain and ovarian Aromatase genes during sexual differentiation in genetic male and female nile tilapia oreochromis niloticus
Molecular Reproduction and Development, 2001Co-Authors: Joon Yeong Kwon, B J Mcandrew, David J PenmanAbstract:A brain Aromatase gene was identified from the Nile tilapia Oreochromis niloticus. The cDNA sequence of this gene differed from that of the ovarian Aromatase gene previously reported from this species. Tissue specific expression for both brain and ovarian Aromatase genes was examined in the tissues of adult tilapia. Brain Aromatase mRNA was expressed in the brain, kidney, eye, ovary, and testis, but not in the liver and spleen. Ovarian Aromatase mRNA was expressed in the brain, spleen, ovary, and testis but not in the eye, kidney, and liver. Differential Aromatase gene expression between the sexes was investigated in all-male (XY) and all-female (XX) groups of tilapia fry from fertilisation throughout the sexual differentiation period. Semi-quantitative RT-PCR analysis revealed that the initiation of expression of both Aromatase genes lay between 3 and 4 dpf (days post fertilisation) in both sexes. The level of brain Aromatase mRNA gradually increased throughout the period studied with little difference between the sexes. This contrasted with marked sexual dimorphism of ovarian Aromatase mRNA expression. In females, the expression level was maintained or increased gradually throughout ontogeny, while the level in males was dramatically down-regulated between 15 and 27 dpf. Subsequently, the level of ovarian Aromatase mRNA expression fluctuated slightly in both sexes, with the expression in females always being higher than in males. These findings clearly suggest that ovarian Aromatase plays a decisive role in sexual differentiation in this species and that this is achieved by down-regulation of the expression of this gene in males. Mol. Reprod. Dev. 59: 359–370, 2001. © 2001 Wiley-Liss, Inc.