scholarly journals Aging and Loss of Circulating 17β-Estradiol Alters the Alternative Splicing of ERβ in the Female Rat Brain

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4187-4199 ◽  
Author(s):  
Cody L. Shults ◽  
Elena Pinceti ◽  
Yathindar S. Rao ◽  
Toni R. Pak
Keyword(s):  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Topoisomerase I ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Hormone Replacement ◽  
Female Rats ◽  
Female Rat ◽  
Age Related ◽  
17Β Estradiol

Loss of circulating 17β-estradiol (E2) that occurs during menopause can have detrimental effects on cognitive function. The efficacy of hormone replacement therapy declines as women become farther removed from the menopausal transition, yet the molecular mechanisms underlying this age-related switch in E2 efficacy are unknown. We hypothesized that aging and varying lengths of E2 deprivation alters the ratio of alternatively spliced estrogen receptor (ER)β isoforms in the brain of female rats. Further, we tested whether changes in global transcriptional activity and splicing kinetics regulate the alternative splicing of ERβ. Our results revealed brain region-specific changes in ERβ alternative splicing in both aging and E2-deprivation paradigms and showed that ERβ could mediate E2-induced alternative splicing. Global transcriptional activity, as measured by phosphorylated RNA polymerase II, was also regulated by age and E2 in specific brain regions. Finally, we show that inhibition of topoisomerase I resulted in increased ERβ2 splice variant expression.

scholarly journals Effects of Combined Estrogen and Progesterone on Brain Infarction in Reproductively Senescent Female Rats

2004 ◽  
Vol 24 (10) ◽  
pp. 1160-1166 ◽  
Author(s):  
Thomas J. Toung ◽  
Tsung-Ying Chen ◽  
Marguerite T. Littleton-Kearney ◽  
Patricia D. Hurn ◽  
Stephanie J. Murphy
Keyword(s):  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Postmenopausal Women ◽  
Brain Infarction ◽  
Combined Therapy ◽  
Hormone Replacement ◽  
Treated Group ◽  
Female Rats ◽  
Female Rat ◽  
Triphenyltetrazolium Chloride

Recent data from the Women's Health Initiative have highlighted many fundamental issues about the utility and safety of long-term estrogen use in women. Current hormone replacement therapy for postmenopausal women incorporates progestin with estrogen, but it is uncertain if combined therapy provides major cerebrovascular risks or benefits to these women. No experimental animal stroke studies have examined combined hormone administration. The authors tested the hypothesis that combined hormone treatment reduces ischemic injury in middle-aged female rat brain. Reproductively senescent female rats underwent 2-hour middle cerebral artery occlusion (MCAO) followed by 22 hours reperfusion. Estrogen implants were placed subcutaneously at least 7 days before MCAO, and progesterone intraperitoneal injections were given 30 minutes before MCAO, at initiation, and at 6 hours of reperfusion. Rats received no hormone, a 25-μg estrogen implant, a 25-μg estrogen implant plus 5 mg/kg intraperitoneal progesterone, or 5 mg/kg intraperitoneal progesterone. Cortical, caudoputamen, and total infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis at 22 hours reperfusion. Cortical and total infarct volumes, except in the acute progesterone-treated group, were significantly attenuated in all estrogen-alone and combined hormone-treated groups. There were no significant differences in caudoputamen infarct volumes in all hormone-treated groups as compared with untreated rats. These data have potential clinical implications relative to stroke for postmenopausal women taking combined hormone replacement therapy.

Flurothyl-induced convulsions delay the onset of sexual maturation in the female rat

1982 ◽  
Vol 95 (1) ◽  
pp. 37-41 ◽  
Author(s):  
M. Wilkinson ◽  
R. Bhanot ◽  
J. A. Pincock ◽  
L. Donald
Keyword(s):  
Sexual Maturation ◽  
Serum Levels ◽  
Female Rats ◽  
Female Rat ◽  
Basal Serum ◽  
Age Related ◽  
Lh Release ◽  
Gonadotrophin Releasing Hormone ◽  
Related Increase

We have investigated whether sexual maturation in female rats is affected by repeated flurothyl-induced convulsions. This treatment had no effect on the normal age-related increase in body weight though puberty (vaginal opening) was significantly delayed when compared with non-convulsed control rats. In an attempt to probe the mechanism of this delaying effect we observed that (1) anterior pituitary response to gonadotrophin releasing hormone in vitro was normal in terms of LH release but FSH secretion was impaired and (2) progesterone injection in oestrogen-primed convulsed rats failed to generate an ovulatory-type surge of LH or FSH. Basal serum levels and basal in-vitro secretion of LH and FSH were normal. We conclude that repeated convulsions adversely affect the hypothalamo-pituitary-gonadotrophin system of immature female rats.

Profound cardioprotection with timolol in a female rat model of aging-related altered left ventricular function

2011 ◽  
Vol 89 (4) ◽  
pp. 277-288 ◽  
Author(s):  
Nazli N. Sozmen ◽  
Erkan Tuncay ◽  
Ayca Bilginoglu ◽  
Belma Turan
Keyword(s):  
Antioxidant System ◽  
Ventricular Myocytes ◽  
Heart Function ◽  
Thioredoxin Reductase ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Beneficial Effects ◽  
Age Related

Increasing evidence shows a marked beneficial effect with β-blockers in heart dysfunction via scavenging reactive oxygen species. Previously we showed that chronic treatment with either timolol or propranolol possessed similar beneficial effects for heart function in male rats as age increased, whereas only timolol exerted similar benefits in female rats. Therefore, in this study, we aimed first to examine the cellular bases for age-related alterations in excitation–contraction coupling in ventricular myocytes from female rats and, second, to investigate the hypothesis that age-related changes in [Ca2+]ihomeostasis and receptor-mediated system can be prevented with chronic timolol treatment. Chronic timolol treatment of 3-month-old female rats abolished age-related decrease in left ventricular developed pressure and the attenuated responses to β-adrenoreceptor stimulation. It also normalized the altered parameters of [Ca2+]itransients, decreased Ca2+loading of sarcoplasmic reticulum and increased basal [Ca2+]i, and decreased L-type Ca2+currents in 12-month-old female rats compared with the 3-month-old group. Adenylyl cyclase activity, β-adrenoreceptor affinity to its agonist, and β-adrenoreceptor density of the 12-month-old group are normalized to those of the 3-month-old group. Moreover, timolol treatment prevented dysfunction of the antioxidant system, including increased lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and decreased activities of thioredoxin reductase and glucose-6-phosphate dehydrogenase, in the left ventricle of hearts from the 12-month-old group. Our data confirmed that aging-related early myocardial impairment is primarily related to a dysfunctional antioxidant system and impairment of Ca2+homeostasis, which can be prevented with chronic timolol treatment.

scholarly journals Protein-DNA cross-linking reveals dramatic variation in RNA polymerase II density on different histone repeats of Drosophila melanogaster.

1987 ◽  
Vol 7 (9) ◽  
pp. 3341-3344 ◽  
Author(s):  
D S Gilmour ◽  
J T Lis
Keyword(s):  
Drosophila Melanogaster ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Topoisomerase I ◽  
Transcriptional Activity ◽  
Base Pairs ◽  
Nontranscribed Spacer ◽  
Short Repeat ◽  
Dramatic Variation

In Drosophila melanogaster the five histone genes are within a 5-kilobase region which is repeated 100 times at a single chromosomal site. These 5-kilobase repeats are of two distinct classes, short and long, that differ by approximately 200 base pairs of DNA in the spacer region between the H1 and H3 genes. Since the mRNA-homologous regions of the repeats are highly conserved, one cannot examine differential expression of the repeats by classical hybridization methods. In this study, we assessed their transcriptional activity by measuring in vivo the relative amounts of RNA polymerase II that were cross-linked by UV irradiation to the two different histone repeats. The RNA polymerase II density on the long repeat in Schneider line 2 cells was strikingly lower (10-fold) than the density on the short repeat. The magnitude of this difference cannot be accounted for by reduced transcription of only one or two genes of the repeat. The density of topoisomerase I, an indicator of transcriptional activity, was also much higher on the short repeat than on the long repeat of line 2 cells. In contrast, the RNA polymerase II density was slightly higher on the long repeat than on the short repeat in a second cell line, KcH. The major difference between active (KcH) and inactive (S2) long repeats resides in the H1-H3 nontranscribed spacer. This portion of the spacer may contain a component necessary for expression that can act over a moderate distance and affect multiple genes of the repeat.

scholarly journals Erythropoietin-producing hepatocellular receptor A7 restrains estrogen negative feedback of luteinizing hormone via ephrin A5 in the hypothalamus of female rats

2020 ◽  
Vol 319 (1) ◽  
pp. E81-E90 ◽  
Author(s):  
Shang Li ◽  
Junyu Zhai ◽  
Bing Xu ◽  
Jiansheng Liu ◽  
Weiwei Chu ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Negative Feedback ◽  
Female Rats ◽  
Female Rat ◽  
Female Reproduction ◽  
Systemic Injection ◽  
Serum Luteinizing Hormone ◽  
Serum Lh ◽  
17Β Estradiol ◽  
Lh Secretion

We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERβ, inhibited Efna5 and gonadotropin-releasing hormone 1 ( Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

Abstract P799: Nicotine Along With Oral Contraceptive Exposure Alters Brain Lipid Metabolism and Exacerbates Ischemic Injury in Female Rats

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Jonathan Siegel ◽  
Francisca Diaz ◽  
Ami P Raval
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Female Rats ◽  
Pathway Enrichment Analysis ◽  
Female Rat ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Activity Measurements ◽  
Metabolic Fingerprint

Background: Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate both global and focal ischemic brain damage in females. While the underlying mechanisms remain elusive, our published study showed that OC exacerbate N toxicity via altered mitochondrial electron transport chain function. Because mitochondria play a central role in cellular metabolism, we examined the metabolic fingerprint of adolescent and adult female rat brains exposed to N +/- OC. Methods: Adolescent (6 weeks old) and adult (12 weeks old) Sprague-Dawley female rats were randomly (n = 8/group) exposed to either saline, N (4.5 mg/kg) +/- OC for 16-21 days. Following treatment, brain tissue was harvested for unbias metabolomic analysis (performed by Metabolon Inc.). The metabolomic profile was complemented with western blot analysis and enzyme activity measurements. Results: Pathway enrichment analysis showed significant alterations in lipid metabolism. Adolescent but not adult females treated with N, OC and N+OC compared to saline showed significant increases in carnitine conjugated fatty acid metabolites such as arachidonoylcarnitine (C20:4), docosahexaenoylcarnitine (C22:6) and stearoylcarnitine (C18). These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, 3-hydroxybutyrate (BHBA) was significantly lower in OC and N+OC treatment group in adolescent animals, implying a complete shunting of acetyl CoA for energy production via TCA cycle. BHBA is a ketone body that increases in concentration as lipid oxidation rates increase with acetyl CoA accumulation. Reduced BHBA levels may also suggest mitochondrial dysfunction in response to OC and N+OC treatment. Conclusion: The observed changes in the metabolic fingerprint and fatty acid metabolism reflect a general alteration in energy metabolism with nicotine treatment exclusively in young animals and these changes are enhanced by N+OC treatment. Discerning the exact effects of N +/- OC on overall brain metabolism and the molecular mechanisms affecting mitochondrial function at different ages will open a new window for future therapeutic intervention.

OSTEOPOROSIS AFTER OOPHORECTOMY IN THE MATURE FEMALE RAT AND THE EFFECT OF OESTROGEN AND/OR PROGESTOGEN REPLACEMENT THERAPY IN ITS PREVENTION

1972 ◽  
Vol 55 (1) ◽  
pp. 79-87 ◽  
Author(s):  
J. M. AITKEN ◽  
E. ARMSTRONG ◽  
J. B. ANDERSON
Keyword(s):  
Replacement Therapy ◽  
Mineral Content ◽  
Unit Length ◽  
Hormone Replacement ◽  
Mature Female ◽  
Relative Increase ◽  
Female Rats ◽  
Female Rat ◽  
New Bone Formation ◽  
Femoral Morphology

SUMMARY Fifty-two mature female rats on a controlled diet were studied to compare the effects of oophorectomy, and hormone replacement therapy after oophorectomy, on femoral morphology and mineral content. Oophorectomy was followed by the development of osteoporosis after 11 months of observation. This was characterized by a reduction in ash per unit length of bone and a diminution of mid-shaft femoral cortical width. The administration of a progestogen (9 μg ethynodiol diacetate/rat/day) for 10 months after oophorectomy prevented the reduction in ash per unit length from occurring, whereas an oestrogen (0·9 μg mestranol/rat/day) had no significant effect on either parameter of osteoporosis. The progestogen appeared to produce this effect by a relative increase in periosteal new bone formation at the expense of increased loss of bone from the endosteal surface.

scholarly journals 17β-Estradiol Increases Astrocytic Vascular Endothelial Growth Factor (VEGF) in Adult Female Rat Hippocampus

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1745-1751 ◽  
Author(s):  
Sharon Barouk ◽  
Tana Hintz ◽  
Ping Li ◽  
Aine M. Duffy ◽  
Neil J. MacLusky ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Adult Female ◽  
Serum Levels ◽  
Female Rats ◽  
Female Rat ◽  
Vascular Endothelial ◽  
17Β Estradiol ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Vascular endothelial growth factor (VEGF) is critical to angiogenesis and vascular permeability. It is also important in the endocrine system, in which VEGF mediates the vascular effects of estrogens in target tissues such as the uterus, a response attributed to an estrogen response element on the VEGF gene. Here we asked whether 17β-estradiol increases VEGF levels in the brain. We focused on the hippocampus, in which 17β-estradiol and VEGF both have important actions, and used immunocytochemistry to evaluate VEGF protein. VEGF immunoreactivity was compared in adult female rats sampled during the estrous cycle when serum levels of 17β-estradiol peak (proestrous morning) as well as when they are low (metestrous morning). In addition, adult rats were ovariectomized and compared after treatment with 17β-estradiol or vehicle. The results demonstrated that VEGF immunoreactivity was increased when serum levels of 17β-estradiol were elevated. Confocal microscopy showed that VEGF immunofluorescence was predominantly nonneuronal, often associated with astrocytes. Glial VEGF labeling was primarily punctate rather than diffuse and labile because glial VEGF immunoreactivity was greatly reduced if tissue sections were left in an aqueous medium overnight. We conclude that VEGF protein in normal female hippocampus is primarily nonneuronal rather than neuronal and suggest that glial VEGF immunoreactivity has been underestimated by past studies with other methods because there is a labile extracellular pool. We suggest that estrogens may exert actions on female hippocampal structure and function by increasing hippocampal VEGF.

scholarly journals Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction

Reproduction ◽  
2016 ◽  
Vol 152 (5) ◽  
pp. 403-415 ◽  
Author(s):  
Paola I Ingaramo ◽  
Jorgelina Varayoud ◽  
María M Milesi ◽  
Marlise Guerrero Schimpf ◽  
Mónica Muñoz-de-Toro ◽  
...  
Keyword(s):  
Reproductive Performance ◽  
Molecular Mechanisms ◽  
Steroid Receptors ◽  
Morphological Changes ◽  
Progesterone Receptors ◽  
Female Rats ◽  
Neonatal Exposure ◽  
Female Rat ◽  
Cell Cycle Regulators ◽  
Adult Rats

In this study, we investigated whether neonatal exposure to a glyphosate-based herbicide (GBH) alters the reproductive performance and the molecular mechanisms involved in the decidualization process in adult rats. Newborn female rats received vehicle or 2 mg/kg/day of a GBH on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate (i) the reproductive performance on gestational day (GD) 19 and (ii) the ovarian steroid levels, uterine morphology, endometrial cell proliferation, apoptosis and cell cycle regulators, and endocrine pathways that regulate uterine decidualization (steroid receptors/COUP-TFII/Bmp2/Hoxa10) at the implantation sites (IS) on GD9. The GBH-exposed group showed a significant increase in the number of resorption sites on GD19, associated with an altered decidualization response. In fact, on GD9, the GBH-treated rats showed morphological changes at the IS, associated with a decreased expression of estrogen and progesterone receptors, a downregulation of COUP-TFII (Nr2f2) and Bmp2 mRNA and an increased expression of HOXA10 and the proliferation marker Ki67(Mki67) at the IS. We concluded that alterations in endometrial decidualization might be the mechanism of GBH-induced post-implantation embryo loss.

scholarly journals Alternative Mechanisms by Which Mediator Subunit MED1/TRAP220 Regulates Peroxisome Proliferator-Activated Receptor γ-Stimulated Adipogenesis and Target Gene Expression

2007 ◽  
Vol 28 (3) ◽  
pp. 1081-1091 ◽  
Author(s):  
Kai Ge ◽  
Young-Wook Cho ◽  
Hong Guo ◽  
Teresa B. Hong ◽  
Mohamed Guermah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cultured Fibroblasts ◽  
Target Gene Expression

ABSTRACT Mediator is a general coactivator complex connecting transcription activators and RNA polymerase II. Recent work has shown that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome proliferator-activated receptor γ (PPARγ)-stimulated adipogenesis of mouse embryonic fibroblasts (MEFs). However, the molecular mechanisms remain undefined. Here, we show an intracellular PPARγ-Mediator interaction that requires the two LXXLL nuclear receptor recognition motifs on MED1/TRAP220 and, furthermore, we show that the intact LXXLL motifs are essential for optimal PPARγ function in a reconstituted cell-free transcription system. Surprisingly, a conserved N-terminal region of MED1/TRAP220 that lacks the LXXLL motifs but gets incorporated into Mediator fully supports PPARγ-stimulated adipogenesis. Moreover, in undifferentiated MEFs, MED1/TRAP220 is dispensable both for PPARγ-mediated target gene activation and for recruitment of Mediator to a PPAR response element on the aP2 target gene promoter. However, PPARγ shows significantly reduced transcriptional activity in cells deficient for a subunit (MED24/TRAP100) important for the integrity of the Mediator complex, indicating a general Mediator requirement for PPARγ function. These results indicate that there is a conditional requirement for MED1/TRAP220 and that a direct interaction between PPARγ and Mediator through MED1/TRAP220 is not essential either for PPARγ-stimulated adipogenesis or for PPARγ target gene expression in cultured fibroblasts. As Mediator is apparently essential for PPARγ transcriptional activity, our data indicate the presence of alternative mechanisms for Mediator recruitment, possibly through intermediate cofactors or other cofactors that are functionally redundant with MED1/TRAP220.

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