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Item 17-Beta estradiol-induced modulation of the immune system(1984) Myers, Michael JosephItem Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel(American Society for Biochemistry and Molecular Biology, 2019-02-22) Ma, Wenzhen; Chen, Xingjuan; Cerne, Rok; Syed, Samreen K.; Ficorilli, James V.; Cabrera, Over; Obukhov, Alexander G.; Efanov, Alexander M.; Cellular and Integrative Physiology, School of MedicineEstrogen hormones play an important role in controlling glucose homeostasis and pancreatic β-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic β-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic β-cells. We show that catechol estrogens, hydroxylated at positions C2 and C4 of the steroid A ring, rapidly potentiated glucose-induced insulin secretion via a nongenomic mechanism. 2-Hydroxyestrone, the most abundant endogenous estrogen metabolite, was more efficacious in stimulating insulin secretion than any other tested catechol estrogens. In insulin-secreting cells, catechol estrogens produced rapid activation of calcium influx and elevation in cytosolic free calcium. Catechol estrogens also generated sustained elevations in cytosolic free calcium and evoked inward ion current in HEK293 cells expressing the transient receptor potential A1 (TRPA1) cation channel. Calcium influx and insulin secretion stimulated by estrogen metabolites were dependent on the TRPA1 activity and inhibited with the channel-specific pharmacological antagonists or the siRNA. Our results suggest the role of estrogen metabolism in a direct regulation of TRPA1 activity with potential implications for metabolic diseases.Item Characterization of Spontaneous and Induced Puberty in Girls with Turner Syndrome(American Association of Clinical Endocrinologists, 2017-07) Folsom, Lisal J.; Slaven, James E.; Nabhan, Zeina M.; Eugster, Erica A.; Medicine, School of MedicineOBJECTIVE: To characterize puberty in girls with Turner syndrome (TS) and determine whether specific patient characteristics are associated with the timing of menarche. We also sought to compare spontaneous versus induced puberty in these patients. METHODS: Medical records of girls followed in our Pediatric Endocrine clinic for TS from 2007 to 2015 were reviewed. RESULTS: Fifty-three girls were included, of whom 10 (19%) achieved menarche spontaneously and 43 (81%) received hormone replacement therapy (HRT). Of girls receiving HRT, a younger age at estrogen initiation correlated with a longer time to menarche (P = .02), and a mosaic karyotype was associated with a shorter time to menarche (P = .02), whereas no relationship was seen for body mass index, estrogen regimen, or maternal age at menarche. Nineteen girls (44%) receiving HRT had bleeding on estrogen alone at a wide dose range and were more likely to be on transdermal than oral preparations (P = .01). Girls with spontaneous puberty achieved menarche at a younger age (P<.01) and were more likely to have mosaic TS (P = .02). CONCLUSION: Significant variability in the timing of menarche exists among girls with TS. However, age at pubertal induction and karyotype were significantly correlated with age at menarche in our patients. A wide range of estrogen doses is seen in girls who bleed prior to progesterone, suggesting extreme variability in estrogen sensitivity among patients with TS. Girls achieving spontaneous menarche are younger and more likely to have a mosaic karyotype than those with induced menarche. Large-scale prospective studies are needed to confirm these results.Item DNA methylation age is elevated in breast tissue of healthy women(Springer, 2017-07) Sehl, Mary E.; Henry, Jill E.; Storniolo, Anna Maria; Ganz, Patricia A.; Horvath, Steve; Medicine, School of MedicineBACKGROUND: Limited evidence suggests that female breast tissue ages faster than other parts of the body according to an epigenetic biomarker of aging known as the "epigenetic clock." However, it is unknown whether breast tissue samples from healthy women show a similar accelerated aging effect relative to other tissues, and what could drive this acceleration. The goal of this study is to validate our initial finding of advanced DNA methylation (DNAm) age in breast tissue, by directly comparing it to that of peripheral blood tissue from the same individuals, and to do a preliminary assessment of hormonal factors that could explain the difference. METHODS: We utilized n = 80 breast and 80 matching blood tissue samples collected from 40 healthy female participants of the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center who donated these samples at two time points spaced at least a year apart. DNA methylation levels (Illumina 450K platform) were used to estimate the DNAm age. RESULTS: DNAm age was highly correlated with chronological age in both peripheral blood (r = 0.94, p < 0.0001) and breast tissues (r = 0.86, p < 0.0001). A measure of epigenetic age acceleration (age-adjusted DNAm Age) was substantially increased in breast relative to peripheral blood tissue (p = 1.6 × 10-11). The difference between DNAm age of breast and blood decreased with advancing chronologic age (r = -0.53, p = 4.4 × 10-4). CONCLUSIONS: Our data clearly demonstrate that female breast tissue has a higher epigenetic age than blood collected from the same subject. We also observe that the degree of elevation in breast diminishes with advancing age. Future larger studies will be needed to examine associations between epigenetic age acceleration and cumulative hormone exposure.Item DVL regulation of tissue-specific aromatase transcripts in breast cancer(Impact Journals, 2018-12-25) O'Hagan, Heather M.; Medical Sciences, IU School of MedicineItem Editorial: Sex steroid hormones: effects on breast cancer risk and etiology(Frontiers Media, 2023-04-19) Mousa, Noha A.; Marino, Natascia; Simões, Bruno M.; Medicine, School of MedicineItem Effects of estrogen depletion and drug treatment on collagen microstructure: implications(SpringerNature, 2015-05-27) Wallace, Joseph M.; Bone, Henry G.; Department of Biomedical Engineering, School of Engineering and TechnologyCommentary on: Cauble MA, Rothman E, Welch K, Fang M, Duong LT, Pennypacker BL, Orr BG, Holl MMB. Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment. BoneKEy 2015; 4: 697. doi:10.1038/ bonekey.2015.66.Item Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance(Wiley, 2022) Conley, Alexander C.; Albert, Kimberly M.; McDonald, Brenna C.; Saykin, Andrew J.; Dumas, Julie A.; Newhouse, Paul A.; Radiology and Imaging Sciences, School of MedicineObjective: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints. Methods: Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). Results: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. Conclusions: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.Item Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia(Elsevier, 2009-04) Erwin, Graham S.; Crisostomo, Paul R.; Wang, Yue; Wang, Meijing; Markel, Troy A.; Guzman, Mike; Sando, Ian C.; Sharma, Rahul; Meldrum, Daniel R.; Surgery, School of MedicineBACKGROUND: Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Our lab has recently shown that gender differences exist in mesenchymal stem cell (MSC) paracrine function. Estrogen is implicated in the cardioprotection found in females. It remains unknown whether 17beta-estradiol (E2) affects MSC paracrine function and whether E2-treated MSCs may better protect injured cardiac tissue. We hypothesize that E2-exposed MSCs infused into hearts prior to ischemia may demonstrate increased vascular endothelial growth factor (VEGF) production and greater protection of myocardial function compared to untreated MSCs. MATERIALS AND METHODS: Untreated and E2-treated MSCs were isolated, cultured, and plated and supernatants were harvested for VEGF assay (enzyme-linked immunosorbent assay). Adult male Sprague-Dawley rat hearts (n = 13) were isolated and perfused via Langendorff model and subjected to 15 min equilibration, 25 min warm global ischemia, and 40 min reperfusion. Hearts were randomly assigned to perfusate vehicle, untreated male MSC, or E2-treated male MSC. Transcoronary delivery of 1 million MSCs was performed immediately prior to ischemia in experimental hearts. RESULTS: E2-treated MSCs provoked significantly more VEGF production than untreated MSCs (933.2 +/- 64.9 versus 595.8 +/- 10.7 pg/mL). Postischemic recovery of left ventricular developed pressure was significantly greater in hearts infused with E2-treated MSCs (66.9 +/- 3.3%) than untreated MSCs (48.7 +/- 3.7%) and vehicle (28.9 +/- 4.6%) at end reperfusion. There was also greater recovery of the end diastolic pressure with E2-treated MSCs than untreated MSCs and vehicle. CONCLUSIONS: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.Item Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner(BioMed Central, 2015-09-18) Ikeda, Mizuko; Swide, Thomas; Vayl, Alexandra; Lahm, Tim; Anderson, Anderson; Hutchens, Michael P.; Department of Medicine, IU School of MedicineINTRODUCTION: There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR. METHODS: CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting. RESULTS: Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females. CONCLUSIONS: Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal ERs. Post-arrest estrogen administration is renoprotective in a sex- and age-dependent manner.