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1
Labus, Jennifer S., Emeran A. Mayer, Kjersti Aagaard, Jean Stains, Katarzyna Broniowska, and Andrea Rapkin. "Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia: An exploratory metabolomics study." Molecular Pain 17 (January 2021): 174480692110418. http://dx.doi.org/10.1177/17448069211041853.
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Provoked vestibulodynia (PVD) is a chronic vulvar pain disorder characterized by hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Knowledge regarding pathophysiological mechanisms contributing to the etiology and production of symptoms in PVD remains incomplete but is considered multifactorial. Using a cross-sectional observational study design, data from untargeted metabolomic profiling of vaginal fluid and plasma in women with PVD and healthy women was combined with pain testing and brain imaging in women with PVD to test the hypotheses that women with PVD compared to healthy women show differences in vaginal and plasma metabolites involved in steroid hormone biosynthesis. Steroid hormone metabolites showing group differences were correlated with vulvar vestibular pain and vaginal muscle tenderness and functional connectivity of brain regions involved in pain processing in women with PVD to provide insight into the functional mechanisms linked to the identified alterations. Sensitivity analyses were also performed to determine the impact of hormonal contraceptive use on the study findings. Women with PVD compared to healthy controls had significant reductions primarily in vaginal fluid concentrations of androgenic, pregnenolone and progestin metabolites involved in steroidogenesis, suggesting localized rather than systemic effects in vagina and vulvar vestibule. The observed reductions in androgenic metabolite levels showed large effect size associations with increased vulvar vestibular pain and vulvar muscle tenderness and decreases in androgenic and progestin metabolites were associated with decreased connectivity strength in primary sensorimotor cortices. Women with PVD showed symptom-associated reductions in vaginal fluid concentrations of metabolites involved in the biosynthesis of steroid hormones previously shown to affect the integrity of vulvar and vaginal tissue and nociceptive processing. Deficiency of certain steroids may be an important mechanism contributing to the pathophysiology of symptoms in PVD may provide potential diagnostic markers that could lead to new targets for therapeutic intervention.
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Habener, J. F. "Regulation of polypeptide-hormone biosynthesis at the level of the genome." American Journal of Physiology-Cell Physiology 249, no. 3 (September 1, 1985): C191—C199. http://dx.doi.org/10.1152/ajpcell.1985.249.3.c191.
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Understanding of gene control mechanisms has greatly accelerated largely due to the application of recombinant DNA techniques. Polypeptide hormone genes encode multiexonic-intronic transcriptional sequences, the exons of which in turn encode polyprotein precursors or prohormones from which the hormones are cleaved during posttranslational processing of the prohormones. Transcriptional processes are regulated by at least two qualitatively different modes of gene regulation. The first mode includes the factors and structural components of a gene that determine whether a gene can or cannot be expressed in a given tissue when the appropriate inducer is present. The second mode is the physiological induction and regulation of the gene that can normally be expressed in a particular tissue. Both cis and trans regulatory mechanisms appear to operate in both tissue-specific expression and physiological regulation. Tissue-specific enhancer sequences consisting of short nucleotide sequences of from 10 to 50 base pairs have been identified in or around genes that are expressed in specific tissues. In many instances trans-acting DNA binding proteins have been found to repress or activate the transcription of the genes. Physiological regulation of hormone genes involves at least two different classes of macromolecules, steroid hormone receptors and phosphoproteins that are formed in response to the binding of ligands to specific surface-located receptors. Although the precise mechanisms by which information encoded in cellular effectors is coupled to cellular responses is incomplete, continued investigations should lead to a more complete understanding of gene control mechanisms and the eventual ability to alter the expression of specific genes.
3
Mullany, Lisa K., Eric A. Hanse, Andrea Romano, Charles H. Blomquist, J. Ian Mason, Bert Delvoux, Chelsea Anttila, and Jeffrey H. Albrecht. "Cyclin D1 regulates hepatic estrogen and androgen metabolism." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 6 (June 2010): G884—G895. http://dx.doi.org/10.1152/ajpgi.00471.2009.
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Cyclin D1 is a cell cycle control protein that plays an important role in regenerating liver and many types of cancer. Previous reports have shown that cyclin D1 can directly enhance estrogen receptor activity and inhibit androgen receptor activity in a ligand-independent manner and thus may play an important role in hormone-responsive malignancies. In this study, we examine a distinct mechanism by which cyclin D1 regulates sex steroid signaling, via altered metabolism of these hormones at the tissue and cellular level. In male mouse liver, ectopic expression of cyclin D1 regulated genes involved in the synthesis and degradation of sex steroid hormones in a pattern that would predict increased estrogen and decreased androgen levels. Indeed, hepatic expression of cyclin D1 led to increased serum estradiol levels, increased estrogen-responsive gene expression, and decreased androgen-responsive gene expression. Cyclin D1 also regulated the activity of several key enzymatic reactions in the liver, including increased oxidation of testosterone to androstenedione and decreased conversion of estradiol to estrone. Similar findings were seen in the setting of physiological cyclin D1 expression in regenerating liver. Knockdown of cyclin D1 in HuH7 cells produced reciprocal changes in steroid metabolism genes compared with cyclin D1 overexpression in mouse liver. In conclusion, these studies establish a novel link between the cell cycle machinery and sex steroid metabolism and provide a distinct mechanism by which cyclin D1 may regulate hormone signaling. Furthermore, these results suggest that increased cyclin D1 expression, which occurs in liver regeneration and liver diseases, may contribute to the feminization seen in these settings.
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Gellersen, B., and J. Brosens. "Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair." Journal of Endocrinology 178, no. 3 (September 1, 2003): 357–72. http://dx.doi.org/10.1677/joe.0.1780357.
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During the menstrual cycle, the ovarian hormones oestradiol and progesterone control the ordered growth and differentiation of uterine cells. This remodelling process is critical for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. Failure of uterine tIssues to respond appropriately to ovarian hormone signalling results in defective placentation, associated with a spectrum of pregnancy disorders such as recurrent miscarriages and preeclampsia. These obstetrical disorders are a major cause of maternal and perinatal morbidity and mortality. Progesterone exerts its action on target cells, at least in part, through binding to the progesterone receptor (PR), a member of the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualization, in the secretory phase of the menstrual cycle is not well understood. Emerging evidence indicates that locally expressed factors and activation of the cAMP second messenger pathway integrate hormonal inputs and confer cellular specificity to progesterone action through the induction of diverse transcription factors capable of modulating PR function.
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Dai, Long-Jun, Gordon Ritchie, Dirk Kerstan, Hyung Sub Kang, David E. C. Cole, and Gary A. Quamme. "Magnesium Transport in the Renal Distal Convoluted Tubule." Physiological Reviews 81, no. 1 (January 1, 2001): 51–84. http://dx.doi.org/10.1152/physrev.2001.81.1.51.
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The distal tubule reabsorbs ∼10% of the filtered Mg2+, but this is 70–80% of that delivered from the loop of Henle. Because there is little Mg2+reabsorption beyond the distal tubule, this segment plays an important role in determining the final urinary excretion. The distal convoluted segment (DCT) is characterized by a negative luminal voltage and high intercellular resistance so that Mg2+reabsorption is transcellular and active. This review discusses recent evidence for selective and sensitive control of Mg2+transport in the DCT and emphasizes the importance of this control in normal and abnormal renal Mg2+conservation. Normally, Mg2+absorption is load dependent in the distal tubule, whether delivery is altered by increasing luminal Mg2+concentration or increasing the flow rate into the DCT. With the use of microfluorescent studies with an established mouse distal convoluted tubule (MDCT) cell line, it was shown that Mg2+uptake was concentration and voltage dependent. Peptide hormones such as parathyroid hormone, calcitonin, glucagon, and arginine vasopressin enhance Mg2+absorption in the distal tubule and stimulate Mg2+uptake into MDCT cells. Prostaglandin E2and isoproterenol increase Mg2+entry into MDCT cells. The current evidence indicates that cAMP-dependent protein kinase A, phospholipase C, and protein kinase C signaling pathways are involved in these responses. Steroid hormones have significant effects on distal Mg2+transport. Aldosterone does not alter basal Mg2+uptake but potentiates hormone-stimulated Mg2+entry in MDCT cells by increasing hormone-mediated cAMP formation. 1,25-Dihydroxyvitamin D3, on the other hand, stimulates basal Mg2+uptake. Elevation of plasma Mg2+or Ca2+inhibits hormone-stimulated cAMP accumulation and Mg2+uptake in MDCT cells through activation of extracellular Ca2+/Mg2+-sensing mechanisms. Mg2+restriction selectively increases Mg2+uptake with no effect on Ca2+absorption. This intrinsic cellular adaptation provides the sensitive and selective control of distal Mg2+transport. The distally acting diuretics amiloride and chlorothiazide stimulate Mg2+uptake in MDCT cells acting through changes in membrane voltage. A number of familial and acquired disorders have been described that emphasize the diversity of cellular controls affecting renal Mg2+balance. Although it is clear that many influences affect Mg2+transport within the DCT, the transport processes have not been identified.
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Shramko, S. V., V. N. Zorina, N. A. Zorin, I. A. Botvinyeva, S. V. Arkhipova, and V. V. Likhacheva. "INTERRELATION OF STEROID RECEPTOR GENE EXPRESSION IN UTERINE TISSUES AND SERUM CONCENTRATIONS OF IMMUNOREGULATORY PROTEINS, CYTOKINES, SEX STEROIDS IN PROLIFERATIVE DISEASES." Medical Immunology (Russia) 20, no. 5 (November 6, 2018): 731–38. http://dx.doi.org/10.15789/1563-0625-2018-5-731-738.
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Pathogenetic mechanisms of uterine leiomyoma, adenomyosis and their combination are complicated and poorly understood, a differential diagnosis of leiomyosarcoma of the uterus is difficult. Our study aimed for a comparative analysis of the serum contents of α2-MG, PAG, some cytokines, sex steroids and the expression of steroid receptor genes in the patients with different variants of uterine proliferative diseases, in order to determine their pathological role, diagnostic and prognostic value. Expression of estrogen receptor genes adenomyosis nodes was 1.5 to 2-fold higher than in leiomyoma, the combined pathology showed intermediate values, and expression of ER and PGR genes in leiomyosarcoma was minimal. In cellular leiomyoma, expression of ER receptor genes in the surrounding myometrium was 2 to 3-fold higher than in cases of simple leiomyomas. At the same time, concentration of estrogen and progesterone in the blood is comparable between the groups and control groups. All the patients have a deficiency of immunomodulatory α2-MG (12-13% for leiomyomas, 20% for adenomyosis, and 23% for malignant pathology). The concentration of immunosuppressive PAG is increased in combined conditions and leiomyosarcoma. In addition, the contents of IL-6 and TNFα increase, the VEGF levels exceed normal values 4 to 4.5-fold, in leiomyoma, 5.5-fold, in combined pathology, 6.5, in adenomyosis, and 10-fold, in leiomyosarcoma.The obtained results confirm that immunomodulatory proteins, cytokines and cell-targeting sex hormones exert an interdependent influence upon each other in the studied diseases, and their significant changes may be used in diagnostics and prognosis.
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Parker, Joseph, and Gary Struhl. "Control of Drosophila wing size by morphogen range and hormonal gating." Proceedings of the National Academy of Sciences 117, no. 50 (November 30, 2020): 31935–44. http://dx.doi.org/10.1073/pnas.2018196117.
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The stereotyped dimensions of animal bodies and their component parts result from tight constraints on growth. Yet, the mechanisms that stop growth when organs reach the right size are unknown. Growth of the Drosophila wing—a classic paradigm—is governed by two morphogens, Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt). Wing growth during larval life ceases when the primordium attains full size, concomitant with the larval-to-pupal molt orchestrated by the steroid hormone ecdysone. Here, we block the molt by genetically dampening ecdysone production, creating an experimental paradigm in which the wing stops growing at the correct size while the larva continues to feed and gain body mass. Under these conditions, we show that wing growth is limited by the ranges of Dpp and Wg, and by ecdysone, which regulates the cellular response to their signaling activities. Further, we present evidence that growth terminates because of the loss of two distinct modes of morphogen action: 1) maintenance of growth within the wing proper and 2) induced growth of surrounding “pre-wing” cells and their recruitment into the wing. Our results provide a precedent for the control of organ size by morphogen range and the hormonal gating of morphogen action.
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Wang, Xun, Yongheng Huang, Shiwen Yuan, Amin Tamadon, Shulan Ma, and Yi Feng. "The Role of Hippocampal Estradiol Receptor-αin a Perimenopausal Affective Disorders-Like Rat Model and Attenuating of Anxiety by Electroacupuncture." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/4958312.
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Hormone replacement therapy is the principal treatment for perimenopausal affective disorders which can cause severe side effects. The present study compared the effects of electroacupuncture (EA) and estradiol treatment on perimenopausal affective disorders at the behavioral and cellular levels. In this randomized experimentalin vivostudy, adult female rats were divided into intact, ovariectomy, chronic unpredictable stress (CUS), and ovariectomy and CUS combination groups. After week 6, all groups were subdivided to three subgroups of control, EA, and estradiol treatment. The behavioral parameters in the open field and the elevated plus maze tests were assessed before and after treatments. Alterations of serum steroid hormones and changes of estradiol receptor-α(ER-α) immunofluorescence neurons in the hippocampus sections were evaluated. EA treatment caused more antianxiety effects than estradiol treatment in CUS group (P<0.05). Notably, estradiol and EA treatments had better significant behavioral effects when the models were not estrogen-deficient. Importantly, within each group, compared to the control group, the numbers of ER-α-positive neurons were significantly larger in EA subgroups. Therefore, EA had antianxiety effects on perimenopausal affective disorders caused by CUS but not by estrogen deficiency and upregulation of hippocampus ER-αneurons may contribute to its mechanism of action.
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Stasinopoulos, Ioannis, Shazia Khan, Logan C. MacKay, Roger W. Brown, Matthew J. Bailey, and Ruth Andrew. "Mapping of Corticosteroids in Murine Kidneys Using Mass Spectrometry Imaging." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A822—A823. http://dx.doi.org/10.1210/jendso/bvab048.1676.
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Abstract Renal sodium reabsorption is important for blood pressure homeostasis and is physiologically regulated by aldosterone; glucocorticoids may also contribute. Abnormal steroid hormone activity within the kidney contributes to hypertension but the mechanisms are not fully defined. Molecular profiling of receptors and metabolising enzymes indicates that steroid hormone action is compartmentalised within the kidney. Ambient steroid concentrations are a critical factor governing bioactivity at a cellular level, but this is largely unknown, and the kidney remains a “black box”. Mass spectrometry imaging (MSI) was applied recently to localise steroids in brain and testes, and here is applied to kidney. Image reconstruction permits characterisation and co-registration of kidney histological regions based on regional markers detectable by MSI. Our aim was to map and quantify glucocorticoids and aldosterone in different histological zones (cortex, medulla) of murine kidneys, using an optimised MSI method. This approach has the potential to map steroids within functional zones of the kidney, providing fundamental new information relevant to hormone action in health and in disease. Cryosections of male C57BL6 mouse kidneys (age 12 weeks, n=6) were subject to MSI following derivatisation using Girard T reagent and α-cyano-4-hydroxycinnamic acid matrix application. Images were reconstructed, and methods optimised to enhance signal and limit diffusion of analytes of interest. Matrix assisted laser desorption/ionisation (MALDI) was used as a sampling method, coupled to Fourier Transform Ion cyclotron mass spectrometry. Ions with m/z 458.3010, 460.3166 and 474.2957 were detected, using MALDI, in renal sections, close to the predicted masses of 458.3013 (Δppm=0.65), 460.3169 (Δppm=0.65), and 474.2962 (Δppm=1.05), for derivatives of 11-dehydrocorticosterone, corticosterone and aldosterone respectively. Untargeted evaluation of ions was conducted to find regional markers that would allow definition of kidney histological zones. The Heat maps generated indicated that corticosterone intensity was higher in the inner cortex area close to the corticomedullary junction than the rest of the kidney. In contrast 11-dehydrocorticosterone was detected mainly in medulla and aldosterone signal was equally strong in medulla and outer cortex. Thus, MSI can be used map the sites where glucocorticoid and mineralocorticoids are most active in regulating renal tubular function. Co-localisation of steroids of interest with zonal markers by MSI permits steroid mapping in functional renal zones of the kidney. This approach provides fundamental new insights into the physiological control of sodium transport by steroids and opens doors to understanding changes in disorders of blood pressure. The project was supported and funded by Kidney Research UK.
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Charlier, Thierry D., Charlotte A. Cornil, and Jacques Balthazart. "Rapid Modulation of Aromatase Activity in the Vertebrate Brain." Journal of Experimental Neuroscience 7 (January 2013): JEN.S11268. http://dx.doi.org/10.4137/jen.s11268.
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Numerous steroid hormones, including 17β-estradiol (E2), activate rapid and transient cellular, physiological, and behavioral changes in addition to their well-described genomic effects. Aromatase is the key-limiting enzyme in the production of estrogens, and the rapid modulation of this enzymatic activity could produce rapid changes in local E2 concentrations. The mechanisms that might mediate such rapid enzymatic changes are not fully understood but are currently under intense scrutiny. Recent studies in our laboratory indicate that brain aromatase activity is rapidly inhibited by an increase in intracellular calcium concentration resulting from potassium-induced depolarization or from the activation of glutamatergic receptors. Phosphorylating conditions also reduce aromatase activity within minutes, and this inhibition is blocked by the addition of multiple protein kinase inhibitors. This rapid modulation of aromatase activity by phosphorylating conditions is a general mechanism observed in different cell types and tissues derived from a variety of species, including human aromatase expressed in various cell lines. Phosphorylation processes affect aromatase itself and do not involve changes in aromatase protein concentration. The control of aromatase activity by multiple kinases suggests that several amino acids must be concomitantly phosphorylated to modify enzymatic activity but site-directed mutagenesis of several amino acids alone or in combination has not to date revealed the identity of the targeted residue(s). Altogether, the phosphorylation processes affecting aromatase activity provide a new general mechanism by which the concentration of estrogens can be rapidly altered in the brain.
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Simmen, R. C. M., J. M. P. Pabona, M. C. Velarde, C. Simmons, O. Rahal, and F. A. Simmen. "The emerging role of Krüppel-like factors in endocrine-responsive cancers of female reproductive tissues." Journal of Endocrinology 204, no. 3 (October 15, 2009): 223–31. http://dx.doi.org/10.1677/joe-09-0329.
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Krüppel-like factors (KLFs), of which there are currently 17 known protein members, belong to the specificity protein (Sp) family of transcription factors and are characterized by the presence of Cys2/His2 zinc finger motifs in their carboxy-terminal domains that confer preferential binding to GC/GT-rich sequences in gene promoter and enhancer regions. While previously regarded to simply function as silencers of Sp1 transactivity, many KLFs are now shown to be relevant to human cancers by their newly identified abilities to mediate crosstalk with signaling pathways involved in the control of cell proliferation, apoptosis, migration, and differentiation. Several KLFs act as tumor suppressors and/or oncogenes under distinct cellular contexts, underscoring their prognostic potential for cancer survival and outcome. Recent studies suggest that a number of KLFs can influence steroid hormone signaling through transcriptional networks involving steroid hormone receptors and members of the nuclear receptor family of transcription factors. Since inappropriate sensitivity or resistance to steroid hormone actions underlies endocrine-related malignancies, we consider the intriguing possibility that dysregulation of expression and/or activity of KLF members is linked to the pathogenesis of endometrial and breast cancers. In this review, we focus on recently described mechanisms of actions of several KLFs (KLF4, KLF5, KLF6, and KLF9) in cancers of the mammary gland and uterus. We suggest that understanding the mode of actions of KLFs and their functional networks may lead to the development of novel therapeutics to improve current prospects for cancer prevention and cure.
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Carnevali, M. Candia, S. Galassi, F. Bonasoro, M. Patruno, and M. Thorndyke. "Regenerative response and endocrine disrupters in crinoid echinoderms: arm regeneration in Antedon mediterranea after experimental exposure to polychlorinated biphenyls." Journal of Experimental Biology 204, no. 5 (March 1, 2001): 835–42. http://dx.doi.org/10.1242/jeb.204.5.835.
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Regenerative phenomena, which have the advantage of reproducing developmental processes in the adult organism, are very sensitive to environmental stress and represent stages that can be monitored for damage at the whole-organism, cellular and molecular levels. Some persistent and ubiquitous pollutants, which can affect the natural environment because of their bioaccumulation in organisms, exert their effects by acting as ‘endocrine disrupters’. In this respect, they can cause dysfunction in steroid hormone production/metabolism and activity by their dramatic effects on gene expression, reproductive competence and growth. The aim of our present research was to assess the impact of such compounds on adult echinoderm reproductive physiology with particular reference to regeneration potential. It is known that vertebrate-type steroids are synthesized by echinoderms and play a role in the control of growth and reproduction. Our experimental model is the crinoid Antedon mediterranea, selected on the basis of its previously explored regenerative capabilities at the level of the arms. The regeneration response, analyzed at the tissue and cellular levels using both light and electron microscopy and immunocytochemistry, was employed to monitor the effects of exposure to persistent endocrine disrupter micropollutants such as polychlorinated biphenyls (PCBs) by means of laboratory tests performed under controlled conditions in terms of environmental variables and contamination levels. Our results indicate that exposure to endocrine disrupter compounds such as PCBs can induce anomalies in regeneration times, morphology and developmental mechanisms that can be interpreted in the light of significant dysfunctions in the endocrine mechanisms controlling regenerative development.
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Jorkasky, D., M. Cox, and G. M. Feldman. "Differential effects of corticosteroids on Na+ transport in rat distal colon in vitro." American Journal of Physiology-Gastrointestinal and Liver Physiology 248, no. 4 (April 1, 1985): G424—G431. http://dx.doi.org/10.1152/ajpgi.1985.248.4.g424.
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We studied rat distal colon during in vitro incubation with aldosterone and dexamethasone. Both hormones caused short-circuit current (Isc) to increase with a latency period of approximately 3 h. At the 7th h of incubation, control colons had a Isc of 72 +/- 8 microA . cm-2 while tissues incubated with 10(-5) M aldosterone and 10(-8) M dexamethasone, the respective maximal stimulatory concentrations, had similarly increased Isc, 211 +/- 21 and 185 +/- 18 microA . cm-2, respectively. The increase in Isc induced by steroids reflected increased net sodium transport: control, 3.4 +/- 0.8; aldosterone, 6.7 +/- 0.7 (P less than 0.05); and dexamethasone, 7.5 +/- 1.0 mueq . h-1 . cm-2 (P less than 0.025). Spironolactone inhibited the response to both steroids, but the molar ratio of antagonist to agonist was less for aldosterone (approximately 5,000:1) than for dexamethasone (approximately 50,000:1). Amiloride inhibited a greater fraction of aldosterone-induced Isc (0.70 +/- 0.07) than that of dexamethasone (0.37 +/- 0.07; P less than 0.025). The latter value was similar to the effect of amiloride on control tissues (0.35 +/- 0.04). These data provide evidence that the cellular mechanisms by which aldosterone and dexamethasone induce Na+ transport are different.
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Ma, Yunyong, Scott A. Juntti, Caroline K. Hu, John R. Huguenard, and Russell D. Fernald. "Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish." Proceedings of the National Academy of Sciences 112, no. 12 (March 9, 2015): 3805–10. http://dx.doi.org/10.1073/pnas.1421851112.
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Initiating and regulating vertebrate reproduction requires pulsatile release of gonadotropin-releasing hormone (GnRH1) from the hypothalamus. Coordinated GnRH1 release, not simply elevated absolute levels, effects the release of pituitary gonadotropins that drive steroid production in the gonads. However, the mechanisms underlying synchronization of GnRH1 neurons are unknown. Control of synchronicity by gap junctions between GnRH1 neurons has been proposed but not previously found. We recorded simultaneously from pairs of transgenically labeled GnRH1 neurons in adult male Astatotilapia burtoni cichlid fish. We report that GnRH1 neurons are strongly and uniformly interconnected by electrical synapses that can drive spiking in connected cells and can be reversibly blocked by meclofenamic acid. Our results suggest that electrical synapses could promote coordinated spike firing in a cellular assemblage of GnRH1 neurons to produce the pulsatile output necessary for activation of the pituitary and reproduction.
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Dai, Long-Jun, Gordon Ritchie, Brian W. Bapty, Dirk Kerstan, and Gary A. Quamme. "Insulin stimulates Mg2+ uptake in mouse distal convoluted tubule cells." American Journal of Physiology-Renal Physiology 277, no. 6 (December 1, 1999): F907—F913. http://dx.doi.org/10.1152/ajprenal.1999.277.6.f907.
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Insulin has been shown to be a magnesium-conserving hormone acting, in part, through stimulation of magnesium absorption within the thick ascending limb. Although the distal convoluted tubule possesses the most insulin receptors, it is unclear what, if any, actions insulin has in the distal tubule. The effects of insulin were studied on immortalized mouse distal convoluted tubule (MDCT) cells by measuring cellular cAMP formation with radioimmunoassays and Mg2+ uptake with fluorescence techniques using mag-fura 2. To assess Mg2+ uptake, MDCT cells were first Mg2+ depleted to 0.22 ± 0.01 mM by culturing in Mg2+-free media for 16 h and then placed in 1.5 mM MgCl2, and the changes in intracellular Mg2+ concentration ([Mg2+]i) were measured with microfluorescence. [Mg2+]i returned to basal levels, 0.53 ± 0.02 mM, with a mean refill rate, d([Mg2+]i)/d t, of 164 ± 5 nM/s. Insulin stimulated Mg2+ entry in a concentration-dependent manner with maximal response of 214 ± 12 nM/s, which represented a 30 ± 5% increase in the mean uptake rate above control values. This was associated with a 2.5-fold increase in insulin-mediated cAMP generation (52 ± 3 pmol ⋅ mg protein−1 ⋅ 5 min−1). Genistein, a tyrosine kinase inhibitor, diminished insulin-stimulated Mg2+ uptake (169 ± 11 nM/s), but did not change insulin-mediated cAMP formation (47 ± 5 pmol ⋅ mg protein−1 ⋅ 5 min−1). PTH stimulates Mg2+ entry, in part, through increases in cAMP formation. Insulin and PTH increase Mg2+ uptake in an additive fashion. In conclusion, insulin mediates Mg2+ entry, in part, by a genistein-sensitive mechanism and by modifying hormone-responsive transport. These studies demonstrate that insulin stimulates Mg2+ uptake in MDCT cells and suggest that insulin acts in concert with other peptide and steroid hormones to control magnesium conservation in the distal convoluted tubule.
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Schirrmacher, Volker. "Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications." Biomedicines 9, no. 3 (March 13, 2021): 293. http://dx.doi.org/10.3390/biomedicines9030293.
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A dose-response relationship to stressors, according to the hormesis theory, is characterized by low-dose stimulation and high-dose inhibition. It is non-linear with a low-dose optimum. Stress responses by cells lead to adapted vitality and fitness. Physical stress can be exerted through heat, radiation, or physical exercise. Chemical stressors include reactive species from oxygen (ROS), nitrogen (RNS), and carbon (RCS), carcinogens, elements, such as lithium (Li) and silicon (Si), and metals, such as silver (Ag), cadmium (Cd), and lead (Pb). Anthropogenic chemicals are agrochemicals (phytotoxins, herbicides), industrial chemicals, and pharmaceuticals. Biochemical stress can be exerted through toxins, medical drugs (e.g., cytostatics, psychopharmaceuticals, non-steroidal inhibitors of inflammation), and through fasting (dietary restriction). Key-lock interactions between enzymes and substrates, antigens and antibodies, antigen-presenting cells, and cognate T cells are the basics of biology, biochemistry, and immunology. Their rules do not obey linear dose-response relationships. The review provides examples of biologic stressors: oncolytic viruses (e.g., immuno-virotherapy of cancer) and hormones (e.g., melatonin, stress hormones). Molecular mechanisms of cellular stress adaptation involve the protein quality control system (PQS) and homeostasis of proteasome, endoplasmic reticulum, and mitochondria. Important components are transcription factors (e.g., Nrf2), micro-RNAs, heat shock proteins, ionic calcium, and enzymes (e.g., glutathion redox enzymes, DNA methyltransferases, and DNA repair enzymes). Cellular growth control, intercellular communication, and resistance to stress from microbial infections involve growth factors, cytokines, chemokines, interferons, and their respective receptors. The effects of hormesis during evolution are multifarious: cell protection and survival, evolutionary flexibility, and epigenetic memory. According to the hormesis theory, this is true for the entire biosphere, e.g., archaia, bacteria, fungi, plants, and the animal kingdoms.
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Lange, Carol A., and Douglas Yee. "Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer." Endocrine-Related Cancer 18, no. 4 (May 25, 2011): C19—C24. http://dx.doi.org/10.1530/erc-11-0112.
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The majority (∼70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+ breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled ‘Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer’, Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors.
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Hewitt, Kylie N., Elizabeth A. Walker, and Paul M. Stewart. "Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity." Endocrinology 146, no. 6 (June 1, 2005): 2539–43. http://dx.doi.org/10.1210/en.2005-0117.
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Abstract Hexose-6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11β-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11β-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11β-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11β-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11β-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.
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Xu, Yue, Ludger Klein-Hitpass, and Milan K. Bagchi. "E1A-Mediated Repression of Progesterone Receptor-Dependent Transactivation Involves Inhibition of the Assembly of a Multisubunit Coactivation Complex." Molecular and Cellular Biology 20, no. 6 (March 15, 2000): 2138–46. http://dx.doi.org/10.1128/mcb.20.6.2138-2146.2000.
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ABSTRACT The steroid hormone progesterone acts via high-affinity nuclear receptors that interact with specific DNA sequences located near the promoter of the hormone-responsive gene. Recent studies suggested that the hormone-occupied progesterone receptor (PR) mediates gene activation by recruiting a cellular coregulatory factor, termed coactivator, to the target promoter. The identity and mechanism of action of the coactivator(s) that regulates transcriptional activity of PR are currently under investigation. Here we provide evidence that the hormone-occupied PR forms a multisubunit receptor-coactivator complex containing two previously described coactivators, CREB-binding protein (CBP) and steroid receptor coactivator 1 (SRC-1, a member of the p160 family of coactivators), in nuclear extracts of human breast tumor T47D cells. The association of CBP and SRC-1/p160 with the receptor complex is entirely hormone dependent. Both CBP and SRC-1/p160 possess intrinsic histone acetyltransferase (HAT) activity, and it has been recently proposed that these coactivators function by modulating chromatin structure at the promoter of the target gene. Interestingly, addition of purified CBP to the nuclear extracts of T47D cells markedly stimulated progesterone- and PR-dependent transcription from a nucleosome-free, progesterone response element (PRE)-linked reporter DNA template. Furthermore, depletion of SRC-1/p160 by immunoprecipitation from these transcriptional extracts also significantly impaired PR-mediated RNA synthesis from a naked PRE-linked DNA template. These results strongly implied that CBP and SRC-1/p160 facilitate receptor-mediated transcription in these cell extracts through mechanisms other than chromatin remodeling. We also observed that the adenoviral oncoprotein E1A, which interacts directly with CBP, repressed PR-mediated transactivation when added to the nuclear extracts of T47D cells. Supplementation with purified CBP overcame this inhibition, indicating that the inhibitory effect of E1A is indeed due to a blockade of CBP function. Most importantly, we noted that binding of E1A to CBP prevented the assembly of a coactivation complex containing PR, CBP, and SRC-1/p160, presumably by disrupting the interaction between CBP and SRC-1/p160. These results strongly suggested that E1A repressed receptor-mediated transcription by blocking the formation or recruitment of coactivation complexes. Collectively, our results support the hypothesis that the assembly of a multisubunit coactivation complex containing PR, CBP, and SRC-1/p160 is a critical regulatory step during hormone-dependent gene activation by PR and that the fully assembled complex has the ability to control transcription through mechanisms that are independent of the histone-modifying activities of its component coactivators.
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Pfiffner, Samantha, Erin Hallman, Jordan Parker, Madison Romanski, Katelyn Farrar, Nicole Sierzenga, and Sumi Dinda. "The Effects of Tert-butyl Hydroquinone (TBHQ) on Estrogen Receptor Alpha (ERα) and Tumor Suppressor Gene p53 in Breast Cancer Cells." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A493—A494. http://dx.doi.org/10.1210/jendso/bvab048.1009.
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Abstract Tert-butyl hydroquinone (TBHQ) is an aromatic compound that is commonly used as a preservative in processed food to prevent rancidity and lengthen shelf life. TBHQ is known to act as an antioxidant by protecting cells from radical oxygen species and thus preventing DNA damage. Although previous studies have found TBHQ to cause cancer cell death at high concentrations, they have also contrastingly found TBHQ, when studied in animal models, to enhance carcinogenic effects. However, the effect of TBHQ on breast cancer has not been thoroughly explored. With the prevalence of breast cancer and the wide use of TBHQ in processed food items, it is imperative that we explore their possible relationship. This study examined the effects of TBHQ, alone and in combination with hormones and anti-hormones, on ERα and p53 expression in both MCF-7 and T-47D breast cancer cell lines. To ensure treatment conditions without the presence of endogenous steroids or growth factors, the cells were cultured with a 5% charcoal-stripped fetal bovine serum (FBS) for six days. Western blot analysis revealed alterations in the expression of ERα and p53 protein levels after 24 hours of treatment with varying concentrations of TBHQ (0.005 to 1 mM). A concentration-dependent decrease of ERα protein levels was observed in both cell lines, with a 49% reduction occurring with 100 µM TBHQ as compared to the control. P53 levels portray a continued increase of expression through concentrations of TBHQ (0.005 to 1 mM), found similarly in both cell lines. To gain further insight into possible similarities between BPS and other known effectors of ERα, the optimal concentration of TBHQ (100 μM) was used in combination with hormones and anti-hormones. Down-regulation of ERα protein levels was observed after 24-hour co-treatment of T-47D & MCF-7 cells with a combination of TBHQ and E2. Antiestrogen ICI with TBHQ showed a significant down-regulation as compared to TBHQ alone, and TBHQ with TAM portrayed no significant differences. A similar trend in the effects on p53 expression was depicted in T-47D and MCF-7 cells. Image cytometric analysis with propidium iodide staining was utilized to quantify cell values and viability changes to further portray the effects of TBHQ on T-47D and MCF-7 cellular growth. The viability assay shows a biphasic effect with increasing concentrations of TBHQ, with a maximum decrease in proliferation seen at a concentration of 100 uM TBHQ. TBHQ alone and in combination with E2 and antiestrogens showed a decreased proliferation compared to the control in T-47D cells. However, cytolocalization of ERα upon treatment with estradiol and TBHQ remained unaltered. Our studies offer a unique perspective on the effects of TBHQ on two different breast cancer cell lines, and provide valuable insight for further exploration of the mechanism of action of TBHQ on tumor suppressor gene and steroid receptors.
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Silvia, W. J., J.-S. Lee, D. S. Trammell, S. H. Hayes, L. L. Lowberger, and J. A. Brockman. "Cellular mechanisms mediating the stimulation of ovine endometrial secretion of prostaglandin F2α in response to oxytocin: role of phospholipase C and diacylglycerol." Journal of Endocrinology 141, no. 3 (June 1994): 481–90. http://dx.doi.org/10.1677/joe.0.1410481.
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Abstract The first objective was to describe and evaluate the relationship between the ability of oxytocin to stimulate the activity of phospholipase (PL) C and its ability to stimulate the release of prostaglandin (PG) F2α in ovine endometrial tissue. Caruncular endometrial tissue was collected from ovariectomized ewes after completion of an 11-day steroid replacement protocol. In experiment 1, explants were incubated either in the presence (10−6 m) or absence of oxytocin for 0, 1, 3, 10, 30 or 100 min to examine the time-course for activation of PLC and release of PGF2α in response to oxytocin. An increase in the activity of PLC was detected at 3 min while an increase in the release of PGF2α was not detected until 10 min (P<0·05). In experiment 2, explants were incubated in the presence of various oxytocin analogues (10−6 m) to compare their abilities to activate PLC and release PGF2α. Oxytocin and three receptor angonists stimulated the activity of PLC and the release of PGF2α (P<0·05) while two oxytocin receptor antagonists had no effect on either response. In experiment 3, explants were incubated in the presence of oxytocin or arginine vasopressin at 10−9 to 10−6 m to establish dose–response curves for the activation of PLC and release of PGF2α. For both hormones, significant increases (P<0·05) in the release of PGF2α were observed at 10−8 m while increases in PLC activity were not detected until 10−7 m was used. In experiment 4, explants were pretreated with either U-73122 (an inhibitor of PLC activity) or U-73343 (an inactive analogue of U-73122). Explants were then treated with control medium, oxytocin or AlF4−. Both oxytocin and AlF4− stimulated the activity of PLC and the release of PGF2α (P<0·05). U-73122 blocked the ability of oxytocin to stimulate the release of PGF2α (P<0·05) but had no effect on its ability to stimulate the activity of PLC (P>0·1). Based on the results from these experiments, the role of PLC in mediating the stimulatory effect of oxytocin on the release of PGF2α remains unclear. The second objective was to evaluate the role of diacylglycerol (DAG) in mediating the stimulatory effect of oxytocin on endometrial secretion of PGF2α. In experiment 5, explants were incubated in vitro with varying doses of two DAG analogues. Both analogues stimulated the release of PGF2α at 10−6 m (P<0·05), the highest dose tested. Corresponding inactive control compounds had no stimulatory effect. In experiment 6, explants were incubated with two synthetic DAGs and two indole-derived analogues of DAG. The indole derivatives stimulated the release of PGF2α. The synthetic DAGs were less effective in stimulating the release of PGF2α at the doses tested. In experiment 7, explants were preincubated with R59022 or LiCl. R59022 enhanced both the basal and oxytocin-stimulated released of PGF2α (P=0·07). LiCl promoted an increase in the accumulation of inositol trisphosphate (P<0·05) but had no effect on the release of PGF2α (P>0·5). These data indicate that DAG stimulates release of PGF2α from ovine endometrial tissue and may mediate the stimulatory effect of oxytocin on release of PGF2α. Journal of Endocrinology (1994) 141, 481–490
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Puissant, C., M. Bayat-Sarmadi, E. Devinoy, and L.-M. Houdebine. "Variation of transferrin mRNA concentration in the rabbit mammary gland during the pregnancy–lactation–weaning cycle and in cultured mammary cells. A comparison with the other major milk protein mRNAs." European Journal of Endocrinology 130, no. 5 (May 1994): 522–29. http://dx.doi.org/10.1530/eje.0.1300522.
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Puissant C, Bayat-Sarmadi M, Devinoy E, Houdebine L-M. Variation of transferrin mRNA concentration in the rabbit mammary gland during the pregnancy–lactation–weaning cycle and in cultured mammary cells. A comparison with the other major milk protein mRNAs. Eur J Endocrinol 1994;130:522–9. ISSN 0804–4643 The concentration of transferrin mRNA was evaluated during pregnancy and lactation in rabbit mammary gland and liver using northern blot and dot blot assays. Transferrin mRNA was present in the virgin rabbit mammary gland and its concentration increased as pregnancy proceeded, with a major enhancement after day 15. A high concentration was reached 3 days after parturition, with no additional increase during lactation and with a marked decline after weaning. During the same period, the concentration of transferrin mRNA showed only a very weak variation in liver. This mRNA was six times more abundant in mammary gland than in liver of lactating rabbit. The accumulation of transferrin mRNA in the mammary gland was concomitant with the accumulation of αs1-, β-, kcasein and WAP (whey acidic protein) mRNAs. The concentration of glyceraldehyde 3-phosphate dehydrogenase mRNA, taken as a non-inducible control mRNA, declined progressively during pregnancy to reach its lower level in lactation. These observations suggest that casein, WAP and transferrin mRNAs are subjected to a similar control mechanism in vivo, at least in the second half of pregnancy and during lactation. Experiments carried out in vitro using isolated rabbit epithelial mammary cells cultured on collagen I gel indicated that transferrin mRNA was abundant and only weakly inducible by the lactogenic hormones insulin, cortisol and prolactin, as opposed to caseins and WAP mRNAs. R5020, an analogue of progesterone, inhibited at most very slightly the accumulation of αs1-casein mRNA in the presence of prolactin and it did not reduce the expression of transferrin gene. The mammary cells cultured on a plastic support contained much less transferrin mRNA than those maintained on collagen gel or on EHS (Engelbreth–Holm–Swarm) extracellular matrix independently of any hormonal stimulation. These data suggest that although caseins, WAP and transferrin mRNAs have parallel variations during the pregnancy–lactation–weaning cycle, they are subjected to different mechanisms of regulation at the molecular level. The accumulation of the mRNAs for caseins and WAP is positively regulated by lactogenic hormones and by the presence of the extracellular matrix, whereas the accumulation of transferrin mRNA is positively regulated essentially by the presence of the matrix. The fact that the levels of all the mRNAs studied here are increased simultaneously as progesterone starts declining suggests that the steroid controls the action of a factor, possibly the presence of the extracellular matrix, that regulates the expression of all the milk protein genes. L-M Houdebine, Unité de Differenciation Cellulaire, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cédex, France
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Seagroves, Tiffany N., John P. Lydon, Russell C. Hovey, Barbara K. Vonderhaar, and Jeffrey M. Rosen. "C/EBPβ (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development." Molecular Endocrinology 14, no. 3 (March 1, 2000): 359–68. http://dx.doi.org/10.1210/mend.14.3.0434.
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Abstract Deletion of the transcription factor CCAAT/enhancer binding protein (C/EBP)β results in a severe inhibition of lobuloalveolar development in the mouse mammary gland. Because progesterone receptor (PR) is requisite for alveolar development, the expression of PR was investigated in C/EBPβ−/− mice. Unexpectedly, the number of PR-positive cells, as well as the levels of PR mRNA, were elevated 3-fold in the mammary glands of C/EBPβ−/− mice. Furthermore, in contrast to wild-type nulliparous mice, in which PR distribution shifted from a uniform to nonuniform pattern between 8–12 weeks of age, C/EBPβ−/− mice exhibited uniform PR distribution throughout all stages of mammary development analyzed. No change in C/EBPβ mRNA levels was observed in the mammary glands of PR−/− mice, suggesting that PR acts in a pathway either in parallel to or downstream of C/EBPβ. The overexpression and disrupted cellular distribution of PR in C/EBPβ−/− mice were coincident with a striking 10-fold decrease in cell proliferation after acute steroid hormone treatment, assayed by incorporation of bromodeoxyuridine. In wild-type mice, PR and bromodeoxyuridine-positive cells were adjacent to each other and rarely colocalized. No differences in the level or pattern of PR expression were observed in the uterus, suggesting that C/EBPβ influences PR in a mam-mary-specific fashion. Together, these data suggest that C/EBPβ may control cell fate decisions in the mammary gland through the appropriate temporal and spatial expression of molecular markers, such as PR, that induce the proliferation of alveolar progenitor cells via juxtacrine mechanisms.
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Aydemir, Işil, Caner Özbey, Oktay Özkan, Şadiye Kum, and Mehmet İbrahim Tuğlu. "Investigation of the effects of bisphenol-A exposure on lymphoid system in prenatal stage." Toxicology and Industrial Health 36, no. 7 (July 2020): 502–13. http://dx.doi.org/10.1177/0748233720941759.
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Bisphenol-A (BPA) used in the production of plastic materials is a temperature-soluble agent. It also has a steroid hormone-like activity; therefore, it poses a danger to human health. In our study, we aimed to investigate the effects of BPA on lymph node and spleen in male rats exposed to this agent during prenatal stage. The pregnant female rats were divided into four groups: control, sham, low dose (300 µg/kg BPA), and high dose (900 µg/kg BPA). BPA was dissolved in 1 mL of corn oil and administered to the pregnant rats every day during pregnancy. On the 21st and 45th day after the birth, male rats’ lymph node and spleen samples were taken and histopathological examination was performed. Samples were stained with hematoxylin and eosin to determine the general histological appearance, and with CD3 and CD20 immunohistochemically. The results of staining were evaluated by H-score, and statistical analysis was performed. In the samples, BPA applications were not found to cause significant tissue damage. But there was a significant decrease in the immunoreactivities of CD3 and CD20 after BPA applications in both 21st and 45th day samples. After high dose BPA administration, decreased CD3 immunoreactivity was statistically significant. It is thought that BPA does not cause histologically significant tissue damage, but it may impair organ function at cellular level. The investigation of molecules involved in organ function will be useful in revealing the mechanisms that will cause dysfunction.
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Bahrami, Afsane, and Amirhossein Sahebkar. "Vitamin D as a Potential Therapeutic Option in Cancer Treatment: Is There a Role for Chemoprevention?" Anti-Cancer Agents in Medicinal Chemistry 20, no. 18 (November 23, 2020): 2138–49. http://dx.doi.org/10.2174/1871520620999200729192728.
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Background: Vitamin D (Vit D) serves as a precursor to the potent steroid hormone calcitriol, which regulates numerous genes that control homeostasis, epithelial cell differentiation, proliferation, and apoptosis. Low level of Vit D is implicated in the development and progression of several diseases including bone fractures, cardiovascular disease, diabetes mellitus, and cancers. The present review highlights the role of vitamin D in cancer with a particular emphasis on genetic variants related to Vit D metabolism as well as clinical trials of Vit D supplementation as a potential therapeutic option in the treatment of cancer patients. Methods: Data were collected following an electronic search in the Web of Science, Medline, PubMed, and Scopus databases by using some keywords such as “cancer”, “tumor”, “malignancy”, “vitamin D”, “cholecalciferol” and “calcitriol”. Results: The collected evidence from the studies revealed a consistent and strong association between Vit D status and cancer risk and survival. The associations between Vit D-related genetic variants and cancer survival support the hypothesis that Vit D may affect cancer outcomes. The mechanisms whereby Vit D reduces cancer risk and increases survival are regulation of cellular differentiation, proliferation and apoptosis as well as decreased angiogenesis in tumor microenvironment and inhibition of metastasis. Conclusion: There is a paucity of evidence-based recommendations for the optimal 25(OH)D levels in patients with cancer and the role of Vit D supplementation for primary or secondary prevention of cancer. Well-designed and sufficiently powered randomized clinical trials are necessary to assess the clinical application of Vit D in enhancing the clinical efficacy of standard and adjuvant chemotherapy regimens.
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Asarian, Lori, and Nori Geary. "Modulation of appetite by gonadal steroid hormones." Philosophical Transactions of the Royal Society B: Biological Sciences 361, no. 1471 (June 19, 2006): 1251–63. http://dx.doi.org/10.1098/rstb.2006.1860.
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Several sex differences in eating, their control by gonadal steroid hormones and their peripheral and central mediating mechanisms are reviewed. Adult female rats and mice as well as women eat less during the peri-ovulatory phase of the ovarian cycle (estrus in rats and mice) than other phases, an effect under the control of cyclic changes in estradiol secretion. Women also appear to eat more sweets during the luteal phase of the cycle than other phases, possibly due to simultaneous increases in estradiol and progesterone. In rats and mice, gonadectomy reveals further sex differences: orchiectomy decreases food intake by decreasing meal frequency and ovariectomy increases food intake by increasing meal size. These changes are reversed by testosterone and estradiol treatment, respectively. A variety of peripheral feedback controls of eating, including ghrelin, cholecystokinin (CCK), glucagon, hepatic fatty acid oxidation, insulin and leptin, has been shown to be estradiol-sensitive under at least some conditions and may mediate the estrogenic inhibition of eating. Of these, most progress has been made in the case of CCK. Neurons expressing estrogen receptor-α in the nucleus tractus solitarius of the brainstem appear to increase their sensitivity to CCK-induced vagal afferent input so as to lead to an increase in the satiating potency of CCK, and consequently decreased food intake, during the peri-ovulatory period in rats. Central serotonergic mechanisms also appear to be part of the effect of estradiol on eating. The physiological roles of other peripheral feedback controls of eating and their central mediators remain to be established.
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Pardridge, W. M. "Plasma protein-mediated transport of steroid and thyroid hormones." American Journal of Physiology-Endocrinology and Metabolism 252, no. 2 (February 1, 1987): E157—E164. http://dx.doi.org/10.1152/ajpendo.1987.252.2.e157.
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The free hormone or free drug hypotheses have traditionally assumed that the concentration of cellular exchangeable hormone (i.e., the pool that drives cellular hormone or drug receptor occupancy) can be reliably estimated by in vitro measurements of unbound hormone concentrations. The corollary of this view is that the large reservoir of bound hormone in blood is passively transported by plasma proteins and is physiologically inactive. However, when these assumptions are subjected to direct empiric testing with either in vivo or perfused organ techniques, it is found that the large pool of bound hormone in blood is operationally available for transport across microcirculatory barriers without the plasma protein, per se, significantly exiting the plasma compartment. This process is believed to involve a mechanism of enhanced dissociation of hormone or drug from the plasma protein caused by transient conformational changes about the ligand binding site within the microcirculation: The biochemical mechanism of the interaction of the plasma protein with the surface of the microcirculation may involve receptor, charged selectivity, or local inhibitor mechanisms.
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Cheng, Yu-Jung, Chieh-Hsin Lin, and Hsien-Yuan Lane. "From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy." International Journal of Molecular Sciences 22, no. 16 (August 11, 2021): 8654. http://dx.doi.org/10.3390/ijms22168654.
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The impacts of menopause on neurodegenerative diseases, especially the changes in steroid hormones, have been well described in cell models, animal models, and humans. However, the therapeutic effects of hormone replacement therapy on postmenopausal women with neurodegenerative diseases remain controversial. The steroid hormones, steroid hormone receptors, and downstream signal pathways in the brain change with aging and contribute to disease progression. Estrogen and progesterone are two steroid hormones which decline in circulation and the brain during menopause. Insulin-like growth factor 1 (IGF-1), which plays an import role in neuroprotection, is rapidly decreased in serum after menopause. Here, we summarize the actions of estrogen, progesterone, and IGF-1 and their signaling pathways in the brain. Since the incidence of Alzheimer’s disease (AD) is higher in women than in men, the associations of steroid hormone changes and AD are emphasized. The signaling pathways and cellular mechanisms for how steroid hormones and IGF-1 provide neuroprotection are also addressed. Finally, the molecular mechanisms of potential estrogen modulation on N-methyl-d-aspartic acid receptors (NMDARs) are also addressed. We provide the viewpoint of why hormone therapy has inconclusive results based on signaling pathways considering their complex response to aging and hormone treatments. Nonetheless, while diagnosable AD may not be treatable by hormone therapy, its preceding stage of mild cognitive impairment may very well be treatable by hormone therapy.
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Chen, Dahu, Padmaja Ganapathy, Li-Ji Zhu, Xueping Xu, Quanxi Li, Indrani C. Bagchi, and Milan K. Bagchi. "Potential Regulation of Membrane Trafficking by Estrogen Receptorα via Induction of Rab11 in Uterine Glands during Implantation." Molecular Endocrinology 13, no. 6 (June 1, 1999): 993–1004. http://dx.doi.org/10.1210/mend.13.6.0287.
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Abstract The steroid hormone estrogen profoundly influences the early events in the uterus leading to embryo implantation. It is thought that estrogen triggers the expression of a unique set of genes in the preimplantation endometrium that in turn control implantation. To identify these estrogen-induced genes, we used a delayed implantation model system in which embryo attachment to endometrium is dependent on estrogen administration. Using a mRNA differential display (DD) method, we isolated a number of cDNAs representing mRNAs whose expression is either turned on or turned off in response to an implantation-inducing dose of estrogen. We identified one of these cDNAs as that encoding rab11, a p21ras-like GTP-binding protein (G protein), which functions in the targeting of transport vesicles to the plasma membrane. In normal pregnant rats, rab11 mRNA was expressed at low levels on days 1–2 of pregnancy, but its expression was markedly enhanced (∼6- to 8-fold) between days 3–5 immediately before implantation. In situ hybridization and immunocytochemistry revealed that rab11 expression in the uterus was predominantly in the glandular epithelium. In ovariectomized rats, the expression of rab11 mRNA was induced in the endometrium in response to estrogen. To determine whether this effect of estrogen was mediated through its nuclear receptors, we examined rab11 expression in a transformed endometrial cell line, Ishikawa. In transient transfection experiments, we observed that overexpression of estrogen receptor (ER) α or β induced endogenous rab11 mRNA in a hormone-dependent manner. ER bound to an antagonist, ICI 182,780, failed to activate this gene expression. These findings, together with the observation that ERα but not ERβ is detected in the glands of the preimplantation uterus, indicate that rab11 is one of the proteins that are specifically induced by estrogen-complexed ERα in rat endometrium at the onset of implantation. Our results imply that estrogen, which induces the synthesis of many growth factors and their receptors and other secretory proteins that are thought to be critical for implantation, may also facilitate their transport to the membrane and/or secretion by stimulating the expression of rab11, a component of the membrane-trafficking pathway. This study therefore provides novel insights into the diverse cellular mechanisms by which estrogen, acting via its nuclear receptors, may influence blastocyst implantation.
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Beato, Miguel, Roni H. G. Wright, and François Le Dily. "90 YEARS OF PROGESTERONE: Molecular mechanisms of progesterone receptor action on the breast cancer genome." Journal of Molecular Endocrinology 65, no. 1 (July 2020): T65—T79. http://dx.doi.org/10.1530/jme-19-0266.
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Gene regulation by steroid hormones has been at the forefront in elucidating the intricacies of transcriptional regulation in eukaryotes ever since the discovery by Karlson and Clever that the insect steroid hormone ecdysone induces chromatin puffs in giant chromosomes. After the successful cloning of the hormone receptors toward the end of the past century, detailed mechanistic insight emerged in some model systems, in particular the MMTV provirus. With the arrival of next generation DNA sequencing and the omics techniques, we have gained even further insight into the global cellular response to steroid hormones that in the past decades also extended to the function of the 3D genome topology. More recently, advances in high resolution microcopy, single cell genomics and the new vision of liquid-liquid phase transitions in the context of nuclear space bring us closer than ever to unravelling the logic of gene regulation and its complex integration of global cellular signaling networks. Using the function of progesterone and its cellular receptor in breast cancer cells, we will briefly summarize the history and describe the present extent of our knowledge on how regulatory proteins deal with the chromatin structure to gain access to DNA sequences and interpret the genomic instructions that enable cells to respond selectively to external signals by reshaping their gene regulatory networks.
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Farman, Nicolette, and Marie-Edith Rafestin-Oblin. "Multiple aspects of mineralocorticoid selectivity." American Journal of Physiology-Renal Physiology 280, no. 2 (February 1, 2001): F181—F192. http://dx.doi.org/10.1152/ajprenal.2001.280.2.f181.
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Aldosterone regulates renal sodium reabsorption through binding to the mineralocorticoid receptor (MR). Because the glucocorticoid receptor (GR) is expressed together with the MR in aldosterone target cells, glucocorticoid hormones bound to GR may also intervene to modulate physiological functions in these cells. In addition, each steroid can bind both receptors, and the MR has equal affinity for aldosterone and glucocorticoid hormones. Several cellular and molecular mechanisms intervene to allow specific aldosterone regulatory effects, despite the large prevalence of glucocorticoid hormones in the plasma. They include the local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11β-hydroxysteroid dehydrogenase; the intrinsic properties of the MR that discriminate between ligands through differential contacts; the possibility of forming homo- or heterodimers between MR and GR, leading to differential transactivation properties; and the interactions of MR and GR with other regulatory transcription factors. The relative contribution of each of these successive mechanisms may vary among aldosterone target cells (epithelial vs. nonepithelial) and according to the hormonal context. All these phenomena allow fine tuning of cellular functions depending on the degree of cooperation between corticosteroid hormones and other factors (hormonal or tissue specific). Such interactions may be altered in pathophysiological situations.
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Littlejohn, Erica L., Stephanie Fedorchak, and Carie R. Boychuk. "Sex-steroid-dependent plasticity of brain-stem autonomic circuits." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 319, no. 1 (July 1, 2020): R60—R68. http://dx.doi.org/10.1152/ajpregu.00357.2019.
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In the central nervous system (CNS), nuclei of the brain stem play a critical role in the integration of peripheral sensory information and the regulation of autonomic output in mammalian physiology. The nucleus tractus solitarius of the brain stem acts as a relay center that receives peripheral sensory input from vagal afferents of the nodose ganglia, integrates information from within the brain stem and higher central centers, and then transmits autonomic efferent output through downstream premotor nuclei, such as the nucleus ambiguus, the dorsal motor nucleus of the vagus, and the rostral ventral lateral medulla. Although there is mounting evidence that sex and sex hormones modulate autonomic physiology at the level of the CNS, the mechanisms and neurocircuitry involved in producing these functional consequences are poorly understood. Of particular interest in this review is the role of estrogen, progesterone, and 5α-reductase-dependent neurosteroid metabolites of progesterone (e.g., allopregnanolone) in the modulation of neurotransmission within brain-stem autonomic neurocircuits. This review will discuss our understanding of the actions and mechanisms of estrogen, progesterone, and neurosteroids at the cellular level of brain-stem nuclei. Understanding the complex interaction between sex hormones and neural signaling plasticity of the autonomic nervous system is essential to elucidating the role of sex in overall physiology and disease.
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Talamillo, Ana, David Martín, Roland Hjerpe, Jonatan Sánchez, and Rosa Barrio. "SUMO and ubiquitin modifications during steroid hormone synthesis and function." Biochemical Society Transactions 38, no. 1 (January 19, 2010): 54–59. http://dx.doi.org/10.1042/bst0380054.
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Steroid hormones control many aspects of animal physiology and behaviour. They are highly regulated, among other mechanisms, by post-translational modifications of the transcription factors involved in their synthesis and response. In the present review, we will focus on the influence of SUMO (small ubiquitin-related modifier) and ubiquitin modifications on the function of transcription factors involved in adrenal cortex formation, steroidogenesis and the hormonal response.
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Moore, Frank L., and Simon J. Evans. "Steroid Hormones Use Non-Genomic Mechanisms to Control Brain Functions and Behaviors: A Review of Evidence." Brain, Behavior and Evolution 54, no. 1 (1999): 41–50. http://dx.doi.org/10.1159/000006610.
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JIANG, YU, and WEIQUN WANG. "POTENTIAL MECHANISMS OF CANCER PREVENTION BY WEIGHT CONTROL." Biophysical Reviews and Letters 03, no. 03 (July 2008): 421–37. http://dx.doi.org/10.1142/s1793048008000824.
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Weight control via dietary caloric restriction and/or physical activity has been demonstrated in animal models for cancer prevention. However, the underlying mechanisms are not fully understood. Body weight loss due to negative energy balance significantly reduces some metabolic growth factors and endocrinal hormones such as IGF-1, leptin, and adiponectin, but enhances glucocorticoids, that may be associated with anti-cancer mechanisms. In this review, we summarized the recent studies related to weight control and growth factors. The potential molecular targets focused on those growth factors- and hormones-dependent cellular signaling pathways are further discussed. It appears that multiple factors and multiple signaling cascades, especially for Ras-MAPK-proliferation and PI3K-Akt-anti-apoptosis, could be involved in response to weight change by dietary calorie restriction and/or exercise training. Considering prevalence of obesity or overweight that becomes apparent over the world, understanding the underlying mechanisms among weight control, endocrine change and cancer risk is critically important. Future studies using "-omics" technologies will be warrant for a broader and deeper mechanistic information regarding cancer prevention by weight control.
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English, Arthur W., Jennifer C. Wilhelm, and Patricia J. Ward. "Exercise, Neurotrophins, and Axon Regeneration in the PNS." Physiology 29, no. 6 (November 2014): 437–45. http://dx.doi.org/10.1152/physiol.00028.2014.
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Electrical stimulation and exercise are treatments to enhance recovery from peripheral nerve injuries. Brain-derived neurotrophic factor and androgen receptor signaling are requirements for the effectiveness of these treatments. Increased neuronal activity is adequate to promote regeneration in injured nerves, but the dosing of activity and its relationship to neurotrophins and sex steroid hormones is less clear. Translation of these therapies will require principles associated with their cellular mechanisms.
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Blobel, G. A., and S. H. Orkin. "Estrogen-induced apoptosis by inhibition of the erythroid transcription factor GATA-1." Molecular and Cellular Biology 16, no. 4 (April 1996): 1687–94. http://dx.doi.org/10.1128/mcb.16.4.1687.
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Steroid hormones regulate diverse biological functions, including programmed cell death (apoptosis). Although steroid receptors have been studied extensively, relatively little is known regarding the cellular targets through which apoptosis is triggered. We show here that the ligand-activated estrogen receptor (ER) induces apoptosis in an erythroid cell line by binding to, and consequently inhibiting the activity of, GATA-1, an erythroid transcription factor essential for the survival and maturation of erythroid precursor cells. GATA-1 inhibition is reflected in the downregulation of presumptive GATA-1 target genes. Constitutive overexpression of a GATA-binding protein resistant to the effects of the ER partially rescues ER-induced apoptosis. Induction of apoptosis by a mutant ER defective in binding to the estrogen response element but active in GATA-1 inhibition suggests that ER-mediated inhibition of GATA-1 is direct and does not require estrogen response element-dependent transcriptional activation. Thus, a lineage-restricted transcription factor, such as GATA-1, constitutes one cellular target through which steroid hormones may control apoptosis. As GATA-binding proteins are evolutionarily conserved, we speculate that members of the steroid receptor family may exert some of their diverse biological functions in different cellular contexts through interference with the function of GATA-binding proteins.
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Talamillo, Ana, Leiore Ajuria, Marco Grillo, Orhi Barroso-Gomila, Ugo Mayor, and Rosa Barrio. "SUMOylation in the control of cholesterol homeostasis." Open Biology 10, no. 5 (May 2020): 200054. http://dx.doi.org/10.1098/rsob.200054.
Full textAbstract:
SUMOylation—protein modification by the small ubiquitin-related modifier (SUMO)—affects several cellular processes by modulating the activity, stability, interactions or subcellular localization of a variety of substrates. SUMO modification is involved in most cellular processes required for the maintenance of metabolic homeostasis. Cholesterol is one of the main lipids required to preserve the correct cellular function, contributing to the composition of the plasma membrane and participating in transmembrane receptor signalling. Besides these functions, cholesterol is required for the synthesis of steroid hormones, bile acids, oxysterols and vitamin D. Cholesterol levels need to be tightly regulated: in excess, it is toxic to the cell, and the disruption of its homeostasis is associated with various disorders like atherosclerosis and cardiovascular diseases. This review focuses on the role of SUMO in the regulation of proteins involved in the metabolism of cholesterol.
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McEwan, Iain J. "Sex, drugs and gene expression: signalling by members of the nuclear receptor superfamily." Essays in Biochemistry 40 (June 1, 2004): 1–10. http://dx.doi.org/10.1042/bse0400001.
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It is almost 20 years since the first steroid receptor cDNAs were cloned, a development that led to the concept of a superfamily of ligand-activated transcription factors: the nuclear receptors. Natural ligands for nuclear receptors are generally lipophilic in nature and include steroid hormones, bile acids, fatty acids, thyroid hormones, certain vitamins and prostaglandins. Nuclear receptors act principally to directly control patterns of gene expression and play vital roles during development and in the regulation of metabolic and reproductive functions in the adult organism. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action and biology of this important family of proteins.
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Ball, Gregory F., and Jacques Balthazart. "Individual variation and the endocrine regulation of behaviour and physiology in birds: a cellular/molecular perspective." Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1497 (November 28, 2007): 1699–710. http://dx.doi.org/10.1098/rstb.2007.0010.
Full textAbstract:
Investigations of the cellular and molecular mechanisms of physiology and behaviour have generally avoided attempts to explain individual differences. The goal has rather been to discover general processes. However, understanding the causes of individual variation in many phenomena of interest to avian eco-physiologists will require a consideration of such mechanisms. For example, in birds, changes in plasma concentrations of steroid hormones are important in the activation of social behaviours related to reproduction and aggression. Attempts to explain individual variation in these behaviours as a function of variation in plasma hormone concentrations have generally failed. Cellular variables related to the effectiveness of steroid hormone have been useful in some cases. Steroid hormone target sensitivity can be affected by variables such as metabolizing enzyme activity, hormone receptor expression as well as receptor cofactor expression. At present, no general theory has emerged that might provide a clear guidance when trying to explain individual variability in birds or in any other group of vertebrates. One strategy is to learn from studies of large units of intraspecific variation such as population or sex differences to provide ideas about variables that might be important in explaining individual variation. This approach along with the use of newly developed molecular genetic tools represents a promising avenue for avian eco-physiologists to pursue.
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Hobkirk, R. "Steroid sulfotransferases and steroid sulfate sulfatases: characteristics and biological roles." Canadian Journal of Biochemistry and Cell Biology 63, no. 11 (November 1, 1985): 1127–44. http://dx.doi.org/10.1139/o85-141.
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This review discusses the biological roles of steroid sulfotransferase enzymes (ST's) and steroid sulfate sulfohydrolases (sulfatases) mainly in mammalian tissues. In addition, some consideration is given to certain characteristics of these enzymes and, where possible, to their biological control. A considerable number of ST's of varying specificities, substrate affinities, and kinetics appear to exist. Several of these possess the properties of regulatory enzymes. ST's which act upon estrogen in reproductive tissues, such as uterus, are of particularly high affinity, appear to be under some biological control, and may exert important effects upon estrogen action. Although biosynthetic pathways involving steroid sulfate intermediates have been described, their importance is difficult to determine. The presence of an esterified sulfate group on a steroid molecule may markedly affect the action of enzymes, such as hydroxylases, upon the steroid structure in both a qualitative and quantitative sense. The number of different steroid sulfatases is not well understood. A sterol sulfatase present in the female reproductive tract appears capable of destabilizing the sperm head membrane by hydrolyzing sterol sulfates necessary for its integrity, and hence enabling the fusion of sperm and ovum. Other sulfatases may utilize blood-borne steroid sulfates for the ultimate production of estrogen which, in fetal membranes, could play a role in parturition and, in breast tumours, could function as a growth promoting agent. Brain sulfatases could possibly produce steroid hormones for purposes of tissue differentiation and (or) feedback control mechanisms, but this is not firmly established.
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Bermudez, Daniela, Priti Azad, Rómulo Figueroa-Mujíca, Gustavo Vizcardo-Galindo, Noemí Corante, Cristina Guerra-Giraldez, Gabriel G. Haddad, and Francisco C. Villafuerte. "Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with chronic mountain sickness." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 1 (January 1, 2020): R49—R56. http://dx.doi.org/10.1152/ajpregu.00250.2019.
Full textAbstract:
Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
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Artemova, Ekaterina Viktorovna, Anna Maksimovna Gorbacheva, Gagik Radikovich Galstyan, Alla Yur'evna Tokmakova, Svetlana Anatol'evna Gavrilova, and Ivan Ivanovich Dedov. "Neurohumoral mechanisms of keratinocytes regulation in diabetes mellitus." Diabetes mellitus 19, no. 5 (December 31, 2016): 366–74. http://dx.doi.org/10.14341/dm8131.
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The extent of damage to the nervous, vascular and microcirculatory systems in diabetic patients determine the regulation of physiological events that lead to the formation of chronic wounds, reduction of patient quality of life and increase of the financial value of medical care. Successful physiological repair is impossible without the successive phases of inflammation, proliferation and wound healing. Keratinocytes are the major cellular barrier components of the epidermis. These cells play an important role in physiological repair, as suggested by recent research, with many cells able to secrete steroid hormones de novo. Damage to the integrity of the skin leads to keratinocyte activation, triggering a cascade of reactions that contribute to changes in epidermal cell phenotype and lead to their proliferation and migration, analogous to changes in cellular adhesion and configuration of the cytoskeleton. An open question remains as to how the keratinocyte cell cycle, which is altered under conditions of hyperglycemia, and neurotransmitter metabolism during different stages of physiological repair are regulated. Understanding these processes will provide a scientific basis for the development of new targets for pharmacotherapies.
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Villablanca, Amparo C., Muthuvel Jayachandran, and Carole Banka. "Atherosclerosis and sex hormones: current concepts." Clinical Science 119, no. 12 (September 1, 2010): 493–513. http://dx.doi.org/10.1042/cs20100248.
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CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities.
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Keay, June, Jamie T. Bridgham, and Joseph W. Thornton. "The Octopus vulgaris Estrogen Receptor Is a Constitutive Transcriptional Activator: Evolutionary and Functional Implications." Endocrinology 147, no. 8 (August 1, 2006): 3861–69. http://dx.doi.org/10.1210/en.2006-0363.
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Steroid hormones such as estrogens and androgens are important regulators of reproduction, physiology, and development in a variety of animal taxa, including vertebrates and mollusks. Steroid hormone receptors, which mediate the classic cellular responses to these hormones, were thought to be vertebrate specific, which left the molecular mechanisms of steroid action in invertebrates unresolved. Recently an estrogen receptor (ER) ortholog was isolated from the sea hare Aplysia californica, but the functional significance of the receptor was unclear because estrogens and other steroids are not known to be important in that species. Furthermore, the Aplysia ER was found to be a constitutive transcriptional activator, but it was unclear whether the estrogen independence of the ER was an Aplysia-specific novelty or a more ancient character general to the mollusks. Here we report on the isolation and functional characterization of the first ER ortholog from an invertebrate in which estrogens are produced and play an apparent role, the cephalopod Octopus vulgaris. We show that the Octopus ER is a strong constitutive transcriptional activator from canonical estrogen response elements. The receptor does not bind estradiol and is unresponsive to estrogens and other vertebrate steroid hormones. These characteristics are similar to those observed with the Aplysia ER and support the hypothesis that the evolving ER gained constitutive activity deep in the mollusk lineage. The apparent reproductive role of estrogens in Octopus and other mollusks is unlikely to be mediated by the ER and may take place through an ancient, non-ER-mediated pathway.
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Maggio, Nicola, and Menahem Segal. "Corticosteroid Regulation of Synaptic Plasticity in the Hippocampus." Scientific World JOURNAL 10 (2010): 462–69. http://dx.doi.org/10.1100/tsw.2010.48.
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Stress, via release of steroid hormones, has been shown to affect several cellular functions in the brain, including synaptic receptors and ion channels. As such, corticosteroids were reported to modulate plasticity, expressed as long-term changes in reactivity to afferent stimulation. The classical view of the effects of stress on synaptic plasticity and cognitive functions assumes an inverted U-shape curve, such that a low stress level facilitates and a high stress level (i.e., corticosterone levels) impairs cognitive functions. This universal view has been challenged recently in a series of studies that show that stress and corticosterone have immediate and opposite effects on the ability to express long-term potentiation (LTP) in the dorsal and ventral sectors of the hippocampus. This differential role of stress may be related to the different functions associated with these sectors of the hippocampus. Herein, we review the known effects of stress hormones on cellular functions and outline the role of molecular mechanisms in stress-related global functions of the hippocampus.
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Olson-Manning, Carrie F. "Elaboration of the Corticosteroid Synthesis Pathway in Primates through a Multistep Enzyme." Molecular Biology and Evolution 37, no. 8 (March 20, 2020): 2257–67. http://dx.doi.org/10.1093/molbev/msaa080.
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Abstract Metabolic networks are complex cellular systems dependent on the interactions among, and regulation of, the enzymes in the network. Although there is great diversity of types of enzymes that make up metabolic networks, the models meant to understand the possible evolutionary outcomes following duplication neglect specifics about the enzyme, pathway context, and cellular constraints. To illuminate the mechanisms that shape the evolution of biochemical pathways, I functionally characterize the consequences of gene duplication of an enzyme family that performs multiple subsequent enzymatic reactions (a multistep enzyme) in the corticosteroid pathway in primates. The products of the corticosteroid pathway (aldosterone and cortisol) are steroid hormones that regulate metabolism and stress response in tetrapods. These steroid hormones are synthesized by a multistep enzyme Cytochrome P450 11B (CYP11B) that performs subsequent steps on different carbon atoms of the steroid derivatives. Through ancestral state reconstruction and in vitro characterization, I find that the primate ancestor of the CYP11B1 and CYP11B2 paralogs had moderate ability to synthesize both cortisol and aldosterone. Following duplication in Old World primates, the CYP11B1 homolog specialized on the production of cortisol, whereas its paralog, CYP11B2, maintained its ability to perform multiple subsequent steps as in the ancestral pathway. Unlike CYP11B1, CYP11B2 could not specialize on the production of aldosterone because it is constrained to perform earlier steps in the corticosteroid synthesis pathway to achieve the final product aldosterone. These results suggest that enzyme function, pathway context, along with tissue-specific regulation, both play a role in shaping potential outcomes of metabolic network elaboration.
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Zhang, Xun, M. Jeyakumar, Sergei Petukhov, and Milan K. Bagchi. "A Nuclear Receptor Corepressor Modulates Transcriptional Activity of Antagonist-Occupied Steroid Hormone Receptor." Molecular Endocrinology 12, no. 4 (April 1, 1998): 513–24. http://dx.doi.org/10.1210/mend.12.4.0089.
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Abstract Synthetic steroid hormone antagonists are clinically important compounds that regulate physiological responses to steroid hormones. The antagonists bind to the hormone receptors, which are ligand-inducible transcription factors, and modulate their gene-regulatory activities. In most instances, a steroid receptor, such as progesterone receptor (PR) or estrogen receptor (ER), is transcriptionally inactive when complexed with an antagonist and competitively inhibits transactivation of a target steroid-responsive gene by the cognate hormone-occupied receptor. In certain cellular and promoter contexts, however, antagonist-occupied PR or ER acquires paradoxical agonist-like activity. The cellular mechanisms that determine the switch from the negative to the positive mode of transcriptional regulation by an antagonist-bound steroid receptor are unknown. We now provide strong evidence supporting the existence of a cellular inhibitory cofactor that interacts with the B form of human PR (PR-B) complexed with the antiprogestin RU486 to maintain it in a transcriptionally inactive state. In the presence of unliganded thyroid hormone receptor (TR) or ER complexed with the antiestrogen 4-hydroxytamoxifen, which presumably sequesters a limiting pool of the inhibitory cofactor, RU486-PR-B functions as a transcriptional activator of a progesterone-responsive gene even in the absence of hormone agonist. In contrast, hormone-occupied TR or ER fails to induce transactivation by RU486-PR-B. Recent studies revealed that a transcriptional corepressor, NCoR (nuclear receptor corepressor), interacts with unliganded TR but not with liganded TR. Interestingly, coexpression of NCoR efficiently suppresses the partial agonistic activity of antagonist-occupied PR-B but fails to affect transactivation by agonist-bound PR-B. We further demonstrate that RU486-PR-B interacts physically with NCoR in vitro. These novel observations suggest that the inhibitory cofactor that associates with RU486-PR-B and represses its transcriptional activity is either identical or structurally related to the corepressor NCoR. We propose that cellular mechanisms that determine the switch from the antagonistic to the agonistic activity of RU486-PR-B involve removal of the corepressor from the antagonist-bound receptor so that it can effect partial but significant gene activation.
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Yaglova, Nataliya V., Sergey S. Obernikhin, Valentin V. Yaglov, Svetlana V. Nazimova, and Ekaterina P. Timokhina. "Cellular mechanisms of impaired mineralocorticoid and glucocorticoid production by endocrine disruptor DDT." Journal of the Belarusian State University. Biology, no. 1 (March 12, 2021): 12–19. http://dx.doi.org/10.33581/2521-1722-2021-1-12-19.
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Developmental exposure to persistent endocrine disruptors is of a great concern. Affection of adrenal hormones production by low-dose exposure to dichlorodiphenyltrichloroethane (DDT) has been revealed recently. Objective of the research – investigation of ultrastructural mechanisms of impaired mineralocorticoid and glucocorticoid production after prenatal and postnatal exposure to endocrine disruptor DDT. Male Wistar rats exposed to low doses of DDT during prenatal and postnatal development were studied. Aldosterone and corticosterone levels in serum were measured by enzyme-linked immunosorbent assay, histological examination and electron microscopy of the adrenals were performed. Pubertal rats, developmentally exposed to low doses of DDT, demonstrated lowered aldosterone and elevated corticosterone serum levels. After puberty the rats showed tendency to normalization of hormones’ production. Morphological examination of the adrenals revealed less developed zona glomerulosa in pubertal period and its relative hyperplasia after puberty. Microcirculatory disorders and focal cell death were observed in outer zona fasciculata. Electron microscopy of glomerulosa cells found signs of suppressed secretory activity in pubertal period and no significant reduction of mitochondria size in adult rats. Total number of mitochondria in 1 µm2 of cytoplasm and percent of mitochondria with swollen matrix were diminished compared to the control. Cells of inner zona fasciculata demonstrated increased functional activity. Age-dependent changes in fine structure of fasciculata cells were similar to the control, but were more pronounced. In this way, cellular mechanism of impaired mineralocorticoid production in rats prenatally and postnatally exposed to low doses of endocrine disruptor DDT, are insufficient mitochondrion function and impaired reorganization of mitochondrial apparatus, which occurs during pubertal period. Mechanisms of elevated glucocorticoid secretion are attributed to enhanced function of mitochondria in fasciculata cells.
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Liu, Suning, Kang Li, Yue Gao, Xi Liu, Weiting Chen, Wei Ge, Qili Feng, Subba R. Palli, and Sheng Li. "Antagonistic actions of juvenile hormone and 20-hydroxyecdysone within the ring gland determine developmental transitions in Drosophila." Proceedings of the National Academy of Sciences 115, no. 1 (December 18, 2017): 139–44. http://dx.doi.org/10.1073/pnas.1716897115.
Full textAbstract:
In both vertebrates and insects, developmental transition from the juvenile stage to adulthood is regulated by steroid hormones. In insects, the steroid hormone, 20-hydroxyecdysone (20E), elicits metamorphosis, thus promoting this transition, while the sesquiterpenoid juvenile hormone (JH) antagonizes 20E signaling to prevent precocious metamorphosis during the larval stages. However, not much is known about the mechanisms involved in cross-talk between these two hormones. In this study, we discovered that in the ring gland (RG) of Drosophila larvae, JH and 20E control each other’s biosynthesis. JH induces expression of a Krüppel-like transcription factor gene Kr-h1 in the prothoracic gland (PG), a portion of the RG that produces the 20E precursor ecdysone. By reducing both steroidogenesis autoregulation and PG size, high levels of Kr-h1 in the PG inhibit ecdysteriod biosynthesis, thus maintaining juvenile status. JH biosynthesis is prevented by 20E in the corpus allatum, the other portion of the RG that produces JH, to ensure the occurrence of metamorphosis. Hence, antagonistic actions of JH and 20E within the RG determine developmental transitions in Drosophila. Our study proposes a mechanism of cross-talk between the two major hormones in the regulation of insect metamorphosis.