Class Of Hormones Research Articles

Testosterone and Cholesterol Vasodilation of Rat Aorta Involves L-Type Calcium Channel Inhibition

Testosterone has rapid nongenomic vasodilator effects which could be involved in protective cardiovascular actions. Several authors suggested specific mechanisms to explain this effect, but this matter was not clarified yet. We studied the actions of testosterone and cholesterol on endothelium-denuded rat aorta and their effects on the L-type Ca2+ current (ICa,L) and potassium current (IK). Testosterone (1–100 μM) totally relaxed, in a rapid and concentration-dependent way, the aortic rings contracted by KCl or by (−)-Bay K8644 (BAY). Cholesterol also fully relaxed the contractions induced by KCl. None of the potassium channel antagonists tested (glibenclamide, tetraethylammonium and 4-aminopyridine) modified significantly the relaxant effect of testosterone. The antagonist of classic testosterone receptors, flutamide, did not modify the vasorelaxant effect of testosterone. Furthermore, testosterone and cholesterol inhibited either basal and BAY-stimulated ICa,L in A7r5 cells and they have no effects on IK. In summary, our results demonstrate that cholesterol and testosterone relax rat aorta by inhibiting LTCC. This effect of testosterone is not mediated by the classic hormone receptor or by potassium channel activation. These results suggest that the vasodilator mechanism of cholesterol and testosterone is the same.

Glucose Transporters in Sex Steroid Hormone Related Cancer

Cancer cells, as with most mammalian cells, depend on a continuous supply of glucose; not only as a precursor of glycoproteins, triglycerides and glycogen, but also as an important source of energy. This review concentrates on GLUT transporter expression in both normal and cancerous classical sex-steroid hormone tissues (i.e. breast, uterus, ovary, testis and prostate, among others). Given the importance of estrogen, progesterone and androgens in carcinogenesis, as well as in survival and propagation of these cancers, this review also highlights the current literature on hormone regulation of glucose transporters and on the role of hypoxia in their expression. Given the recent explosion of information on the newer GLUT6-12 family members, a brief overview on their function and general expression has been included. Finally, an insight into the use of glucose transporters as markers of cancer progression and clinical outcome is also discussed.

Neuroendocrine activity of the melanocyte

More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress. Examples of the above are catecholamines, serotonin, N-acetyl-serotonin, melatonin, proopiomelanocortin-derived adrenocorticotropic hormone, beta-endorphin or melanocyte-stimulating hormone peptides, corticotropin releasing factor, related urocortins and corticosteroids including cortisol and corticosterone as well as their precursors. Furthermore, their production is not random, but hierarchical and follows the structures of classical neuroendocrine organizations such as hypothalamic-pituitary-adrenal axis, serotoninergic, melatoninergic and catecholaminergic systems. An example of an intrinsic but overlooked neuroendocrine activity is production and secretion of melanogenesis intermediates including l-DOPA or its derivatives that could enter circulation and act on distant sites. Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis.

Benefits: Biological effects of phytoestrogens following long term exposure

Isoflavones (ISO) are bioactive food ingredients of the traditional East Asian diet and currently discussed as alternatives to classical hormone replacement therapies. The initial „health claim“ towards menopausal applications of ISO containing products stems from epidemiologic observations as soy isoflavones seem to reduce the prevalence of hormone-dependent cancers, e.g. endometrial, breast or prostate cancer. These claims were further supported by the observation, that neonatal exposure to ISO can prevent DMBA induced mammary cancer in rats. Although there are numerous studies on ISO phytoestrogens, experimental animal data on their long-term effects eventually supporting or disapproving observations in epidemiological studies are scarce. Therefore we and others [1] performed dietary exposure studies in rats

Characterization and influences of classical insect hormones on the expression profiles of a molting carboxypeptidase A from the cotton bollworm (Helicoverpa armigera)

Molting is a very important physiological behavior to arthropods. During molting, integument apolysis occurs, which is the digestion and absorption of the old endocuticle for new cuticle formation. Proteases play critical roles in this process. Molting carboxypeptidase A (Ha-CPA) is characterized from Helicoverpa armigera. The Ha-CPA transcript was mainly present in the integument from the 5th instar larvae. In the integument, the transcription level of the gene reached its peak at the 5th instar molting stage and the 6th instar prepupal stage, respectively. The examination of immunohistochemistry revealed that Ha-CPA could distribute into the molting fluid in the molting- and prepupal-stage larvae. The expression of Ha-CPA could be up-regulated by 20-hydroxyecdysone (20E). These facts indicate that Ha-CPA participates in the apolysis of the integument during larval molting and metamorphosis.

Testosterone treatment diminishes sickness behavior in male songbirds

Males of many vertebrate species are typically more prone to disease and infection than female conspecifics, and this sexual difference is partially influenced by the immunosuppressive properties of testosterone (T) in males. T-induced immunosuppression has traditionally been viewed as a pleiotropic handicap, rather than an adaptation. Recently, it has been hypothesized that suppression of sickness behavior, or the symptoms of infection, may have adaptive value if sickness interferes with the expression of T-mediated behaviors important for male reproductive success. We conduct a classic hormone replacement experiment to examine if T suppresses sickness behavior in a seasonally-breeding songbird, Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii). Triggered experimentally by bacterial lipopolysaccharide (LPS), sickness behavior includes decreased activity, anorexia, and weight loss. Gonadectomized (GDX) males that were treated with silastic implants filled with T exhibited suppression of behavioral and physiological responses to LPS compared to GDX and sham-GDX controls given empty implants. Sickness responses of control groups were statistically indistinguishable. T-implanted birds had significantly higher plasma T than control groups and levels were within the range associated with aggressive interactions during male-to-male contests. These findings imply that suppression of sickness behavior could occur when T is elevated to socially-modulated levels. Alternatively, it is possible that this suppressive effect is mediated through a stress-induced mechanism, as corticosterone levels were elevated in T-implanted subjects compared to controls. We propose that males wounded and infected during contests may gain a brief selective advantage by suppressing sickness responses that would otherwise impair competitive performance. The cost of immunosuppression would be manifested in males through an increased susceptibility to disease, which is presumably offset by capitalizing upon limited reproductive opportunities.

Long-term effects of dietary isoflavones on uterine gene expression profiles

Isoflavones (ISOs) are bioactive food ingredients of the traditional East Asian diet and currently discussed as alternatives to classical hormone replacement therapies and for reducing the prevalence of hormone-dependent cancers. Although there are many studies on ISOs, not much is known about their long-term effects. Therefore, we performed an animal experiment analyzing the effects of three different diets: a phytoestrogen-free diet, a diet supplemented with genistein (700 μg/g diet) and an ISO-high diet (232 μg daidzein and 240 μg genistein/g) at two distinct time points, juvenile (21 days) and adult (97 days). Exposure started prior to mating of the parents and throughout the life of the offspring. We observed a stronger increase of uterine wet weights in juvenile offspring with genistein exposure (1018 ± 350 mg/kg BW) than with ISO-high diet (497 ± 133 mg/kg BW). Whereas the expression of proliferation related genes ( PCNA; Ki67; IGF-1; IGF-1R), analyzed by real-time-qPCR and Western blot, were significantly down-regulated in juvenile animals exposed to genistein. Additionally, genistein exposure led to estrogenic responses, observed upon increase of complement C3 and decrease of estrogen receptors gene expressions, while the exposure to ISO-high diet did not show these effects. In conclusion, both the time point on which phytoestrogen exposure starts together with the composition of the ingested phytoestrogen containing diet are of great importance for the biological response of the offspring.

Involvement of Thyroid Hormones in the Alterations of T-Cell Immunity and Tumor Progression Induced by Chronic Stress

Stress alters the neuroendocrine system, immunity, and cancer. Although the classic stress hormones are glucocorticoids and catecholamines, thyroid hormones have also been related to stress. We recently reported that chronic restraint stress impairs T-cell mediated immunity and enhances tumor growth in mice. To study the participation of these hormones on the stress-induced alterations of the immune function and lymphoma growth, mice were subjected to acute or chronic stress, with or without thyroxin supplementation. Hormone levels, immune status, and cancer progression were evaluated. Differential endocrine alterations were observed in response to acute and chronic stress. Although corticosterone and noradrenaline levels were increased by acute stress, they were restored after prolonged exposure to the stressor. Instead, thyroid hormone levels were only reduced in chronically stressed animals in comparison with control subjects. Correlating, chronic but not acute stress impaired T-cell reactivity. Thyroxin replacement treatment of chronic restraint stress-exposed mice, which restored the euthyroid status, reversed the observed reduction of T-cell lymphoproliferative responses. Moreover, therapeutic thyroid replacement also reversed the alterations of lymphoma growth induced by chronic stress in syngeneic mice bearing tumors as well as Interleukin-2 production and specific cytotoxic response against tumor cells. Finally, we found that the isoforms theta and alpha of the protein kinase C are involved in these events. These results show for the first time that thyroid hormones are important neuroendocrine regulators of tumor evolution, most probably acting through the modulation of T-cell mediated immunity affected by chronic stress.

Expression analysis of phytohormone-regulated microRNAs in rice, implying their regulation roles in plant hormone signaling

Twenty-two conserved miRNAs were chosen to investigate the expression pattern in response to phytohormone treatments, in which the effects of five classic plant hormone stresses were surveyed in Oryza sativa. The results showed that 11 miRNAs were found to be dysregulated by one or more phytohormone treatments. The target genes of these miRNAs were validated in vivo and their expression profiling were revealed. We also analyzed the promoter regions of the 22 conserved miRNAs for phytohormone-responsive elements and the existence of the elements provided further evidences supporting our results. These findings enable us to further investigate the role of miRNAs in phytohormone signaling.

The hormonal action of IGF1 in postnatal mouse growth

The mammalian insulin-like growth factor 1 (IGF1), which is a member of a major growth-promoting signaling system, is produced by many tissues and functions throughout embryonic and postnatal development in an autocrine/paracrine fashion. In addition to this local action, IGF1 secreted by the liver and circulating in the plasma presumably acts systemically as a classical hormone. However, an endocrine role of IGF1 in growth control was disputed on the basis of the results of a conditional, liver-specific Igf1 gene knockout in mice, which reduced significantly the level of serum IGF1, but did not affect average body weight. Because alternate interpretations of these negative data were tenable, we addressed genetically the question of hormonal IGF1 action by using a positive experimental strategy based on the features of the cre/loxP recombination system. Thus, we generated bitransgenic mice carrying in an Igf1 null background a dormant Igf1 cDNA placed downstream of a transcriptional "stop" DNA sequence flanked by loxP sites (floxed) and also a cre transgene driven by a liver-specific promoter. The Igf1 cDNA, which was inserted by knock-in into the mutated and inactive Igf1 locus itself to ensure proper transcriptional regulation, was conditionally expressed from cognate promoters exclusively in the liver after Cre-mediated excision of the floxed block. Our genetic study demonstrated that the endocrine IGF1 plays a very significant role in mouse growth, as its action contributes approximately30% of the adult body size and sustains postnatal development, including the reproductive functions of both mouse sexes.

Red clover extract

Currently, red clover extract is used to treat menopausal disorders as an alternative to classic hormone therapy. Several human and animal studies have attributed hypolipidemic, hypoglycemic, or antiatherosclerotic effects to red clover extract or isoflavones. This study was designed to determine the peroxisome proliferator-activated receptor (PPAR) gamma activation by red clover extract. The PPARgamma binding affinities and the transactivation activities of red clover extracts, isoflavones, and their metabolites were analyzed. The presence of specific substances in the extracts was proved by high-performance liquid chromatography/electrospray ionization/mass spectrometry. The red clover extracts and the compounds genistein and biochanin A were potent PPARgamma ligands and activators. Several metabolites exerted higher binding affinities or transactivational activities than their precursor molecules. 6-Hydroxydaidzein exerted a more than 100-fold higher binding affinity than its precursor daidzein. The maximal transactivational activity of 6-hydroxydaidzein and 3'-hydroxygenistein exceeded even that of rosiglitazone, a known PPARgamma agonist. Equol and O-desmethylangolensin showed an approximately fivefold higher binding affinity and, in the case of O-desmethylangolensin, a fourfold higher PPARgamma agonistic activity than the precursor. The daily dose of Menoflavon forte, a widely used red clover extract for treatment of menopausal disorders, provides theoretically 15% to 30% of the daily recommended dose of rosiglitazone. Considering the more active metabolites formed, activity must be higher in vivo. This study shows that red clover extracts, the major compounds, and especially several main metabolites exert significant PPARgamma binding and transactivational activity. Red clover extract, which is currently used for treating menopausal disorders, could be simultaneously used for ameliorating the metabolic syndrome.

Distribution of vitamin D binding protein expressing neurons in the rat hypothalamus

We observed immunostaining for vitamin D binding protein (DBP) in rat hypothalamus. Part of the supraoptic and of the paraventricular neurons showed DBP immunoreactivity, in part colocalized with Arg-vasopressin. DBP was also observed in widespread axonal projections throughout the lateral hypothalamus, the median eminence and the posterior pituitary lobe. A portion of ependymal cells, the choroids plexus epithelium and some of the endocrine cells in the anterior pituitary lobe contained DBP immunoreactivity. In situ hybridization of semithin sections with a synthetic oligonucleotide probe to DBP mRNA resulted in staining of magnocellular hypothalamic neurons, but not of ependymal cells or anterior lobe cells. Our observations indicate an intrinsic expression of DBP in the rat hypothalamus. DBP may be synthesized and transported along with the classical neurohypophyseal hormones. The multiple locations of DBP-expressing neurons indicate multiple functional properties: DBP may be released from in the posterior lobe, it may act as a hypophyseotropic factor and as a central neuroactive substance.

Cell-specific signal transduction pathways regulating Na+-K+-ATPase. Focus on “Short-term effects of thyroid hormones on the Na+-K+-ATPase activity of chick embryo hepatocytes during development: focus on signal transduction”

the na+-k+-atpase is a complex integral membrane protein that carries out active transport of sodium and potassium across the cell plasma membrane, maintaining the ionic gradients. Each subunit has multiple isozymes that are expressed in tissue and developmental specific fashion. In addition to

Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels

The mechanisms that subserve ghrelin-evoked vasodilatation have not been elucidated in previous studies. Changes in perfusion pressure evoked by ghrelin and its N-terminal fragments were examined ex vivo in phenylephrine-constricted perfused mesenteric vascular beds of male Sprague Dawley rats maintained at a constant flow rate. Both ghrelin (maximum effect [ E max] 45%) and des-acyl ghrelin ( E max 43%) evoked vasodilatation at concentrations between 10 pM and 1 nM, compared to acetylcholine (median effective concentration [EC 50] 3 nM; E max 93%). Those responses were abolished in endothelium-denuded preparations, and in endothelium-intact preparations exposed to either calcium-activated potassium channel, or a depolarizing stimulus, or in the presence of a combination of either apamin and 1,2-chlorophenyl diphenylmethyl-1 H-pyrazole (triarylmethane-34 [TRAM-34]), or ouabain and barium. ATP-activated potassium channel blockade, or a combination of nitric oxide synthase and cyclooxygenase inhibition had no effect. The classical growth hormone secretagogue antagonist, [ d-Lys 3]-growth hormone-releasing peptide (10 nM), or several N-terminal fragments of des-acyl ghrelin, including the tripeptide glycine–serine–serine (G–S–S [1 nM]), showed endothelium-dependent vasodilatation like des-acyl ghrelin, while responses to glycine–serine or serine–serine were relatively lower. A higher concentration (100 μM) of l-serine, but not glycine, evoked vasodilatation of similar magnitude. The serine dense N-terminal sequence of des-acyl ghrelin mediates endothelium-dependent vasodilatation via activation of apamin + TRAM-34 sensitive small- and intermediate-conductance calcium-activated potassium channels present on the mesenteric endothelium. Thus, the vasodilator response to ghrelins in the perfused rat mesenteric vascular bed is not mediated by the classical growth hormone secretagogue receptor type 1a.

Reprint of Phytoestrogens: endocrine disrupters or replacement for hormone replacement therapy?

Objectives: This review presents findings with clear statements from the literature as well as own results of effects of soy, red clover and their isoflavones as well as of the Cimicifuga racemosa extract BNO 1055. Experimental and clinical effects on climacteric complaints, osteoprotective effects, activity in the urogenital tract, and risks concerning cardiovascular diseases and mammary and endometrial tissue will be compared, also in comparison to classical hormone preparations. The question whether soy and red clover products and/or Cimicifuga racemosa (CR) preparations are endocrine disrupters or may fulfill the criteria of the so-called phyto-SERMs will be discussed. Methods: Review of selected publications since 1980 and summary of unpublished own results of the authors. Results: Experimental and clinical evidences suggest that soy/red clover and their isoflavones do not fulfill the criteria of an ideal SERM. They appear to have mild osteoprotective effects but do not improve climacteric complaints. Furthermore, they seem to stimulate uterine growth and mammary epithelial proliferation. In ovariectomized rats, the CR extract BNO 1055 showed many of the beneficial effects of 17b-estradiol, including effects in the brain/hypothalamus to reduce serum LH levels, effects in the bone to prevent osteoporosis and estrogenic effects in the urinary bladder. The CR extract BNO 1055 had no uterotrophic effect. Conclusion: If clinical studies confirm these results, the Cimicifuga racemosa preparation BNO 1055 would appear as an ideal SERM and may therefore be an alternative to hormone replacement therapy.

Gonadotropin‐releasing hormone (GnRH)‐I regulation of interleukin (IL)‐1b and IL‐1 receptor antagonist expression in cultured human endometrial stromal cells

Human endometrium is an active site of cytokine production and action. Among these cytokines, the interleukin-1 (IL-1) system seems to be relevant to the embryonic implantation process. We have previously reported the production of GnRH-I by human blastocyst, as well as the presence of GnRH-I receptor in human endometrium. This suggests a close interaction between the immune and endocrine systems through these cytokine mediators in embryonic implantation. To test the relevance of this interaction during embryonic implantation, we investigated GnRH-I regulation of IL-1b and IL-1ra mRNA and protein expression in human endometrial stromal cells using quantitative competitive polymerase chain reaction and ELISA. IL-1b mRNA and protein expression in cultured human endometrial stromal cells was significantly enhanced by GnRH-agonist in comparison to control groups. IL-1ra mRNA and protein was significantly decreased by GnRH-agonist in comparison to control groups. In contrast, the GnRH-antagonist ablated the regulatory effects of GnRH agonist in 1b and IL-1ra mRNA and protein levels in a dose-dependent manner. In conclusion, these results suggest a possible close interaction between the immune and endocrine systems in human embryonic implantation through the classical neuropeptide hormone GnRH and its receptor.

Phenotypic Analysis of Arabidopsis Mutants: Ethylene Hormone Response: Figure 1.

Ethylene is one of the five classic plant hormones, having profound effects at all stages of plant growth and development from seed germination to tissue senescence. Tremendous strides have been made in our understanding of the molecular components of the ethylene signal transduction pathway through the identification of mutants having altered responses to ethylene. These mutants were isolated by screening for seedlings with an altered triple-response phenotype, which is manifested upon exposure to high levels of ethylene in the dark. The triple response consists of the formation of a pronounced apical hook, along with a shortening and thickening of both the hypocotyl and root and a proliferation of root hairs. This is unlike an untreated seedling, which normally has a long etiolated hypocotyl, normal root, and no apical hook formation. To carry out an ethylene gas treatment, seedlings must be grown in an enclosed system to maintain the levels of ethylene desired. This protocol describes ethylene treatment of seedlings in wide-mouth Mason jars sealed with canning jar lids.

Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism

about 180 liters of filtrate are produced by the human kidneys every day, with more than 99% of the filtered salt and water being subsequently reabsorbed along the nephron. In view of this high level of renal filtration, even slight alterations in the balance between filtration and reabsorption will

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-A resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

Thyronamines Are Isozyme-Specific Substrates of Deiodinases

3-Iodothyronamine (3-T 1 AM) and thyronamine (T AM) are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T(3)) actions. Their proposed biosynthesis from thyroid hormones would require decarboxylation and more or less extensive deiodination. Deiodinases (Dio1, Dio2, and Dio3) catalyze the removal of iodine from their substrates. Because a role of deiodinases in thyronamine biosynthesis requires their ability to accept thyronamines as substrates, we investigated whether thyronamines are converted by deiodinases. Thyronamines were incubated with isozyme-specific deiodinase preparations. Deiodination products were analyzed using a newly established method applying liquid chromatography and tandem mass spectrometry (LC-MS/MS). Phenolic ring deiodinations of 3,3',5'-triiodothyronamine (rT3AM), 3',5'-diiodothyronamine (3',5'-T2AM), and 3,3'-diiodothyronamine (3,3'-T2AM) as well as tyrosyl ring deiodinations of 3,5,3'-triiodothyronamine (T3AM) and 3,5-diiodothyronamine (3,5-T2AM) were observed with Dio1. These reactions were completely inhibited by the Dio1-specific inhibitor 6n-propyl-2-thiouracil (PTU). Dio2 containing preparations also deiodinated rT(3)AM and 3',5'-T2AM at the phenolic rings but in a PTU-insensitive fashion. All thyronamines with tyrosyl ring iodine atoms were 5(3)-deiodinated by Dio3-containing preparations. In functional competition assays, the newly identified thyronamine substrates inhibited an established iodothyronine deiodination reaction. By contrast, thyronamines that had been excluded as deiodinase substrates in LC-MS/MS experiments failed to show any effect in the competition assays, thus verifying the former results. These data support a role for deiodinases in thyronamine biosynthesis and contribute to confining the biosynthetic pathways for 3-T 1 AM and T 0 AM.