Ancient Hormone Research Articles

Ultrasonication affects the melatonin and auxin levels and the antioxidant system in potato in vitro.

Melatonin is an ancient hormone whose physiological effects have been extensively studied in animals and human. We now know that it also plays a prominent role in the growth and development of plants. In our present experiment, the relationship between endogenous melatonin and the antioxidant system was investigated in potato plant grown in vitro. Changes in redox homeostasis under ultrasound stress were examined. The concentration of small molecule antioxidants and enzymes of the three-level antioxidant pathway was measured. ELISA method was used to determine the melatonin levels in plant tissues at each growth stage (0 h, 24 h, 48 h, 1 week, and 4 weeks after subculturing the explants) both in control and ultrasound-treated plants. Ultrasound stress activated the three-level defense system and decreased the endogenous melatonin levels. Melatonin was able to provide protection against membrane damage caused by drastic ultrasound treatment. Melatonin at the heart of the redox network is a key component regulating various biochemical, cellular, and physiological responses. It has a dual role, as it is able to act both as a growth regulator and an antioxidant. A close relationship was evidenced between the plant hormone indole-3-acetic acid and melatonin and ascorbic acid.

Seasonality of prolactin in birds and mammals.

In most animals, annual rhythms in environmental cues and internal programs regulate seasonal physiology and behavior. Prolactin, an evolutionarily ancient hormone, serves as a molecular correlate of seasonal timing in most species. Prolactin is highly pleiotropic with a wide variety of well-documented physiological effects; in a seasonal context prolactin is known to regulate annual changes in pelage and molt. While short-term homeostatic variation of prolactin secretion is under the control of the hypothalamus, long-term seasonal rhythms of prolactin are programmed by endogenous timers that reside in the pituitary gland. The molecular basis of these rhythms is generally understood to be melatonin dependent in mammals. Prolactin rhythmicity persists for several years in many species, in the absence of hypothalamic signaling. Such evidence in mammals has supported the hypothesis that seasonal rhythms in prolactin derive from an endogenous timer within the pituitary gland that is entrained by external photoperiod. In this review, we describe the conserved nature of prolactin signaling in birds and mammals and highlight its role in regulating multiple diverse physiological systems. The review will cover the current understanding of the molecular control of prolactin seasonality and propose a mechanism by which long-term rhythms may be generated in amniotes.

Thyroid Hormone Distributor Proteins During Development in Vertebrates

Thyroid hormones (THs) are ancient hormones that not only influence the growth, development and metabolism of vertebrates but also affect the metabolism of (at least some) bacteria. Synthesized in the thyroid gland (or follicular cells in fish not having a discrete thyroid gland), THs can act on target cells by genomic or non-genomic mechanisms. Either way, THs need to get from their site of synthesis to their target cells throughout the body. Despite being amphipathic in structure, THs are lipophilic and hence do not freely diffuse in the aqueous environments of blood or cerebrospinal fluid (in contrast to hydrophilic hormones). TH Distributor Proteins (THDPs) have evolved to enable the efficient distribution of THs in the blood and cerebrospinal fluid. In humans, the THDPs are albumin, transthyretin (TTR), and thyroxine-binding globulin (TBG). These three proteins have distinct patterns of regulation in both ontogeny and phylogeny. During development, an additional THDP with higher affinity than those in the adult, is present during the stage of peak TH concentrations in blood. Although TTR is the only THDP synthesized in the central nervous system (CNS), all THDPs from blood are present in the CSF (for each species). However, the ratio of albumin to TTR differs in the CSF compared to the blood. Humans lacking albumin or TBG have been reported and can be asymptomatic, however a human lacking TTR has not been documented. Conversely, there are many diseases either caused by TTR or that have altered levels of TTR in the blood or CSF associated with them. The first world-wide RNAi therapy has just been approved for TTR amyloidosis.

Suppression of Insulin Production and Secretion by a Decretin Hormone

Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown ofCG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.

Prolactin Hormone and Cardiovascular System

The Prolactin (PRL) hormone, a very ancient hormone, first discovered by Oscar Riddle and his colleagues in the late 1920s, is a 199 amino acid multifunctional polypeptide hormone, that has been found in all vertebrates to influence more than 300 physiologic functions of the body. This review discusses the prolactin structure, mechanism of synthesis, control of secretions, receptors, its intracellular signal transduction and its possible implications on the cardiovascular system.

Urotensin II and the kidney

Urotensin II (UTS2), the most potent vasoconstrictor identified thus far, is an undecapeptide hormone with a structure that is highly conserved through mammalian phylogeny. In spite of its broad expression across the invertebrate and vertebrate world, the precise role of UTS2 in physiology and disease is still unknown. The first description of human UTS2 and its receptor brought initial promise of a potential therapeutic target for progressive renal disease, with vasoconstrictive and profibrotic actions within an autocrine and paracrine system and local renal generation that was upregulated with renal pathology. However, the last decade has not brought the successful development of new treatments first hoped for, with one small human clinical trial bearing negative results. What has become apparent is that the spectrum of actions of UTS2 is broad and often paradoxical. This ancient hormone has both vasoconstrictor and vasodilatory actions, has both profibrotic and antiapoptotic activity, as well as actions which are highly contextual on the particular vascular bed studied and on the presence or absence of superimposed disease state. With current development of newer UTS2 antagonists attempting to more closely replicate the ligand-receptor kinetics of UTS2 and its receptor, the focus on potential clinical applications of UTS2 inhibition has moved away from the kidney to the treatment of chronic lung and cardiovascular diseases.

Vitamin D and Lipids

The interest in vitamin D has exploded during the last decade, illustrated by the number of new vitamin D–related articles registered in PubMed, which is between 50 and 100 every week. This is also reflected in the lay press, with numerous articles promoting the beneficial effects of the D-lightful sunshine hormone vitamin D. If read uncritically, vitamin D appears to be good for almost any condition thinkable and is today the hottest magic cure. But why has this happened? Article see p 270 First of all, vitamin D is nature's own product, an ancient hormone produced in the skin by sun exposure. It promotes the intestinal calcium absorption, has a well-known effect in preventing and curing rickets, and the role of vitamin D in calcium metabolism and skeletal health is indisputable.1 Secondly, the enzyme necessary for the final activation of vitamin D as well as the vitamin D receptor have recently been identified in tissues throughout the body, and extraskeletal effects of vitamin D were therefore to be expected.2 Thus, when methods for measuring 25(OH)D (the most abundant vitamin D metabolite and the one used to evaluate a subject's vitamin D status) became widely available, numerous observational studies were published. And almost without exception, high serum 25(OH)D levels were associated with good health, whereas low levels were predictors of type II diabetes mellitus, cancer, cardiovascular disease, immunologic diseases, and even mortality.3 In 4751 participants in the Tromso study from Northern Norway, over a follow-up period of 11 years those in the lowest serum 25(OH)D quartile had a 32% increased mortality risk as compared with those in the highest 25(OH)D quartile.4 And similarly, in the 1739 subjects in the Framingham Offspring Study followed for 5.4 years, those with serum 25(OH)D levels <10 ng/mL had a hazard ratio …

Plasma profile of microRNA after supplementation with high doses of vitamin D3 for 12 months

BackgroundRecently a large number of short non-coding-RNAs (microRNAs, (miRNA)) have been identified. These miRNAs act as post-transcriptional regulators where they generally have an inhibitory function. miRNAs are present in all human cells, and they are also detected in serum or plasma. The miRNAs have a broad range of actions, and their biogenesis must therefore be under tight control. One putative regulator of miRNA biogenesis or miRNA level could be vitamin D, an ancient hormone with effects on cell growth and differentiation, apoptosis and the immune system. In our study miRNA were reversed transcribed in total RNA isolated from plasma and analyzed by quantitative real-time PCR (qPCR) using the miRCURY LNA Universal RT microRNA PCR system (Exiqon). In 10 pilot subjects 136 miRNAs were detected in one or more plasma samples drawn at baseline and after 12 months of vitamin D supplementation. The twelve miRNAs that showed the greatest change in expression in these pilots were further analyzed by RT-qPCR of RNA from baseline and 12 months plasma samples in 40 subjects given high dose vitamin D3 (20.000 – 40.000 IU per week) and 37 subjects given placebo.ResultsAt baseline there was a significant and positive correlation between serum 25-hydroxyvitamin D and miR-532-3p expression (r = 0.24, P = 0.04). The change in expression of miR-221 from baseline to 12 months (ddCp value) was also significantly different between the vitamin D and placebo group (P =0.04), mainly due to a change in the placebo group.ConclusionsWe have not been able to demonstrate a consistent effect of vitamin D supplementation on the expression profile of miRNA in plasma. However, further studies are needed as this approach might potentially throw light on unknown aspects of vitamin D physiology.

NUCLEAR RECEPTORS

NUCLEAR RECEPTORS

Thyroid hormone deiodination in target tissues--a regulatory role for the trace element selenium?

The three isozymes catalyzing deiodination of thyroid hormones and iodothyronines derived thereof exert a major role in tissue- and development-specific expression of thyroid hormone action in target tissues by activating the prohormone T4 to thyromimetically active T3 or by inactivating the prohormone T4 or active T3 in non-target tissues at inappropriate time points. These three isozymes, in cooperation with the enzymes responsible for non-deiodinative degradation of iodothyronines, thus act as "guardians of the gate" to nuclear thyroid hormone receptors and other cellular target sites for thyroid hormone action. Strict and distinct hormonal, nutritional and nerval regulation of expression of the deiodinase isozymes warrants a closely coordinated control of thyroid hormone action, which directs growth, differentiation, and basal metabolic functions in the developing and the adult organism both in the periphery and in the central nervous system. The integrative action of this essential homeostatic and dynamic ancient hormone system in higher vertebrates is under the influence of two essential trace elements, iodine and selenium, which both are inadequately available for man and life stock in great parts of the world. As soon as, and only if, iodine supplementation is achieved, attempts to establish adequate selenium supply for thyroid hormone synthesis, activation, metabolism and action should be made, but not the other way around. In this review, the physiological, biochemical and pharmacological properties of the three deiodinase isozymes are discussed in detail, with special attention to the role of selenium in regulation of type I 5'-deiodinase expression. The contribution of each deiodinase izozyme to the activation and inactivation of thyroid hormones in specific tissues is reviewed.

Decidual Cells Produce a Heparin-binding Prolactin Family Cytokine with Putative Intrauterine Regulatory Actions

Pregnancy in mice and rats is associated with the production of a large family of hormones/cytokines related to prolactin (PRL). The hormones/cytokines are hypothesized to coordinate maternal and fetal adaptations to pregnancy. In this study, PRL-like protein-J (PLP-J, also known as PRL family 3, subfamily c, member 1 (Prl3c1)) is shown to be a product of the uterine decidua and a regulator of postimplantation intrauterine events. PLP-J-specific antibodies and a series of recombinant PLP-J proteins were generated and used to investigate PLP-J expression and as ligands for investigating biological targets. Decidual PLP-J migrates as a 29-kDa protein and localizes to a band of decidual cells surrounding the trophoblast cell layer on gestation day 8.5. PLP-J ligands specifically bound in situ to the surrounding uterine stromal cells and vasculature within the decidua of gestation day 8.5 implantation sites. We then investigated the in vitro actions of PLP-J on uterine stromal cells and endothelial cells. PLP-J specifically interacted with both cell populations. PLP-J promoted uterine stromal cell proliferation and inhibited endothelial cell proliferation. We determined that PLP-J does not interact with PRL receptors. Instead, PLP-J interacts with heparin-containing molecules, including syndecan-1, which is expressed in gestation day 8.5 pregnant uteri, as well as in uterine stromal cells and endothelial cells. The restricted expression of PLP-J and its specific interactions with uterine stromal cells and endothelial cells suggests that it acts locally and regulates decidual cell development and the endometrial vasculature.

Prescient Hormone Receptor Evolution?

Highly integrated biological systems can provide a challenge in terms of understanding how such systems arose during the course of evolution. One such system involves the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which arose from a gene duplication deep in the vertebrate lineage. MR binds to and is activated by the hormone aldosterone, which only appeared much later, in the lineage leading to tetrapods, raising the question of how each component "anticipated" the presence of the other. Bridgham et al. (see the Perspective by Adami) analyze the evolution of this system by reconstructing the ancestral corticoid receptor (AncCR) that gave rise to MR and GR and show that it already had substantial affinity for aldosterone as a consequence of its affinity for other more ancient hormones, possibly including 11-deoxycorticosterone. Furthermore, two single-nucleotide mutations in the AncCR yield a GR-like receptor with present-day low affinity for aldosterone. J. T. Bridgham, S. M. Carroll, J. W. Thornton, Evolution of hormone-receptor complexity by molecular exploitation. Science 312 , 97-101 (2006). [Abstract] [Full Text] C. Adami, Reducible complexity. Science 312 , 61-63 (2006). [Summary] [Full Text]

Urotensin II: Ancient Hormone with New Functions in Vertebrate Body Fluid Regulation

Urotensin II (UII), described in many fish species, is secreted by the caudal neurosecretory system, a unique fish neuroendocrine structure. We have examined UII secretion and its control in euryhaline fish, supporting a proposed role in osmoregulation. However, it is now apparent that UII is present in other vertebrates, including mammals. The 12-amino-acid peptide has been highly conserved and the key cyclic region is common from fish to humans. Our UII radioimmunoassay for flounder, directed to this cyclic region, has shown circulating UII levels in humans and rats comparable with those in fish. In mammals, UII cardiovascular effects vary between species, with vasoconstriction only evident in specific vascular beds. The kidney expresses UII receptors and responds to UII administration by a reduction in glomerular filtration rate, urine flow, and excretion of the major ions. Interestingly, plasma levels of UII are chronically elevated in rat models of hypertension. These observations imply an unforeseen role for this ancient fish hormone in the physiological and perhaps pathophysiological regulation of body fluids in higher vertebrates, including humans.

Using gene expression arrays to elucidate transcriptional profiles underlying prolactin function.

Prolactin is an ancient hormone, with different functions in many species. The binding of prolactin to its receptor, a member of the cytokine receptor superfamily, results in the activation of different intracellular signaling pathways, such as JAK2/STAT5, MAP kinase, and PI3K/AKT. How prolactin elicits so many different biological responses remains unclear. Recently, microarray technology has been applied to identify prolactin target genes in different systems. Here, we attempt to summarize and compare the available data. Our comparison of the genes reported to be transcriptionally regulated by prolactin indicates that there are few genes in common between the different tissues. Among the organs studied, mammary and prostate glands displayed the largest number of overlaps in putative prolactin target genes. Some of the candidates have been implicated in tumorigenesis. The relevance and validation of microarray data, as well as comparison of the results obtained by different groups, will be discussed.

The structure and regulation of the oxytocin receptor.

The oxytocin receptor (OTR) is part of an ancient hormone system expressed in diverse phyla in relation to acute reproductive smooth muscle responses, such as egg-laying, birth, or milk letdown. The regulation of the OTR gene, while correlating with steroid levels in vivo, remains elusive. There appear to be both inhibitory and stimulatory influences acting upon a constitutive pattern of basal expression. We have found no evidence, however, for an effect of the sex steroids either directly on gene transcription, or on the receptor itself at the protein level. In the prostatic carcinoma cell line Du145, we have shown that up-regulation of the OTR gene transcription can be effected by cAMP. In an attempt to characterize the expression of the OTR protein in vivo, we have shown, using ligand-blotting, that the OTR can be expressed at different sizes in transfected cells and in myometrium. Also, in the myometrium at term, immunohistochemistry suggests that there is both an increase in OTR protein per cell, as well as in the number of smooth muscle cells expressing OTR, emphasizing that perinatal changes are the results of both individual gene activation events and gross cellular differentiation. The OTR is a valuable model system reflecting molecular changes in the perinatal period. When we understand how this important molecule is regulated, we will also be a long way towards understanding the mechanisms controlling myometrial contractility at birth. Experimental Physiology (2001) 86.2, 289-296.

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Insulin Through the Ages: Phylogeny of a Growth Promoting and Metabolic Regulatory Hormone

Insulin was discovered in 1922 as the causative factor for a human metabolic disorder (diabetes mellitus), but it was recognized early that the hormone had a broad phylogenetic distribution. By the mid 1970s, insulin had been isolated and sequenced from all classes of vertebrates, including Agnatha. Also it was discovered that the insulin gene family in vertebrates included two closely related hormones named insulin-like growth factor (IGF)-I and -II. More recently, the application of recombinant DNA techniques have identified insulin-like peptide genes in invertebrates, including insects, molluscs and nematode and these findings clearly establish that insulin is an evolutionarily ancient hormone which is present in all metazoa. Here we briefly review the structure and function of the insulin/IGF gene family in vertebrates and invertebrates. Although these studies are ongoing, it appears that in invertebrates the insulin-like peptides function predominately as mitogenic growth factors that act to promote tissue growth and development. However, in vertebrates the mitogenic growth function has been subsumed by IGF-I and -II while insulin has acquired the function of being primarily a metabolic regulatory hormone. The gene duplication and divergence events necessary for this development probably occurred early during vertebrate evolution in the transition from protochordates, represented by extant amphioxus, to primitive jawless vertebrates, represented by extant lamprey and hagfish.

Insulin Through the Ages: Phylogeny of a Growth Promoting and Metabolic Regulatory Hormone1

Insulin was discovered in 1922 as the causative factor for a human metabolic disorder (diabetes mellitus), but it was recognized early that the hormone had a broad phylogenetic distribution. By the mid 1970s, insulin had been isolated and sequenced from all classes of vertebrates, including Agnatha. Also it was discovered that the insulin gene family in vertebrates included two closely related hormones named insulin-like growth factor (IGF)-I and -II. More recently, the application of recombinant DNA techniques have identified insulin-like peptide genes in invertebrates, including insects, molluscs and nematode and these findings clearly establish that insulin is an evolutionarily ancient hormone which is present in all metazoa. Here we briefly review the structure and function of the insulin/IGF gene family in vertebrates and invertebrates. Although these studies are ongoing, it appears that in invertebrates the insulin-like peptides function predominately as mitogenic growth factors that act to promote tissue growth and development. However, in vertebrates the mitogenic growth function has been subsumed by IGF-I and -II while insulin has acquired the function of being primarily a metabolic regulatory hormone. The gene duplication and divergence events necessary for this development probably occurred early during vertebrate evolution in the transition from protochordates, represented by extant amphioxus, to primitive jawless vertebrates, represented by extant lamprey and hagfish.

Insulin: new roles for an ancient hormone.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Elasmobranch color change: A short review and novel data on hormone regulation

Skins of Potamotrygon reticulatus are light in color in vitro, exhibiting punctate melanophores. Alpha-Melanocyte stimulating hormone (EC(50) = 4.58 x 10(-9) M) and prolactin (EC(50) = 1.44 x 10(-9) M) darken the skins in a dose-dependent manner. The endothelins ET-1, ET-2 and ET-3, and the purines, ATP, and uracil triphosphate (UTP) were not able to induce either skin lightening or darkening. Forskolin and the calcium ionophore A23187 promoted a dose-dependent darkening response, whereas N(2), 2'-O-dibutyryl guanosine 3'-5'-cyclic monophosphate (db cyclic GMP), phorbol-12-myristate-13-acetate (TPA), and 1-oleoyl-2-acetyl-sn-glycerol (OAG) were ineffective. The maximal response obtained with the calcium ionophore A23187 was only 76% of maximal darkening. These results indicate that the cyclic adenosine 3'-5'-monophosphate (cAMP) pathway is probably involved in the pigment dispersion of P. reticulatus melanophores. Other experiments should be done to further investigate how cytosolic calcium may be physiologically increased, and the existence of a putative cross-talk between calcium and cAMP signals. In conclusion, the only hormones effective on P. reticulatus melanophores were prolactin and alpha-MSH. No aggregating agent has been shown to antagonize these actions. Prolactin effect on elasmobranch melanophores adds a novel physiological role to this ancient hormone. J. Exp. Zool. 284:485-491, 1999.