The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

In clinic, the luteinizing (LH) and follicle-stimulating (FSH) hormones and human chorionic gonadotropin (hCG) are used to treat reproductive dysfunctions and in assisted reproductive technology. They are the αβ-heterodimeric complexes and specifically bind to ectodomain of G protein-coupled LH and FSH receptors. This leads to activation of many signaling cascades; some of which are responsible for steroidogenesis, folliculogenesis, and spermatogenesis, while the others, such as β-arrestin pathways, trigger the downregulation of gonadotropin receptors. A low selectivity of the intracellular signaling of gonadotropins and a large number of their isoforms are the main causes of undesirable effects of gonadotropins, limiting their clinical applications. Unlike gonadotropins, the low-molecular-weight (LMW) ligands interact with an allosteric site located in the transmembrane domain of the LH and FSH receptors and selectively activate the certain signaling pathway, preventing a number of side effects of gonadotropins. The LMW ligands are characterized by activity of the full and inverse agonists and neutral antagonists, as well as the positive and negative modulators, and they have the in vivo activity, including when administered orally. This review focuses on the advances in the development of LMW allosteric ligands of the LH and FSH receptors and the prospects for their use in reproductive medicine

Optical issues for the diagnostic stations for the ELI-NP compton gamma source

A high brightness electron Linac is being built in the Compton Gamma Source at the ELI Nuclear Physics facility in Romania. To achieve the design luminosity, a train of 32 bunches, 16 ns spaced, with a nominal charge of 250 pC will collide with the laser beam in the interaction point. Electron beam spot size is measured with optical transition radiation (OTR) profile monitors. In order to measure the beam properties, the optical radiation detecting system must have the necessary accuracy and resolution. This paper deals with the studies of different optic configurations to achieve the magnification, resolution and accuracy in order to measure very small beam (below 30 μm) or to study the angular distribution of the OTR and therefore the energy of the beam. Several configurations of the optical detection line will be studied both with simulation tools (e.g. Zemax) and experimentally. The paper will deal also with the sensibility of optic system (in terms of depth of field, magnification and resolution) to systematic error

The Regulation of the Male Hypothalamic-Pituitary-Gonadal Axis and Testosterone Production by Adipokines

There is evidence that the mass and metabolic status of the adipose tissue that produces adipokines significantly affect the activity of the hypothalamic-pituitary-gonadal (HPG) axis and the synthesis of testosterone. This is due to the fact that adipokines, such as leptin, adiponectin, visfatin and resistin have an important role in the regulation of the male HPG axis and steroidogenesis in the testes. The regulation of the HPG axis by adipokines can be carried out both through the changes the plasma levels of adipokines (a systemic regulation) and through the changes in the expression and activity of adipokines in the pituitary and testes, the components of the HPG axis (an autonomous regulation). This review presents the comprehensive analysis of the involvement of leptin, adiponectin, resistin and visfatin in the regulation of the male HPG axis and the testosterone production, as well as of the possible mechanisms of this regulation. The role of adipokines in the dysregulation of the male reproductive system and the impaired steroidogenic activity in the testes in obesity and type 2 diabetes mellitus are also discussed

A versatile THz source from high-brightness electron beams: Generation and characterization

Ultra-short electron bunches, such as those delivered by a high-brightness photo-injector, are suitable to produce high peak power THz radiation, both broad and narrow band, with sub-picosecond down to femtosecond pulse shaping. The features of this kind of source in the THz range of the electromagnetic spectrum are extremely appealing for frequency-and time-domain experiments in a wide variety of fields. The present manuscript will overview the method of generation and characterization of THz radiation produced by high-brightness electron beams, as those available at the SPARC_LAB test facility

Clathrate hydrates as a sink of noble gases in Titan's atmosphere

We use a statistical thermodynamic approach to determine the composition of clathrate hydrates which may form from a multiple compound gas whose composition is similar to that of Titan's atmosphere. Assuming that noble gases are initially present in this gas phase, we calculate the ratios of xenon, krypton and argon to species trapped in clathrate hydrates. We find that these ratios calculated for xenon and krypton are several orders of magnitude higher than in the coexisting gas at temperature and pressure conditions close to those of Titan's present atmosphere at ground level. Furthermore we show that, by contrast, argon is poorly trapped in these ices. This trapping mechanism implies that the gas-phase is progressively depleted in xenon and krypton when the coexisting clathrate hydrates form whereas the initial abundance of argon remains almost constant. Our results are thus compatible with the deficiency of Titan's atmosphere in xenon and krypton measured by the {\it Huygens} probe during its descent on January 14, 2005. However, in order to interpret the subsolar abundance of primordial Ar also revealed by {\it Huygens}, other processes that occurred either during the formation of Titan or during its evolution must be also invoked.Comment: Astronomy & Astrophysics Letters, in pres

The Role of Apelin in the Functioning of the Reproductive System

Adipokine apelin through the apelin receptors activates a wide range of signaling cascades in the target cells and controls their growth, differentiation, apoptosis, and energy metabolism. In the recent years, the evidence has been obtained that all components of the hypothalamic-pituitary-gonad axis, in which apelin and its receptor are expressed, are targets of apelin. In the hypothalamus, apelin modulates the activity of the melanocortin and ghrelin systems and indirectly affects the production of gonadoliberin. In the ovaries, it controls the growth and maturation of the follicles, stimulates the angiogenesis, and affects the basal and stimulated by the other factors steroidogenic activity in follicular cells. The changes in the apelin signaling system are closely associated with dysfunctions of the female reproductive system, such as polycystic ovary syndrome, endometriosis, and cancer. Information on the regulation of the male reproductive system by apelin is limited to animal studies showing the effect of apelin on the hypothalamic components of the gonad axis. The participation of apelin in the regulation of the reproductive system opens up the broad opportunities for the development of new approaches for the correction of abnormalities in this system and for the treatment of infertility

Gonadoliberin – Synthesis, Secretion, Molecular Mechanisms and Targets of Action

Decapeptide gonadoliberin (GnRH) is the most important regulator of the hypothalamic-pituitary-gonadal (HPG) axis that controls the synthesis and secretion of the luteinizing and follicle-stimulating hormones by gonadotrophs in the adenohypophysis. GnRH is produced by the specialized hypothalamic neurons using the site-specific proteolysis of the precursor protein and is secreted into the portal pituitary system, where it binds to the specific receptors. These receptors belong to the family of G protein-coupled receptors, and they are located on the surface of gonadotrophs and mediate the regulatory effects of GnRH on the gonadotropins production. The result of GnRH binding to them is the activation of phospholipase C and the calcium-dependent pathways, the stimulation of different forms of mitogen-activated protein kinases, as well as the activation of the enzyme adenylyl cyclase and the triggering of cAMP-dependent signaling pathways in the gonadotrophs. The gonadotropins, kisspeptin, sex steroid hormones, insulin, melatonin and a number of transcription factors have an important role in the regulation of GnRH1 gene expression, which encodes the GnRH precursor, as well as the synthesis and secretion of GnRH. The functional activity of GnRH-producing neurons depends on their migration to the hypothalamic region at the early stages of ontogenesis, which is controlled by anosmin, ephrins, and lactosamine-rich surface glycoconjugate. Dysregulation of the migration of GnRH-producing neurons and the impaired production and secretion of GnRH, lead to hypogonadotropic hypogonadism and other dysfunctions of the reproductive system. This review is devoted to the current state of the problem of regulating the synthesis and secretion of GnRH, the mechanisms of migration of hypothalamic GnRH-producing neurons at the early stages of brain development, the functional activity of the GnRH-producing neurons in the adult hypothalamus and the molecular mechanisms of GnRH action on the pituitary gonadotrophs. New experimental data are analyzed, which significantly change the current understanding of the functioning of GnRH-producing neurons and the secretion of GnRH, which is very important for the development of effective approaches for correcting the functions of the HPG axis