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Phoenixin (PNX) is a newly discovered peptide produced by proteolytic cleavage of a small integral membrane protein 20 (Smim20), which acts as an important regulator of energy homeostasis and reproduction. Since dysfunction of reproduction is characteristic in polycystic ovarian syndrome (PCOS), the role of PNX in pathogenesis of PCOS needs further investigation. The objective of this study was to determine expression of Smim20, PNX-14 and its receptor GRP173 in the hypothalamus, ovary and periovarian adipose tissue (PAT) of letrozole induced PCOS rats. Phosphorylation of extracellular signal-regulated kinase (ERK1/2), protein kinases A (PKA) and B (Akt) were also estimated. We observed that PCOS rats had high weight gain and a number of ovarian cyst, high levels of testosterone, luteinizing hormone and PNX-14, while low estradiol. Smim20 mRNA expression was higher in the ovary and PAT, while PNX-14 peptide production was higher only in the ovary of PCOS rat. Moreover, in PCOS rats Gpr173 level was lower in PAT but at the protein level increased only in the ovary. Depending on the tissues, kinases phosphorylation were significantly differ in PCOS rats. Our results showed higher levels of PNX-14 in PCOS rats and indicated some novel findings regarding the mechanisms of PCOS pathophysiology.

The function of estrogen-related receptor (ERR) in testicular cells is at the beginning of exploration. Our previous findings showed that expression pattern of estrogen-related receptor (ERR) in mouse Leydig cell depends on physiological status of the cell. Exogenous hormones/hormonally active chemicals affect ERR expression. In Leydig cells in vitro, ERRα and ERRγ show opposing regulatory properties. The aim of this study was to examine the role of ERR in epigenetic processes in cells with altered level of secreted estrogens; mouse tumor Leydig cells and bank vole Leydig cells, respectively. In Leydig cells, ERRα and ERRγ were silenced via siRNA. mRNA and protein expression and protein localization of molecules required for miRNA biogenesis and function (Exportin 5, Dicer, Drosha and Argonaute 2; Ago2) were studied with the use of qRT-PCR, Western blotting, and immunohistochemistry. Global DNA methylation and histone deacetylation status together with estradiol secretion were determined with fluorometric, and immunoenzymatic assays. Regardless of ERR type knockdown in tumor Leydig cells, downregulation (P 0.05; P 0.01; P 0.001) of Exportin5, Dicer, Drosha but not Ago2 was revealed while at protein level only Drosha was downregulated (P 0.01) by both ERRα and ERRγ. Oppositely, Exportin5, Dicer and Ago2 showed ERR type-dependent regulation (downregulation; P 0.01 by ERRα and upregulation; P 0.01; P 0.001 by ERRγ). In ERR-silenced vole Leydig cells, expression of Exportin5, endonucleases and Ago2 was not changed. Immunolocalization of Dicer and Ago2 was independent of the cell origin in contrast to localization of Exportin5 and Drosha which was dependent on the cell origin and ERR type knockdown. Absence of ERR effected on cell methylation status (ERRα increased it; P 0.01 while ERRγ decreased it; P 0.01, P 0.001) but it not changed histone deacetylates activity. ERRα and ERRγ silencing decreased (P 0.01, P 0.001) estradiol secretion in both tumor and vole Leydig cells. In mouse and bank vole Leydig cell, Exportin5, Dicer, Drosha and Ago2 expression as well as methylation status are regulated by ERR in a manner related to receptor type, molecule type, cell origin and level of secreted estrogen.

Background Onset of spermatogenesis at puberty is critically dependent on the activity of hypothalamic-pituitary-gonadal axis and testosterone production by Leydig cells. The aim of this study was to examine whether activation of Notch receptors and expression of Notch ligands and effector genes in rat seminiferous epithelium are controlled by androgen signaling during puberty. Methods Peripubertal (5-week-old) Wistar rats received injections of flutamide (50 mg/kg bw) daily for 7 days to reduce androgen receptor (AR) signaling or a single injection of ethanedimethane sulphonate (EDS; 75 mg/kg bw) to reduce testosterone production. Gene and protein expressions were analyzed by real-time RT-PCR and western blotting, respectively, protein distribution by immunohistochemistry, and steroid hormone concentrations by enzyme-linked immunosorbent assay. Statistical analyses were performed using one-way ANOVA followed by Tukey’s post hoc test or by Kruskal-Wallis test, followed by Dunn’s test. Results In both experimental models changes of a similar nature in the expression of Notch pathway components were found. Androgen deprivation caused the reduction of mRNA and protein expression of DLL4 ligand, activated forms of Notch1 and Notch2 receptors and HES1 and HEY1 effector genes (p p p p p p Conclusions Androgens and androgen receptor signaling may be considered as factors regulating Notch pathway activity and the expression of Hes and Hey genes in rat seminiferous epithelium during pubertal development. Further studies should focus on functional significance of androgen-Notch signaling cross-talk in the initiation and maintenance of spermatogenesis.

Estrogen-related receptors (ERRs) α, β and γ appear to be novel molecules implicated in estrogen signaling. We blocked and activated ERRs in mouse (C57BL/6) adrenals and adrenocortical cells (H295R) using pharmacological agents XCT 790 (ERRα antagonist) and DY131 (ERRβ/γ agonist), respectively. Mice were injected with XCT 790 or DY131 (5 μg/kg bw) while cells were exposed to XCT 790 or DY131 (0.5 μg/L). Irrespectively of the agent used, changes in adrenocortical cell morphology along with changes in lutropin, cholesterol levels and estrogen production were found. Diverse and complex ERRs regulation of multilevel-acting steroidogenic proteins (perilipin; PLIN, cytochrome P450 side-chain cleavage; P450scc, translocator protein; TSPO, steroidogenic acute regulatory protein; StAR, hormone sensitive lipase; HSL and HMG-CoA reductase; HMGCR) was revealed. Blockage of ERRα decreased P450scc, StAR and TSPO expressions. Activation of ERRβ/γ increased P450scc, StAR and HMGCR while decreased HSL expressions. PLIN expression increased either after XCT 790 or DY131 treatment. Additionally, treatment with both XCT 790 or DY131 decreased activity of Ras/Raf, Erk and Akt indicating their involvement in control of morphology and steroidogenic function of cortex cells. ERRs are important in maintaining morpho-function of cortex cells through action in specific, opposite, or common manner on steroidogenic molecules.

Communication in biological systems involves diverse-types of cell-cell interaction including cross-talk between receptors expressed by the target cells. Recently, novel sort of estrogen receptors (G protein - coupled estrogen receptor; GPER and estrogen-related receptor; ERR) that signal directly via estrogen binding and/or via mutual interaction-regulated estrogen signaling were reported in various organs including testis. Peroxisome proliferator - activated receptor (PPAR) is responsible for maintaining of lipid homeostasis that is critical for sex steroid production in the testis. Here, we investigated the role of interaction between GPER, ERRβ and PPARγ in steroidogenic Leydig cells of immature boar testis. Testicular fragments cultured ex vivo were treated with GPER or PPARγ antagonists. Then, cell ultrastructure, expression and localization of GPER, ERRβ, PPARγ together with the molecular receptor mechanism, through cyclic AMP and Raf/Ras/extracellular signal activated kinases (ERK), in the control of cholesterol concentration and estrogen production by Leydig cells were studied. In the ultrastructure of antagonist-treated Leydig cells, mitochondria were not branched and not bifurcated as they were found in control. Additionally, in PPARγ-blocked Leydig cells changes in the number of lipid droplets were revealed. Independent of used antagonist, western blot revealed decreased co-expression of GPER, ERRβ, PPARγ with exception of increased expression of ERRβ after PPARγ blockage. Immunohistochemistry confirmed presence of all receptors partially located in the nucleus or cytoplasm of Leydig cells of both control and treated testes. Changes in receptor expression, decreased cholesterol and increased estradiol tissue concentrations occurred through decreased cAMP level (with exception after GPER blockage) as well as Raf/Ras/ERK pathway expression. These all findings indicate that GPER-ERRβ-PPARγ interaction exists in immature boar testis and regulates Leydig cell function. Further detailed studies and considerations on GPER-ERRβ-PPARγ as possible diagnosis/therapy target in disturbances of testis steroidogenic function are needed.

Leydig cell tumors (LCT) are the most common type of testicular sex cord-stromal tumor. In this report, we implicate the G-coupled estrogen receptor (GPER) and peroxisome proliferator receptor (PPAR) in regulation of lipid homeostasis and the expression of steroidogenesis-controlling molecules in clinical specimens of LCTs and cell line (mouse tumor Leydig cells; MA-10). We also show the general structure and morphology of human LCTs with the use of scanning electron microscopy and light microscopy, respectively. In LCTs, protein immunoblotting and immunohistochemical analysis revealed increased expression of GPER and decreased expression of PPARα, β and γ. Concomitantly, changes in expression pattern of the lutropin receptor (LHR), protein kinase A (PKA), perilipin (PLIN), hormone sensitive lipase (HSL), steroidogenic acute regulatory protein (StAR), translocator protein (TSPO), HMG-CoA synthase (HMGCA), and HMG-CoA reductase (HMGCR) were observed.Using MA-10 cells treated with GPER and PPAR antagonists (alone and in combination), we demonstrated there is a GPER-PPAR mediated control of cholesterol concentration. In addition, GPER-PPARα regulated estradiol secretion, while GPER-PPARγ affected cGMP concentration. It is assumed that GPER and PPAR can be altered in LCT, resulting in a perturbed lipid balance and steroidogenesis. In LCTs, the phosphatidylinositol-3-kinase (PI3K)-Akt-mTOR signaling pathway was disturbed. Thus, PI3K-Akt-mTOR, together with cGMP, can play a role in LCT proliferation, growth, and metastasis as well as lipid balance control.In conclusion, we discuss the implications of GPER-PPAR interaction with lipid metabolism and steroidogenesis controlling-molecules in LCT biology that can be used in future studies as potential targets of diagnostic and therapeutic implementations.

We tested whether G-coupled membrane estrogen receptor (GPER) and peroxisome proliferator activated receptor (PPAR) partnership exists and whether this interaction regulates mouse Leydig cell function. Mature and aged mice were treated with the antagonist of GPER (G-15; 50 μg/kg b.w). Leydig cells (MA-10) were treated with G-15 (10 nM) alone or in combination with peroxisome proliferator-activated receptor α or γ antagonists, respectively (PPARα, 10 μM; PPARγ, 10 μM). GPER blockage affected testis steroidogenic status via changes in lutropin and cholesterol levels as well as protein expression alterations of the lutropin receptor, acute steroidogenesis activating protein, translocator protein, and protein kinase A in mouse Leydig cells both in vivo and in vitro. Inactivation of both GPER and PPAR in vitro revealed expressional modulation of other steroidogenesis-controlling molecules acting on various steps of lipid homeostasis e.g. cytochrome P450scc, perilipin, hormone sensitive lipase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. Concomitantly, microscopic analysis of cells treated with antagonists showed changes in morphology, migration competences and cytoskeleton structure. In the above processes, the action of GPER and PPARα was regulated through the PI3K/Akt pathway, while PPARγ was mediated by the Ras/Raf pathway. In addition, GPER and PPARs specifically controlled individual signaling proteins. For the first time, we report here the importance of GPER-PPARα and -PPARγ 'neopartnership' in maintenance of Leydig cell morpho-functional status.

In this study, G-coupled estrogen receptor (GPER) was inactivated, by treatment with antagonist (G-15), in testes of C57BL/6 mice: immature (3 weeks old), mature (3 months old) and aged (1.5 years old) (50 μg/kg bw), as well as MA-10 mouse Leydig cells (10 nM/24 h) alone or in combination with 17β-estradiol or antiestrogen (ICI 182,780). In G-15-treated mice, overgrowth of interstitial tissue was found in both mature and aged testes. Depending on age, differences in structure and distribution of various Leydig cell organelles were observed. Concomitantly, modulation of activity of the mitochondria and tubulin microfibers was revealed. Diverse and complex GPER regulation at the mRNA level and protein of estrogen signaling molecules (estrogen receptor α and β; ERα, ERβ and cytochrome P450 aromatase; P450arom) in G-15 Leydig cells was found in relation to age and the experimental system utilized (in vivo and in vitro). Changes in expression patterns of ERs and P450arom, as well as steroid secretion, reflected Leydig cell heterogeneity to estrogen regulation throughout male life including cell physiological status.We show, for the first time, GPER with ERs and P450arom work in tandem to maintain Leydig cell architecture and supervise its steroidogenic function by estrogen during male life. Full set of estrogen signaling molecules, with involvement of GPER, is crucial for proper Leydig cell function where each molecule acts in a specific and/or complementary manner. Further understanding of the mechanisms by which GPER controls Leydig cells with special regard to male age, cell of origin and experimental system used is critical for predicting and preventing testis steroidogenic disorders based on perturbations in estrogen signaling.

Monte Carlo simulations are used to analyse the behavior of the extended Ashkin-Teller model in two dimensions from the ratio of the square of the second moment of the order parameter to its fourth moment. The critical surface in three dimensional parameter space is calculated in regions where the Ising transitions are expected. The continuity of the order parameter at the critical surface is verified by a finite size scaling analysis for both ferromagnetic and antiferromagnetic parts of the phase diagram.

We study the phase diagram of a generalization of the Ashkin-Teller model in two dimensions using the mean-field renormalization group (MFRG) theory. We calculate critical surfaces for this three-parameter Hamiltonian of the model using two different approaches, and we discuss the resulting phase diagram and compare it with the results from the molecular-field approximation.

We add a term to the original Ashkin-Teller Hamiltonian in order to reduce the degeneracy. It is shoen that a certain class of terms all lead to the same Hamiltonian. The phase diagram of the isotropic model is discussed in the framework of mean field theory. It exhibits a wealth of critical phenomena.

Resolution exacte du modele generalise en incluant des interactions spin-pseudospin supplementaires des plus proches voisins suivant la direction x. Ce nouveau modele peut etre interprete en termes de couplage magneto-elastique

On montre notamment que les transitions de phase vers la phase paramagnetique sont discontinues pour toutes les valeurs des parametres, qu'il n'y a pas de transitions ordre-ordre entre les phases Ai et Fi, et que, pour certaines surfaces tres petites dans l'espace du parametre, la transition a la phase paramagnetique est accompagnee d'un changement de signe de la fonction de correlation nn

A simple mechanism is proposed to explain details of the thermomagnetic curve for NiFe 0.5 V 0.5 O 3−δ . It is shown that the Ising model with random-bond quenched disorder is sufficient to describe this phenomenon.

Possible generalizations of the Ashkin-Teller model are analysed aiming at reduction of degeneracy of the energy levels. The extended isotropic case is considered in the framework of the molecular field approximation. Assuming six order parameters a three dimensional phase diagram is calculated.

From 1976 to 1980, 377 randomized patients were entered in a multicentric study supported by the W.H.O. Melanoma Group. In this report, only 196 patients are considered for analysis: 31.6 % were excluded because of inadequate treatment or protocol violations. Three arms of treatment were compared: DTIC alone, DTIC plus bacillus Calmette-Guérin, and DTIC plus Corynebacterium parvum. No significant difference in terms of complete response plus partial response was detected among the three regimens. Twenty-five patients (12.7 %) responded with complete tumor regression, and 18 (9.3 %) with partial regression. Complete plus partial responses were thus achieved in 22 % of evaluable patients. Responders had a longer median survival than nonresponders. Overall median survival was 6 months. Brain metastases were detected in 17 % of the patients. Median time from the beginning of treatment to the diagnosis of CNS involvement was 4 months. There is no evidence that active aspecific immunotherapy added to DTIC increases the response rate in patients with disseminated disease. The toxic effects were acceptable, and no drug-related death was observed.

A new model of metamagnetic phase transition with temperature in Mn3GaC is proposed. The magnetoelastic Hamiltonian takes into account two independent strains (trigonal and isotropic ones) as functions of temperature, calculated similarly to the microscopic theory of magnetostriction. Necessary conditions for the transition are established within the molecular field approximation and the fit with experiment is discussed.

The paramagnetic phase of the antiferromagnetic binary alloy of magnetic and nonmagnetic atoms is considered. Taking into account the coupling with elastic energy we obtain the phase transition related to the abrupt change in the following characteristics: strain, paramagnetic susceptability and distribution of both types of atoms. Such a situation probably occurs in some perovskite materials.

A new model of the temperature-induced metamagnetic phase transitions is considered for the class of the two-sublattice magnets with axial symmetry. The model Hamiltonian contains the usual Ising term as well as the coupling of the uniform strain with both exchange interaction and single ion anisotropy. Within the MFA all these couplings are found to be necessary to produce the metamagnetic phase change. The results are compared with experiment. [Russian Text Ignored].

Calcul au moyen d'un modele de type Heisenberg, deja decrit, dans l'approximation de phase aleatoire

New theoretical possibilities of temperature-induced antiferromagnetic ordering in the singlet-triplet model are considered. Within the framework of mean-field theory the phase diagrams in the temperature--magnetic-field plane have been determined. They exhibit several possibilities of re- entrant phase transitions to the paramagnetic and to the antiferromagnetic phases, as well as several multicritical points. One of the phase diagrams is a simplified version of the case of HoSb.

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The temperature dependence of magnetization M ( T ) of new polycrystalline ilmenite Ni 2 FeVO 6−δ shows remarkable singularities which can be interpreted as a result of coexistence of three magnetic phases in its magnetic structure. A fit of the dependences following four different models, each of which a combination of three functions of chosen type, to the M ( T ) experimental dependence has been made.