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Journal Article 2009; 30(5): 629-636 PubMed PMID: 20035271 Citation  Keywords:  Adolescent, Child, Child, Preschool, Drug Resistance:physiology, Female, Humans, I-kappa B Proteins:metabolism, Male, NF-KappaB Inhibitor alpha, Nephrotic Syndrome:metabolism, Receptors, Glucocorticoid:metabolism, Transcription Factor RelA:metabolism, You.   

OBJECTIVES: The aim of our study was to investigate levels of glucocorticoid receptor (GRalpha), nuclear factor kappa B (NFkappaB) p65/p50 and inhibitor of NFkappaB alpha (IkappaBalpha) in the peripheral mononuclear blood cells (PMBC) of children with idiopathic nephrotic syndrome (INS).

METHODS: The expression of GRalpha, NFkappaBp65/p50 and IkappaBalpha was determined in 59 patients (age 10.2+/-5.1) and 25 healthy controls (CO) (age 13.1+/-3.4) using Western blot analysis. Patients were labeled according to their clinical sensitivity to glucocorticoids (GCs) as responders (RE), partial responders (PR), and non-responders (NR).

RESULTS: Significantly higher expressions of GRalpha were observed in RE than in PR, NR (p<0.01) and even CO (p<0.05). Similarly, expression of NFkappaBp65 was higher in RE in comparison to PR, NR and CO (p<0.05). These differences were more emphasized in the relapse: levels of GRalpha were significantly lower in PR than in RE and CO (p<0.01). Significant differences were also observed in expression of NFkappaB: RE showed significantly higher expression of NFkappaBp65 in comparison to PR, NR and even CO (p<0.01).

CONCLUSIONS: Lower levels of both GRalpha and NFkappaBp65 are associated with poor or no response to GCs and the difference is more pronounced in patients experiencing relapse of INS....

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Journal Article 2009; 30(5): 657-662 PubMed PMID: 20035258 Citation  Keywords:  Animals, Cell Line, Tumor, Colonic Neoplasms:metabolism, Humans, Melatonin:metabolism, Mice, Receptors, Melatonin:antagonists & inhibitors, Tetrahydronaphthalenes:metabolism, Tryptamines:metabolism,.   

OBJECTIVE: Our earlier studies have shown that MLT exerts the inhibitory effect on murine cancer via membrane and nuclear receptors. We have found that the antagonist of MT1 receptors does not diminish the antiproliferative effect of MLT on Colon 38 cells, and the contribution of MT2 receptors has been suggested to be responsible. Therefore, in the present study we have examined the influence of the 4-phenyl-2-propionamidotetralin (4P-PDOT), which is a selective antagonist of MT2 membrane receptor, and luzindole - an antagonist of both membrane receptors, on an oncostatic action of MLT.

MATERIALS AND METHODS: The murine cancer cell line Colon 38 was used in the experiments. In 48 hrs cell culture the effects of MLT, 4P-PDOT and luzindole administered alone and MLT applied jointly with either 4P-PDOT or luzindole were examined. The growth of cancer cells was assessed using the modified colorimetric Mosmann method.

RESULTS: Melatonin at both examined concentrations (10-7, 10-9 M) significantly decreased the viability of cancer cells. The selective antagonist of MT2 membrane receptor, namely 4P-PDOT and luzindole applied separately did not have an effect on the growth of Colon 38 cells. The addition of 4P-PDOT to MLT did not change the inhibitory effect of MLT, whereas luzindole given together with MLT diminished, but failed to block totally, the oncostatic properties of MLT.

CONCLUSIONS: The obtained data and our previous studies conducted on Colon 38 cancer indicate that membrane melatonin receptors are not indispensable to the oncostatic action of melatonin and thus other pathways such as nuclear signaling and receptor-independent mechanism may be also involved....

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Journal Article 2009; 30(2): 195-203 PubMed PMID: 19675526 Citation  Keywords:  Animals, DNA-Binding Proteins, Dose-Response Relationship, Drug, Drosophila Proteins, Estradiol:blood, Estrogen Receptor alpha:metabolism, Estrogen Receptor beta:metabolism, Estrogens:blood, Female, Glial Fibrillary Acidic Protein:metabolism, Hippocampus:.   

OBJECTIVES: The aim of present work was to examine estrogen influence on neurogenesis in the model of predegenerated peripheral nerve grafts implantation into the rat hippocampal dentate gyrus.

METHODS: Experiment was carried out on female rats divided into three experimental groups: NO - non-ovariectomized, OV - ovariectomized and E - heterogeneous group with various 17-beta-estradiol substitution after ovariectomy. Proliferating cells were labeled with BrdU. Brains were subjected to immunohistochemical procedures to visualize nestin, GFAP and estrogen receptors (ERalpha and ERbeta).

RESULTS: Proliferation rate was highest in E groups with estrogen levels resembling that in proestrus phase. Ovariectomy resulted in higher than in NO group number of new neurons, while high hyperestrogenemia worsened the results. The proportions of nestin-labeled cells correlated in similar way with different hormonal state. We found also distinct co-localization of nestin and GFAP in E group (proestrus). It may suggest the presence of radial glia, a potential source of new neurons in adult mammals. Nerve graft induced ERalpha expression at the site of injury in all groups. Distribution of ERbeta in hippocampus was estradiol-dose-dependent and correlated with cell proliferation.

CONCLUSION: In our model, 17-beta-estradiol and predegenerated nerve graft implantation had synergistic effect on hippocampal neurogenesis....

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Journal Article 2009; 30(2): 153-179 PubMed PMID: 19675519 Citation  Keywords:  Animals, Behavior:physiology, Bone and Bones:metabolism, Cannabinoid Receptor Modulators:antagonists & inhibitors, Cardiovascular System:metabolism, Endocannabinoids, Gastrointestinal Tract:metabolism, Humans, Immune System:metabolism, Neoplasms:metabolis.   

: The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction system. The CB2R is mainly expressed in the immune system regulating its functions. Endocannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent advances have correlated the ECS with drug addiction and alcoholism. The growing number of preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a number of diseases currently treated inadequately. The ECS dysregulation has been correlated to obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters. However, safety conerns have led to its withrawal. The role of endocannabinoids in mammalian reproduction is an emerging research area given their implication in fertilization, preimplantation embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new perspectives as a target to improve infertility and reproductive health in humans....

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Journal Article 2008; 29(6): 977-980 PubMed PMID: 19112405 Citation  Keywords:  Administration, Oral, Animals, Coumestrol:administration & dosage, Dogs, Epididymis:drug effects, Male, Phytoestrogens:administration & dosage, Random Allocation, Receptors, Estrogen:drug effects, Seminiferous Tubules:drug effects, Testis:drug effects,.   

INTRODUCTION: Estrogens are well recognized as important hormones in male reproduction and act as ligands to alpha and beta estrogen receptors. Both estrogen receptors could interact with estrogen-mimicking compounds such as the fluorescent phytoestrogen coumestrol, which acts both in an agonist or antagonist fashion.

OBJECTIVE: To investigate the presence of Coumestrol-Estrogen Receptor complexes by fluorescence in testis and epididymis, its effect in the ER expression by immunostain in the same tissues and the effect of this binding in the testis histological characteristics.

DESIGN: Adult healthy and sexually active dogs were assigned to either the experimental or control group .Coumestrol impregnated dog biscuits were given to each animal from the experimental group once a week for a 4 week period. The control group received a biscuit with no Coumestrol, also once a week and for the same period. Testis morphology, ER immunodetection, and coumestrol-receptor binding were evaluated.

SETTING: The experiment was done in the facilities of the Mexico City canine shelter. Animals were caged individually with food and water ad libitum and having at least two daily hours for exercise.

RESULTS: Morphological alterations in testis after oral administration of coumestrol were detected. The main alterations include decreased germinal epithelium in tubule, and the loss of a continuous proliferation and differentiation gamete layer. Fluorescence signals in testis interstitial Leydig cells and epididymus indicating ER-coumestrol complexes were detected at the same points to those Immunohystochemically detected ER.

CONCLUSIONS: Coumestrol administration induces testis alterations and coumestrol-ER complexes can be co-localized by binding-enhanced fluorescence and immunoprecipitation....

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Journal Article 2008; 29(6): 981-989 PubMed PMID: 19112400 Citation  Keywords:  Amino Acid Substitution:genetics, Animals, Cattle:genetics, Female, Gene Expression Regulation:genetics, Haplotypes, Insulin-Like Growth Factor I:genetics, Liver:metabolism, Male, Polymorphism, Single Nucleotide:genetics, Receptors, Somatotropin:genetics,.   

BACKGROUND: Polymorphisms in the bovine ghr and igf1 genes. Ghr and igf1 genes have been associated with milk and meat production of cattle. However, the molecular and physiological mechanisms underlying such associations are unknown. The objective of this study was to examine the effects of polymorphisms in 5'-regions of the bovine ghr and igf1 genes on the igf1 gene expression in the liver and on the level of IGF1 in blood of Polish Holstein-Friesian cattle.

METHODS: Individual and combined effects of single nucleotide polymorphisms (SNPs) in the 5'noncoding regions of the bovine igf1 and ghr genes on the IGF1 level in blood and igf1 gene expression in liver were examined. One SNP in the igf1 gene and four SNPs in the ghr gene were analyzed. IGF1 level in blood was measured by radioimmunoassay (RIA) in 211 heifers and bulls of Polish Holstein-Friesian cattle (of Black-and-White type). The igf1 gene expression was measured in livers of bulls carrying different igf1 and ghr genotypes (from three to nine animals per genotype) using real-time reverse transcription-PCR methods with the gapdh gene as a reference.

RESULTS: We showed that C/T transition in the promoter region of the igf1 gene influences the gene expression; relative igf1 expression was higher for animals with the CC genotype than for those with the TT and CT genotypes. TESS analysis showed that C/T transition in the igf1 gene co-localizes with the NF1 transcription factor binding site. Also, the ghr genotype appeared to significantly influence the igf1 gene expression in the liver, and we found the highest expression for the genotypes: RFLP-AluI (AT), RFLP-Fnu4HI(CC), and RFLP-NsiI(GA), and for the combined ghr genotype: AluI(AT)/ Fnu4HI(CC)/NsiI(GA). We discovered a significant association between the igf1 genotype and the IGF1 blood level. The highest IGF1 content in blood serum was found in CC genotype animals (1024 ng/ml) vs 698 ng/m and 859 ng/min in the TT and CT igf1 genotypes, respectively. Moreover, we noticed significant differences between ghr genotypes. The highest blood levels of IGF1 were for the animals carrying the ghr genotypes: RFLP-AluI(AA), RFLP-Fnu4HI(CC), and RFLP-NsiI(AG). Ghr haplotypes also significantly affected the IGF1 blood level. Animals of the combined ghr genotypes AluI(AA)/AccI(CC)/Fnu4HI(CC)/NsiI(AG) and AluI(AA)/AccI(CT)/Fnu4HI (CC)/ NsiI(AG) had a higher IGF1 concentration in blood than other genotype carriers.

CONCLUSIONS: The present results indicate that the effects of polymorphism in the igf1 and ghr genes on cattle milk or meat production traits could be at least partially mediated through their effects on the igf1 gene expression in the liver and the IGF1 level in blood....

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Journal Article 2008; 29(6): 846-851 PubMed PMID: 19112386 Citation  Keywords:  Animals, Contraception, Humans, Kisspeptins, Ovulation Induction, Receptors, G-Protein-Coupled:physiology, Reproduction:physiology, Sexual Maturation:physiology, Tumor Suppressor Proteins:physiology,.   

: KISS1 encodes the kisspeptin (KP) family of peptides which were originally characterised as potent antimetastatic agents in breast cancer and malignant melanoma cells. One member of this family of arginine-phenylalanine amide peptides, KP-54, was subsequently identified as the natural ligand for the G-protein coupled receptor-54 (GPR54). In addition to its importance as a metastatic suppressor, KP has been found to play a major neuroregulatory role in governing endogenous gonadotropin release by its modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been localised to the hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Although GPR54 is expressed in human pituitary cells, it is not presently known if gonadotrope cells themselves are targets for significant KP activity. It was recently shown that full disruption of the KP/GPR54 complex resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that KP/GPR54 signalling during gestation is necessary for sexual differentiation and implicates activation of the KP/GPR54 complex as the single most important upstream event regulating GnRH release. Several compelling studies have placed KP as the leading candidate molecule responsible for initiating puberty, making this receptor-ligand complex of fundamental importance to the neuroendocrinology of reproduction. Here, we discuss key KP/GPR54 discovery events and present an evolution of KP biology in the context of recent animal and human experimental work. With evidence pointing to proper KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation, elucidation of how this pathway is modulated is likely to bring novel pharmacologic strategies for fertility treatment (and contraception) within reach. Because the physiological significance KP is now acknowledged to extend well beyond cancer biology (and may also contribute to the pathophysiology of pre-eclampsia), KP represents an exciting research theme in human reproductive biology and neuroendocrinology....

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Journal Article 2008; 29(4): 399-404 PubMed PMID: 18766164 Citation  Keywords:  Animals, Decision Making:physiology, Economics, Humans, Mathematics, Models, Neurological, Physical Phenomena, Physics, Receptors, Neurotransmitter:metabolism, Risk, Risk-Taking,.   

: Decision under risk and uncertainty has been attracting attention in neuroeconomics and neuroendocrinology of decision-making. This paper demonstrated that the neurotransmitter receptor theory-based value (utility) function can account for human and animal risk-taking behavior. The theory predicts that (i) when dopaminergic neuronal response is efficiently coupled to the formation of ligand-receptor complex, subjects are risk-aversive (irrespective of their satisfaction level) and (ii) when the coupling is inefficient, subjects are risk-seeking at low satisfaction levels, consistent with risk-sensitive foraging theory in ecology. It is further suggested that some anomalies in decision under risk are due to inefficiency of the coupling between dopamine receptor activation and neuronal response. Future directions in the application of the model to studies in neuroeconomics of addiction and neuroendocrine modulation of risk-taking behavior are discussed....

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