<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective.</bold> The aim of the present investigation was to study the expression of genes encoding IRS1 (insulin receptor substrate 1) and some other functionally active proteins in U87 glioma cells under silencing of polyfunctional chaperone HSPB8 for evaluation of the possible significance of this protein in intergenic interactions.<bold>Methods.</bold> Silencing of HSPB8 mRNA was introduced by HSPB8 specific siRNA. The expression level of <italic>HSPB8</italic>, <italic>IRS1</italic>, <italic>HK2</italic>, <italic>GLO1</italic>, <italic>HOMER3</italic>, <italic>MYL9</italic>, <italic>NAMPT</italic>, <italic>PER2</italic>, <italic>PERP</italic>, <italic>GADD45A</italic>, and <italic>DEK</italic> genes was studied in U87 glioma cells by quantitative polymerase chain reaction.<bold>Results.</bold> It was shown that silencing of HSPB8 mRNA by specific to HSPB8 siRNA led to a strong down-regulation of this mRNA and significant modification of the expression of IRS1 and many other genes in glioma cells: strong up-regulated of <italic>HOMER3</italic>, <italic>GLO1</italic>, and <italic>PERP</italic> and down-regulated of <italic>MYL9</italic>, <italic>NAMPT</italic>, <italic>PER2</italic>, <italic>GADD45A</italic>, and <italic>DEK</italic> gene expressions. At the same time, no significant changes were detected in the expression of <italic>HK2</italic> gene in glioma cells treated by siRNA, specific to HSPB8. Moreover, the silencing of HSPB8 mRNA enhanced the glioma cells proliferation rate.<bold>Conclusions.</bold> Results of this investigation demonstrated that silencing of HSPB8 mRNA affected the expression of <italic>IRS1</italic> gene as well as many other genes encoding tumor growth related proteins. It is possible that the dysregulation of most of the studied genes in glioma cells after silencing of HSPB8 is reflected by a complex of intergenic interactions and that this polyfunctional chaperone is an important factor for the stability of genome function and regulatory mechanisms contributing to the tumorigenesis control.</abstract>

Insulin receptor substrate 1 gene expression is strongly up-regulated by HSPB8 silencing in U87 glioma cells

<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective.</bold> The aim of this investigation was to study the expression of genes encoding cAMP-activated protein kinase catalytic and regulatory A subunits (PRKACA and PRKAR1A) and related proteins such as cAMP-dependent protein kinase inhibitors A and G (PKIA and PKIG), catalytic subunit A of protein phosphatase 3 (PPP3CA), A-kinase anchoring protein 12 (AKAP12), and praja ring finger ubiquitin ligase 2 (PJA2) in U87 glioma cells in response to glucose deprivation in both control U87 glioma cells and cells with ERN1 (endoplasmic reticulum to nucleus signaling 1) knockdown, the major pathway of the endoplasmic reticulum stress signaling, for evaluation of possible significance of glucose deprivation in ERN1 dependent regulation of glioma growth.<bold>Methods.</bold> The expression level of PRKA related genes was studied in control (transfected by vector) and ERN1 knockdown U87 glioma cells under glucose deprivation by real-time quantitative polymerase chain reaction.<bold>Results.</bold> It was shown that the expression level of <italic>PRKACA</italic> and <italic>PKIA</italic> genes was down-regulated in control glioma cells treated by glucose deprivation, but <italic>PJA2</italic> gene was up-regulated. At the same time, the expression of four other genes (<italic>PRKAR1A</italic>, <italic>PKIG</italic>, <italic>AKAP12</italic>, and <italic>PPP3CA</italic>) was resistant to this experimental condition. Furthermore, ERN1 knockdown of glioma cells significantly modified the effect glucose deprivation on the expression almost all studied genes. Thus, treatment of glioma cells with inhibited ERN1 enzymatic activity by glucose deprivation lead to a more significant down-regulation of the expression level of <italic>PKIA</italic> and to suppression <italic>PRKAR1A</italic> gene expressions. Moreover, the ERN1 knockdown introduced up-regulation of <italic>PKIG</italic> and <italic>AKAP12</italic> gene expressions in glioma cells treated by glucose deprivation and eliminated the sensitivity of <italic>PJA2</italic> gene to this experimental condition.<bold>Conclusions.</bold> Results of this investigation demonstrated that ERN1 knockdown significantly modified the sensitivity of most studied PRKA related gene expressions to glucose deprivation and that these changes are a result of complex interactions of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to the suppression of glioma cell proliferation and their possibly chemoresistance.</abstract>

Glucose deprivation affects the expression of genes encoding cAMP-activated protein kinase and related proteins in U87 glioma cells in ERN1 dependent manner

<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective.</bold> Individual stress tests characterized by social evaluative threat and uncontrollability are known to elicit strong neuroendocrine responses. We tested whether a psychosocial stressor submitted to a larger group of participants (up to 60) may elicit comparable stress responses.<bold>Methods.</bold> A total of 59 adult subjects (33 women, 26 men) participated in the study, whereas 24 of them suffered from allergy and 35 were healthy. The stress test consisted of a distraction stress task followed by a speech task, in which the participants were randomly subjected to questions related to a topic that they had to prepare as well as arithmetic questions in front of their peers and a committee that responded in standardized and non-supporting manner. State and trait anxiety inventory (STAI) for anxiety state was administrated before and after the test and salivary samples taking. The test was repeated after five months.<bold>Results.</bold> The results showed that the shared psychosocial stress application in a larger group of subjects was prosperous. The larger group test (LGST) resulted in an enhanced subjectively experienced stress and an intensive sympathetic nervous system activation, reflected by elevated salivary alpha-amylase activity and the heart rate. The cortisol increment after exposure to the stress test was not significant. Repeated exposure to the test failed to reproduce the original stress responses with exception of the heart rate rise.<bold>Conclusions.</bold> In a larger group of subjects, the psychosocial stress test did elicit stress responses similar to the individual stress tests. Our data indicate that the above-mentioned stress test is apparently not an appropriate approach for the repeated use.</abstract>

Department of Psychology, Faculty of Arts

Neuroendocrine responses to a psychosocial stress test for larger groups of participants: comparison of two test exposures

<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective.</bold> Mutations of the <italic>KCNJ11</italic> gene are the most common cause of the permanent neonatal diabetes mellitus (PNDM). Majority of people with KNCJ11-PNDM have a de-novo mutation. We aimed to compare diabetes phenotype in two children and their mothers with PNDM carrying the same sulfonylurea-sensitive <italic>KCNJ11</italic> variants.<bold>Methods.</bold> We have compared glibenclamide (sulfonylurea) dose, C-peptide, and HbA1c serum levels in two children and their mothers with PNDM up to 5.5-year follow-up. All of them were carrying a heterozygous activating <italic>KCNJ11</italic> pathogenic variant (p.R201H in Family 1 or p.H46Y in Family 2). The mothers were initially treated with insulin and successfully switched to sulfonylurea at the age of 24 and 11 years, respectively. Both children were treated with sulfonylurea since the diagnosis of PNDM.<bold>Results.</bold> Glibenclamide dose was similar in both children (0.02–0.03 mg/kg/day), but lower compared to their mothers (0.1–0.4 mg/kg/day) (p&lt;0.002). Fasting serum C-peptide levels were also lower in children (70–210 pmol/l) than in their mothers (263–720 pmol/l) (p&lt;0.002), but no significant differences were observed in postprandial C-peptide levels. HbA1c was lower only in the son of SVK4 (Family 2) compared to his mother, as she had poor adherence to the sulfonylurea therapy during the first years after the sulfonylurea switch.<bold>Conclusions.</bold> Evaluation of the treatment in people with sulfonylurea-sensitive KNCJ11-PNDM should respect the age of patients together with the type of mutation and duration of diabetes at therapy start and may differ within one family.</abstract>

Children Diabetes Centre of the Slovak Republic at the Department of Paediatrics

Medical Faculty of Comenius University and National Institute for Children′s Diseases

Comparison of diabetes phenotype in children and their mothers with permanent neonatal diabetes mellitus carrying the same <italic>KCNJ11</italic> variants

<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective.</bold> Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats.<bold>Methods.</bold> Thirty two male Wistar rats (200–220g) were randomly divided into: control, VitC, CIS, and CIS + VitC groups. Animals received VitC (500 mg/kg/day)/saline by gavage for 3 weeks. For 24 h cumulative and post 18–20 h fasting food intake, fasting plasma ghrelin level, and body weight were measured. Gastric histopathology was also evaluated.<bold>Results.</bold> Results showed a marked increase in fasting plasma ghrelin and food intake in stressed rats compared to controls. VitC prevented the increases in stressed rats. Histological assessment indicated a positive effect of VitC on gastric glandular cells compared to control, an effect that might partially be a reason of significant increase of plasma ghrelin levels in VitC rats. Elevated plasma ghrelin in VitC group was even higher than that one in stressed group, whereas there were no significant changes in the food intake. Assessment of the percentage of changes in body weight during 21 days showed a significant increase in stressed rats compared to controls. Vitamin C treatment prevented this increase. Stressed rats also displayed depression-like behavior as indicated by sucrose test, whereas VitC ameliorated it.<bold>Conclusions.</bold> The data of the present study indicate that VitC may overcome ghrelin-induced hyperphagia and improve the abnormal feeding and depressive behavior in CIS rats.</abstract>

Department of Anatomy, School of Medicine

Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats

<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objectives.</bold> Bisphenol A (BPA), as an indispensable plastic additive, has also been proven as an endocrine disruptor associated with adverse health effects including impaired ovarian function and cancer. Due to the restrictions of its usage, several analogs have been employed to replace BPA. Although many studies revealed a harmfulness in the biological effects of BPA analogs, their specific targets remain largely unknown. Nuclear receptors (NRs) may be one of the most important targets of bisphenols. Therefore, in this study, our attention was directed to explore the effect of BPA and its analogs, AF and S, on the mRNA expression of selected NRs involved in the steroidogenic and carcinogenic pathways in the human granulosa cell line COV434. The NRs investigated included: thyroid hormone receptor α (THRA), peroxisome proliferator activating receptor β/δ (PPARD), retinoid X receptor α (RXRA), chicken ovalbumin upstream promoter-transcription factor II (COUPTFII), nuclear receptor-related protein 1 (NURR1), and liver receptor homolog-1 (LRH1).<bold>Methods.</bold> COV434 cells were treated with the bisphenols at the concentrations of 10−9 M, 10−7 M, and 10−5 M, and after 24 and 48 h, cell viability was monitored by the MTS assay and gene expressions were analyzed using RT-qPCR.<bold>Results.</bold> Bisphenol treatment did not alter the COV434 cell viability. After 24 h, the expression of neither of the NRs was changed. Likewise, after 48 h, the expression of the selected genes was not altered. However, both BPAF and BPS increased, at the highest concentration (10−5 M) used, the mRNA levels of both <italic>PPARD</italic> and <italic>NURR1</italic> NRs after 48 h of the treatment. In the BPA-treated groups, no significant upregulation was observed.<bold>Conclusions.</bold> In the present study, the effect of bisphenols on COUP-TFII, Nurr1, and LRH-1 NRs was investigated for the first time. Although generally we did not observe that BPs provoked any alterations in the expression of the selected NRs in COV434 cells, at specific concentrations and time points they might alter mRNA expression of certain NRs (<italic>NURR1</italic>, <italic>PPARD</italic>).</abstract>

Effect of selected bisphenol derivatives on nuclear receptor expression in ovarian cell line COV434

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