Errata Corrige: Stress-Induced Phosphorylation of C-Jun-N-Terminal Kinases and Nuclear Translocation of Hsp70 in the Wistar Rat Hippocampus (Vol 61, Pg 1, 2009)

In the paper entitled: Adžić, M., Đorđević, A., Krstić-Demonacos, M., & Radojčić, M. B. (2009). Stress-induced phosphorylation of c-Jun-N-terminal kinases and nuclear translocation of Hsp70 in the Wistar rat hippocampus. Archives of Biological Sciences, 61(1), 1-8. Fig. 1, on page 4, section b, should read "Nucleus" instead of "Cytoplasm

Stress effects on the phosphorylation of c-jun-nterminal kinases and on nuclear translocation of hsp70 in rat hippocampus

Glucocorticoids have diverse effects in cellular processes in hippocampus (HIPPO) under stress. Beside genomic pathways, their effects are also mediated by direct activation of subfamily of mitogen-activated protein kinases termed, c-Jun-Nterminal kinases (JNKs). We analysed the phosphorylation status of cytoplasmic and nuclear JNK isoforms, and expression of its inhibitor Hsp70 protein in HIPPO of rats exposed to diverse types of stress. Activity of JNK1 in cytoplasm and nucleus was decreased in all types of stress, while the activity of cytoplasmic JNK2/3 was markedly higher in acute stress, and unaltered or lowered in chronic and combined stress. Hsp70 was significantly decreased in cytoplasm and increased in nucleus under all stress conditions indicating its cytoplasmic-nuclear translocation.Physical chemistry 2008 : 9th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 24-28 September 200

Effects of Chronic Psychosocial Isolation on Limbic Brain Structures of Wistar Rats

Chronic stress is recognized as an etiological factor for the onset and exacerbation of many psychiatric disorders. Among chronic stressors, those of psychosocial and emotional origin are considered of particular importance for prominent depletion of physiological and psychological resources. The key mechanisms underlying deleterious effects of chronic stress are thought to emerge from the compromised stress response at the level of hypothalamic-pituitary-adrenal (HPA) axis feedback, and limbic brain structures, such as hippocampus (HIPPO) and prefrontal cortex (PFC). In this review we summarize and discuss effects of chronic psychosocial isolation (CPSI) using animal model of male Wistar rats, housed individually for 21 days lacking physical and visual contact. CPSI, as an important distress factor for normally gregarious Wistar rats, resulted in diminishment of serum corticosterone and blood glucose, and did not alter catecholamine levels, which opposes most other chronic stressors that elevate stress hormones. In the context of possibly aberrant feedback mechanism at the molecular level, we discuss altered glucocorticoid receptor (GR) distribution and appearance of GR phosphoisoform excessively phosphorylated on serine 232 (pGR S232), as well as, altered activities of JNK and CDK kinases that target GR for phosphorylation. The appearance of pGR S232 in the nucleus and the mitochondria of HIPPO and PFC is potentially related to a marked transcriptional activation/repression of several GR regulated nuclear genes (GR itself, CRH, BDNF) and mitochondrial genes (COX1, COX3). Another important stress and redox state sensitive transcription factor, nuclear factor kappa B (NFțB) is also discussed in terms of the disturbed redox balance (illustrated by the altered ratio of the activity of an array of antioxidant enzymes) and altered proapoptotic/proplastic signalling, since it regulates transcription of a wide array of genes (like Bcl-2, NCAM). Such cellular conditions, provoked by CPSI, are also shown to affect susceptibility to mitochondrially triggered apoptosis (illustrated by redistribution of Bcl family members and DNA fragmentation, more prominent in the PFC) and to simultaneously affect expression of main neural plasticity protein, polysialylated NCAM (PSA-NCAM). In summary, we present novel causal connection between the redox imbalance in the CNS, altered signalling via JNK and CDK kinases, GR phosphorylation/transactivity and NFțB transactivity, as well as their cellular imbalance, the parameters which all together yield inadequate CNS and systemic stress response

Stress-induced phosphorylation of c-Jun-N-terminal kinases and nuclear translocation of Hsp70 in the Wistar rat hippocampus

Abstract — Glucocorticoids are key regulators of the neuroendocrine stress response in the hippocampus. Their action is partly mediated through the subfamily of MAPKs termed c-Jun-N-terminal kinases (JNKs)� � whose activation correlates with neurodegeneration. The stress response also involves activation of cell protective mechanisms through various heat shock proteins (HSPs) that mediate neuroprotection. We followed both JNKs and Hsp70 signals in the cytoplasmic and nuclear compartments of the hippocampus of Wistar male rats exposed to acute� � chronic� � and combined stress. The activ� ity of JNK1 was decreased in both compartments by all three types of stress� � while the activity of cytoplasmic JNK2/3 was elevated in acute and unaltered or lowered in chronic and combined stress. Under all stress conditions� � Hsp70 trans� location to the nucleus was markedly increased. The results suggest that neurodegenerative signaling of JNKs may be counteracted by increase of nuclear Hsp70� � especially under chronic stress. Key words: Wistar rat� � neuroendocrine stress� � hippocampus� � JN�� � Hsp70 Udc 577.25:612.819:59:591.481.

Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: Effects on energy metabolism

Antidepressants affect glucocorticoid receptor (GR) functioning partly through modulation of its phosphorylation but their effects on mitochondrial GR have remained undefined. We investigated the ability of chronic fiuoxetine treatment to affect chronic stress-induced changes of mitochondrial GR and its phosphoisoforms (pGRs) in the prefrontal cortex and hippocampus of female and male rats. Since mitochondrial GR regulates oxidative phosphorylation, expression of mitochondrial-encoded subunits of cytochrome (cyt) c oxidase and its activity were also investigated. Chronic stress caused accumulation of the GR in mitochondria of female prefrontal cortex, while the changes in the hippocampus were sex-specific at the levels of pGRs. Expression of mitochondrial COXs genes corresponded to chronic stress-modulated mitochondrial GR in both tissues of both genders and to cyt c oxidase activity in females. Moreover, the metabolic parameters in stressed animals were affected by fiuoxetine therapy only in the hippocampus. Namely, fluoxetine effects on mitochondrial COXs and cyt c oxidase activity in the hippocampus seem to be conveyed through pGR232 in females, while in males this likely occurs through other mechanisms. In summary, sex-specific regulation of cyt c oxidase by the stress and antidepressant treatment and its differential convergence with mitochondrial GR signaling in the prefrontal cortex and hippocampus could contribute to clarification of sex-dependent vulnerability to stress-related disorders and sex-specific clinical impact of antidepressants. (C) 2013 Elsevier Ltd. All rights reserved.Ministry of Science of the Republic of Serbia [41029, 41009

Downregulation of c-fos and c-myc expression and apoptosis induction by tiazofurin and 8-Cl-cAMP in human melanoma cells

Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective against various cancer cells in vitro and in vivo. Through specific mechanisms of action they modulate the cellular signal transduction pathway, thereby causing growth inhibition, cell differentiation, apoptosis and downregulation of c-ras and c-myc gene expression. We examined the effects of 8-Cl-cAMP and tiazofurin, either separately or together, on apoptosis induction and c-fos and c-myc expression in melanoma cells. 8-Cl-cAMP and tiazofurin inhibited the growth of melanoma cells in a dose-responsive manner. Whether used separately or together, each agent induced apoptotic cell death. Apoptosis was accompanied by a marked inhibition of c-fos and c-mye gene expression. RT-PCR analysis showed that 8-Cl-cAMP, together with tiazofurin, promoted 61% and 75% decreases of c-myc and c-fos expression in melanoma cells respectively. These results clearly indicate that the combination of 8-Cl-cAMP and tiazofurin could provide a promising therapeutic approach for melanoma treatment

Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: Effects on energy metabolism

Antidepressants affect glucocorticoid receptor (GR) functioning partly through modulation of its phosphorylation but their effects on mitochondrial GR have remained undefined. We investigated the ability of chronic fiuoxetine treatment to affect chronic stress-induced changes of mitochondrial GR and its phosphoisoforms (pGRs) in the prefrontal cortex and hippocampus of female and male rats. Since mitochondrial GR regulates oxidative phosphorylation, expression of mitochondrial-encoded subunits of cytochrome (cyt) c oxidase and its activity were also investigated. Chronic stress caused accumulation of the GR in mitochondria of female prefrontal cortex, while the changes in the hippocampus were sex-specific at the levels of pGRs. Expression of mitochondrial COXs genes corresponded to chronic stress-modulated mitochondrial GR in both tissues of both genders and to cyt c oxidase activity in females. Moreover, the metabolic parameters in stressed animals were affected by fiuoxetine therapy only in the hippocampus. Namely, fluoxetine effects on mitochondrial COXs and cyt c oxidase activity in the hippocampus seem to be conveyed through pGR232 in females, while in males this likely occurs through other mechanisms. In summary, sex-specific regulation of cyt c oxidase by the stress and antidepressant treatment and its differential convergence with mitochondrial GR signaling in the prefrontal cortex and hippocampus could contribute to clarification of sex-dependent vulnerability to stress-related disorders and sex-specific clinical impact of antidepressants. (C) 2013 Elsevier Ltd. All rights reserved.Ministry of Science of the Republic of Serbia [41029, 41009

Downregulation of c-fos and c-myc expression and apoptosis induction by tiazofurin and 8-Cl-cAMP in human melanoma cells

Tiazofurin and 8-Cl-cAMP are novel antineoplastic agents that have been shown to be effective against various cancer cells in vitro and in vivo. Through specific mechanisms of action they modulate the cellular signal transduction pathway, thereby causing growth inhibition, cell differentiation, apoptosis and downregulation of c-ras and c-myc gene expression. We examined the effects of 8-Cl-cAMP and tiazofurin, either separately or together, on apoptosis induction and c-fos and c-myc expression in melanoma cells. 8-Cl-cAMP and tiazofurin inhibited the growth of melanoma cells in a dose-responsive manner. Whether used separately or together, each agent induced apoptotic cell death. Apoptosis was accompanied by a marked inhibition of c-fos and c-mye gene expression. RT-PCR analysis showed that 8-Cl-cAMP, together with tiazofurin, promoted 61% and 75% decreases of c-myc and c-fos expression in melanoma cells respectively. These results clearly indicate that the combination of 8-Cl-cAMP and tiazofurin could provide a promising therapeutic approach for melanoma treatment