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1

Immunosuppresants attenuate HMGB1 expression and release from primary astrocyte cultures exposed to combined oxygen-glucose deprivation

100%
Gabryel B., Bielecka A., Bernacki J.
Acta Neurobiologiae Experimentalis
|
2009
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tom 69
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nr 3
Protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro suggesting novel therapeutic application of these drugs. On account of fact that high mobility group box 1 (HMGB1) protein has recently been reported to be involved to ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease HMGB1 expression and release in astrocytes exposed to ischemia-simulating conditions (combined oxygen glucose deprivation, OGD). We also studied the infl uence of these drugs on expression of NFκB, inducibleNO synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, we investigated whether the immunosuppressants could attenuate of necrosis in astrocyte cultures exposed to OGD. Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 mM). Our study has provided evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. The present results provide further information about the cytoprotective mechanisms of immunosuppressants towards ischemic astrocytes, in relation to the pathophysiology of ischemic brain injury. It appears that the immunosuppressants stimulated protective effects could be mediated in part by suppression of HMGB1 expression and release in astrocytes, what leads to attenuation of ischemia-induced necrosis and neuroinfl ammation.
2

Metformin reduces the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures

100%
Labuzek K., Liber S., Okopien B., Gabryel B.
Acta Neurobiologiae Experimentalis
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2011
|
tom 71
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nr 1
The results of recent studies suggest that metformin, in addition to its application for treating of type 2 diabetes, may also have therapeutic potential for treating neuroinflammatory diseases where reactive microglia play an essential role. However, the molecular mechanisms of action by which metformin exerts its anti-inflammatory effects remain largely unknown. Activation of AMP-activated protein kinase (AMPK) constitutes the best-known mechanism of metformin action. It is also known that some of metformin biological responses are not limited to activation of AMPK but mediated by AMPK-independent mechanisms. In this study we attempt to evaluate the effects of metformin on non-stimulated and LPS-activated rat primary microglial cell cultures. Our results support the conclusion that AMPK activated by metformin is involved in the regulating the release of TNF-alpha at the early phase of secretion. Furthermore, we found that the effects of metformin on the release of TNF-alpha at the later phases of secretion, IL-1beta, IL-6, IL-10 and TGF-beta1 as well as on the expression of arginase I, iNOS, NF-kappaB p65 and PGC-1- alpha are not AMPK-dependent because the pretreatment of LPSactivated microglia with compound C (a pharmacological inhibitor of AMPK) did not reverse the effect of metformin. Considering the described properties of metformin, we suppose that the shift of microglia towards “alternative activation” may form the basis of the drug’s beneficial effects observed in animal models of neurological disorders.
3

Endogenous AMPK is involved in autophagy in astrocyte exposed to combined oxygen-glucose deprivation

88%
Gabryel B., Kasprowska D., Kost A., Machnik G., Wiaderkiewicz R.
Acta Neurobiologiae Experimentalis
|
2011
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tom 71
|
nr S
AMPK is a highly conserved heterotrimeric serine/threonine kinase involved in the regulation of cellular metabolism and energy distribution. AMPK is an intracellular metabolic sensor which, through the reduction of adenosine-5′-triphosphate (ATP)- consuming processes and stimulation of ATP-generating pathways, maintains cellular energy homeostasis. AMPK activation occurs through phosphorylation at a specific threonine residue (Thr172) on the α subunit. It was proved that neuronal AMPK has been implicated in pathology of cerebral ischemia. However, whether AMPK activation in astrocytes is responsible for intensification autophagy contributing to their ischemic injury remains to be determined. The aim of the present study was to investigate the time-dependent activation of AMPK as well as to evaluate the autophagy induction in astrocytes exposed to combined oxygen glucose deprivation (OGD). It was shown that exposure of cultured astrocytes to OGD (0.5 – 24 h) causes an increase in AMPK expression and activity. The role of endogenous AMPK in the process of autophagy activation was also demonstrated. The work was supported by grant N N401 072139 from the Ministry of Science and Higher Educations (BG), Warsaw, Poland.
4

Involvement of multiple protein kinases in cPLA2 phosphorylation, AA release and cell death in astrocyte treated with 1-methyl-4-phenylpyridinium-the possible key role of PKG

88%
Chalimoniuk M., Stolecka A., Gabryel B., Malecki A., Langfort J.
Acta Neurobiologiae Experimentalis
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2009
|
tom 69
|
nr 1
Cytosolic phospholipase A2 (cPLA2) demonstrates selective affi nity to arachidonic acid (AA) liberation, which is known to be elevated in PD. We indicated that NO/GC/cGMP pathway was upregulated in the primary astrocyte culture treated with MPP+. We investigated if the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway was involved in 1-methyl-4-phenylpyridinium (MPP+)-induced cPLA2 activation of the primary astrocyte culture. We found increased levels of total and phosphorylated cPLA2 and increased AA release in the primary astrocyte culture exposed to MPP+. We used cPLA2-specifi c inhibitors and Ca2+- independent PLA2 (iPLA2), and we found that cPLA2 released more AA after stimulation with MPP+ than iPLA2 and that there was a time-dependent delay of AA release by iPLA2 compared to cPLA2. The PKG inhibitor KT5823 decreased MPP-induced AA release in the primary astrocyte culture. KT5823, in addition to PKC and ERK1/2 inhibitors, decreased cPLA2 activity as well as total and phosphorylated cPLA2 protein levels in the astrocyte treated with MPP+. Dual treatment with PKG and PKC or ERK1/2 inhibitors had the same effect on cPLA2 activity and protein levels. PKG is involved in the enhancement of cPLA2 phosphorylation at Serine-505 and in AA release in the astrocyte exposed to MPP+. Our results indicate that the nNOS/cGMP/ PKG pathway stimulates cPLA2 phosphorylation at Ser-505 by activation of PKC or ERK1/2. These results suggest that activation of cPLA2 by upregulation nNOS/cGMP pathway may play important role in MPP+-induced astrocyte activation, neurotoxicity and oxidative stress in the nigrostriatal system.
5

Effects of coal dusts with different concentrations of metals on structure, hepatocellular enzymatic markers, and cytochrome P-450-dependent monooxygenase system in rat liver

88%
Trzeciak H. I., Kaminski M., Plewka A., Malecki A., Gabryel B.
Polish Journal of Environmental Studies
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1996
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tom 05
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nr 1
For three months rat livers absorbed coal dust containing low or high concentrations of heavy metals. We found that these concentrations of heavy metals significantly decrease cytochrome P-450 content in hepatic microsomes, and that this decrease correlates with the concentration of heavy metals. Furthermore, we have shown that only coal dust with high heavy metal content produces such structural lesions as necrosis and apoptosis in zone III of the acinus. These lesions are accompanied by increased intracellular catabolism (acid phosphatase), and by considerably decreased activities of enzymes, which are markers of energy production (succinate and lactate dehydrogenase), glycogen metabolism (gluco- se-6-phosphatase), and active excretion of metabolites into bile (adenosine triphosphatase stimulated by Mg++).
6

Effect of captopril and thiorphan on the proliferation of human neoplastic cell lines and their influence on cytostatic activity of interferon alpha or cytotoxic activity of doxorubicin

76%
Kowalski J., Belowski D., Wielgus J., Gabryel B., Klin M., Herman Z. S.
Archivum Immunologiae et Therapiae Experimentalis
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1995
|
tom 43
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nr 1
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