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1

Sphingosine-1-phosphate and its receptors signaling in neurodegeneration/neuroprotection

100%
Strosznajder J. B., Motyl J., Czubowicz K., Strosznajder R.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
Sphingosine -1-phosphate (S1P) is synthesized by sphingosine kinases (SphK1/2E.C. 2.7.1.91) and exerts its function as intracellular messenger or acts in an autocrine or paracrine fashion through specific G protein operated receptors (S1P1-S1P5). Depending on SphK type and its localization S1P may influence different cell functions. S1P synthesized by SphK1 is involved in cell survival while produced by SphK2 may activate death signaling. S1P is degraded by phosphohydrolyses and irreversibly by S1P lyase (SPL, E.C.4.1.2.27) which appears to be very important in sphingolipid homeostasis. The alterations of sphingolipid rheostat is suggested to be crucial in pathogenesis/pathomechanism of neurodegenerative disorders. In our study we have evaluated the SphKs and SPL expression/activity as well as the role of S1P in different types of oxidative stress involved in neurodegenerative disorders. Moreover, the implications of SphK/S1P in the cell models of Alzheimer’s disease induced by amyloid peptides (AB) and alfa synuclein (ASN) were determined. Oxidative stress alters SphKs and SPL expression, activity and cells viability. In AD model significant decrease of SphK expression and activity/lower S1P synthesis leads to series of the following consecutive events: oxidative stress, down regulation of antiapoptotic protein Bcl-2, up-regulation of pro-apoptotic BAX and HrK and finally to cell’s death. Exogenous S1P and the agonist(s) of S1P1 or S1P3 receptors exert cytoprotective effects which are mediated by PI3/ Akt signaling pathway and by regulation of Bcl2 proteins. Summarizing, our data suggest that S1P, its receptor(s) agonists and inhibitors of SPL should be considered in therapy of neurodegenerative disorders. Supported by NCN grant 5870/P01/2011/40
2

Neuroprotective effect of fingolimod and pramipexole in Parkinson's disease animal model

88%
Motyl J., Przykaza L., Kosson P., Boguszewski P. M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
|
nr Supl.
BACKGROUND AND AIMS: Recently sphingolipids alterations have been shown to play an important role in pathomechanism of neurodegenerative diseases. Our last study indicated suppression of gene expression and activity of sphingosine kinases (Sphk1/2)/ sphingosine-1-phosphate (S1P) synthesis in cellular model of Parkinson’s disease (PD). Moreover, the cytoprotective effect of S1P and its analog Fingolimod (P-FTY720) in this PD model was observed. The fundamental goal of current research was to determine the impact of FTY720 and dopamine D2/D3 receptors agonist – pramipexole (PPX) on death signalling and motor activity in mice PD model. METHODS: Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 40 mg/kg) was administrated ip to adult C57BL/6 mice. FTY720 (1 mg/kg) or PPX (1 mg/kg) was injected ip during 10 days. Then behavioral tests (open field, rota-rod, and pole test) were performed. Midbrain and striatum were used for further studies. The immunochemical, spectrofluorometrical, and QPCR methods were applied. RESULTS: Our results indicated significant reduction in the number of dopaminergic cells in the midbrain of MPTP treated animals. Moreover, in this PD model alterations of Sphk1/2 and Akt kinase mediated signalling were found. It was also detected that gene expression of pro-apoptotic proteins in midbrain cells was activated. FTY720 and PPX protected dopaminergic cells against death as a result of Sphks up-regulation and apoptotic signalling suppression. In behavioural examination, MPTP mice exhibited impaired motor coordination in rota-rod test. Total time spent on the accelerating rota-rod was increased two-fold after FTY720 and PPX administration. We have also observed total distance elongation in animals treated with both above mentioned compounds during open-field test. CONCLUSIONS: In conclusion, this study indicated that FTY720 and PPX contribute to improvement of mice motor activity and they offer opportunities for PD therapy. Supported by NCN grant 2013/09/N/NZ4/02045.
3

Effect of quinapril and perndopril therapies on the glutathione concentration and the glutathione peroxidase and glutathione-S-transferase activities in aged patients with arterial hypertension ( a preliminary study)

76%
Kotlowska K., Szewczyk-Golec K., Czuczejko J., Pawluk H., Kedziora-Kornatowska K., Motyl J., Kedziora J.
Acta Biochimica Polonica
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2003
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tom 50
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nr Supplement 1
4

Sphingosine kinase-1, the new target in the neuroprotective effect of fingolimod and pramipexole in Parkinson’s disease animal model

76%
Motyl J., Wencel P. L., Przykaza L., Kosson P., Boguszewski P. M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Sphingosine kinase (Sphk1) synthetizing sphingosine-1-phoshate (S1P) is a key enzyme responsible for the regulation of cell fate. Sphk1/S1P could be the attractive target in Parkinson’s disease (PD) neuroprotective therapy. Our previous data showed inhibition of Sphk1 expression/activity in PD in vitro model and indicated neuroprotective effect of S1P analog phospho‑fingolimod (FTY720-P). AIM(S): The aim of current research was to investigate the effect of FTY720 and dopamine D2/D3 receptors agonist – pramipexole (PPX) on Sphk1 dependent molecular pathway(s) in selected parts of the brain and on locomotor activity in PD animal model. METHOD(S): Neurotoxin 1-methyl-4-phenyl-1,2,3,6- -tetrahydropyridine (MPTP, 40 mg/kg) was administrated i.p. to adult C57BL/6 mice. FTY720 (1 mg/kg) or PPX (1 mg/kg) were injected i.p. during 10 days. Behavioral tests (open field, rota-rod) were performed. Midbrain and striatum were separated. The immunochemical, spectrofluorometrical, and QPCR methods were applied. RESULTS: Our data indicated that PD mice exhibited significant loss of dopaminergic nerve terminals within striatum, evaluated by reduced tyrosine hydroxylase immunoreactivity level (TH-IR). Moreover we found the lower level of mRNA/ immunoreactivity and activity of Sphk1 in the midbrain of PD mice. Both FTY720 and PPX significantly increased TH-IR in MPTP mice striatum. FTY720 and PPX protected against MPTP-evoked Sphk1 alterations and significantly elevated pro-survival Akt kinase phosphorylation, which indicated its activation. Subsequently, FTY720 increased BAD protein phosphorylation in MPTP mice midbrain, which may protect cells against BAD-mediated death. Then it was observed that FTY-720 and PPX improved locomotor impairment in PD mice. CONCLUSIONS: Our data indicated the new neuroprotective mechanism of PPX and FTY720 action connected with sphingolipid signaling and demonstrated beneficial properties of these compounds on movement alterations in PD animal model. FINANCIAL SUPPORT: This abstract is financially supported by The National Science Centre grant 2013/09/N/ NZ4/02045.
5

The effect of quinapril and perindopril therapies on the level of malondialdehyde and superoxide dismutase and catalase activities in erythrocytes of geriatric patients with essential hypertension

76%
Czuczejko J., Szewczyk-Golec K., Kedziora-Kornatowska K., Motyl J., Pawluk H., Kotlowska K., Kedziora J.
Acta Biochimica Polonica
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2003
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tom 50
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nr Supplement 1
6

The markers of oxidative stress and activity of the antioxidant system in the blood of elderly patients with essential arterial hypertension

64%
Kedziora-Kornatowska K., Cuczejko J., Pawluk H., Kornatowski T., Motyl J., Szadujkis-Szadurski L., Szewczyk-Golec K., Kedziora J.
Cellular and Molecular Biology Letters
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2004
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tom 09
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nr 4A
635-641
We estimated the nitrate/nitrite, carbonyl groups, reduced glutathione (GSH) and malondialdehyde (MDA) concentrations and Cu,Zn superoxide dismutase (SOD-1), catalase (CAT), glutathione peroxidase (cGSH-Px) and glutathione S-transferase (GST) activities in the blood of 17 normotensive young subjects (mean age 39±7.0 years), 21 normotensive elderly subjects (mean age 82±8.2 years) and 38 patients with essential arterial hypertension (mean age 73±8.0 years). Our examinations showed that hypertension in the elderly is associated with greater than normal levels of protein and lipid oxidation, decreased nitric oxide concentration and an imbalance in antioxidant status (decreased GSH concentration and SOD-1 activity). The increased activity of GST compensated the decreased activity of cGSH-Px in the blood of hypertensive patients. Our study confirms that the degree of oxidative stress in elderly patients intensifies, especially if said patients have associated essential arterial hypertension.
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