The Group IVA Cytosolic Phospholipase A2/C1P Interaction and Its Role in Eicosanoid Synthesis and Inflammation

In the presented study, we demonstrate that the interaction of group IVA cytosolic phospholipase A2 and ceramide-1-phosphate is crucial for production of eicosanoid synthesis in inflammation. Inflammation is a critical component of many disease states including anaphylaxis, cancer, cardiovascular disease, rheumatoid arthritis, diabetes and asthma. Eicosanoids are well established mediators of inflammation, and the initial rate limiting step in the production of eicosanoids is the liberation of arachidonic acid (AA) from membrane phospholipids by a phospholipase A2 (PLA2). The major phospholipase involved in this liberation of AA during the inflammatory response is group IVA cytosolic phospholipase A2 (cPLA2α). Previous studies from our laboratory demonstrated that the bioactive sphingolipid, ceramide-1-phosphate (C1P), binds cPLA2α at a three amino acid sequence, which is located in the cationic β-groove of the C2 domain of cPLA2α. In this study we examined the effects of the genetic ablation of ceramide kinase (CERK) on eicosanoid synthesis, as CERK is the only known enzyme to produce C1P in mammalian systems. We utilized primary mouse fibroblasts (MEFs) and macrophages isolated from CERK-/- and +/+ mice. The ceramide-1-phosphate and eicosanoid profiles were investigated, and both ceramide-1-phosphate and eicosanoid levels in CERK-/- MEFs were found to be dysregulated. This study also presents the development of a global eicosanoid method to analyze eicosanoids via LC-ESI-MS/MS. Using this new analysis method, we demonstrated that there are significant differences in eicosanoid levels in ex vivo CERK-/- cells when compared to wild type counterparts, but the effect of the genetic ablation of CERK on eicosanoid synthesis and the serum levels of C1P was not apparent in vivo

Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial

Background: The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina.Methods: Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS II–IV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (≥ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment.Results: The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period.Conclusions: Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia

Sphingolipids as critical players in retinal physiology and pathology

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established toparticipate in numerousprocesses, suchas neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) has emerged as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine- 1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1- phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.Fil: Simon, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Basu, Sandip K.. University of Tennessee; Estados UnidosFil: Qaladize, Bano. University of Tennessee; Estados UnidosFil: Grambergs, Richards. University of Tennessee; Estados UnidosFil: Rotstein, Nora Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Mandal, Nawajes .A.. University of Tennessee; Estados Unido

Rozvoj forem zvyšování účasti pracujících na řízení

Prezenční156 - Katedra národohospodářskáNeuveden

Návrh projektu výstupní linky minerálně vláknitých desek

Import 20/04/2006Prezenční výpůjčkaVŠB - Technická univerzita Ostrava. Fakulta strojní. Katedra (345) mechanické technologi

The Influence of Genetic Variations in the CD86 Gene on the Outcome after Allogeneic Hematopoietic Stem Cell Transplantation

CD86 molecule is the ligand for both costimulatory (CD28) and coinhibitory (CTLA-4) molecules, and it regulates immune response after allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we postulate that CD86 gene variations might influence the outcome after alloHSCT. Altogether, 295 adult patients (pts) undergoing related (105 pts) and unrelated (190 pts) donor-matched HSCT were genotyped for the following CD86 gene polymorphisms: rs1129055, rs9831894, and rs2715267. Moreover, the donors’ rs1129055 polymorphism was determined. None of the investigated SNPs alone were associated with aGvHD and rate of relapse. However, we showed that rs2715267 SNP influenced overall survival (OS) after alloHSCT. The 24-month OS for the rs271526GG recipients was worse than that for the recipients possessing T allelle (TT or GT genotypes) (p=0.009). Moreover, analysis of gene-gene interaction between CD86 and CTLA-4 showed that having both the A allele for CD86 rs1129055 and the CTLA-4 CT60GG genotype in recipients increased the risk of aGvHD about 3.5 times. Interestingly, the donors’ rs1129055GG genotype and the recipients’ CT60GG genotype also increased the risk of aGvHD about 2.7-fold. We postulate that recipients’ CD86 gene polymorphisms influence the overall survival after alloHSCT and, together with CTLA-4 polymorphisms, might be considered a risk factor for aGvHD