A5088322762- Sphingolipid Metabolism and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Nitric Oxide and Endothelin Effects
- Ion Transport and Channel Regulation
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Biomedical Research and Pathophysiology
- Eicosanoids and Hypertension Pharmacology
- Adenosine and Purinergic Signaling
- Endoplasmic Reticulum Stress and Disease
- Renin-Angiotensin System Studies
- Inflammasome and immune disorders
- Renal Diseases and Glomerulopathies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Erythrocyte Function and Pathophysiology
- Immune Response and Inflammation
- Chronic Kidney Disease and Diabetes
- Neuroinflammation and Neurodegeneration Mechanisms
- Sirtuins and Resveratrol in Medicine
- Enzyme function and inhibition
- Pharmacogenetics and Drug Metabolism
- Circadian rhythm and melatonin
- Redox biology and oxidative stress
- Fibroblast Growth Factor Research
- Phagocytosis and Immune Regulation
University of Bern
2015-2024
University Hospital of Bern
2015-2024
Goethe University Frankfurt
2004-2015
Klinikum Frankfurt Höchst
2015
Novartis (Switzerland)
1991-2015
University Hospital Frankfurt
2012-2015
Ludwig-Maximilians-Universität München
2015
Center for NanoScience
2015
German Centre for Cardiovascular Research
2015
Shanghai East Hospital
2015
Abstract The modulation of cell signaling by free radicals is important for the pathogenesis inflammatory diseases. Recently, we have shown that NO reduces IL-1β-induced matrix metalloproteinase (MMP-9) expression in glomerular mesangial cells (MC). Here report exogenously administrated superoxide, generated hypoxanthine/xanthine oxidase system (HXXO) or redox cycler 2,3-dimethoxy-1,4-naphtoquinone, caused a marked amplification IL-1β-primed, steady state, MMP-9 mRNA level and an increase...
Interleukin 1 is the prototype of an inflammatory cytokine, and evidence suggests that it uses sphingomyelin pathway ceramide production to trigger mitogen-activated protein kinase (MAPK) activation subsequent gene expression required for acute processes. To identify downstream signaling targets ceramide, a radioiodinated photoaffinity labeling analog ([125I] 3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramide) was employed. It observed specifically binds activates c-Raf, leading MAPK...
In this study, we investigated the molecular mechanisms underlying ATP analogue adenosine-5′-O-(3-thio)triphosphate–induced nucleocytoplasmic shuttling of mRNA stabilizing factor HuR in human (h) mesangial cells (MC). Using synthetic protein kinase C (PKC) inhibitors and small interfering RNA approaches, demonstrated that knockdown PKCα efficiently blocked ATP-dependent nuclear export to cytoplasm. The functional importance is highlighted by high cytosolic content detected hMC stably...
Exposure of renal mesangial cells to sphingosine 1-phosphate (S1P) leads a rapid and transient activation the mitogen- stress-activated protein kinases but also kinase B. Here, we show that S1P induces phosphorylation Smad proteins, which are members transforming growth factor-beta (TGF-beta) signaling device. However, occurred more slowly with maximal effect after 20-30 min stimulation when compared MAPKs. Interestingly, is increased by pertussis toxin, in contrast complete inhibition...
The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate human mesangial cells (hMC) amplification cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase stability. Using promoter constructs with different portions 3' untranslated region COX-2, found stability attributable to distal class...
During sepsis, activation of phagocytes leads to the overproduction proinflammatory cytokines, causing systemic inflammation. Despite substantial information regarding underlying molecular mechanisms that lead several elements in pathway remain be elucidated. We found enzyme sphingosine kinase 1 (SphK1) is up-regulated stimulated human and peritoneal patients with severe sepsis. Blockade SphK1 inhibited phagocyte production endotoxin-induced cytokines. observed protection against sepsis mice...
Background— Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in inflammatory processes contributing to pathogenesis atherosclerosis. However, reports stimulatory effects on endothelial NO production animal models suggest antiatherosclerotic molecule. Therefore, we investigated long-term generation human cells. Methods and Results— In umbilical vein cells (HUVECs) HUVEC-derived EA.hy 926 cells, C6-ceramide ( N -hexanoyl- d...
Exogenous NO is able to trigger apoptosis of renal mesangial cells, and thus may contribute acute lytic phases as well resolution glomerulonephritis. However, the mechanism involved in these events still unclear. We report here that chronic exposure cells for 24 h compounds releasing NO, including spermine-NO, (<i>Z</i>)-1-{<i>N</i>-methyl-<i>N</i>-[6-(<i>N</i>-methylammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA-NO), <i>S</i>-nitrosoglutathione (GS-NO),...
Sphingosine kinases (SphKs), enzymes that produce the bioactive lipids dihydrosphingosine 1-phosphate (dhS1P) and sphingosine (S1P), are associated with various diseases, including cancer infections. For this reason, a number of SphK inhibitors have been developed. Although off-target effects described for selected agents, mostly used in research without monitoring on sphingolipidome. We now investigated seven commonly (5c, ABC294640 (opaganib), N,N-dimethylsphingosine, K145, PF-543,...
Excessive production of eicosanoids is characteristic many inflammatory diseases. In this study we show that ceramide, which an early messenger cytokine action, exerts a dual effect on the cytosolic phospholipase A2 (cPLA2), rate-limiting enzyme in arachidonic acid release and subsequent eicosanoid formation. Stimulation renal mesangial cells with exogenous short-chain ceramide analogs for 30 60 min leads to concentration-dependent increase not blocked by specific inhibitors...
Ceramide is an important lipid second messenger produced by sphingolipid metabolism in cells exposed to a limited number of agonists and turn triggers several cell responses protein kinase C (PKC)-dependent manner. Stimulation mesangial with radioiodinated photoaffinity labeling analogue ceramide, (N-[3-[[[2-(125I)iodo-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl]oxy]carbonyl]propanoyl]-d-erythro-sphingosine) ([125I]-TID-ceramide), defines PKC-α PKC-δ as direct targets ceramide. No binding...
Exposure of mesangial cells to platelet-derived growth factor (PDGF) BB caused a significant stimulation cell proliferation and protein synthesis, as measured by [3H]thymidine incorporation [3H]leucine respectively. In contrast, treated with angiotensin II had no increase in incorporation, but demonstrated marked incorporation. Furthermore, significantly increased total content per cell. These data show that, whereas PDGF-BB is mitogen stimulates mesangial-cell hyperplasia, causes...
1. Extracellular ATP and UTP have been reported to activate a nucleotide receptor that mediates phosphoinositide phosphatidylcholine hydrolysis by phospholipases C D, respectively. Here we report potently stimulate mesangial cell proliferation. 2. Both nucleotides phosphorylation activation of mitogen-activated protein kinase biphasic the up-stream kinase. 3. When added at 100 microM, gamma S, were most potent activators beta gamma-imido-ATP was somewhat less active ADP 2-methylthio-ATP...
Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine bioactive metabolite 1-phosphate (S1P). Although platelets able secrete S1P on activation, little is about potential intrinsic effect platelet function.To investigate Sphk1- Sphk2-derived regulation function.We found 100-fold reduction intracellular levels derived from Sphk2(-/-) mutants compared with Sphk1(-/-) or wild-type mice, as analyzed by mass...