A5035424393- Lysosomal Storage Disorders Research
- Sphingolipid Metabolism and Signaling
- Carbohydrate Chemistry and Synthesis
- Cellular transport and secretion
- Immune Cell Function and Interaction
- Biomedical Research and Pathophysiology
- Autoimmune and Inflammatory Disorders Research
- Calcium signaling and nucleotide metabolism
- Metabolomics and Mass Spectrometry Studies
- Endoplasmic Reticulum Stress and Disease
- Trypanosoma species research and implications
- Cancer, Lipids, and Metabolism
- Mast cells and histamine
- Glycosylation and Glycoproteins Research
- Cytomegalovirus and herpesvirus research
- Metabolism and Genetic Disorders
- Autophagy in Disease and Therapy
- Genetics, Aging, and Longevity in Model Organisms
- Sulfur Compounds in Biology
- Polysaccharides and Plant Cell Walls
- Research on Leishmaniasis Studies
- Ion Transport and Channel Regulation
- Adenosine and Purinergic Signaling
- Analytical Methods in Pharmaceuticals
- Anesthesia and Sedative Agents
Charles University
2015-2024
General University Hospital in Prague
2018-2024
Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve survival time patients, who are often diagnosed too late at an incurable stage. Several studies report dysregulation lipid metabolism in tumor cells, suggesting that changes blood lipidome accompany growth. Here we show comprehensive mass spectrometric determination a wide range serum lipids reveals statistically significant differences between pancreatic patients and healthy controls, as...
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is toxic organophosphates that induce human paralysis severe axonopathy large neurons. Mutations in cause spastic paraplegia characterized by motor neuron degeneration. Here we identify childhood blindness seven families with degeneration,...
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons cardiomyocytes from ER stress apoptosis. The mechanism of action extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal response, we identified the gene Y54G2A.23 as evolutionarily conserved C. elegans orthologue. We find binds to lipid sulfatide, also known 3-O-sulfogalactosylceramide present in serum...
Prosaposin deficiency (pSap-d) and saposin B (SapB-d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for 65-70 kDa prosaposin protein, which is precursor four sphingolipid activator proteins, saposins A-D. We report on two new patients with defects; one, pSap-d, who had a severe neurovisceral dystrophy died as neonate, other SapB-d, presented metachromatic leukodystrophy-like disorder but normal arylsulfatase activity. Screening urinary sphingolipids was...
Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, a limited knowledge about underlying pathophysiological processes. Here we aimed at getting in-depth insight into disease mechanisms using transgenic mouse model HCU (I278T). We assessed metabolic, proteomic sphingolipidomic changes, mitochondrial function in tissues body fluids I278T mice WT controls. Furthermore, evaluated the...
Acid sphingomyelinase deficiency (ASMD), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is divided into infantile neurovisceral ASMD (Niemann-Pick type A), chronic (intermediate form, Niemann-Pick A/B) and visceral B). We conducted a long-term observational, single-center study including 16 patients with ASMD. 12 were diagnosed childhood 4 others adulthood, oldest at age of 50. The mean time follow-up was approximately 10 years (range: 6 months – 36 years)....
Fabry disease (FD) is an X-linked lysosomal storage resulting from pathogenic variants in the GLA gene coding α-galactosidase A (AGAL) and cleaving terminal alpha-linked galactose. Globotriaosylceramide (Gb3) predominantly accumulated sphingolipid. Gb3, deacylated-Gb3 (lysoGb3), methylated-Gb3 (metGb3) have been suggested as FD biomarkers.
Key Points The clinical significance of a number missense variants α -galactosidase A is often ambiguous. Defective proteostasis some induced chronic endoplasmic reticulum stress and the unfolded protein response. Endoplasmic response may explain manifestations non-classic Fabry disease. Background Classic disease caused by GLA mutations that result in loss enzymatic activity A, lysosomal storage globotriaosylceramide, resulting multisystemic In disease, patients have preserved milder...
Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die childhood, while SMA-PME can live until adulthood. There is no treatment for or SMA-PME. Hematopoietic stem cell transplantation (HSCT) gene therapy strategies of ACDase deficiency...
The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis sphingolipids mammalian cells inhibited family three ORMDL proteins (ORMDL1, 2, 3). However, cell tissue-specific functions signaling poorly understood. This study aimed to determine cross-talk ORMDL2 ORMDL3 IgE-mediated responses. To end, we prepared mice with whole-body...
Abstract Acid ceramidase catalyzes the degradation of ceramide into sphingosine and a free fatty acid. deficiency results in lipid accumulation many tissues leads to development Farber disease (FD). Typical manifestations classical FD include formation subcutaneous nodules joint contractures as well hoarse voice. Healthy skin depends on unique profile form barrier that confers protection from pathogens, prevents excessive water loss, mediates cell–cell communication. Ceramides comprise ~50%...
Sphingolipid ceramide N-deacylase (SCDase, EC 3.5.1.69) is a hydrolytic enzyme isolated from Pseudomonas sp. TK 4. In addition to its primary deacylation function, this able reacylate lyso-sphingolipids under specific conditions. We immobilised on magnetic macroporous cellulose and used it semisynthesise C17:0 glucosylceramide sulphatide, which are required internal standards for quantification of the corresponding glycosphingolipids (GSL) by tandem mass spectrometry. A high rate conversion...
A series of six full-term placentas and umbilical cords were examined using the in situ detection globotriaosylceramide (Gb3Cer), GM1 ganglioside (GM1), GM3 (GM3), cholesterol caveolin 1. Immunohistochemical study showed uniform distinct staining apical membrane villous capillary endothelial cells for Gb3Cer, GM1, cholesterol. There was also a strong signal The immunophenotype suggests presence caveola-associated raft microdomains. almost completely shared with extravillous intravascular...
Abstract Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity milder course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic mutated AGAL, impairment functions, other pathogenic factors important,...
Abstract In mammals, the ORMDL family of evolutionarily conserved sphingolipid regulators consists three highly homologous members, ORMDL1, ORMDL2 and ORMDL3. ORMDL3 gene has been associated with childhood-onset asthma other inflammatory diseases in which mast cells play an important role. We previously described increased IgE-mediated activation simultaneous deletions proteins. this study, we prepared mice Ormdl1 knockout thereafter, produced primary reduced expression one, two or all The...
Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or NPC2 gene. multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts mutations, we examined fibroblast cultures 26 NP-C1 patients with clinical phenotypes ranging infantile to adult neurologic onset forms. The cells were tested multiple assays including mRNA expression levels and allele ratios, assessment promoter haplotypes,...
Leukotrienes and sphingolipids are critical lipid mediators participating in numerous cellular signal transduction events developing various disorders, such as bronchial hyperactivity leading to asthma. Enzymatic reactions initiating production of these involve 5-lipoxygenase (5-LO)-mediated conversion arachidonic acid leukotrienes serine palmitoyltransferase (SPT)-mediated de novo synthesis sphingolipids. Previous studies have shown that ER membrane protein ORMDL3 inhibits the activity SPT...