The long-term research interest of Laboratory for beta-cell biology is focussed on the understanding of molecular mechanisms that are involved in the development of beta-cell dysfunction and type 2 diabetes pathogenesis. Our research aims primarily at the effect of nutrients (particularly saturated and unsaturated fatty acids) and persistent organochlorine pollutants (particularly DDT and DDE) on function and viability of pancreatic beta-cells. We are also interested in the role of hypoxia as a potential predisposing factor for the development of beta-cell dysfunction.
The long-term research interest of Laboratory for beta-cell biology aims at the understanding of molecular mechanisms by which various factors of environment contribute to pancreatic beta-cell dysfunction and pathogenesis of type 2 diabetes. In our recent projects, we are especially interested in the effect of (1) fatty acids, (2) persistent organochlorine pollutants and (3) hypoxia on function and viability of pancreatic beta-cells.
Increased level of fatty acids in the blood is considered as one of the main causes of pancreatic β-cell dysfunction and consequent β-cell death in type 2 diabetes. As we also demonstrated in our laboratory, increased level of saturated fatty acid species (e.g., palmitate, stearate) leads to beta-cell apoptosis, in contrast to unsaturated fatty acid species (e.g., palmitoleate, oleate) which are significantly less toxic and are even able to inhibit pro-apoptotic effects of saturated fatty acids. Molecular mechanisms of these effects, despite their great therapeutic potential in many fields of medicine, are not clear yet.
Employing human pancreatic beta-cell line NES2Y, we have characterized stearate-induced apoptosis in respect to the involvement of various caspases and kinases activation, mitochondrial apoptotic pathway activation and ER stress induction. We found that all pro-apoptotic effects of stearate we found so far are inhibited by oleate co-application. In our current research, we aim to reveal the point of anti-apoptotic intervention of unsaturated fatty acids into pro-apoptotic signaling exerted by saturated fatty acids.
Persistent organochlorine pollutant, e.g., DDT and DDE, despite the prohibition of their usage in our country for many years, are still present in the environment and inevitably accumulate in our bodies via the food chain. Employing proteomic and other methods, we have revealed several effects of DDT and DDE on beta-cell function and insulin secretion. Our current research is aimed at elucidation of the molecular mechanisms of these effects with a specific interest focused on a role of vitamin D-binding protein.
Hypoxia often accompanies type 2 diabetes due to high coincidence of sleep apnea. Therefore, we are also interested in the effect of hypoxic conditions on beta-cell viability, including its impact on pro- and anti-apoptotic potential of saturated and unsaturated fatty acids.
Group leader
RNDr. Vlasta Němcová, Ph.D., e-mail: ,
Post-doc
Mgr. Nela Pavlíková, Ph.D. e-mail: ,
RNDr. Jan Šrámek, Ph.D., email: ,
Němcová-Fürstová V, Balušíková K, Halada P, Pavlíková N, Šrámek J, Kovář J.: Stearate-induced apoptosis in human pancreatic β-cells is associated with changes in membrane protein expression and these changes are inhibited by oleate. Proteomics Clin Appl. 2019, doi: 10.1002/prca.201800104.
Jelínek M, Balušíková K, Daniel P, Němcová-Fürstová V, Kirubakaran P, Jaček M, Wei L, Wang X, Vondrášek J, Ojima I, Kovář J.: Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel. Toxicol Appl Pharmacol. 2018; 347:79-91. doi: 10.1016/j.taap.2018.04.002.
Brynychova V, Hlavac V, Ehrlichova M, Vaclavikova R, Nemcova-Furstova V, Pecha V, Trnkova M, Mrhalova M, Kodet R, Vrana D, Gatek J, Bendova M, Vernerova Z, Kovar J, Soucek P.: Transcript expression and genetic variability analysis of caspases in breast carcinomas suggests CASP9 as the most interesting target. Clin Chem Lab Med. 2017; 55(1):111-122. doi: 10.1515/cclm-2016-0271.
Jelinek M, Kabelova A, Sramek J, Seitz J, Ojima I, Kovar J.: Differing Mechanisms of Death Induction by Fluorinated Taxane SB-T-12854 in Breast Cancer Cells. Anticancer Res. 2017; 37(4):1581-1590. doi: 10.21873/anticanres.11488
Šrámek J, Němcová-Fürstová V, Pavlíková N, Kovář J.: Effect of Saturated Stearic Acid on MAP Kinase and ER Stress Signaling Pathways during Apoptosis Induction in Human Pancreatic β-Cells Is Inhibited by Unsaturated Oleic Acid. Int J Mol Sci. 2017; 18(11). pii: E2313. doi: 10.3390/ijms18112313.
Brynychova V, Ehrlichova M, Hlavac V, Nemcova-Furstova V, Pecha V, Leva J, Trnkova M, Mrhalova M, Kodet R, Vrana D, Kovar J, Vaclavikova R, Gut I, Soucek P.: Genetic and functional analyses do not explain the association of high PRC1 expression with poor survival of breast carcinoma patients. Biomed Pharmacother. 2016; 83:857-864. doi: 10.1016/j.biopha.2016.07.047.
Němcová-Fürstová V, Kopperová D, Balušíková K, Ehrlichová M, Brynychová V, Václavíková R, Daniel P, Souček P, Kovář J.: Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. Toxicol Appl Pharmacol. 2016; 310:215-228. doi: 10.1016/j.taap.2016.09.020.
Šrámek J, Němcová-Fürstová V, Kovář J.: Kinase Signaling in Apoptosis Induced by Saturated Fatty Acids in Pancreatic β-Cells. Int J Mol Sci. 2016; 17(9). pii: E1400. doi: 10.3390/ijms17091400.
Šrámek J, Němcová-Fürstová V, Balušíková K, Daniel P, Jelínek M, James RF, Kovář J.: 38 MAPK Is Activated but Does Not Play a Key Role during Apoptosis Induction by Saturated Fatty Acid in Human Pancreatic β-Cells. Int J Mol Sci. 2016; 17(2):159. doi: 10.3390/ijms17020159.
Weiszenstein M, Pavlikova N, Elkalaf M, Halada P, Seda O, Trnka J, Kovar J, Polak J.: The Effect of Pericellular Oxygen Levels on Proteomic Profile and Lipogenesis in 3T3-L1 Differentiated Preadipocytes Cultured on Gas-Permeable Cultureware. PLoS One. 2016; 29;11(3):e0152382. doi: 10.1371/journal.pone.0152382.
Jiroutková K, Krajčová A, Ziak J, Fric M, Waldauf P, Džupa V, Gojda J, Němcova-Fürstová V, Kovář J, Elkalaf M, Trnka J, Duška F.: Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness. Crit Care. 2015; 19:448. doi: 10.1186/s13054-015-1160-x.
Jelínek M, Balušíková K, Schmiedlová M, Němcová-Fürstová V, Šrámek J, Stančíková J, Zanardi I, Ojima I, Kovář J.: The role of individual caspases in cell death induction by taxanes in breast cancer cells. Cancer Cell Int. 2015; 15(1):8. doi: 10.1186/s12935-015-0155-7.
Pavlikova N, Weiszenstein M, Pala J, Halada P, Seda O, Elkalaf M, Trnka J, Kovar J, Polak J.: The effect of cultureware surfaces on functional and structural components of differentiated 3T3-L1 preadipocytes. Cell Mol Biol Lett. 2015; 20(5):919-36. doi: 10.1515/cmble-2015-0054.
Pavlikova N, Smetana P, Halada P, Kovar J.: Effect of prolonged exposure to sublethal concentrations of DDT and DDE on protein expression in human pancreatic beta cells. Environ Res. 2015; 142:257-63. doi: 10.1016/j.envres.2015.06.046.
Pavlikova N, Bartonova I, Dincakova L, Halada P, Kovar J.: Differentially expressed proteins in human breast cancer cells sensitive and resistant to paclitaxel. Int J Oncol. 2014; 45(2):822-30. doi: 10.3892/ijo.2014.2484.
Jelínek M, Balušíková K, Kopperová D, Nĕmcová-Fürstová V, Šrámek J, Fidlerová J, Zanardi I, Ojima I, Kovář J.: Caspase-2 is involved in cell death induction by taxanes in breast cancer cells. Cancer Cell Int. 2013 ; 13(1):42. doi: 10.1186/1475-2867-13-42.
Němcová-Fürstová V, Balušíková K, Srámek J, James RF, Kovář J.: Caspase-2 and JNK activated by saturated fatty acids are not involved in apoptosis induction but modulate ER stress in human pancreatic β-cells. Cell Physiol Biochem. 2013; 31(2-3):277-89. doi: 10.1159/000343367.
Third Faculty of Medicine
Charles University
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Czech Republic
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