New findings may help to improve diagnostic methods for breast cancer (23.8. 2021)
2-hydroxyglutarate (2HG) is a metabolite resembling normal cell metabolite 2-oxoglutarate (2OG), however, its accumulation in cells might lead to amplification of processes in cancer development. R-2HG is a product or bi-product of several metabolic enzymes, including mitochondrial ones. We investigated whether production of mitochondrial 2HG is elevated in breast cancer cell lines and identified active competition for initial substrate, 2OG, between enzymes isocitrate dehydrogenase IDH2 and alcohol dehydrogenase ADHFE1. We have also investigated possible substrate and cofactor NADPH channeling between the two IDH2 molecules within mitochondria. We characterized several situations when either IDH2 and ADHFE1 produce a non-negligible amount of 2HG, which is then actively exported from cells. This can serve as a basis for clinical application of our findings. We have therefore quantified 2HG levels in the urine of breast carcinoma patients after resection of their tumors and showed a positive correlations between cancer stages and 2HG levels. Note that cancer stages I to IV differ by the existence, localization and severity of metastases. A future extension of these findings might help to improve diagnostic approaches of breast carcinoma.
Špačková; Jitka - Gotvaldová; Klára - Dvořák; Aleš - Urbančoková; Alexandra - Pospíšilová; K. - Větvička; D. - Leguina-Ruzzi; Alberto A. - Tesařová; P. - Vítek; L. - Ježek; Petr - Smolková; Katarína . Biochemical Background in Mitochondria Affects 2HG Production by IDH2 and ADHFE1 in Breast Carcinoma . Cancers (Basel). 2021; 13(7)); 1709 . IF = 6.639 [ASEP] [ DOI ]
Palmitoylation controls NMDA receptor susceptibility to neurosteroids (3.5. 2021)
N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that are crucial for synaptic transmission, learning, and memory acquisition. Their overactivation leads to pathology associated, for example, with stroke or Alzheimer's disease. Overactivation of NMDA receptors can be inhibited by a number of substances, including neurosteroids.
Using electrophysiological and molecular-biological techniques, we have elucidated the molecular mechanism by which NMDA receptor susceptibility to inhibitory neurosteroids is increased. This change is due to depalmitoylation of three cysteines (C849, C854, C871) in the intracellular part of the GluN2B receptor subunit, which occurs after a transient increase in intracellular concentration of Ca2+. Beyond the pharmacological consequences, depalmitoylation of the receptor results in a change in kinetic parameters in favor of the closed state. Increased sensitivity of NMDA receptors to inhibitory neurosteroids is thus another of the neuroprotective mechanisms that prevents excitotoxic damage to nerve tissue.
Hubálková, Pavla - Ladislav, Marek - Vyklický, Vojtěch - Smejkalová, Tereza - Hrčka Krausová, Barbora - Kysilov, Bohdan - Krůšek, Jan - Naimová, Žaneta - Kořínek, Miloslav - Chodounská, Hana -Kudová, Eva - Černý, Jiří - Vyklický ml., Ladislav Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity. Journal of Neuroscience 2021. 41 (10) 2119-2134, F: 5.674 DOI
Clove oil alleviates cold-induced toothache by blocking the TRPC5 ion channel (30.4. 2021)
Touching a cold drink can be a suffering for us when we have tooth decay. An international team of scientists led by Prof. Katharina Zimmermann (Friedrich - Alexander University Erlangen - Nuremberg in Germany), together with scientists from the Institute of Physiology of the Czech Academy of Sciences in Prague, found out how teeth detect cold and determined the molecular basis of cold-induced dental pain. In both mice and humans, dental cells called odontoblasts contain special cold sensors, the TRPC5 ion channels, which transmit information about a painful stimulus to the nervous system. The study also offers an explanation for why clove oil, which has been used for centuries in dentistry, can alleviate toothache. Clove oil contains a chemical eugenol that blocks the TRPC5 protein and prevents it from activating nerves. Video
Odontoblasts containing the ion channel TRPC5 (green) tightly pack the area between the pulp and the dentin in a mouse’s molar. The cells’ long-haired extensions fill the thin canals in dentin that extend towards the enamel. Sensory nerves are indicated in red (bIII-tubulin). Cell nuclei are stained with Hoechst 33258. (Credit: L. Bernal et al./Science Advances 2021)
Bernal, L. - Sotelo-Hitschfeld, P. - König, Ch. - Sinica, Viktor - Wyatt, A. - Winter, Z. - Hein, A. - Touška, Filip - Reinhardt, S. - Tragl, A. - Kusuda, R. - Wartenberg, P. - Sclaroff, A. - Pfeifer, J. D. -Ectors, F. - Dahl, A. - Freichel, M. - Vlachová, Viktorie - Brauchi, S. - Roza, C. - Boehm, U. - Clapham, D. E. - Lennerz, J. K. - Zimmermann, K. Odontoblast TRPC5 channels signal cold pain in teeth. Science Advances. Roč. 7, č. 13 (2021), č. článku eabf5567. ISSN 2375-2548. IF: 13.117, rok: 2019. DOI
Nanocellulose as a promising cell carrier for applications in regenerative medicine (8.4. 2021)
Cellulose in the form of a fabric has been used for thousands of years as a traditional wound dressing material. Nowadays, it can be used not only for passive wound covering, but also for active wound healing, e.g. with controlled delivery of various drugs or cells for regenerating the damaged tissue. A suitable form of cellulose for this purpose is nanocellulose, i.e. cellulose in the form of nanofibrils, simulating the architecture of the native extracellular matrix. This form of cellulose is produced by some species of bacteria, or can be isolated from higher plants, including wood. In our experiments, we have focused on the development of “intelligent” wound dressings, capable of delivering skin and stem cells into skin wounds. These dressings are based on electrically-charged cellulose nanofibrils, attached to a microfibrous cellulose fabric. Anionic nanocellulose provided a suitable substrate for the adhesion and growth of human dermal fibroblasts and human adipose tissue-derived stem cells, while cationic nanocellulose provided better support for cell-cell adhesion and for the formation of cell aggregates, which was apparent mainly in fibroblasts (Fig. 1). This difference was due to the preferential adsorption of albumin from the serum supplement of the culture medium, which is non-adhesive for cells, on cationic nanocellulose. However, both types of nanocellulose are useful in regenerative medicine. Anionic nanocellulose is suitable for creating continuous cell sheets, which can be delivered into the wound either spontaneously or after release from the substrate using cellulase enzymes, while cationic cellulose is suitable for creating cell spheroids, i.e. important structures for developing organoids and for tissue engineering.
Fig. 1 Morphology of normal human dermal fibroblasts (NHDFs; A) and human adipose tissue-derived stem cells (ADSCs; B), guided by the topography of cellulose meshes coated with anionic or cationic cellulose nanofibrils (a600, c600, respectively) after seven days of cultivation. 3D projection of microscopy images (front view and side view) of the cells on the material. F-actin of the cell cytoskeleton is stained in red, vinculin in the cells is stained in green. Confocal microscope with objective magnification 40x.
Pajorova J, Skogberg A, Hadraba D, Broz A, Travnickova M, Zikmundova M, Honkanen M, Hannula M, Lahtinen P, Tomkova M, Bacakova L, Kallio P. A cellulose mesh with charged nanocellulose coatings as a promising carrier of skin and stem cells for regenerative applications. Biomacromolecules, 2020, 21: 4857-4870, https://dx.doi.org/10.1021/acs.biomac.0c01097; IF = 6.092; DOI
Fat mass is controlled by the balance of triacylglycerol (TAG) degradation and synthesis. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are key players in TAG catabolism providing fatty acids (FAs) as energy substrates and metabolic intermediates. In collaboration with colleagues from University of Graz, Université de Montpellier and Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, we discovered that ATGL and HSL metabolize TAGs containing antidiabetic lipid mediators (FA esters of hydroxy FAs), distinctly controlling the release of bioactive lipids. Our paper connects lipolysis-mediated TAG metabolism with the regulation of antidiabetic signaling lipids.
Glycerol-bound FAHFAs in TAG, named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. We found that ATGL alone or co-activated by comparative gene identification-58 (CGI-58) efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo.
K. Brejchova, F.P.W. Radner, L. Balas, V. Paluchova, T. Cajka, H. Chodounska, E. Kudova, M. Schratter, R. Schreiber, T. Durand, R. Zechner, O. Kuda. Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides. Proceedings of the National Academy of Sciences of the United States of America 118(2) (2021) e2020999118. IF = 9.412 DOI
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