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2. Pharmacologic modulation of intracellular Na⁺ concentration with ranolazine impacts inflammatory response in humans and mice

Author

Lenz, Max, Salzmann, Manuel, Ciotu, Cosmin I., Kaun, Christoph, Krychtiuk, Konstantin A., Likozar, Andreja Rehberger, Sebestjen, Miran, Goederle, Laura, Rauscher, Sabine, Krivaja, Zoriza, Binder, Christoph J., Huber, Kurt, Hengstenberg, Christian, Podesser, Bruno K., Fischer, Michael J. M., Wojta, Johann, Hohensinnerb, Philipp J., and Speidl, Walter S.

Published
2022

9. Sensory Neurons Release Cardioprotective Factors in an In Vitro Ischemia Model.

Author

Hoebart, Clara, Kiss, Attila, Podesser, Bruno K., Tahir, Ammar, Fischer, Michael J. M., and Heber, Stefan

Subjects
SENSORY neurons, CELL physiology, EXTRACELLULAR vesicles, REPERFUSION injury, FIBROBLASTS
Abstract

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Development of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples

Author

Muratspahić, Edin, primary, White, Andrew M., additional, Ciotu, Cosmin I., additional, Hochrainer, Nadine, additional, Tomašević, Nataša, additional, Koehbach, Johannes, additional, Lewis, Richard J., additional, Spetea, Mariana, additional, Fischer, Michael J. M., additional, Craik, David J., additional, and Gruber, Christian W., additional

Published
2023
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14. Schwann cell stimulation induces functional and structural changes in peripheral nerves

Author

Ciotu, Cosmin I; https://orcid.org/0000-0002-6832-0647, Kistner, Katrin, Kaindl, Ulrich, Millesi, Flavia, Weiss, Tamara, Radtke, Christine, Kremer, Andreas, Schmidt, Katy, Fischer, Michael J M; https://orcid.org/0000-0002-3811-7066, Ciotu, Cosmin I; https://orcid.org/0000-0002-6832-0647, Kistner, Katrin, Kaindl, Ulrich, Millesi, Flavia, Weiss, Tamara, Radtke, Christine, Kremer, Andreas, Schmidt, Katy, and Fischer, Michael J M; https://orcid.org/0000-0002-3811-7066

Abstract

Signal propagation is the essential function of nerves. Lysophosphatidic acid 18:1 (LPA) allows the selective stimulation of calcium signaling in Schwann cells but not neurons. Here, the time course of slowing and amplitude reduction on compound action potentials due to LPA exposure was observed in myelinated and unmyelinated fibers of the mouse, indicating a clear change of axonal function. Teased nerve fiber imaging showed that Schwann cell activation is also present in axon-attached Schwann cells in freshly isolated peripheral rat nerves. The LPA receptor 1 was primarily localized at the cell extensions in isolated rat Schwann cells, suggesting a role in cell migration. Structural investigation of rat C-fibers demonstrated that LPA leads to an evagination of the axons from their Schwann cells. In A-fibers, the nodes of Ranvier appeared unchanged, but the Schmidt-Lanterman incisures were shortened and myelination reduced. The latter might increase leak current, reducing the potential spread to the next node of Ranvier and explain the changes in conduction velocity. The observed structural changes provide a plausible explanation for the functional changes in myelinated and unmyelinated axons of peripheral nerves and the reported sensory sensations such as itch and pain.

Published
2023

16. TRPA1 as Target in Myocardial Infarction

Author

Hoebart, Clara, primary, Kiss, Attila, additional, Pilz, Patrick M., additional, Szabo, Petra L., additional, Podesser, Bruno K., additional, Fischer, Michael J. M., additional, and Heber, Stefan, additional

Published
2023
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22. Pharmacologic modulation of intracellular Na + concentration with ranolazine impacts inflammatory response in humans and mice

Author

Lenz, Max, primary, Salzmann, Manuel, additional, Ciotu, Cosmin I., additional, Kaun, Christoph, additional, Krychtiuk, Konstantin A., additional, Rehberger Likozar, Andreja, additional, Sebestjen, Miran, additional, Goederle, Laura, additional, Rauscher, Sabine, additional, Krivaja, Zoriza, additional, Binder, Christoph J., additional, Huber, Kurt, additional, Hengstenberg, Christian, additional, Podesser, Bruno K., additional, Fischer, Michael J. M., additional, Wojta, Johann, additional, Hohensinner, Philipp J., additional, and Speidl, Walter S., additional

Published
2022
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24. The formalin test does not probe inflammatory pain but excitotoxicity in rodent skin

Author

Hoffmann, Tal, primary, Klemm, Florian, additional, I Kichko, Tatjana, additional, Sauer, Susanne K, additional, Kistner, Katrin, additional, Riedl, Bernhard, additional, Raboisson, Patrick, additional, Luo, Lei, additional, Babes, Alexandru, additional, Kocher, Laurence, additional, Carli, Giancarlo, additional, Fischer, Michael J. M., additional, and Reeh, Peter W., additional

Published
2022
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25. Additional file 1 of SAFit2 reduces neuroinflammation and ameliorates nerve injury-induced neuropathic pain

Author

Wedel, Saskia, Mathoor, Praveen, Rauh, Oliver, Heymann, Tim, Ciotu, Cosmin I., Fuhrmann, Dominik C., Fischer, Michael J. M., Weigert, Andreas, de Bruin, Natasja, Hausch, Felix, Geisslinger, Gerd, and Sisignano, Marco

Abstract

Additional file 1: Figure S1. Gene expression of neuronal stress and oxidative stress markers in lumbar DRGs and spinal cord of SAFit2 treated mice 21 days after SNI. Figure S2. Cytokine and chemokine levels in lumbar DRGs and spinal cord of SAFit2 treated SNI mice after 21 days. Figure S3. Synthesis of ddSAFit 12 and competitive fluorescence assay (FPA) of SAFit2 and ddSAFit2. Figure S4. Cytotoxic and metabolic influence of SAFit2 on primary bone marrow derived macrophages. Figure S5. SAFit2 has no impact on the TRPA1 activity in primary sensory neurons. Figure S6. SAFit2 has no direct impact on the human hTRPV1 channel in HEK-293t cells. Figure S7. Extracellularly or intracellularly administered SAFit2 has no effect on the amplitude and kinetics of capsaicin-activated TRPV1 currents in HEK-293 cells. Figure S8. Uncropped Western Blot images for NF-κB signaling pathway.

Published
2022
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29. A Model Predicting Mortality of Hospitalized Covid-19 Patients Four Days After Admission: Development, Internal and Temporal-External Validation

Author

Heber, Stefan, primary, Pereyra, David, additional, Schrottmaier, Waltraud C., additional, Kammerer, Kerstin, additional, Santol, Jonas, additional, Rumpf, Benedikt, additional, Pawelka, Erich, additional, Hanna, Markus, additional, Scholz, Alexander, additional, Liu, Markus, additional, Hell, Agnes, additional, Heiplik, Klara, additional, Lickefett, Benno, additional, Havervall, Sebastian, additional, Traugott, Marianna T., additional, Neuböck, Matthias J., additional, Schörgenhofer, Christian, additional, Seitz, Tamara, additional, Firbas, Christa, additional, Karolyi, Mario, additional, Weiss, Günter, additional, Jilma, Bernd, additional, Thålin, Charlotte, additional, Bellmann-Weiler, Rosa, additional, Salzer, Helmut J. F., additional, Szepannek, Gero, additional, Fischer, Michael J. M., additional, Zoufaly, Alexander, additional, Gleiss, Andreas, additional, and Assinger, Alice, additional

Published
2022
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30. Analgesic Action of Acetaminophen via Kv7 Channels.

Author

Stampf, Jan-Luca, Ciotu, Cosmin I., Heber, Stefan, Boehm, Stefan, Fischer, Michael J. M., and Salzer, Isabella

Subjects
ACTION potentials, ACETAMINOPHEN, LIVER analysis, CEREBROSPINAL fluid, CONOTOXINS, POTASSIUM channels, ANALGESIA
Abstract

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress

Author

Mihai, Dragos Paul, primary, Ungurianu, Anca, additional, Ciotu, Cosmin I., additional, Fischer, Michael J. M., additional, Olaru, Octavian Tudorel, additional, Nitulescu, George Mihai, additional, Andrei, Corina, additional, Zbarcea, Cristina Elena, additional, Zanfirescu, Anca, additional, Seremet, Oana Cristina, additional, Chirita, Cornel, additional, and Negres, Simona, additional

Published
2021
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34. Proton-sensing GPCRs in health and disease

Author

Sisignano, Marco, Fischer, Michael J. M., Geisslinger, Gerd, Sisignano, Marco, Fischer, Michael J. M., and Geisslinger, Gerd

Abstract

The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.

Published
2021

35. No functional TRPA1 in cardiomyocytes

Author

Hoebart, Clara, primary, Rojas‐Galvan, Natalia S., additional, Ciotu, Cosmin I., additional, Aykac, Ibrahim, additional, Reissig, Lukas F., additional, Weninger, Wolfgang J., additional, Kiss, Attila, additional, Podesser, Bruno K., additional, Fischer, Michael J. M., additional, and Heber, Stefan, additional

Published
2021
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38. Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Author

Lenz, Max, Salzmann, Manuel, Ciotu, Cosmin I., Kaun, Christoph, Krychtiuk, Konstantin A., Likozar, Andreja Rehberger, Sebestjen, Miran, Goederle, Laura, Rauscher, Sabine, Krivaja, Zoriza, Binder, Christoph J., Huber, Kurt, Hengstenberg, Christian, Podesser, Bruno K., Fischer, Michael J. M., Wojta, Johann, Hohensinner, Philipp J., and Speidl, Walter S.

Subjects
INFLAMMATION, ACUTE coronary syndrome, CORONARY artery disease, ATHEROSCLEROTIC plaque, HIGH-fat diet
Abstract

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLINTIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Afferent renal innervation in anti-Thy1.1 nephritis in rats

Author

Rodionova, Kristina, primary, Veelken, Roland, additional, Hilgers, Karl F., additional, Paulus, Eva-Maria, additional, Linz, Peter, additional, Fischer, Michael J. M., additional, Schenker, Martina, additional, Reeh, Peter, additional, Tiegs, Gisa, additional, Ott, Christian, additional, Schmieder, Roland, additional, Schiffer, Mario, additional, Amann, Kerstin, additional, and Ditting, Tilmann, additional

Published
2020
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42. Non-Canonical Ion Channel Behaviour in Pain

Author

Ciotu, Cosmin I., Tsantoulas, Christoforos, Meents, Jannis, Lampert, Angelika, McMahon, Steve, Ludwig, Andreas, and Fischer, Michael J. M.

Subjects
life_sciences_other
Abstract

Ion channels contribute fundamental properties to all cell membranes. The ion channels are highly diverse in conductivity, structure, location and function. However, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Considering primarily pain-related ion channels, this review covers more novel and less known features of ion channel function, also with the aim to transfer knowledge between fields, which get inevitably more separate due to their size.

Published
2019

43. STAT3β is a tumor suppressor in acute myeloid leukemia

Author

Aigner, Petra, Mizutani, Tatsuaki, Horvath, Jaqueline, Eder, Thomas, Heber, Stefan, Lind, Karin, Just, Valentin, Moll, Herwig P., Yeroslaviz, Assa, Fischer, Michael J. M., Kenner, Lukas, Győrffy, Balázs, Sill, Heinz, Grebien, Florian, Moriggl, Richard, Casanova, Emilio, and Stoiber, Dagmar

Subjects
STAT3 Transcription Factor, Myeloid Neoplasia, Gene Expression Regulation, Leukemic, Biopsy, Gene Expression Profiling, Tumor Suppressor Proteins, Prognosis, Immunohistochemistry, Cell Line, Disease Models, Animal, Leukemia, Myeloid, Acute, Mice, hemic and lymphatic diseases, Animals, Humans, Disease Susceptibility, Biomarkers
Abstract

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9–dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML.

Published
2019

48. STAT3β is a tumor suppressor in acute myeloid leukemia

Author

Aigner, Petra, primary, Mizutani, Tatsuaki, additional, Horvath, Jaqueline, additional, Eder, Thomas, additional, Heber, Stefan, additional, Lind, Karin, additional, Just, Valentin, additional, Moll, Herwig P., additional, Yeroslaviz, Assa, additional, Fischer, Michael J. M., additional, Kenner, Lukas, additional, Győrffy, Balázs, additional, Sill, Heinz, additional, Grebien, Florian, additional, Moriggl, Richard, additional, Casanova, Emilio, additional, and Stoiber, Dagmar, additional

Published
2019
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50. Effect of a calcitonin gene-related peptide-binding L-RNA aptamer on neuronal activity in the rat spinal trigeminal nucleus

Author

Fischer, Michael J. M., Schmidt, Jakob, Koulchitsky, Stanislav, Klussmann, Sven, Vater, Axel, and Messlinger, Karl

Subjects
Male, Neurons, Nociception, Calcitonin Gene-Related Peptide, Migraine Disorders, lcsh:R, Headache, lcsh:Medicine, Aptamers, Nucleotide, Rats, Disease Models, Animal, Meninges, Medizinische Fakultät, Meningeal nociception, Animals, RNA, ddc:610, Rats, Wistar, Trigeminal Nucleus, Spinal, Migraine, Research Article, Receptors, Calcitonin Gene-Related Peptide
Abstract

Background Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown to lower spinal trigeminal neuron activity in animal models of meningeal nociception. Methods In a rat model of meningeal nociception, single cell activity of neurons in the spinal trigeminal nucleus with meningeal afferent input was recorded to test a further pharmacological approach, scavenging CGRP with a CGRP-binding l-RNA oligonucleotide, the l-aptamer NOX-C89. Cumulative ascending doses of NOX-C89 were intravenously infused. Results Spontaneous activity of spinal trigeminal neurons did not change after 0.05 mg/kg NOX-C89, however, after additional infusion of 0.5 mg/kg and 5 mg/kg NOX-C89, spontaneous activity was dose-dependently reduced. Identical doses of a control l-aptamer had no effect. This pharmacological effect of NOX-C89 was observed 10–25 min after infusion, but no difference was detected in the period 0–5 min. For comparison, the previously investigated CGRP receptor antagonist olcegepant had reduced activity within 5 min after infusion. Alongside the reduced spontaneous activity, after infusion of NOX-C89 the heat-induced neuronal activity was abolished. Conclusions Scavenging CGRP by mirror-image RNA aptamers provides further evidence that this approach can be used to control spinal trigeminal activity.

Published
2018

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