Prof. Dr. Carsten Culmsee

BackgroundPharmacists can improve quality of cancer care and patient quality of life, but systematical investigations of the quantitative improvement of patient safety by integrated ward pharmacists (WP) in cancer care teams are still rare.AimTo systematically investigate the effect of an implemented ward pharmacist on the reduction of medication errors (ME) and thus increasing patient safety.MethodsP0 (retrospective control phase) forms the baseline with no pharmaceutical intervention. In P1 and P2 (prospective intervention phases) WP acted as a team member, performing interventions, and solving ME as part of the daily routine. Throughout all phases, two pharmacists independently identified all remaining ME from archived patient files. ME were considered as clinically relevant after confirmation by an oncologist.ResultsThe three phases with 52, 46, and 50 patients, respectively, were comparable regarding the …

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic …

Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases.

BackgroundModern oral antineoplastic and immune-modulating drugs offer an array of therapeutic advantages, and yet pose challenges in daily use for patients, physicians and pharmacists. In contrast to intravenous administration, these drugs are not subject to direct medical control. Recently, we have seen a huge rise in sales of non-prescription over-the-counter (OTC) medicines via the internet without any advice from a healthcare professional.ObjectivesThe aim of this study was to investigate whether the risk of known potential drug-drug interactions between modern oral antineoplastic and immune-modulating drugs and OTC drugs differs between sales in traditional community pharmacies versus online pharmacies.DesignReal-life sales data from community and online pharmacies were used as basis for the analysis.MethodsWe determined the most frequently purchased antineoplastic and immune …

Correction: Dying transplanted neural stem cells mediate survival bystander effects in the injured brain - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Cell Death Dis v.14(3); 2023 Mar PMC10027688 Other Formats PDF (369K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Cell Death Dis v.14(3); 2023 Mar PMC10027688 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of cddis Cell Death Dis. 2023 Mar; 14(3): 203. Published online 2023 Mar 20…

Background: Specialized pro-resolving mediators (SPMs) and especially resolvin (Rv) E1 can actively terminate inflammation and promote healing during acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients show neurocognitive impairments.Methods: To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs, genetically omega-3 polyunsaturated fatty acid (PUFA)-enriched Fat-1 mice were crossbred with ChemR23 (CR) or LTB4 receptor 1 (LR) knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10µg). Mice were sacrificed at 0h, 4h, 24h, 72h and 120h post inflammation and effects on lung, liver and brain were assessed by RT-PCR, multiplex, immunohistochemistry, western blot and LC-MS/MS.Results: Humoral pathways to the brain did not seem to …

Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective “farewell” secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting …

Ferroptosis is a type of oxidative cell death that can occur in neurodegenerative diseases and involves damage to mitochondria. Previous studies demonstrated that preventing mitochondrial dysfunction can rescue cells from ferroptotic cell death. However, the complexity of mitochondrial dysfunction and the timing of therapeutic interventions make it difficult to develop an effective treatment strategy against ferroptosis in neurodegeneration conditions. In this study, we explored the use of mitochondrial transplantation as a novel therapeutic approach for preventing ferroptotic neuronal cell death. Our data showed that isolated exogenous mitochondria were incorporated into both healthy and ferroptotic immortalized hippocampal HT-22 cells and primary cortical neurons (PCN). The mitochondrial incorporation was accompanied by increased metabolic activity and cell survival through attenuating lipid peroxidation and …

Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers.

In the central nervous system (CNS), insulin‐like growth factor 1 (IGF‐1) regulates myelination by oligodendrocyte (ODC) precursor cells and shows anti‐apoptotic properties in neuronal cells in different in vitro and in vivo systems. Previous work also suggests that IGF‐1 protects ODCs from cell death and enhances remyelination in models of toxin‐induced and autoimmune demyelination. However, since evidence remains controversial, the therapeutic potential of IGF‐1 in demyelinating CNS conditions is unclear. To finally shed light on the function of IGF1‐signaling for ODCs, we deleted insulin‐like growth factor 1 receptor (IGF1R) specifically in mature ODCs of the mouse. We found that ODC survival and myelin status were unaffected by the absence of IGF1R until 15 months of age, indicating that IGF‐1 signaling does not play a major role in post‐mitotic ODCs during homeostasis. Notably, the absence of …

Cinnamic acid, ferulic acid, and the flavonoids quercetin and taxifolin (dihydroquercetin) are naturally occurring compounds found in plants. They are often referred to as polyphenols and are known, among others, for their pharmacological effects supporting health through the inhibition of aging processes and oxidative stress. To improve their bioavailability, pharmacological activities, and safety, the creation of novel flavonoid–phenolic acid hybrids is an area of active research. Previous work showed that such hybridization products of phenolic acids and flavonoids enhanced the resilience of neuronal cells against oxidative stress in vitro, and attenuated cognitive impairment in a mouse model of Alzheimer’s disease (AD) in vivo. Notably, the therapeutic effects of the hybrid compounds we obtained were more pronounced than the protective activities of the respective individual components. The underlying mechanisms mediated by the flavonoid–phenolic acid hybrids, however, remained unclear and may differ from the signaling pathways activated by the originating structures of the respective individual phenolic acids or flavonoids. In this study, we characterized the effects of four previously described potent flavonoid–phenolic acid hybrids in models of oxidative cell death through ferroptosis. Ferroptosis is a type of iron-dependent regulated cell death characterized by lipid peroxidation and mitochondrial ROS generation and has been linked to neurodegenerative conditions. In models of ferroptosis induced by erastin or RSL3, we analyzed mitochondrial (lipid) peroxidation, mitochondrial membrane integrity, and Ca2+ regulation. Our results …

Ferroptosis is a form of oxidative cell death that is characterized by enhanced lipid peroxidation and mitochondrial impairment. The enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase (LPCAT) play an essential role in the biosynthesis of polyunsaturated fatty acid (PUFA)-containing phospholipids, thereby providing the substrates for lipid peroxidation and promoting ferroptosis. To examine the impact of mitochondria in ACSL4/LPCAT2-driven ferroptosis, HEK293T cells overexpressing ACSL4 and LPCAT2 (OE) or empty vector controls (LV) were exposed to 1S, 3R-RSL3 (RSL3) for induction of ferroptosis. The ACSL4/LPCAT2 overexpression resulted in higher sensitivity against RSL3-induced cell death compared to LV-transfected controls. Moreover, mitochondrial parameters such as mitochondrial reactive oxygen species (ROS) formation, mitochondrial membrane potential, and mitochondrial respiration deteriorated in the OE cells, supporting the conclusion that mitochondria play a significant role in ACSL4/LPCAT2-driven ferroptosis. This was further confirmed through the protection of OE cells against RSL3-mediated cell death by the mitochondrial ROS scavenger mitoquinone (MitoQ), which exerted protection via antioxidative properties rather than through previously reported metabolic effects. Our findings implicate that mitochondrial ROS production and the accompanying organelle disintegration are essential for mediating oxidative cell death initiated through lipid peroxidation in ferroptosis.

Aim This study investigates how cell damage caused by UVB irradiation in mouse embryonic fibroblasts is mediated by reactive oxygen species and whether Ze 450 attenuates the excess of free radicals to protect the cells from oxidative stress.Method Fibroblastic cells were exposed to UVB radiation and afterwards the influence of Cimicifuga racemosa extract on cell death, lipid peroxidation and senescence associated regulation of β-galactosidase was analysed using fluorescence-activated cell scanning (FACS). To understand the underlying cell death mechanisms, these effects were further compared to different inhibitors of apoptosis and ferroptosis.Results Cimicifuga extract Ze 450 mitigated UVB-induced cell death in mouse embryonic fibroblasts, which could also be prevented by inhibition of caspases and Bid, and partially by a p53-inhibitor, which previously were demonstrated to block ferroptosis and …

BackgroundCimicifuga racemosa extracts (CRE) have obtained a “well-established use status” in the treatment of postmenopausal (i.e., climacteric) complaints, which predominantly include vasomotor symptoms such as hot flushes and sweating, as well as nervousness, irritability, and metabolic changes. Although characteristic postmenopausal complaints are known for a very long time and the beneficial effects of CRE on climacteric symptoms are well accepted, both the pathophysiology of postmenopausal symptoms and the mechanism of action of CREs are not yet fully understood. In particular, current hypotheses suggest that changes in the α-adrenergic and serotonergic signaling pathways secondary to estrogen depletion are responsible for the development of hot flushes.PurposeSome of the symptoms associated with menopause cannot be explained by these hypotheses. Therefore, we attempted to extend …

This study addresses the eventual consequence of cytochrome c oxidase (CytOx) inhibition by ATP at high ATP/ADP ratio in isolated rat heart mitochondria. Earlier, it has been demonstrated that the mechanism of allosteric ATP inhibition of CytOx is one of the key regulations of mitochondrial functions. It is relevant that aiming to maintain a high ATP/ADP ratio for the measurement of CytOx activity effectuating the enzymatic inhibition as well as mitochondrial respiration, optimal concentration of mitochondria is critically important. Likewise, only at this concentration, were the differences in ΔΨm and ROS concentrations measured under various conditions significant. Moreover, when CytOx activity was inhibited in the presence of ATP, mitochondrial respiration and ΔΨm both remained static, while the ROS production was markedly decreased. Consubstantial results were found when the electron transport chain was inhibited by antimycin A, letting only CytOx remain functional to support the energy production. This seems to corroborate that the decrease in mitochondrial ROS production is solely the effect of ATP binding to CytOx which results in static respiration as well as membrane potential.

LPS-induced changes in immunometabolism and the role of the psychiatric risk gene Cacna1c in microglia logo search Research Study About KU Leuven Download PDF 88th Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT), Date: 2022/03/07 - 2022/03/10, Location: ELECTR NETWORK Publication date: 2022-03-01 Volume: 395 Pages: S57 - S57 Publisher: Springer (part of Springer Nature) Naunyn-Schmiedebergs Archives Of Pharmacology LPS-induced changes in immunometabolism and the role of the psychiatric risk gene Cacna1c in microglia Author: Michels, S Eichberg, J ; Picard, F ; Braun, M ; Kisko, T ; Schwarting, R ; Woehr, M ; Garn, H ; Alferink, J ; Culmsee, C Keywords: Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, 1115 Pharmacology and Pharmaceutical Sciences, 1116 Medical Physiology, 3214 …

PurposePreviously, we have shown that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine), a pharmacological small-conductance calcium-activated potassium (SK)–channel positive modulator, antagonizes lipopolysaccharide (LPS)-induced cytokine expression in microglial cells. Here, we aimed to test its therapeutic potential for brain-controlled sickness symptoms, brain inflammatory response during LPS-induced systemic inflammation, and peripheral metabolic pathways in mice.MethodsMice were pretreated with CyPPA (15 mg/kg IP) 24 hours before and simultaneously with LPS stimulation (2.5 mg/kg IP), and the sickness response was recorded by a telemetric system for 24 hours. A second cohort of mice were euthanized 2 hours after CyPPA or solvent treatment to assess underlying CyPPA-induced mechanisms. Brain, blood, and liver samples were analyzed for inflammatory …

Aim The aim of the present study was to investigate mechanisms by which the Cimicifuga extract Ze 450 regulates mitochondrial metabolism and function under physiological conditions and in the context of menopause and age-related (metabolic) diseases.Method To gain a comprehensive insight into the signaling effects of the extract on the mitochondrial proteome, neuronal HT22 cells were treated with Ze 450 and analyzed by mass spectrometry. Simultaneous measurement of mitochondrial and glycolytic respiration also detected acute effects of the Cimicifuga extract on the mitochondrial energy turnover. MitoPlates™ were used to understand how substrate utilization and metabolic activity are reprogrammed upon treatment.Results Ze 450 extract exerts strong effects on mitochondrial metabolism by reducing substrate utilisation, especially of glutamine and glucose in the TCA cycle. This led to a reduced activity …

Ferroptosis is a form of oxidative cell death that is increasingly recognized as a key mechanism not only in neurodegeneration but also in regulated cell death, causing disease in other tissues. In neurons, major hallmarks of ferroptosis involve the accumulation of lipid reactive oxygen species (ROS) and impairment of mitochondrial morphology and function. Compounds that interfere with ferroptosis could provide novel treatment options for neurodegenerative disorders and other diseases involving ferroptosis. In the present study, we developed new compounds by refining structural elements of the BH3 interacting-domain death agonist inhibitor BI-6c9, which was previously demonstrated to block ferroptosis signaling at the level of mitochondria. Here, we inserted an antioxidative diphenylamine (DPA) structure to the BI-6c9 structure. These DPA compounds were then tested in models of erastin, and Ras-selective …