TY - JOUR A1 - Salvador, Ellaine A1 - Köppl, Theresa A1 - Hörmann, Julia A1 - Schönhärl, Sebastian A1 - Bugaeva, Polina A1 - Kessler, Almuth F. A1 - Burek, Malgorzata A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier JF - Pharmaceutics N2 - In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. KW - blood-brain barrier KW - Tumor-Treating Fields (TTFields) KW - CNS disorders KW - human brain microvascular endothelial cells (HBMVEC) KW - human cells KW - 3D in vitro model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304830 SN - 1999-4923 VL - 15 IS - 1 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Kessler, Almuth F. A1 - Domröse, Dominik A1 - Hörmann, Julia A1 - Schaeffer, Clara A1 - Giniunaite, Aiste A1 - Burek, Malgorzata A1 - Tempel-Brami, Catherine A1 - Voloshin, Tali A1 - Volodin, Alexandra A1 - Zeidan, Adel A1 - Giladi, Moshe A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Förster, Carola Y. A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) reversibly permeabilize the blood–brain barrier in vitro and in vivo JF - Biomolecules N2 - Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. KW - blood–brain barrier KW - TTFields KW - CNS disorders Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288057 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Nowacka-Chmielewska, Marta A1 - Grabowska, Konstancja A1 - Grabowski, Mateusz A1 - Meybohm, Patrick A1 - Burek, Malgorzata A1 - Małecki, Andrzej T1 - Running from stress: neurobiological mechanisms of exercise-induced stress resilience JF - International Journal of Molecular Sciences N2 - Chronic stress, even stress of a moderate intensity related to daily life, is widely acknowledged to be a predisposing or precipitating factor in neuropsychiatric diseases. There is a clear relationship between disturbances induced by stressful stimuli, especially long-lasting stimuli, and cognitive deficits in rodent models of affective disorders. Regular physical activity has a positive effect on the central nervous system (CNS) functions, contributes to an improvement in mood and of cognitive abilities (including memory and learning), and is correlated with an increase in the expression of the neurotrophic factors and markers of synaptic plasticity as well as a reduction in the inflammatory factors. Studies published so far show that the energy challenge caused by physical exercise can affect the CNS by improving cellular bioenergetics, stimulating the processes responsible for the removal of damaged organelles and molecules, and attenuating inflammation processes. Regular physical activity brings another important benefit: increased stress robustness. The evidence from animal studies is that a sedentary lifestyle is associated with stress vulnerability, whereas a physically active lifestyle is associated with stress resilience. Here, we have performed a comprehensive PubMed Search Strategy for accomplishing an exhaustive literature review. In this review, we discuss the findings from experimental studies on the molecular and neurobiological mechanisms underlying the impact of exercise on brain resilience. A thorough understanding of the mechanisms underlying the neuroprotective potential of preconditioning exercise and of the role of exercise in stress resilience, among other things, may open further options for prevention and therapy in the treatment of CNS diseases. KW - stress KW - stress resilience KW - anxiety KW - depression KW - neuropsychiatric disorders KW - physical activity KW - exercise Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297407 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Wend, David A1 - Lauer, Mara J. A1 - Monoranu, Camelia M. A1 - Glas, Martin A1 - Kleinschnitz, Christoph A1 - Ernestus, Ralf-Ingo A1 - Braunger, Barbara M. A1 - Meybohm, Patrick A1 - Hagemann, Carsten A1 - Burek, Malgorzata T1 - Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients JF - International Journal of Molecular Sciences N2 - Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects. KW - glioblastoma multiforme KW - glioma KW - astrocytoma KW - recurrence KW - relapse KW - mRNA KW - protein KW - brain KW - expression KW - PCDHGC3 KW - WNT signaling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284433 SN - 1422-0067 VL - 23 IS - 15 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Reifschläger, Leonie A1 - Strähle, Linus A1 - Feldheim, Jonas A1 - Feldheim, Julia J. A1 - Schmitt, Constanze A1 - Kiesel, Matthias A1 - Herbert, Saskia-Laureen A1 - Wöckel, Achim A1 - Meybohm, Patrick A1 - Burek, Malgorzata T1 - Analysis of microRNAs in exosomes of breast cancer patients in search of molecular prognostic factors in brain metastases JF - International Journal of Molecular Sciences N2 - Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use. KW - breast cancer KW - breast cancer metastases KW - blood-brain barrier KW - patient serum KW - exosomes KW - microRNA KW - gene expression KW - prognostic marker Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284476 SN - 1422-0067 VL - 23 IS - 7 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Kiesel, Ludwig A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Anti-hormonal therapy in breast cancer and its effect on the blood-brain barrier JF - Cancers N2 - Simple Summary Anti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases. Abstract The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer. KW - anti-hormonal therapy KW - brain-metastasis KW - blood-brain barrier KW - breast cancer Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290320 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Sun, Aili A1 - Blecharz-Lang, Kinga G. A1 - Małecki, Andrzej A1 - Meybohm, Patrick A1 - Nowacka-Chmielewska, Marta M. A1 - Burek, Malgorzata T1 - Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro JF - Frontiers in Drug Delivery N2 - The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases. KW - blood-brain barrier KW - microRNA KW - stroke KW - traumatic brain injury KW - tight junctions KW - transporter Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-291423 SN - 2674-0850 VL - 2 ER - TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Löhr, Mario A1 - Nagai, Michiaki A1 - Hagemann, Carsten A1 - Förster, Carola Y. T1 - Senescence and associated blood-brain barrier alterations in vitro JF - Histochemistry and Cell Biology N2 - Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within. KW - senescence KW - in vitro model KW - aging KW - CNS diseases KW - blood–brain barrier Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267435 SN - 1432-119X VL - 156 IS - 3 ER - TY - JOUR A1 - Teles, Ramon Handerson Gomes A1 - Yano, Rafael Sussumu A1 - Villarinho, Nicolas Jones A1 - Yamagata, Ana Sayuri A1 - Jaeger, Ruy Gastaldoni A1 - Meybohm, Patrick A1 - Burek, Malgorzata A1 - Freitas, Vanessa Morais T1 - Advances in breast cancer management and extracellular vesicle research, a bibliometric analysis JF - Current Oncology N2 - Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers. KW - breast cancer KW - metastasis KW - exosomes KW - extracellular vesicles KW - bibliometrics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284321 SN - 1718-7729 VL - 28 IS - 6 SP - 4504 EP - 4520 ER -