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  1. Article ; Online: Editorial (Thematic Issue: Pharmacological Targeting of Biological Barriers).

    Wilhelm, Imola

    Current pharmaceutical design

    2016  Volume 22, Issue 35, Page(s) 5311–5312

    MeSH term(s) Drug Delivery Systems ; Pharmaceutical Preparations
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2016-07-01
    Publishing country United Arab Emirates
    Document type Editorial
    ZDB-ID 1304236-1
    ISSN 1873-4286 ; 1381-6128
    ISSN (online) 1873-4286
    ISSN 1381-6128
    DOI 10.2174/1381612822666160826122402
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Breast adenocarcinoma cells adhere stronger to brain pericytes than to endothelial cells.

    Csonti, Katalin / Fazakas, Csilla / Molnár, Kinga / Wilhelm, Imola / Krizbai, István A / Végh, Attila G

    Colloids and surfaces. B, Biointerfaces

    2024  Volume 234, Page(s) 113751

    Abstract: Most of the malignancies detected within the brain parenchyma are of metastatic origin. As the brain lacks classical lymphatic circulation, the primary way for metastasis relies on hematogenous routes. Dissemination of metastatic cells to the brain ... ...

    Abstract Most of the malignancies detected within the brain parenchyma are of metastatic origin. As the brain lacks classical lymphatic circulation, the primary way for metastasis relies on hematogenous routes. Dissemination of metastatic cells to the brain implies attachment to the luminal surface of brain endothelial cells, transmigration through the vessel wall, and adhesion to the brain surface of the vasculature. During this process, tumor cells must interact with brain endothelial cells and later on with pericytes. Physical interaction between tumor cells and brain vascular cells might be crucial in the successful extravasation of metastatic cells through blood vessels and later in their survival within the brain environment. Therefore, we applied single-cell force spectroscopy to investigate the nanoscale adhesive properties of living breast adenocarcinoma cells to brain endothelial cells and pericytes. We found target cell type-dependent adhesion characteristics, i.e. increased adhesion of the tumor cells to pericytes in comparison to endothelial cells, which underlines the existence of metastatic potential-related nanomechanical differences relying partly on membrane tether dynamics. Varying adhesion strength of the tumor cells to different cell types of brain vessels presumably reflects the transitory adhesion to endothelial cells before extravasation and the long-lasting strong interaction with pericytes during survival and proliferation in the brain. Our results highlight the importance of specific mechanical interactions between tumor cells and host cells during metastasis formation.
    MeSH term(s) Humans ; Endothelial Cells ; Pericytes ; Brain/pathology ; Endothelium ; Adenocarcinoma/metabolism
    Language English
    Publishing date 2024-01-11
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1500523-9
    ISSN 1873-4367 ; 0927-7765
    ISSN (online) 1873-4367
    ISSN 0927-7765
    DOI 10.1016/j.colsurfb.2024.113751
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Editorial: Targeting Neuro-Immuno-Vascular Interactions in the Brain and the Periphery.

    Wilhelm, Imola / Krizbai, István A / Gherghiceanu, Mihaela / Szőke, Éva / Helyes, Zsuzsanna

    Frontiers in pharmacology

    2022  Volume 13, Page(s) 893384

    Language English
    Publishing date 2022-04-26
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2022.893384
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development.

    Mészáros, Ádám / Molnár, Kinga / Fazakas, Csilla / Nógrádi, Bernát / Lüvi, Adél / Dudás, Tamás / Tiszlavicz, László / Farkas, Attila Elek / Krizbai, István Adorján / Wilhelm, Imola

    Acta neuropathologica communications

    2023  Volume 11, Issue 1, Page(s) 155

    Abstract: Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 ... ...

    Abstract Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases.
    MeSH term(s) Humans ; Animals ; Mice ; Inflammasomes ; Astrocytes ; Triple Negative Breast Neoplasms ; NLR Family, Pyrin Domain-Containing 3 Protein ; Brain Neoplasms ; Indenes ; Sulfonamides/pharmacology ; Tumor Microenvironment
    Chemical Substances Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Indenes ; Sulfonamides
    Language English
    Publishing date 2023-09-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-023-01646-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury.

    Molnár, Kinga / Nógrádi, Bernát / Kristóf, Rebeka / Mészáros, Ádám / Pajer, Krisztián / Siklós, László / Nógrádi, Antal / Wilhelm, Imola / Krizbai, István A

    Journal of neuroinflammation

    2022  Volume 19, Issue 1, Page(s) 68

    Abstract: Background: Peripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to ... ...

    Abstract Background: Peripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to understand how inflammasomes participate in central inflammatory reactions accompanying peripheral nerve injury.
    Methods: After axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing.
    Results: In the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4-L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels.
    Conclusions: Our results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.
    MeSH term(s) Humans ; Inflammasomes/metabolism ; Motor Neurons/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neuroinflammatory Diseases ; Peripheral Nerve Injuries ; Sciatic Nerve/injuries
    Chemical Substances Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein
    Language English
    Publishing date 2022-03-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-022-02427-9
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  6. Article ; Online: miRNAs in Health and Disease

    Marta Sereno / Mafalda Videira / Imola Wilhelm / István A. Krizbai / Maria Alexandra Brito

    Cells, Vol 9, Iss 1790, p

    A Focus on the Breast Cancer Metastatic Cascade towards the Brain

    2020  Volume 1790

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the- ... ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the-art review summarizes the current knowledge about miRNAs and illustrates their role as powerful regulators of physiological processes. Moreover, it highlights their aberrant expression in disease, including specific cancer types and the differential hosting-metastases preferences that influence several steps of tumorigenesis. Considering the incidence of breast cancer and that the metastatic disease is presently the major cause of death in women, emphasis is put in the role of miRNAs in breast cancer and in the regulation of the different steps of the metastatic cascade. Furthermore, we depict their involvement in the cascade of events underlying breast cancer brain metastasis formation and development. Collectively, this review shall contribute to a better understanding of the uniqueness of the biologic roles of miRNAs in these processes, to the awareness of miRNAs as new and reliable biomarkers and/or of therapeutic targets, which can change the landscape of a poor prognosis and low survival rates condition of advanced breast cancer patients.
    Keywords biomarkers ; blood–brain barrier ; brain metastases ; breast cancer ; metastatic cascade ; microRNAs ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: miRNAs in Health and Disease: A Focus on the Breast Cancer Metastatic Cascade towards the Brain.

    Sereno, Marta / Videira, Mafalda / Wilhelm, Imola / Krizbai, István A / Brito, Maria Alexandra

    Cells

    2020  Volume 9, Issue 8

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the- ... ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the-art review summarizes the current knowledge about miRNAs and illustrates their role as powerful regulators of physiological processes. Moreover, it highlights their aberrant expression in disease, including specific cancer types and the differential hosting-metastases preferences that influence several steps of tumorigenesis. Considering the incidence of breast cancer and that the metastatic disease is presently the major cause of death in women, emphasis is put in the role of miRNAs in breast cancer and in the regulation of the different steps of the metastatic cascade. Furthermore, we depict their involvement in the cascade of events underlying breast cancer brain metastasis formation and development. Collectively, this review shall contribute to a better understanding of the uniqueness of the biologic roles of miRNAs in these processes, to the awareness of miRNAs as new and reliable biomarkers and/or of therapeutic targets, which can change the landscape of a poor prognosis and low survival rates condition of advanced breast cancer patients.
    MeSH term(s) Blood-Brain Barrier/metabolism ; Breast Neoplasms/genetics ; Female ; Humans ; MicroRNAs/metabolism ; Neoplasm Metastasis
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2020-07-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9081790
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  8. Article ; Online: In vitro models of the blood-brain barrier for the study of drug delivery to the brain.

    Wilhelm, Imola / Krizbai, István A

    Molecular pharmaceutics

    2014  Volume 11, Issue 7, Page(s) 1949–1963

    Abstract: The most important obstacle to the drug delivery into the brain is the presence of the blood-brain barrier, which limits the traffic of substances between the blood and the nervous tissue. Therefore, adequate in vitro models need to be developed in order ...

    Abstract The most important obstacle to the drug delivery into the brain is the presence of the blood-brain barrier, which limits the traffic of substances between the blood and the nervous tissue. Therefore, adequate in vitro models need to be developed in order to characterize the penetration properties of drug candidates into the central nervous system. This review article summarizes the presently used and the most promising in vitro BBB models based on the culture of brain endothelial cells. Robust models can be obtained using primary porcine brain endothelial cells and rodent coculture models, which have low paracellular permeability and express functional efflux transporters, showing good correlation of drug penetration data with in vivo results. Models mimicking the in vivo anatomophysiological complexity of the BBB are also available, including triple coculture (culture of brain endothelial cells in the presence of pericytes and astrocytes), dynamic, and microfluidic models; however, these are not suitable for rapid, high throughput studies. Potent human cell lines would be needed for easily available and reproducible models which avoid interspecies differences.
    MeSH term(s) Animals ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems/methods ; Endothelial Cells/metabolism ; Humans ; In Vitro Techniques/methods ; Models, Biological ; Permeability ; Pharmaceutical Preparations/metabolism
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2014-07-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/mp500046f
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    In stock of ZB MED Cologne/Königswinter

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  9. Article: SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood-Brain Barrier.

    Molnár, Kinga / Lőrinczi, Bálint / Fazakas, Csilla / Szatmári, István / Fülöp, Ferenc / Kmetykó, Noémi / Berkecz, Róbert / Ilisz, István / Krizbai, István A / Wilhelm, Imola / Vécsei, László

    Pharmaceutics

    2021  Volume 13, Issue 1

    Abstract: By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the ... ...

    Abstract By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood-brain barrier. One possibility to overcome this problem is to use analogues with similar biological activity as kynurenic acid, but with an increased permeability through the blood-brain barrier. We synthesized six novel aminoalkylated amide derivatives of kynurenic acid, among which SZR-104 (
    Language English
    Publishing date 2021-01-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics13010061
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  10. Article ; Online: Neurovascular Inflammaging in Health and Disease.

    Mészáros, Ádám / Molnár, Kinga / Nógrádi, Bernát / Hernádi, Zsófia / Nyúl-Tóth, Ádám / Wilhelm, Imola / Krizbai, István A

    Cells

    2020  Volume 9, Issue 7

    Abstract: Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network ... ...

    Abstract Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.
    MeSH term(s) Aging/metabolism ; Aging/pathology ; Animals ; Humans ; Inflammasomes/metabolism ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Signal Transduction ; Stroke/metabolism ; Stroke/pathology
    Chemical Substances Inflammasomes
    Language English
    Publishing date 2020-07-04
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9071614
    Database MEDical Literature Analysis and Retrieval System OnLINE

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