0000000000206930
AUTHOR
Jana Hedrich
showing 13 related works from this author
Volatile Anesthetics Influence Blood-Brain Barrier Integrity by Modulation of Tight Junction Protein Expression in Traumatic Brain Injury
2012
Disruption of the blood-brain barrier (BBB) results in cerebral edema formation, which is a major cause for high mortality after traumatic brain injury (TBI). As anesthetic care is mandatory in patients suffering from severe TBI it may be important to elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ) such as zonula occludens-1 (ZO-1) and claudin-5 (cl5) play a central role for BBB stability. First, the influence of the volatile anesthetics sevoflurane and isoflurane on in-vitro BBB integrity was investigated by quantification of the electrical resistance (TEER) in murine brain endothelial monolayers and neurovascular co-cultures of the B…
A Polyphenylene Dendrimer Drug Transporter with Precisely Positioned Amphiphilic Surface Patches
2014
The design and synthesis of a polyphenylene dendrimer (PPD 3) with discrete binding sites for lipophilic guest molecules and characteristic surface patterns is presented. Its semi-rigidity in combination with a precise positioning of hydrophilic and hydrophobic groups at the periphery yields a refined architecture with lipophilic binding pockets that accommodate defined numbers of biologically relevant guest molecules such as fatty acids or the drug doxorubicin. The size, architecture, and surface textures allow to even penetrate brain endothelial cells that are a major component of the extremely tight blood-brain barrier. In addition, low to no toxicity is observed in in vivo studies using…
The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10
2012
The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin…
Demethylation treatment restores hic1 expression and impairs aggressiveness of head and neck squamous cell carcinoma.
2010
Promoter hypermethylation of tumor suppressor genes is a common feature of primary cancer cells. However, at date the somatic epigenetic events that occur in head and neck squamous cell carcinoma (HNSCC) tumorigenesis are not yet been well defined. In the present study we analysed the methylation status of the gene hypermethylated in cancer-1 (hic1), a gene located on chromosome 17p13.3, a region frequently lost in HNSCC. We analysed 22 HNSCC samples and three cell lines using methylation specific PCR (MSP). We found hic1 methylated in 21 out of 22 samples and in all three cell lines. Treatment of the cell lines with the demethylating agent 5-Azacytidin (5-Aza) resulted in the demethylation…
Cell type specific impact of cannabinoid receptor signaling in somatosensory barrel map formation in mice
2019
Endocannabinoids and their receptors are highly abundant in the developing cerebral cortex and play major roles in early developmental processes, for example, neuronal proliferation, migration, and axonal guidance as well as postnatal plasticity. To investigate the role of the cannabinoid type 1 receptor (CB1) in the formation of sensory maps in the cerebral cortex, the topographic representation of the whiskers in the primary somatosensory cortex (barrel field) of adult mice with different cell type specific genetic deletion of CB1 was studied. A constitutive absence of CB1 (CB1-KO) significantly decreased the total area of the somatosensory cortical map, affecting barrel, and septal areas…
A Neurovascular Blood–Brain Barrier In Vitro Model
2014
The cerebral microvasculature possesses certain cellular features that constitute the blood-brain barrier (BBB) (Abbott et al., Neurobiol Dis 37:13-25, 2010). This dynamic barrier separates the brain parenchyma from peripheral blood flow and is of tremendous clinical importance: for example, BBB breakdown as in stroke is associated with the development of brain edema (Rosenberg and Yang, Neurosurg Focus 22:E4, 2007), inflammation (Kuhlmann et al., Neurosci Lett 449:168-172, 2009; Coisne and Engelhardt, Antioxid Redox Signal 15:1285-1303, 2011), and increased mortality. In vivo, the BBB consists of brain endothelial cells (BEC) that are embedded within a precisely regulated environment conta…
Polymer Complexes in Biological Applications
2013
This chapter summarizes the influence of polyelectrolyte topology on biological functions and biomedical applications such as cell uptake, drug delivery, and gene transfection. Polyelectrolytes utilized are spherical structures derived from dendrimers and albumin or cylindrical brushes, all of which are decorated with various polypeptide chains.
Unraveling In vivo brain transport of protein‐coated fluorescent nanodiamonds
2019
The blood–brain barrier is the biggest hurdle to overcome for the treatment of neurological disorders. Here, protein‐coated nanodiamonds are delivered to the brain and taken up by neurovascular unit cells after intravenous injection. Thus, for the first time, nanodiamonds with their unique properties and a flexible protein coating for the attachment of therapeutics emerge as a potential platform for nanotheranostics of neurological disorders.Nanotheranostics, combining diagnostics and therapy, has the potential to revolutionize treatment of neurological disorders. But one of the major obstacles for treating central nervous system diseases is the blood–brain barrier (BBB) preventing systemic…
Fetuin-A and Cystatin C Are Endogenous Inhibitors of Human Meprin Metalloproteases
2010
Meprin α and β, zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1β, interleukin 18, or tumor growth factor α. Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin α and a K(i) of 1.1 × 10(-6) M meprin β. This correlated with data obtained for a fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin α and β…
Increased basic fibroblast growth factor release and proliferation in xenotransplanted squamous cell carcinoma after combined irradiation/anti-vascul…
2012
Novel strategies of cancer therapy combine irradiation and anti-angiogenic active compounds. However, little is known concerning the undesired cellular and molecular effects caused by this novel treatment concept. We used a mouse squamous cell carcinoma (SCC) xenotransplantation model to evaluate the potential undesired effects which compromise the success of this therapeutic combination. SCCs were subcutanously implanted in nude mice. Animals were treated with a fractionated irradiation scheme (5x4 Gy) alone or in combination with daily injections of anti-vascular endothelial growth factor (VEGF) antibodies. Controls remained untreated. Before and after treatment, resonance imaging (MRI), …
Let it flow: Morpholino knockdown in zebrafish embryos reveals a pro-angiogenic effect of the metalloprotease meprin alpha2.
2010
BACKGROUND: Meprin metalloproteases are thought to be involved in basic physiological functions such as cell proliferation and tissue differentiation. However, the specific functions of these enzymes are still ambiguous, although a variety of growth factors and structural proteins have been identified as meprin substrates. The discovery of meprins alpha(1), alpha(2) and beta in teleost fish provided the basis for uncovering their physiological functions by gene silencing in vivo. METHODOLOGY/PRINCIPAL FINDINGS: A Morpholino knockdown in zebrafish embryos targeting meprin alpha(1) and beta mRNA caused defects in general tissue differentiation. But meprin alpha(2) morphants were affected more…
Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates
2018
Abstract Neurological disorders are undoubtedly among the most alarming diseases humans might face. In treatment of neurological disorders, the blood‐brain barrier (BBB) is a challenging obstacle preventing drug penetration into the brain. Advances in dendrimer chemistry for central nervous system (CNS) treatments are presented here. A poly(amido)amine (PAMAM) dendrimer bioconjugate with a streptavidin adapter for the attachment of dendrons or any biotinylated drug is constructed. In vitro studies on porcine or murine models and in vivo mouse studies are performed and reveal the permeation of dendronized streptavidin (DSA) into the CNS. The bioconjugate is taken up mainly by the caveolae pa…
Deficiency of Plasminogen Activator Inhibitor Type 2 Limits Brain Edema Formation after Traumatic Brain Injury
2019
Plasminogen activator inhibitor-2 (PAI-2/SerpinB2) inhibits extracellular urokinase plasminogen activator (uPA). Under physiological conditions, PAI-2 is expressed at low levels but is rapidly induced by inflammatory triggers. It is a negative regulator of fibrinolysis and serves to stabilize clots. In the present study, PAI-2 expression is upregulated 25-fold in pericontusional brain tissue at 6 h after traumatic brain injury (TBI), with a maximum increase of 87-fold at 12 h. To investigate a potentially detrimental influence of PAI-2 on secondary post-traumatic processes, male PAI-2-deficient (PAI-2-KO) and wild-type mice (WT) were subjected to TBI by controlled cortical impact injury. Br…