5459
2012
eng
article
1
2012-01-30
--
--
Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells
During stroke the blood–brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907% after 6 h OGD and was still higher (210%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells.
urn:nbn:de:bvb:20-opus-67241
6724
Neuroscience Letters (2012) 506, 44– 49; http://dx.doi.org/10.1016/j.neulet.2011.10.045
241778
Deutsches Urheberrecht
Winfried Neuhaus
Malgorzata Burek
Cholpon C Djuzenova
Serge C Thal
Hermann Koepsell
Norbert Roewer
Carola Y Förster
deu
swd
Blut-Hirn-Schranke
deu
swd
Schlaganfall
deu
swd
Glucosetransportproteine
deu
swd
NMDA-Antagonist
deu
swd
NMDA-Rezeptor
eng
uncontrolled
blood-brain barrier
eng
uncontrolled
MK801
eng
uncontrolled
NMDAR
eng
uncontrolled
stroke
eng
uncontrolled
glut1
eng
uncontrolled
sglt1
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5459/Foerster_Neuhaus_NeuroscienceLetters506.pdf
12606
2015
eng
e0137247
9
10
article
1
2016-01-28
--
--
Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation
Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1–4.0% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion
PLoS One
10.1371/journal.pone.0137247
urn:nbn:de:bvb:20-opus-126068
PLoS ONE 10 (9): e0137247. doi:10.1371/journal.pone.0137247
Martin Alexander Schick
Wolfgang Baar
Raphael Romano Bruno
Jakob Wollborn
Christopher Held
Reinhard Schneider
Sven Flemming
Nicolas Schlegel
Norbert Roewer
Winfried Neuhaus
Christian Wunder
eng
uncontrolled
colloids
eng
uncontrolled
kidneys
eng
uncontrolled
histopathology
eng
uncontrolled
blood
eng
uncontrolled
creatinine
eng
uncontrolled
sepsis
eng
uncontrolled
urine
eng
uncontrolled
inflammation
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Medizinische Klinik und Poliklinik I
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12606/Schick_journal.pone.0137247.pdf
12547
2015
eng
e0136221
8
10
article
1
2016-01-26
--
--
Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups
Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.
PLoS One
10.1371/journal.pone.0136221
urn:nbn:de:bvb:20-opus-125471
PLoS ONE 10(8): e0136221. doi:10.1371/journal.pone.0136221
241778
Winfried Neuhaus
Marian Schlundt
Markus Fehrholz
Alexander Ehrke
Steffen Kunzmann
Stefan Liebner
Christian P. Speer
Carola Y. Förster
eng
uncontrolled
endothelial cells
eng
uncontrolled
protein expression
eng
uncontrolled
central nervous system
eng
uncontrolled
mouse models
eng
uncontrolled
pregnancy
eng
uncontrolled
tight junctions
eng
uncontrolled
sheep
eng
uncontrolled
angiogenesis
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12547/journal.pone.0136221.pdf
11829
2014
eng
352
8
article
1
2015-08-21
--
--
The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier
Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro.
Frontiers in Cellular Neuroscience
10.3389/fncel.2014.00352
1662-5102
urn:nbn:de:bvb:20-opus-118297
Frontiers in Cellular Neuroscience 8:352. doi:10.3389/fncel.2014.00352
241778
Winfried Neuhaus
Fabian Gaiser
Anne Mahringer
Jonas Franz
Christoph Riethmüller
Carola Förster
eng
uncontrolled
oxygen/glucose deprivation
eng
uncontrolled
ischemia
eng
uncontrolled
traumatic brain injury
eng
uncontrolled
cerebEND
eng
uncontrolled
C6
eng
uncontrolled
stroke
eng
uncontrolled
in vitro
eng
uncontrolled
blood-brain barrier
Humanphysiologie
open_access
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11829/017_Neuhaus_Frontiers_in_Cellular_Neuroscience.pdf
11999
2014
eng
e86806
1
9
article
1
2015-10-08
--
--
Transport Rankings of Non-Steroidal Antiinflammatory Drugs across Blood-Brain Barrier In Vitro Models
The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison.
PLoS ONE
10.1371/journal.pone.0086806
urn:nbn:de:bvb:20-opus-119992
PLoS ONE 9(1): e86806. doi:10.1371/journal.pone.0086806
Iveta Novakova
Eva-Anne Subileau
Stefan Toegel
Daniela Gruber
Bodo Lachmann
Ernst Urban
Christophe Chesne
Christian R. Noe
Winfried Neuhaus
eng
uncontrolled
NSAIDs
eng
uncontrolled
astrocytes
eng
uncontrolled
transport inhibition assay
eng
uncontrolled
drug-drug interactions
eng
uncontrolled
diazepam
eng
uncontrolled
permeability
eng
uncontrolled
glioma
eng
uncontrolled
scanning electron microscopy
Humanphysiologie
open_access
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11999/068_Novakova_PLOS_ONE.pdf
9028
2012
eng
294-304
4
84
article
1
--
--
--
Lung endothelial cells strengthen, but brain endothelial cells weaken barrier properties of a human alveolar epithelium cell culture model
The blood-air barrier in the lung consists of the alveolar epithelium, the underlying capillary endothelium, their basement membranes and the interstitial space between the cell layers. Little is known about the interactions between the alveolar and the blood compartment. The aim of the present study was to gain first insights into the possible interplay between these two neighboured cell layers. We established an in vitro Transwell model of the alveolar epithelium based on human cell line H441 and investigated the influence of conditioned medium obtained from human lung endothelial cell line HPMEC-ST1.6R on the barrier properties of the H441 layers. As control for tissue specificity H441 layers were exposed to conditioned medium from human brain endothelial cell line hCMEC/D3. Addition of dexamethasone was necessary to obtain stable H441 cell layers. Moreover, dexamethasone increased expression of cell type I markers (caveolin-1, RAGE) and cell type II marker SP-B, whereas decreased the transepithelial electrical resistance (TEER) in a concentration dependent manner. Soluble factors obtained from the lung endothelial cell line increased the barrier significantly proven by TEER values and fluorescein permeability on the functional level and by the differential expression of tight junctional proteins on the molecular level. In contrast to this, soluble factors derived from brain endothelial cells weakened the barrier significantly. In conclusion, soluble factors from lung endothelial cells can strengthen the alveolar epithelium barrier in vitro, which suggests communication between endothelial and epithelial cells regulating the integrity of the blood-air barrier.
Differentiation
10.1016/j.diff.2012.08.006
http://www.sciencedirect.com/science/article/pii/S0301468112001144
23023065
urn:nbn:de:bvb:20-opus-90284
Department of Medicinal Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
Differentiation 2012 Nov 84(4):294-304. doi: 10.1016/j.diff.2012.08.006
241778
Deutsches Urheberrecht
Winfried Neuhaus
Fabian Samwer
Steffen Kunzmann
Ralph Muellenbach
Michael Wirth
Christian P. Speer
Norbert Roewer
Carola Förster
eng
uncontrolled
alveolar epithelium in vitro model, claudin-1, claudin-3, claudin-4, claudin-5
Medizin und Gesundheit
open_access
Kinderklinik und Poliklinik
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9028/Differentiation-Manuscriptaccepted-OPUSopenaccess.pdf
14826
2015
eng
e0136221
8
10
article
1
2017-05-10
--
--
Multiple antenatal dexamethasone treatment alters brain vessel differentiation in newborn mouse pups
Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.
PLoS ONE
10.1371/journal.pone.0136221
urn:nbn:de:bvb:20-opus-148268
PLoS ONE 10(8): e0136221 (2015). DOI: 10.1371/journal.pone.0136221
HEALTH-F2-2009-241778
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Winfried Neuhaus
Marian Schlundt
Markus Fehrholz
Alexander Ehrke
Steffen Kunzmann
Stefan Liebner
Christian P. Speer
Carola Y. Förster
eng
uncontrolled
preterm birth
eng
uncontrolled
fetal lung
eng
uncontrolled
corticosteroids
eng
uncontrolled
glucocorticoids
eng
uncontrolled
exposure
eng
uncontrolled
endothelial cells
eng
uncontrolled
in vitro
eng
uncontrolled
barrier
eng
uncontrolled
expression
eng
uncontrolled
rat
Gynäkologie, Geburtsmedizin, Pädiatrie, Geriatrie
open_access
Kinderklinik und Poliklinik
Klinik und Poliklinik für Anästhesiologie (ab 2004)
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14826/008_Neuhaus_PLoS_ONE.PDF
21942
2020
eng
23
17
article
1
--
2020-11-27
--
Assessment of human health risks posed by nano-and microplastics is currently not feasible
The exposure of humans to nano-and microplastic particles (NMPs) is an issue recognized as a potential health hazard by scientists, authorities, politics, non-governmental organizations and the general public. The concentration of NMPs in the environment is increasing concomitantly with global plastic production and the usage of plastic materials. NMPs are detectable in numerous aquatic organisms and also in human samples, therefore necessitating a risk assessment of NMPs for human health. So far, a comprehensive risk assessment of NMPs is hampered by limited availability of appropriate reference materials, analytical obstacles and a lack of definitions and standardized study designs. Most studies conducted so far used polystyrene (PS) spheres as a matter of availability, although this polymer type accounts for only about 7% of total plastic production. Differently sized particles, different concentration and incubation times, and various biological models have been used, yielding hardly comparable data sets. Crucial physico-chemical properties of NMPs such as surface (charge, polarity, chemical reactivity), supplemented additives and adsorbed chemicals have been widely excluded from studies, although in particular the surface of NMPs determines the interaction with cellular membranes. In this manuscript we give an overview about the critical parameters which should be considered when performing risk assessments of NMPs, including novel reference materials, taking into account surface modifications (e.g., reflecting weathering processes), and the possible role of NMPs as a substrate and/or carrier for (pathogenic) microbes. Moreover, we make suggestions for biological model systems to evaluate immediate toxicity, long-term effects and the potential of NMPs to cross biological barriers. We are convinced that standardized reference materials and experimental parameters along with technical innovations in (nano)-particle sampling and analytics are a prerequisite for the successful realization of conclusive human health risk assessments of NMPs.
International Journal of Environmental Research and Public Health
1660-4601
10.3390/ijerph17238832
urn:nbn:de:bvb:20-opus-219423
2020-12-18T18:39:12+00:00
sword
swordwue
attachment; filename=deposit.zip
7aee1cb00be7e7cf79c69a904ffab254
International Journal of Environmental Research and Public Health (2020) 17:23, 8832. https://doi.org/10.3390/ijerph17238832
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Andreas Brachner
Despina Fragouli
Iola F. Duarte
Patricia M. A. Farias
Sofia Dembski
Manosij Ghosh
Ivan Barisic
Daniela Zdzieblo
Jeroen Vanoirbeek
Philipp Schwabl
Winfried Neuhaus
eng
uncontrolled
nanoplastics
eng
uncontrolled
nanoparticles
eng
uncontrolled
microplastics
eng
uncontrolled
microparticles
eng
uncontrolled
human exposure
eng
uncontrolled
biological barriers
eng
uncontrolled
biofilm
eng
uncontrolled
microbe carrier
eng
uncontrolled
toxicity
eng
uncontrolled
neurotoxicity
Medizin und Gesundheit
open_access
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21942/ijerph-17-08832.pdf
17098
2017
eng
894-906
4
8
article
1
2018-11-02
--
--
Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells
In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Ω cm\(^{2}\) and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.
Stem Cell Reports
10.1016/j.stemcr.2017.02.021
28344002
urn:nbn:de:bvb:20-opus-170982
Stem Cell Reports 2017, 8(4), 894-906. DOI: 10.1016/j.stemcr.2017.02.021
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Antje Appelt-Menzel
Alevtina Cubukova
Katharina Günther
Frank Edenhofer
Jörg Piontek
Gerd Krause
Tanja Stüber
Heike Walles
Winfried Neuhaus
Marco Metzger
eng
uncontrolled
blood-brain barrier (BBB) model
eng
uncontrolled
human induced pluripotent stem cells (hiPSCs)human induced pluripotent stem cells (hiPSCs)
eng
uncontrolled
multipotent fetal neural stem cells (fNSCs)
eng
uncontrolled
neurovascular unit in vitro
Medizin und Gesundheit
open_access
Frauenklinik und Poliklinik
Institut für Anatomie und Zellbiologie
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17098/082_Appelt-Menzelt_STEM-CELL-RESEARCH.pdf
14933
2015
eng
13-23
1
6
article
1
2017-05-24
--
--
Phosphodiesterase-4 inhibition with rolipram attenuates hepatocellular injury in hyperinflammation in vivo and in vitro without influencing inflammation and HO-1 expression
Objective: To investigate the impact of the phophodiesterase-4 inhibition (PD-4-I) with rolipram on hepatic integrity in lipopolysaccharide (LPS) induced hyperinflammation. Materials and Methods: Liver microcirculation in rats was obtained using intravital microscopy. Macrohemodynamic parameters, blood assays, and organs were harvested to determine organ function and injury. Hyperinflammation was induced by LPS and PD-4-I rolipram was administered intravenously one hour after LPS application. Cell viability of HepG2 cells was measured by EZ4U-kit based on the dye XTT. Experiments were carried out assessing the influence of different concentrations of tumor necrosis factor alpha (TNF-α) and LPS with or without PD-4-I. Results: Untreated LPS-induced rats showed significantly decreased liver microcirculation and increased hepatic cell death, whereas LPS + PD-4-I treatment could improve hepatic volumetric flow and cell death to control level whithout influencing the inflammatory impact. In HepG2 cells TNF-α and LPS significantly reduced cell viability. Coincubation with PD-4-I increased HepG2 viability to control levels. The heme oxygenase 1 (HO-1) pathway did not induce the protective effect of PD-4-I. Conclusion: Intravenous PD-4-I treatment was effective in improving hepatic microcirculation and hepatic integrity, while it had a direct protective effect on HepG2 viability during inflammation.
Journal of Pharmacology and Pharmacotherapeutics
10.4103/0976-500X.149138
urn:nbn:de:bvb:20-opus-149336
Journal of Pharmacology and Pharmacotherapeutics 2015, 6(1), 13-23. DOI: 10.4103/0976-500X.149138
CC BY-NC-SA: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Weitergabe unter gleichen Bedingungen 4.0 International
Jakob Wollborn
Christian Wunder
Jana Stix
Winfried Neuhaus
Rapahel R. Bruno
Wolfgang Baar
Sven Flemming
Norbert Roewer
Nicolas Schlegel
Martin A. Schick
eng
uncontrolled
acute liver failure
eng
uncontrolled
endotoxemia
eng
uncontrolled
phosphodiesterase
eng
uncontrolled
rolipram
eng
uncontrolled
sepsis
Krankheiten
open_access
Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Universität Würzburg
21850
2020
eng
1
55
article
1
--
--
--
Human iPSC‐Derived Blood‐Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development?
Translating basic biological knowledge into applications remains a key issue for effectively tackling neurodegenerative, neuroinflammatory, or neuroendocrine disorders. Efficient delivery of therapeutics across the neuroprotective blood‐brain barrier (BBB) still poses a demanding challenge for drug development targeting central nervous system diseases. Validated in vitro models of the BBB could facilitate effective testing of drug candidates targeting the brain early in the drug discovery process during lead generation. We here review the potential of mono‐ or (isogenic) co‐culture BBB models based on brain capillary endothelial cells (BCECs) derived from human‐induced pluripotent stem cells (hiPSCs), and compare them to several available BBB in vitro models from primary human or non‐human cells and to rodent in vivo models, as well as to classical and widely used barrier models [Caco‐2, parallel artificial membrane permeability assay (PAMPA)]. In particular, we are discussing the features and predictivity of these models and how hiPSC‐derived BBB models could impact future discovery and development of novel CNS‐targeting therapeutics.
Current Protocols in Stem Cell Biology
10.1002/cpsc.122
urn:nbn:de:bvb:20-opus-218509
2020-12-07T15:07:23+00:00
sword
swordwue
attachment; filename=deposit.zip
c087f8b78220cee285f9dd0fbe88b535
Current Protocols in Stem Cell Biology 2020, 55(1), e122. DOI: 10.1002/cpsc.122
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Antje Appelt‐Menzel
Sabrina Oerter
Sanjana Mathew
Undine Haferkamp
Carla Hartmann
Matthias Jung
Winfried Neuhaus
Ole Pless
eng
uncontrolled
blood‐brain barrier (BBB)
eng
uncontrolled
CNS disease
eng
uncontrolled
drug permeability screening
eng
uncontrolled
human‐induced pluripotent stem cells (hiPSC)
eng
uncontrolled
preclinical drug discovery
Biowissenschaften; Biologie
open_access
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21850/CPSC_CPSC122.pdf
29037
2022
eng
20
11
article
1
--
2022-10-19
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A human stem cell-derived brain-liver chip for assessing blood-brain-barrier permeation of pharmaceutical drugs
Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood–brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.
Cells
2073-4409
10.3390/cells11203295
urn:nbn:de:bvb:20-opus-290375
2022-11-04T10:55:15+00:00
sword
swordwue
attachment; filename=deposit.zip
5ce4e704914e2993e3653d29386c7d5f
Cells (2022) 11:20, 3295. https://doi.org/10.3390/cells11203295
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true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Leopold Koenig
Anja Patricia Ramme
Daniel Faust
Manuela Mayer
Tobias Flötke
Anna Gerhartl
Andreas Brachner
Winfried Neuhaus
Antje Appelt-Menzel
Marco Metzger
Uwe Marx
Eva-Maria Dehne
eng
uncontrolled
blood-brain barrier (BBB) model
eng
uncontrolled
human induced pluripotent stem cells (hiPSCs)
eng
uncontrolled
microphysiological systems (MPS)
eng
uncontrolled
multi-organ chip
eng
uncontrolled
brain–liver chip
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Lehrstuhl für Tissue Engineering und Regenerative Medizin
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/29037/cells-11-03295-v2.pdf