An important hallmark of Alzheimer's disease (AD) is the increase of Aβ1-42 burden and its accumulation to senile plaques, leading the reactive gliosis and neurodegeneration. The modulation of glia ...cell function represents an attractive therapeutic strategy, but is currently limited by an incomplete understanding of its relevance for AD. The chemotactic G-protein coupled formyl peptide receptor (FPR), which is known to modulate Aβ1-42 uptake and signal transduction, might be one candidate molecule regulating glia function in AD. Here, we investigate whether the modulation of FPR exerts beneficial effects in an AD preclinical model.
To address this question, APP/PS1 double-transgenic AD mice were treated for 20 weeks with either the pro-inflammatory FPR agonist fMLF, the FPR1/2 antagonist Boc2 or the anti-inflammatory FPR2 agonist Ac2-26. Spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining, gene expression studies, and flow cytometry analyses were performed to study neuronal loss, gliosis, and Aß-load in the hippocampus and cortex, respectively.
FPR antagonism by Boc2-treatment significantly improved spatial memory performance, reduced neuronal pathology, induced the expression of homeostatic growth factors, and ameliorated microglia, but not astrocyte, reactivity. Furthermore, the elevated levels of amyloid plaques in the hippocampus were reduced by Boc2-treatment, presumably by an induction of amyloid degradation.
We suggest that the modulation of FPR signaling cascades might be considered as a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Additional studies are now needed to address the downstream effectors as well as the safety profile of Boc2.
The Nrf2 signaling pathway prevents cancer initiation, but genetic mutations that activate this pathway are found in various types of cancer. The molecular mechanisms underlying this Janus-headed ...character are still not understood. Here, we show that sustained Nrf2 activation induces proliferation and dedifferentiation of a Wnt-responsive perivenular hepatic progenitor cell population, transforming them into metastatic cancer cells. The neoplastic lesions display many histological features known from human hepatoblastoma. We describe an Nrf2-induced upregulation of β-catenin expression and its activation as the underlying mechanism for the observed malignant transformation. Thus, we have identified the Nrf2–β-catenin axis promoting proliferation of hepatic stem cells and triggering tumorigenesis. These findings support the concept that different functional levels of Nrf2 control both the protection against various toxins as well as liver regeneration by activating hepatic stem cells. Activation of the hepatic stem cell compartment confers the observation that unbridled Nrf2 activation may trigger tumorigenesis.
It is time for a new approach to nineteenth-century interactions between literary texts and practices of consumption. Instead of treating antebellum America and the century's turn as two discrete ...periods, the editors aim for a more flexible framework. They propose reading Progressive Era classics side by side with literary and popular texts exploring – and feeding – the flow of commodities long before Theodore Dreiser portrayed department stores. Discussing the intricate relationships of mass consumption and literary representation, European and North American contributors focus on Nathaniel Hawthorne, William Dean Howells, Henry James, Mark Twain, Paul Laurence Dunbar, and Edith Wharton. They also turn to less securely canonized fields: New England 'factory girl' literature, multimedia abolitionist spectacle, and the formative years of literary tourism.
Superhero narratives have always been deeply entangled with questions of justice, and their characters, crisis situations, and narrative solutions have changed in close relationship with the ...socio-historic contexts they responded to. Hence, the article argues, it is fruitful to read current superhero movies as both reflections of and comments on the post-9/11 legal and political landscape characterized by an ongoing state of exception and the resulting suspension of certain laws and civil rights. Analyzing Suicide Squad, Batman v Superman: Dawn of Justice, and Captain America: Civil War (all released in 2016) in terms of genre, narrative as well as characters and their symbolic implications, the article shows how the films comment in ambiguous, even contradictory ways on the current terrain of justice. Although they are critical of the loss of a democratic conception of justice, in which laws and the ways they are upheld and enforced are subject to independent control instances, the films also emphasize the necessity of suspending laws during crisis situations, thus supporting an ongoing state of exception in the face of contemporary terrorist threats.
Abstract
Background
Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. ...The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis.
Methods
Wildtype (WT) and
Fpr1
- and
Fpr2
-deficient mice were intrathecally infected with
Streptococcus pneumoniae
D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection.
Results
Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated
Fpr1
-deficient mice, this protective effect was not observed in
Fpr2
-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in
Fpr2
-deficient compared to
Fpr1
-deficient mice.
Conclusions
In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for
Streptococcus pneumoniae
-induced meningitis.
When the scandal of U.S. American soldiers torturing Iraqi prisoners in Abu Ghraib broke after pictures began to circulate on the media in the spring of 2004, the public was shocked and outraged to ...find out that such atrocities had in fact been committed. However, as Susan Sontag pointed out, written reports about these incidents had circulated for over a year but went ignored by politicians. Unlike such reports, which can easily be suppressed, “the pictures will not go away” but “continue ...
The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ
1-42
) has been shown to induce neurotoxicity ...and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ
1-42
were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2
−/−
) were treated with fibrillary Aβ
1-42
, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and Aβ load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aβ
1-42
-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFкB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load.
These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.
Das DFG-Projekt Der deutsche Sprachraum aus Sicht linguistischer Laien - wahrnehmungsdialektologische Grundlagenforschung und die Rekonstruktion von Laienkonzeptualisierungen zur deutschen Sprache ...hatte linguistische, geographische, soziale, kognitive und visualisierte Raumkonzeptionen von regionalen Varietaten des Deutschen aus der Sicht deutschsprachiger linguistischer Laien zum Gegenstand. Im vorliegenden Band werden erstmals Ergebnisse aus allen Bereichen der Untersuchung vorgestellt: Wie konzeptualisieren linguistische Laien ihren sprachlichen Nahebereich? Wie sieht die dialektale Landkarte (mental map) linguistischer Laien aus, wenn der gesamte deutschsprachige Raum im Fokus ist? Welche sprachlichen Merkmale sind fur die Gewahrspersonen salient (perzipierte und assoziierte Dialektmerkmale)? In welcher Weise haben linguistische Laien uberhaupt Zugriff auf ihr eigenen Varietatenwissen und wie ist dieses Wissen strukturiert? Welche Sprachnormvorstellungen haben linguistische Laien? Wie werden einzelne Dialektraume konzeptualisiert und welche Einflusse sind z.B. durch die regionale Herkunft der Probanden messbar? Der Band bietet somit eine vielseitige Literaturgrundlage fur Forschende und fortgeschrittene Studierende.
•CCL3 lack resulted in an ineffective immune response against bacteria in the brain.•There is less neutrophils infiltration into the CNS.•Decrease of banded neutrophils in the blood of infected CCL3 ...mice.•CCL3-KO mice showed an decreased cytokine expression profile after infection.
Pneumococcal meningitis, caused by Streptococcus pneumoniae, is the most common type of bacterial meningitis. The clinical management of this disease has been challenged by the emergence of multidrug-resistant Streptococcus pneumoniae, requiring the urgent development of new therapeutic alternatives. Over the course of bacterial meningitis, pathogen invasion is accompanied by a massive recruitment of peripheral immune cells, especially neutrophil granulocytes, which are recruited under the coordination of several cytokines and chemokines. Here, we used chemokine (C-C motif) ligand 3 (Ccl3)-deficient mice to investigate the functional role of CCL3 in a mouse model of pneumococcal meningitis.
Following intrathecal infection with Streptococcus pneumoniae Ccl3-deficient mice presented a significantly shorter survival and higher bacterial load than wildtype mice, paralleled by an ameliorated infiltration of neutrophil granulocytes into the CNS. Blood sample analysis revealed that infected Ccl3-deficient mice showed a significant decrease in erythrocytes, hemoglobin and hematocrit as well as in the number of banded neutrophils. Moreover, infected Ccl3-deficient mice showed an altered cytokine expression profile. Glial cell activation remained unchanged in both genotypes.
In summary, this study demonstrates that CCL3 is beneficial in Streptococcus pneumoniae-induced meningitis. Pharmacological modulation of the CCL3 pathways might, therefore, represent a future therapeutic option to manage Streptococcus pneumoniae meningitis.
Particularly during the westward expansion, the frontier was not just a concrete site of conquest, exploration, and settlement but also a space of projection and imagination of (future) ...possibilities. People not only imagined the frontier in a variety of sometimes incompatible ways. They also used such imaginations to process and order their experience of the concrete, ‘real-life’ space so that the frontier becomes a space in which both, the lived and the imagined space, overlap and merge. This essay looks at how two popular antebellum writers used material objects and related cultural practices in their narrative construction of frontier space, arguing that, from this perspective, narrative space ceases to be only a property of the text and extends into the object world. Drawing on their own experience of life in the east, Caroline Kirkland and Eliza Farnham use gender- and class-based ideologies of taste and refinement to make the unknown space of the frontier meaningful and familiar, thus turning it from a mere place to live into something like a home. Such a use of material culture in the narrative construction of this space allows both writers to comment on and shape the ideological underpinnings of the frontier and, by extension, take part in the (narrative) construction of future America.
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