113 research outputs found
The Historical Turn in Democratization Studies: A New Research Agenda for Europe and Beyond. CES Working Paper Series No. 177, 2010
The paper lays the theoretical and methodological foundations of a new historically-minded approach to the comparative study of democratization, centered on the analysis of the creation, development and interaction of democratic institutions. Historically, democracy did not emerge as a singular coherent whole but rather as a set of different institutions, which resulted from conflicts across multiple lines of social and political cleavage that took place at different moments in time. The theoretical advantage of this approach is illustrated by highlighting the range of new variables that come into focus in explaining democracy's emergence. Rather than class being the single variable that explains how and why democracy came about, we can see how religious conflict, ethnic cleavages, and the diffusion of ideas played a much greater role in Europe's democratization than has typically been appreciated. Above all, we argue that political parties were decisive players in how and why democracy emerged in Europe and should be at the center of future analyses
S100B inhibitor pentamidine attenuates reactive gliosis and reduces neuronal loss in a mouse model of Alzheimer's disease
Among the different signaling molecules released during reactive gliosis occurring in Alzheimerâs disease (AD), the astrocytederived S100B protein plays a key role in neuroinflammation, one of the hallmarks of the disease. The use of pharmacological tools targeting S100B may be crucial to embank its effects and some of the pathological features of AD. The antiprotozoal drug pentamidine is a good candidate since it directly blocks S100B activity by inhibiting its interaction with the tumor suppressor p53. We used a mouse model of amyloid beta- (A-) induced AD, which is characterized by reactive gliosis and neuroinflammation in the brain, and we evaluated the effect of pentamidine on the main S100B-mediated events. Pentamidine caused the reduction of glial fibrillary acidic protein, S100B, and RAGE protein expression, which are signs of reactive gliosis, and induced p53 expression in astrocytes. Pentamidine also reduced the expression of proinflammatory mediators and markers, thus reducing neuroinflammation in AD brain. In parallel, we observed a significant neuroprotection exerted by pentamidine on CA1 pyramidal neurons. We
demonstrated that pentamidine inhibits A-induced gliosis and neuroinflammation in an animal model of AD, thus playing a role in slowing down the course of the disease
Formal Versus Functional Method in Comparative Constitutional Law
In the field of comparative constitutional law, the dominant approach to concept formation and research design is formal. That is, comparative projects generally identify what counts as the supreme law that can be enforced against all other sources of law based on the âconstitutionalâ label of the positive law (written constitutions and the jurisprudence of constitutional courts) and the law books. This formal method, however, has significant limitations when compared with the functional method used in the field of comparative law more generally speaking. After a brief exposition of the functional method, this article explores the advantages of the functional method as applied to comparative constitutional law with the problem of judicial review (based on the supreme law) of social and economic policy-making in France, the United States, and Germany. Only in Germany is this law contained in constitutional law. In France, the supreme law is to be found largely in administrative law, because the constitutional court faces an institutional competitor, some would say superior, in the highest administrative court (Conseil dâĂtat). In the United States, the supreme law is to be found in administrative law because economic and social rightsâthe rights that most directly affect this area of state activityâhave largely been read out of constitutional law. Based on the functional method, the article proceeds to identify the similarities that unite the law of France and Germany and that set it apart from the law of the United States. It also outlines the important avenues of theoretical inquiry triggered by these similarities and differences in judicial review. The article concludes by sketching a functional agenda for empirical research in comparative constitutional law
Enteric glia: A new player in inflammatory bowel diseases
In addition to the well-known involvement of macrophages and neutrophils, other cell types have been recently reported to substantially contribute to the onset and progression of inflammatory bowel diseases (IBD). Enteric glial cells (EGC) are the equivalent cell type of astrocyte in the central nervous system (CNS) and share with them many neurotrophic and neuro-immunomodulatory properties. This short review highlights the role of EGC in IBD, describing the role played by these cells in the maintenance of gut homeostasis, and their modulation of enteric neuronal activities. In pathological conditions, EGC have been reported to trigger and support bowel inflammation through the specific over-secretion of S100B protein, a pivotal neurotrophic factor able to induce chronic inflammatory changes in gut mucosa. New pharmacological tools that may improve the current therapeutic strategies for inflammatory bowel diseases (IBD), lowering side effects (i.e. corticosteroids) and costs (i.e. anti-TNFα monoclonal antibodies) represent a very important challenge for gastroenterologists and pharmacologists. Novel drugs capable to modulate enteric glia reactivity, limiting the pro-inflammatory release of S100B, may thus represent a significant innovation in the field of pharmacological interventions for inflammatory bowel diseases
Rifaximin improves Clostridium difficile toxin A-induced toxicity in Caco-2 cells by the PXR-dependent TLR4/MyD88 /NF-?B pathway
Background: Clostridium difficile infections (CDIs) caused by Clostridium difficile toxin A (TcdA) lead to severe ulceration,
inflammation and bleeding of the colon, and are difficult to treat.
Aim: The study aimed to evaluate the effect of rifaximin on TcdA-induced apoptosis in intestinal epithelial cells and investigate the role of PXR in its mechanism of action.
Methods: Cacoâ2 cells were incubated with TcdA and treated with rifaximin (0.1â10 ÎŒM) with or without ketoconazole (10 ÎŒM). The transepithelial electrical resistance (TEER) and viability of the treated cells was determined. Also, the expression of zona occludensâ1 (ZOâ1), tollâlike receptor 4 (TLR4), Bclâ2âassociated X protein (Bax), transforming growth factorâÎČâactivated kinaseâ1 (TAK1), myeloid differentiation factor 88 (MyD88) and nuclear factorâkappaB (NFâÎșB) was determined.
Results Rifaximin treatment (0.1, 1.0 and 10 ÎŒM) caused a significant and concentration-dependent increase in the TEER of Caco-2 cells (360%, 480% and 680% vs TcdA treatment) 24 hours after the treatment and improved their viability (61%, 79% and 105%). Treatment also concentration-dependently decreased the expression of Bax protein (â29%, â65% and â77%) and increased the expression of ZO-1 (25%, 54% and 87%) and occludin (71%, 114% and 262%) versus TcdA treatment. The expression of TLR4 (â33%, â50% and â75%), MyD88 (â29%, â60% and â81%) and TAK1 (â37%, â63% and â79%) were also reduced with rifaximin versus TcdA treatment. Ketoconazole treatment inhibited these effects.
Conclusions: Rifaximin improved TcdAâinduced toxicity in Cacoâ2 cells by the PXRâdependent TLR4/MyD88/NFâÎșB pathway mechanism, and may be useful in the treatment of CDIs
Gender-dependent resiliency to stressful and metabolic challenges following prenatal exposure to high-fat diet in the p66Shc mouse
Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway
Activation of intestinal human pregnane X receptor
(PXR) has recently been proposed as a promising strategy for
the chemoprevention of inflammation-induced colon cancer.
The present study was aimed at evaluating the effect of rifaximin,
a non-absorbable antibiotic, in inhibiting angiogenesis
in a model of human colorectal epithelium and investigating
the role of PXR in its mechanism of action. Caco-2 cells were
treated with rifaximin (0.1, 1.0 and 10.0 ÎŒM) in the presence
or absence of ketoconazole (10 ÎŒM) and assessed for cell
proliferation, migration and expression of proliferating cell
nuclear antigen (PCNA). The release of vascular endothelial
growth factor (VEGF) and nitric oxide (NO), expression of
Akt, mechanistic target of rapamycin (mTOR), p38 mitogen
activated protein kinases (MAPK), nuclear factor ÎșB (NF-ÎșB)
and metalloproteinase-2 and -9 (MMP-2 and -9) were also
evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 ÎŒM
caused significant and concentration-dependent reduction of
cell proliferation (-25, -40 and -68%), cell migration (-18, -30
and -46%) and PCNA expression (-29, -53 and -76%) in the
Caco-2 cells vs. untreated cells. Treatment downregulated
VEGF secretion (-32, -45 and -72%), NO release (-40, -69 and
-87%), VEGFR-2 expression (-33, -58 and -65%) and MMP-2
(-25, -62 and -87%) and MMP-9 expression (-38, -56 and -78%)
vs. untreated cells. Rifaximin treatment also resulted in a
concentration-dependent decrease in the phosphorylation of
Akt (-50, -75 and -86%), mTOR (-38, -56 and -78%), p38MAPK
(-24, -62 and -71%) and inhibition of HIF-1α (-65, -82 and
-92%), p70S6K (-27, -55 and -85%) and NF-ÎșB (-29, -55 and
-61%). Ketoconazole (PXR antagonist) treatment inhibited
these effects. These findings demonstrated that rifaximin
causes PXR-mediated inhibition of angiogenic factors in
Caco-2 cell line and may be a promising anticancer tool
S100Bâp53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporinâ4 and metalloproteinaseâ2 inhibition in C6 glioma cells
S100 calciumâbinding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100Bâp53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro. The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3â[4,5âdimethylthiazolâ2âyl]â2,5 diphenyltetrazolium bromideâformazan assay. Significant doseâdependent decreases in proliferation were observed at pentamidine concentrations of 0.05 ÎŒM (58.5±5%; P<0.05), 0.5 ÎŒM (40.6±7%; P<0.01) and 5 ÎŒM (13±4%; P<0.001) compared with the control (100% viability). Furthermore, treatment with 0.05, 0.5 and 5 ÎŒM pentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of Bâcell lymphomaâ2 (Bclâ2)âassociated X protein (100%, P<0.05; 453%, P<0.01; and 1000%, P<0.001, respectively) and Bclâ2 (â60%, P<0.001; â80.13%, P<0.001; â95%, P<0.001, respectively). In addition, the administration of 0.05, 0.5 and 5 ÎŒM pentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, P<0.05; 1244±94.3%, P<0.01; and 2244±111%, P<0.001, respectively), and significantly downregulated the expression levels of matrix metalloproteinaseâ2 (42±2.3%, P<0.05; 71±2.5%, P<0.01; and 95.8±3.3%, P<0.001, respectively) and aquaporin 4 (38±2.5%, P<0.05; 69±2.6%, P<0.01; and 88±3.0%, P<0.001, respectively), compared with the untreated cells. The wound healing assay demonstrated that cell migration was significantly impaired by treatment with 0.05, 0.5 and 5 ÎŒM pentamidine compared with untreated cells (88±4.2%, P<0.05; 64±2%, P<0.01; and 42±3.1%, P<0.001, respectively). Although additional in vivo studies are required to clarify the current in vitro data, the present study indicates that pentamidine and S100Bâp53 inhibitors may represent a novel approach for the treatment of glioma
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