Abstract
Background
Activation of NF-kappaB RelA deacetylated at the lysine residues, except the lysine 310, drives pro-apoptotic transcription in noxious brain ischemia. We showed that the ...sinergistic combination of the histone deacetilase inhibitor MS-275 with the sirtuin 1 activator resveratrol, at very low doses, restores normal RelA acetylation and elicit neuroprotection in mice subjected to transient middle cerebral artery occlusion (tMCAO) and primary cortical neurons exposed to oxygen-glucose-deprivation (OGD). The present study aims at corroborating the neuroprotective potential of the epigenetic treatment in a model of permanent brain ischemia and investigate its effect on post-ischemic inflammation and microglia activation.
Methods
Male mice subjected to permanent occlusion of the distal MCAO (pMCAO) were treated with vehicle or MS-275 (20 μg/kg) and resveratrol (680 μg/kg) i.p. immediately after the ischemia. Microglia-containing mixed glial cultures were prepared from the brain of 1–3-day-old mice. Primary cortical neurons were prepared from 15-day-old embryonic mice.
Results
MS-275 and resveratrol in combination, but not individually, reduced infarct volume and neurological deficits evaluated 48 h after the pMCAO. At 24 h, the treatment inhibited the RelA binding to
Nos2
promoter, reduced the elevated expression of
Nos2, Il6, Il1b, Mrc1
and
Ym1
and the leukocytes infiltration in the ischemic area. The effect was nonpermanent. The treatment did not limit the sustained leukocyte infiltration or
Nos2
and
Il1b
transcription observed at 7 days. Though, it induced alternative activation markers of microglia/macrophages,
Arg1, Ym1
and
Fcgr2b
that could be added to
Mrc1, Tgfb1
and
Trem2
spontaneously increased at 7 days after ischemia.
At 24 hours the drug treatment quenched the microglia/macrophages activation in the ischemic cortical sections, as shown by the recovered ramified morphology and lowered iNOS or CD68 immunoreactivity in Iba1-positive cells.
Both microglia and astrocytes in mixed glial cultures, but not pure astrocytes, displayed signs of activation and iNOS-immunoreactivity when treated with a conditioned medium (NCM) from OGD-exposed cortical neurons. The epigenetic drugs limited the OGD-NCM-mediated activation.
Conclusions
Our findings indicate that single treatment with MS-275 and resveratrol can reduce stroke-mediated brain injury and inflammation observed 2 days after the pMCAO and put the rational to test repeated administration of the drugs. The anti-inflammatory property of MS-275 and resveratrol combination can be ascribed to both primary direct inhibition of microglia/macrophage activation and secondary glial/macrophages inhibition mediated by neuroprotection.
Abstract Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons ...and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε−3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
Hyperglycaemia is frequent in acute ischemic stroke and denotes a bad prognosis, even in the absence of pre-existing diabetes. However, in clinical trials treatment of elevated glucose levels with ...insulin did not improve stroke outcome, suggesting that collateral effects rather than hyperglycaemia itself aggravate ischemic brain damage. As reactive glucose metabolites, glyoxal and methylglyoxal are candidates for mediating the deleterious effects of hyperglycaemia in acute stroke.
In 135 patients with acute stroke, we used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to measure glyoxal, methylglyoxal and several of their glycated amino acid derivatives in serum. Results were verified in a second cohort of 61 stroke patients. The association of serum concentrations with standard stroke outcome scales (NIHSS, mRS) was tested.
Glucose, glyoxal, methylglyoxal, and the glyoxal-derived glycated amino acid N
-(5-hydro-4-imidazolon-2-yl)ornithine (G-H1) were positively correlated with a bad stroke outcome at 3 months as measured by mRS90, at least in one of the two cohorts. However, the glycated amino acids N
-carboxyethyllysine (CEL) and in one cohort pyrraline showed an inverse correlation with stroke outcome probably reflecting lower food intake in severe stroke. Patients with a poor outcome had higher serum concentrations of glyoxal and methylglyoxal.
The glucose-derived α-dicarbonyl glyoxal and glycated amino acids arising from a reaction with glyoxal are associated with a poor outcome in ischemic stroke. Thus, lowering α-dicarbonyls or counteracting their action could be a therapeutic strategy for hyperglycaemic stroke.
Cell therapy raises hopes high for better treatment of brain disorders. However, the majority of transplanted cells often die soon after transplantation, and those that survive initially continue to ...die in the subacute phase, diminishing the impact of transplantations. In this study, we genetically modified transplanted human neural stem cells (hNSCs), from 2 distant embryonic stem cell lines (H9 and RC17), to express 1 of 4 prosurvival factors - Hif1a, Akt1, Bcl-2, or Bcl-xl - and studied how these modifications improve short- and long-term survival of transplanted hNSCs. All genetic modifications dramatically increased survival of the transplanted hNSCs. Importantly, 3 out of 4 modifications also enhanced the exit of hNSCs from the cell cycle, thus avoiding aberrant growth of the transplants. Bcl-xl expression provided the strongest protection of transplanted cells, reducing both immediate and delayed cell death, and stimulated hNSC differentiation toward neuronal and oligodendroglial lineages. By designing hNSCs with drug-controlled expression of Bcl-xl, we demonstrated that short-term expression of a prosurvival factor can ensure the long-term survival of transplanted cells. Importantly, transplantation of Bcl-xl-expressing hNSCs into mice suffering from stroke improved behavioral outcome and recovery of motor activity in mice.
Since the beginning of the corona pandemic at the beginning of 2020, virologists have been present in the mass media and are often guests on (political) talk shows. Here, different discourse logics ...and norms meet, namely those of science, politics, and the media. In this area of conflict, discourse-pragmatic adjustments on the part of scientists occur. In this article, we investigate 1) how scientists establish themselves as epistemic authorities in the different formats and 2) how they try to enforce scientific discourse routines in media-mediated and politically framed discourses. As a basis of this empirical research, we compiled a corpus of press conferences organized by the Science Media Center Germany in Cologne and political talk shows of the public broadcasters in the period from March 2020 to April 2021. It turns out that the scientists behave in accordance with their scientific discourse norms and are hardly prepared to cross borders. The article aims to show in detail which strategies scientists use to hold on to their scientific discourse routines.
Since spring 2020, the SARS-CoV-2 pandemic has presented an international challenge that requires expert knowledge from a wide variety of disciplines. From the very beginning, virological expertise ...was particularly in demand in order to advise politicians and to inform the population about the virus, its multiplication rate and its spread as well as typical symptoms of an infection. Virological expertise has been mediated through institutions that specialize in science communication and science journalism (e. g. the Science Media Center Germany in Cologne) and to a large extent through mass media. Against this backdrop, this article explores the demarcation practices of virologists in political talk shows. Our corpus consists of 25 political talk shows which were broadcast on publicly available channels in Germany between March 2020 and April 2021. The article addresses the tensions between the domains of science, politics, and media and demonstrates how virologists try to maintain and defend the borders between these domains. On the basis of interactional linguistics, we analyse the pointing practices of three virologists (Melanie Brinkmann, Alexander Kekulé and Hendrik Streeck) to identify crucial demarcation practices employed.
Designästhetik Oliver Ruf, Stefan Neuhaus / Oliver Ruf, Stefan Neuhaus
2020
eBook
Design ist allgegenwärtig - es durchtränkt gleichsam das Leben, oftmals unbewusst, doch immer durchscheinend und folgenhaft. Es ist Bestandteil des Habitus und unverzichtbarer Teil einer jeden ...Identität. Selbst im bewussten Verzicht auf Design kommt eine spezifische Designästhetik zum Ausdruck, die anders sein möchte. Doch welche Normierungen greifen hier und dienen als Orientierung für Absetzbewegungen? Dies zeigt sich vor allem in der Prägung durch massenmediale Diskurse.Die Beiträge des Bandes entwickeln zu diesem zentralen Dispositiv einen theoretischen wie praktischen Rahmen und reflektieren Indikatoren für entsprechende Leistungen.
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