Ein Beitrag zum Toxnetz-Explorer: Blut und blutbildendes System

Das kardiovaskuläre System stellt einen wesentlichen Grundbaustein des menschlichen Körpers dar. Insbesondere das Gewebe Blut und die damit verbundenen blutbildenden Komponenten sind in diesem Kontext Betrachtungspunkte für toxikologische Interaktionen. In diesem Dokument wird der Ansatz einer dreistufigen Wissensvermittlung zur Gewähr-leistung eines interdisziplinären Erkenntnisgewinns für das Blut sowie das blutbildende System angewendet. In der ersten Stufe werden die anatomischen s vorgestellt. Darauf aufbauend werden die Bestandteile des Blutes sowie dessen individuelle Eigenschaften erläutert. Anschließend werden Interaktionen ausgewählter toxischer Noxen diskutiert. Final werden ausgewählte Mechanismen dargestellt, um nutzerorientiert in geeignete Medienfunktionen des „Toxnetz-Explorers“ überführt zu werde

Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice

The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins with large extracellular domains. α-Klotho exists as a full-length membrane-bound and as a soluble form after cleavage of the extracellular domain. Due to gene splicing, a short extracellular Klotho form can be expressed and secreted. Inactivation of α-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the α-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human α-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human α-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, α-Klotho overexpression increased hippocampal synaptic transmission in response to standardized stimulation strengths, altered paired-pulse facilitation of synaptic transmission, and enhanced activity-dependent synaptic plasticity. These results indicate that memory formation benefits from an augmented level of secreted α-Klotho

Apoptosis signal-regulating kinase 1 (Ask1) deficiency alleviates MPP+-induced impairment of evoked dopamine release in the mouse hippocampus

The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson’s disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP+ using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 (Ask1) in various animal-disease-like models, the study also aimed to determine whether Ask1 knockdown restores MPP+-altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP+ reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that Ask1 deficiency attenuated the detrimental effects of MPP+ on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP+ exposure. Notably, Ask1 deficiency was found to downregulate the expression of Slc5a7, a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that Slc5a7 plays a role in Ask1 deficiency-mediated protection against MPP+ neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP+. In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of Ask1 deficiency in PD

Nuclear Translocation of Jacob in Hippocampal Neurons after Stimuli Inducing Long-Term Potentiation but Not Long-Term Depression

Background: In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity. Methodology/Principal Findings: We have analyzed the dynamics of Jacob’s nuclear import following induction of NMDA-receptor dependent LTP or LTD at Schaffer collateral-CA1 synapses in rat hippocampal slices. Using time-lapse imaging of neurons expressing a Jacob-Green-Fluorescent-Protein we found that Jacob rapidly translocates from dendrites to the nucleus already during the tetanization period of LTP, but not after induction of LTD. Immunocytochemical stainings confirmed the nuclear accumulation of endogenous Jacob in comparison to apical dendrites after induction of LTP but not LTD. Complementary findings were obtained after induction of NMDA-receptor dependent chemical LTP and LTD i

Identification of major dioxin-like compounds and androgen receptor antagonist in acid-treated tissue extracts of high trophic-level animals

We evaluated the applicability of combining in vitro bioassays with instrument analyses to identify potential endocrine disrupting pollutants in sulfuric acid-treated extracts of liver and/or blubber of high trophic-level animals. Dioxin-like and androgen receptor (AR) antagonistic activities were observed in Baikal seals, common cormorants, raccoon dogs, and finless porpoises by using a panel of rat and human cell-based chemical-activated luciferase gene expression (CALUX) reporter gene bioassays. On the other hand, no activity was detected in estrogen receptor α (ERα)-, glucocorticoid receptor (GR)-, progesterone receptor (PR)-, and peroxisome proliferator-activated receptor γ2 (PPARγ2)-CALUX assays with the sample amount applied. All individual samples (n = 66) showed dioxin-like activity, with values ranging from 21 to 5500 pg CALUX-2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (TEQ)/g-lipid. Because dioxins are expected to be strong contributors to CALUX-TEQs, the median theoretical contribution of dioxins calculated from the result of chemical analysis to the experimental CALUX-TEQs was estimated to explain up to 130% for all the tested samples (n = 54). Baikal seal extracts (n = 31), but not other extracts, induced AR antagonistic activities that were 8-150 μg CALUX-flutamide equivalent (FluEQ)/g-lipid. p,p′-DDE was identified as an important causative compound for the activity, and its median theoretical contribution to the experimental CALUX-FluEQs was 59% for the tested Baikal seal tissues (n = 25). Our results demonstrate that combining in vitro CALUX assays with instrument analysis is useful for identifying persistent organic pollutant-like compounds in the tissue of wild animals on the basis of in vitro endocrine disruption toxicity. © 2011 American Chemical Society

Ein Beitrag zum Toxnetz-Explorer: Blut und blutbildendes System

Das kardiovaskuläre System stellt einen wesentlichen Grundbaustein des menschlichen Körpers dar. Insbesondere das Gewebe Blut und die damit verbundenen blutbildenden Komponenten sind in diesem Kontext Betrachtungspunkte für toxikologische Interaktionen. In diesem Dokument wird der Ansatz einer dreistufigen Wissensvermittlung zur Gewähr-leistung eines interdisziplinären Erkenntnisgewinns für das Blut sowie das blutbildende System angewendet. In der ersten Stufe werden die anatomischen s vorgestellt. Darauf aufbauend werden die Bestandteile des Blutes sowie dessen individuelle Eigenschaften erläutert. Anschließend werden Interaktionen ausgewählter toxischer Noxen diskutiert. Final werden ausgewählte Mechanismen dargestellt, um nutzerorientiert in geeignete Medienfunktionen des „Toxnetz-Explorers“ überführt zu werde

Ein Beitrag zum Toxnetz-Explorer: Blut und blutbildendes System

Das kardiovaskuläre System stellt einen wesentlichen Grundbaustein des menschlichen Körpers dar. Insbesondere das Gewebe Blut und die damit verbundenen blutbildenden Komponenten sind in diesem Kontext Betrachtungspunkte für toxikologische Interaktionen. In diesem Dokument wird der Ansatz einer dreistufigen Wissensvermittlung zur Gewähr-leistung eines interdisziplinären Erkenntnisgewinns für das Blut sowie das blutbildende System angewendet. In der ersten Stufe werden die anatomischen s vorgestellt. Darauf aufbauend werden die Bestandteile des Blutes sowie dessen individuelle Eigenschaften erläutert. Anschließend werden Interaktionen ausgewählter toxischer Noxen diskutiert. Final werden ausgewählte Mechanismen dargestellt, um nutzerorientiert in geeignete Medienfunktionen des „Toxnetz-Explorers“ überführt zu werde