Amyloid-beta Leads to Impaired Cellular Respiration, Energy Production and Mitochondrial Electron Chain Complex Activities in Human Neuroblastoma Cells

Evidence suggests that amyloid-beta (Aβ) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been recently proposed that mitochondria are involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Here we investigated the specific effects of Aβ on mitochondrial function under physiological conditions. Mitochondrial respiratory functions and energy metabolism were analyzed in control and in human wild-type amyloid precursor protein (APP) stably transfected human neuroblastoma cells (SH-SY5Y). Mitochondrial respiratory capacity of mitochondrial electron transport chain (ETC) in vital cells was measured with a high-resolution respirometry system (Oxygraph-2k). In addition, we determined the individual activities of mitochondrial complexes I-IV that compose ETC and ATP cellular levels. While the activities of complexes I and II did not change between cell types, complex IV activity was significantly reduced in APP cells. In contrast, activity of complex III was significantly enhanced in APP cells, as compensatory response in order to balance the defect of complex IV. However, this compensatory mechanism could not prevent the strong impairment of total respiration in vital APP cells. As a result, the respiratory control ratio (state3/state4) together with ATP production decreased in the APP cells in comparison with the control cells. Chronic exposure to soluble Aβ protein may result in an impairment of energy homeostasis due to a decreased respiratory capacity of mitochondrial electron transport chain which, in turn, may accelerate neurons demis

Immunohistochemical localization of angiotensin-converting enzyme, angiotensin II and AT1 receptor in human ocular tissues

We investigated the immunohistochemical distribution of 3 components of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE), angiotensin II (AngII) and AT1 receptor (AT1), in the human eye. ACE and AngII were localized to nonpigmented epithelial cells of the ciliary body, to endothelial and epithelial cells of the cornea, to epithelial cells of the conjunctiva and to trabecular meshwork cells in the anterior part of the eye. In the posterior part of the eye, ACE and AngII were localized to ganglion cells, some cells in the inner nuclear layer, photoreceptor cells and to endothelial cells of the retinal and choroidal vessels. The overall intensity of AT1 immunoreactivity was weak in all ocular tissues, but the main localization was in ganglion cells. As a preliminary investigation, we were able to include 2 Alzheimer's disease (AD) cases. In AD, no differences from controls were found in the cellular distribution and staining intensity of all 3 antigens. The manifold localization sites of the observed antigens point to rather generalized functions of the RAS in human ocular tissues, such as regulatory effects on neuronal cells, vessels and vitreous humor homeostasis

Improving animal welfare using continuous nalbuphine infusion in a long-term rat model of sepsis

Abstract Background Sepsis research relies on animal models to investigate the mechanisms of the dysregulated host response to infection. Animal welfare concerns request the use of potent analgesics for the Refinement of existing sepsis models, according to the 3Rs principle. Nevertheless, adequate analgesia is often missing, partly because the effects of analgesics in this particular condition are unknown. We evaluated the use of nalbuphine, an opioid with kappa agonistic and mu antagonistic effects, in rats with and without experimental sepsis. Methods Male Wistar rats were anesthetized with isoflurane and instrumented with a venous line for drug administration. Arterial cannulation allowed for blood pressure measurements and blood sampling in short-term experiments of non-septic animals. Nalbuphine (or placebo) was administered intravenously at a dose of 1 mg/kg/h. Long-term (48 h) experiments in awake septic animals included repetitive clinical scoring with the Rat Grimace Scale and continuous heart rate monitoring by telemetry. Sepsis was induced by intraperitoneal injection of faecal slurry. Nalbuphine plasma levels were measured by liquid chromatography—high resolution mass spectrometry. Results In anesthetized healthy animals, nalbuphine led to a significant reduction of respiratory rate, heart rate, and mean arterial pressure during short-term experiments. In awake septic animals, a continuous nalbuphine infusion did not affect heart rate but significantly improved the values of the Rat Grimace Scale. Nalbuphine plasma concentrations remained stable between 4 and 24 h of continuous infusion in septic rats. Conclusions In anaesthetised rats, nalbuphine depresses respiratory rate, heart rate, and blood pressure. In awake animals, nalbuphine analgesia improves animal welfare during sepsis

TIMASSS: The IRAS16293-2422 Millimeter And Submillimeter Spectral Survey. I. Observations, calibration and analysis of the line kinematics

While unbiased surveys observable from ground-based telescopes have previously been obtained towards several high mass protostars, very little exists on low mass protostars. To fill up this gap, we carried out a complete spectral survey of the bands at 3, 2, 1 and 0.8 mm towards the solar type protostar IRAS16293-2422. The observations covered about 200\,GHz and were obtained with the IRAM-30m and JCMT-15m telescopes. Particular attention was devoted to the inter-calibration of the obtained spectra with previous observations. All the lines detected with more than 3 sigma and free from obvious blending effects were fitted with Gaussians to estimate their basic kinematic properties. More than 4000 lines were detected (with sigma \geq 3) and identified, yielding a line density of approximatively 20 lines per GHz, comparable to previous surveys in massive hot cores. The vast majority (~2/3) of the lines are weak and due to complex organic molecules. The analysis of the profiles of more than 1000 lines belonging 70 species firmly establishes the presence of two distinct velocity components, associated with the two objects, A and B, forming the IRAS16293-2422 binary system. In the source A, the line widths of several species increase with the upper level energy of the transition, a behavior compatible with gas infalling towards a ~1 Mo object. The source B, which does not show this effect, might have a much lower central mass of ~0.1 Mo. The difference in the rest velocities of both objects is consistent with the hypothesis that the source B rotates around the source A. This spectral survey, although obtained with single-dish telescope with a low spatial resolution, allows to separate the emission from 2 different components, thanks to the large number of lines detected. The data of the survey are public and can be retrieved on the web site http://www-laog.obs.ujf-grenoble.fr/heberges/timasss.Comment: 41 pages (26 pages of online Tables), 7 Tables and 6 Figure

Funktion und Normativität bei Darwin und Aristoteles

In immer mehr Bereichen der modernen Humanwissenschaften wird die Evolutionstheorie als maßgebliches Erklärungsmodell angewendet. Die Attraktivität dieses Modells für andere Wissenschaften besteht in der Verbindung der historischen Entwicklungsdimension mit einer naturwissenschaftlich-nüchternen Betrachtungsweise, in der Phänomene funktional als auf Anpassung ausgerichtete Zusammenhänge begriffen werden. Mit Blick auf die Moral scheint dies jedoch auf die Alternative hinauszulaufen, entweder die Moral auf evolutionäre Anpassungsleistungen zurückzuführen oder moralische Normativität als irreduzibel anzukennen, was dann aber dazu führt, dass Ethik und Evolutionstheorie als zwei Perspektiven, unter denen menschliches Verhalten betrachtet werden kann, unvermittelt nebeneinander stehen. Dieser Befund ist jedoch insofern defizitär, als in der gegenwärtigen philosophischen Ethik in zunehmendem Maße die Notwendigkeit gesehen wird, menschliches Verhalten an die Natur zurückzubinden. Daher wird im modernen ethischen Diskurs nicht nur die Vernünftigkeit des Menschen, sondern auch seine biologische Verfassung zum Gegenstand der Untersuchung. Dieser Perspektivwechsel ist maßgeblich mit einer Wiederaufnahme aristotelischer Grundfiguren verbunden, so dass sogar von einer ‚Re-Aristotelisierung der praktischen Philosophie‘ (Höffe) gesprochen wird. Was diese antike Ethik so attraktiv erscheinen lässt, ist die Verwendung eines Naturbegriffs (physis), der zugleich die Grundlage der aristotelischen Naturphilosophie darstellt. Es scheint somit, dass die aristotelische Philosophie die Möglichkeit eröffnet, den Menschen sowohl als natürliches als auch als moralisches Wesen zu begreifen, ohne die moralische Dimension auf Naturvorgänge zu reduzieren. Der Sammelband diskutiert unter anderem die Frage, inwieweit Aristoteles’ Philosophie mögliche Lösungsansätze für das oben beschriebene Problem der Disparität von Moral und Evolutionstheorie anbieten kann

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa

Individualized preventive psychiatry : syndrome and vulnerability diagnostics

The development of prevention and treatment strategies of psychiatric disorders will depend on a more profound knowledge of the complex relationships between gene-environment interactions, particularly the interplay of vulnerability and resilience factors within a person's biography. In this article, the advantages and limitations of the current psychiatric classification systems will be discussed. New directions for a future multiaxial system including biological, psychological, social, life span, gender and cultural factors based on the DSM-V- and ICD-11-research agenda are going to be outlined. Psychiatry without psychopathology is impossible. However, in the future, psychopathology will be closer linked to the biological and psychological nature of the disease process and more function-based. Future diagnostic classification manuals should include dimensional and categorical aspects as well as vulnerability and resilience diagnostic elements. There is a need for a personalized integrative diagnosis and care