Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid peptides ((A; the widely accepted major toxic factor in AD) is less well understood. Here, we show that A(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, A(1-42) raises peroxynitrite levels in astrocytes, and A(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following A(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from A(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by A(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and A(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that A(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system

Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Aβ(1-42) raises peroxynitrite levels in astrocytes, and Aβ(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Aβ(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from Aβ(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Aβ(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and Aβ(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Aβ(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system

In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes

Single-walled carbon nanotubes are particularly attractive for biomedical applications, because they exhibit a fluorescent signal in a spectral region where there is minimal interference from biological media. Although single-walled carbon nanotubes have been used as highly sensitive detectors for various compounds, their use as in vivo biomarkers requires the simultaneous optimization of various parameters, including biocompatibility, molecular recognition, high fluorescence quantum efficiency and signal transduction. Here we show that a polyethylene glycol ligated copolymer stabilizes near-infrared-fluorescent single-walled carbon nanotubes sensors in solution, enabling intravenous injection into mice and the selective detection of local nitric oxide concentration with a detection limit of 1 µM. The half-life for liver retention is 4 h, with sensors clearing the lungs within 2 h after injection, thus avoiding a dominant route of in vivo nanotoxicology. After localization within the liver, it is possible to follow the transient inflammation using nitric oxide as a marker and signalling molecule. To this end, we also report a spatial-spectral imaging algorithm to deconvolute fluorescence intensity and spatial information from measurements. Finally, we demonstrate that alginate-encapsulated single-walled carbon nanotubes can function as implantable inflammation sensors for nitric oxide detection, with no intrinsic immune reactivity or other adverse response for more than 400 days.National Institutes of Health (U.S.) (T32 Training Grant in Environmental Toxicology ES007020)National Cancer Institute (U.S.) (Grant P01 CA26731)National Institute of Environmental Health Sciences (Grant P30 ES002109)Arnold and Mabel Beckman Foundation (Young Investigator Award)National Science Foundation (U.S.). Presidential Early Career Award for Scientists and EngineersScientific and Technological Research Council of Turkey (TUBITAK 2211 Research Fellowship Programme)Scientific and Technological Research Council of Turkey (TUBITAK 2214 Research Fellowship Programme)Middle East Technical University. Faculty Development ProgrammeSanofi Aventis (Firm) (Biomedical Innovation Grant

Land-use effects on local biodiversity in tropical forests vary between continents

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The role of cognitive emotion regulation on the vicarious emotional response

Perceiving another in need may provoke two possible emotional responses: empathic concern and personal distress. This research aims to test whether different emotion regulation strategies (i.e., reappraisal and rumination) may lead to different vicarious emotional responses (i.e., empathic concern and personal distress). In this sense, we hypothesized that reappraisal may lead to a greater feeling of empathic concern, whereas rumination may lead to a higher feeling of personal distress. To test the hypotheses we used experimental instructions (Study 1) and a priming procedure (Study 2) to manipulate the emotion regulation strategies. The results supported our hypotheses. Furthermore in the rumination condition the emotional experience was described as being more negative and more highly arousing than in the reappraisal condition. We discuss the effect of these two forms of cognitive emotion regulation on empathic concern and personal distress

Implant removal associated complications in children with limb fractures due to trauma

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Cytotoxic Effect of Poly-Dispersed Single Walled Carbon Nanotubes on Erythrocytes In Vitro and In Vivo

Single wall Carbon Nanotubes (SWCNTs) are hydrophobic and do not disperse in aqueous solvents. Acid functionalization of SWCNTs results in attachment of carboxy and sulfonate groups to carbon atoms and the resulting acid functionalized product (AF-SWCNTs) is negatively charged and disperses easily in water and buffers. In the present study, effect of AF-SWCNTs on blood erythrocytes was examined. Incubation of mouse erythrocytes with AF-SWCNTs and not with control SWCNTs, resulted in a dose and time dependent lysis of erythrocyte. Using fluorescence tagged AF-SWCNTs, binding of AF-SWCNTs with erythrocytes could be demonstrated. Confocal microscopy results indicated that AF-SWCNTs could enter the erythrocytes. Treatment with AF-SWCNTs resulted in exposure of hydrophobic patches on erythrocyte membrane that is indicative of membrane damage. A time and dose dependent increase in externalization of phosphatidylserine on erythrocyte membrane bilayer was also found. Administration of AF-SWCNTs through intravenous route resulted in a transient anemia as seen by a sharp decline in blood erythrocyte count accompanied with a significant drop in blood haemoglobin level. Administration of AF-SWCNTs through intratracheal administration also showed significant decline in RBC count while administration through other routes (gavage and intra-peritoneal) was not effective. By using a recently developed technique of a two step in vivo biotinylation of erythrocytes that enables simultaneous enumeration of young (age <10 days) and old (age>40 days) erythrocytes in mouse blood, it was found that the in vivo toxic effect of AF-SWCNTs was more pronounced on older subpopulation of erythrocytes. Subpopulation of old erythrocytes fell after treatment with AF-SWCNTs but recovered by third day after the intravenous administration of AF-SWCNTs. Taken together our results indicate that treatment with AF-SWCNTs results in acute membrane damage and eventual lysis of erythrocytes. Intravenous administration of AF-SWCNTs resulted in a transient anemia in which older erythrocytes are preferably lysed