Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes

Activating Transcription Factor 3 (ATF3), a member of the ATF/CREB family, is induced rapidly by various stresses. Its induction mechanism and role in response to changes in cellular redox status, however, have not been elucidated. Here, we found that NF-E2-related factor 2 (Nrf2), a transcription factor known to bind to antioxidant response element (ARE) in promoters, transcriptionally upregulated ATF3 expression in astrocytes. Treatment with Nrf2 activators and oxidants provoked ATF3 induction in astrocytes, whereas its expression was reduced in Nrf2-depleted cells. We further demonstrated that the consensus ARE in the ATF3 promoter is critical for Nrf2-mediation by promoter analyses using an ATF3 promoter-driven luciferase construct and a chromatin immunoprecipitation assay. In addition, we found that Nrf2-dependent ATF3 induction contributed to the antioxidative and cytoprotective functions of Nrf2 in astrocytes. Taken together, our findings suggest that ATF3 is a new target for Nrf2 and has a cytoprotective function in astrocytes

Adaptive regulation of the brain's antioxidant defences by neurons and astrocytes

AbstractThe human brain generally remains structurally and functionally sound for many decades, despite the post-mitotic and non-regenerative nature of neurons. This is testament to the brain’s profound capacity for homeostasis: both neurons and glia have in-built mechanisms that enable them to mount adaptive or protective responses to potentially challenging situations, ensuring that cellular viability and functionality is maintained. The high and variable metabolic and mitochondrial activity of neurons places several demands on the brain, including the task of neutralizing the associated reactive oxygen species (ROS) produced, to limit the accumulation of oxidative damage. Astrocytes play a key role in providing antioxidant support to nearby neurons, and redox regulation of the astrocytic Nrf2 pathway represents a powerful homeostatic regulator of the large cohort of Nrf2-regulated antioxidant genes that they express. In contrast, the Nrf2 pathway is weak in neurons, robbing them of this particular homeostatic device. However, many neuronal antioxidant genes are controlled by synaptic activity, enabling activity-dependent increases in ROS production to be offset by enhanced antioxidant capacity of both glutathione and thioredoxin-peroxiredoxin systems. These distinct homeostatic mechanisms in neurons and astrocytes together combine to promote neuronal resistance to oxidative insults. Future investigations into signaling between distinct cell types within the neuro-glial unit are likely to uncover further mechanisms underlying redox homeostasis in the brain

Regulation of neuronal development and function by ROS.

Reactive oxygen species (ROS) have long been studied as destructive agents in the context of nervous system ageing, disease and degeneration. Their roles as signalling molecules under normal physiological conditions is less well understood. Recent studies have provided ample evidence of ROS-regulating neuronal development and function, from the establishment of neuronal polarity to growth cone pathfinding; from the regulation of connectivity and synaptic transmission to the tuning of neuronal networks. Appreciation of the varied processes that are subject to regulation by ROS might help us understand how changes in ROS metabolism and buffering could progressively impact on neuronal networks with age and disease

Differential interaction of helical beta particles with liquid enantiomers

Typescript (photocopy).Two hypotheses exist to explain the origin of biomolecular homochirality; (i) that the selection of D-sugars and L-amino acids was determined by chance, a "frozen accident" or (ii) that the asymmetry of biomolecules is related to the intrinsic asymmetry of matter. Experiments designed to investigate a differential interaction between the parity violating weak interactions and chiral molecules have been conducted for thirty years; however, results are inconclusive. Electrons or positrons emitted during beta decay of radioactive nuclides are spin polarized; data presented here indicate that the helical particles travel further in one liquid enantiomer than in its mirror image isomer. Five chiral pairs were examined by Cerenkov pulse height spectroscopy; radiation originated with β- from ³²P or β+ from ²²Na, and the Bethe equation solved. Measured and calculated differences for ³²P in R and S 2-phenylbutyric acid (PBA) were significant to 2 sigma; differences for R and S α-pinene were significant to 1 sigma. The other enantiomers were on the brink of significance for β- form ³²P. Non-polarized Compton electrons gave superimposable spectra. Significance was reached for ²²Na in PBA; for the other isomers differences may be obscured by concomitant Compton electrons from gamma irradiation. The aromatic PBA was also measured by scintillation pulse height spectroscopy; additional nuclides included ³H and ³⁵S. Artifical contamination studies indicated that the displacement of the pulse height spectra of one enantiomer with respect to the other was not due to the presence of an impurity. The analogy between pulse height spectroscopy and circular dichroism is discussed; bombardment of chiral molecules by electrons from dissolved nuclides probes the absolute sense of the helical potential field of enantiomers. The results presented here favor the second hypothesis; chiral molecules are recognized by spin polarized β particles form parity violating radioactive decay

Differential interaction of helical beta particles with liquid enantiomers

Typescript (photocopy).Two hypotheses exist to explain the origin of biomolecular homochirality; (i) that the selection of D-sugars and L-amino acids was determined by chance, a "frozen accident" or (ii) that the asymmetry of biomolecules is related to the intrinsic asymmetry of matter. Experiments designed to investigate a differential interaction between the parity violating weak interactions and chiral molecules have been conducted for thirty years; however, results are inconclusive. Electrons or positrons emitted during beta decay of radioactive nuclides are spin polarized; data presented here indicate that the helical particles travel further in one liquid enantiomer than in its mirror image isomer. Five chiral pairs were examined by Cerenkov pulse height spectroscopy; radiation originated with β- from ³²P or β+ from ²²Na, and the Bethe equation solved. Measured and calculated differences for ³²P in R and S 2-phenylbutyric acid (PBA) were significant to 2 sigma; differences for R and S α-pinene were significant to 1 sigma. The other enantiomers were on the brink of significance for β- form ³²P. Non-polarized Compton electrons gave superimposable spectra. Significance was reached for ²²Na in PBA; for the other isomers differences may be obscured by concomitant Compton electrons from gamma irradiation. The aromatic PBA was also measured by scintillation pulse height spectroscopy; additional nuclides included ³H and ³⁵S. Artifical contamination studies indicated that the displacement of the pulse height spectra of one enantiomer with respect to the other was not due to the presence of an impurity. The analogy between pulse height spectroscopy and circular dichroism is discussed; bombardment of chiral molecules by electrons from dissolved nuclides probes the absolute sense of the helical potential field of enantiomers. The results presented here favor the second hypothesis; chiral molecules are recognized by spin polarized β particles form parity violating radioactive decay

RETINAL VASCULAR ABNORMALITIES RELATED TO NEUROFIBROMATOSIS TYPE 1

PURPOSE: To analyze and classify neurofibromatosis type 1 (NF1) related retinal vascular abnormalities (RVAs), their natural history and correlation with disease severity, in a large cohort of patients.METHODS: This was an observational longitudinal study with prospective enrollment. Four hundred and seventy-three patients affected by NF1 and 150 age-matched healthy subjects were consecutively enrolled. RVAs were detected by means of near-infrared reflectance and studied by optical coherence tomography angiography (OCTA). The superficial vascular plexus (SVP) and the deep vascular complex (DVC) were quantitatively and qualitatively analyzed.RESULTS: We identified RVAs in 82 of 473 (17%) NF1 patients, but in none of the 150 healthy subjects. A comparison revealed that NF1 patients with RVAs showed a higher number of NF1 diagnostic criteria (4.3 ± 1.5 versus 3.9 ±1.5, respectively; p=0.02) than patients without RVAs. Three different RVA types were identified on OCTA: macrovascular angiomatosis of the sole SVP; macrovascular angiomatosis of the SVP combined with microvascular angiomatosis of the DVC; and combined macrovascular angiomatosis of both SVP and DVC. The prospective analysis of OCTA images showed no significant longitudinal evolution of RVAs (mean follow-up: 3.7 ± 2.8 years). A single patient developed de novo a single RVA, and two RVAs showed detectable changes during follow-up.CONCLUSION: In NF1 patients RVAs are a characteristic sign that correlates with a more severe systemic disease expression, usually remaining stable during time. OCTA allows for the identification of different RVAs subtypes