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

Persistent sulfate formation from London Fog to Chinese haze

Sulfate aerosols exert profound impacts on human and ecosystem health, weather, and climate, but their formation mechanism remains uncertain. Atmospheric models consistently underpredict sulfate levels under diverse environmental conditions. From atmospheric measurements in two Chinese megacities and complementary laboratory experiments, we show that the aqueous oxidation of SO2 by NO2 is key to efficient sulfate formation but is only feasible under two atmospheric conditions: on fine aerosols with high relative humidity and NH3 neutralization or under cloud conditions. Under polluted environments, this SO2 oxidation process leads to large sulfate production rates and promotes formation of nitrate and organic matter on aqueous particles, exacerbating severe haze development. Effective haze mitigation is achievable by intervening in the sulfate formation process with enforced NH3 and NO2 control measures. In addition to explaining the polluted episodes currently occurring in China and during the 1952 London Fog, this sulfate production mechanism is widespread, and our results suggest a way to tackle this growing problem in China and much of the developing world

Autophagy and protein aggregation after brain ischemia

Autophagy is the main degradation pathway responsible for eliminating abnormal protein aggregates and damaged organelles prevalent in neurons after transient cerebral ischemia. This study investigated whether accumulation of protein aggregate-associated organelles in postischemic neurons is a consequence of changes in autophagy. Electron microscopic (EM) analysis indicated that both autophagosomes (AP) and autolysosomes (AL) are significantlly upregulated in hippocampal CA1 and DG neurons after ischemia. The LC3-II conjugate, a marker for APs assessed by Western blotting, was upregulated in postischemic brain tissues. Confocal microscopy showed that LC3 isoforms were located in living postischemic neurons. Treatment with chloriquine (CQ) resulted in accumulation of LC3-II in sham-operated rats, but did not further change the LC3-II levels in postischemic brain tissues. The results indicate that at least part of the accumulation of protein aggregate-associated organelles seen following ischemia is likely to be due to failure of the autophagy pathway. The resulting protein aggregation on subcellular organelle membranes could lead to multiple organelle damage and to delayed neuronal death after transient cerebral ischemia

The singularity of the partially coherent beam in biological tissue

The singularity of the partially coherent beam propagating in biological tissue has been demonstrated, mainly including the properties of the normalized intensity distribution and phase evolution. It is shown that as the propagation distance increases, the evolution of the normalized intensity distribution undergoes several different stages, as well as the transformation of phase singularities takes place. Especially, the effect of the topological charge, the radial index, beam wave length and spatial coherence length on the beam singularity is analyzed, respectively

Neuroprotective Effects of TRPM7 Deletion in Parvalbumin GABAergic vs. Glutamatergic Neurons following Ischemia

Oxidative stress induced by brain ischemia upregulates transient receptor potential melastatin-like-7 (TRPM7) expression and currents, which could contribute to neurotoxicity and cell death. Accordingly, suppression of TRPM7 reduces neuronal death, tissue damage and motor deficits. However, the neuroprotective effects of TRPM7 suppression in different cell types have not been investigated. Here, we found that induction of ischemia resulted in loss of parvalbumin (PV) gamma-aminobutyric acid (GABAergic) neurons more than Ca2+/calmodulin-kinase II (CaMKII) glutamatergic neurons in the mouse cortex. Furthermore, brain ischemia increased TRPM7 expression in PV neurons more than that in CaMKII neurons. We generated two lines of conditional knockout mice of TRPM7 in GABAergic PV neurons (PV-TRPM7−/−) and in glutamatergic neurons (CaMKII-TRPM7−/−). Following exposure to brain ischemia, we found that deleting TRPM7 reduced the infarct volume in both lines of transgenic mice. However, the volume in PV-TRPM7−/− mice was more significantly lower than that in the control group. Neuronal survival of both GABAergic and glutamatergic neurons was increased in PV-TRPM7−/− mice; meanwhile, only glutamatergic neurons were protected in CaMKII-TRPM7−/−. At the behavioral level, only PV-TRPM7−/− mice exhibited significant reductions in neurological and motor deficits. Inflammatory mediators such as GFAP, Iba1 and TNF-α were suppressed in PV-TRPM7−/− more than in CaMKII-TRPM7−/−. Mechanistically, p53 and cleaved caspase-3 were reduced in both groups, but the reduction in PV-TRPM7−/− mice was more than that in CaMKII-TRPM7−/− following ischemia. Upstream from these signaling molecules, the Akt anti-oxidative stress signaling was activated only in PV-TRPM7−/− mice. Therefore, deleting TRPM7 in GABAergic PV neurons might have stronger neuroprotective effects against ischemia pathologies than doing so in glutamatergic neurons

Novel triethylamine catalyzed S -> O acetyl migration reaction to generate candidate thiols for construction of topological and functional sulfur-containing polymers

We describe a novel triethylamine catalyzed S -> O acetyl migration reaction for yielding thiol compounds under mild conditions through the formation of a transitional 5-membered ring. A series of epoxy compounds have been transformed into their thiol counterparts which could be used for construction of topological and functional sulfur-containing polymers. The one-pot two-step processes including the S -> O acetyl migration and the following thiol-click reactions avoided separation of thiol intermediates. Applying these processes on a new-type latent polythiols overcomes crosslinking problem usually met in preparation of multithiol compounds due to the formation of disulfide bonds

Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection

Phase II metabolic enzymes are a battery of critical proteins that detoxify xenobiotics by increasing their hydrophilicity and enhancing their disposal. These enzymes have long been studied for their preventative and protective effects against mutagens and carcinogens and for their regulation via the Keap1 (Kelch-like ECH associated protein 1)/Nrf2 (Nuclear factor erythroid 2 related factor 2)/ARE (antioxidant response elements) pathway. Recently, a series of studies have reported the altered expression of phase II genes in postmortem tissue of patients with various neurological diseases. These observations hint at a role for phase II enzymes in the evolution of such conditions. Furthermore, promising findings reveal that overexpression of phase II genes, either by genetic or chemical approaches, confers neuroprotection in vitro and in vivo. Therefore, there is a need to summarize the current literature on phase II genes in the central nervous system (CNS). This should help guide future studies on phase II genes as therapeutic targets in neurological diseases. In this review, we first briefly introduce the concept of phase I, II and III enzymes, with a special focus on phase II enzymes. We then discuss their expression regulation, their inducers and executors. Following this background, we expand our discussion to the neuroprotective effects of phase II enzymes and the potential application of Nrf2 inducers to the treatment of neurological diseases. © 2012 Elsevier Ltd