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Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in neurons or cancer cells, chemically diverse inhibitors of MEK did not block hemin-induced ferroptosis, nor did the forced expression of the ERK-selective MAP kinase phosphatase (MKP)3. We conclude that hemin or hemoglobin-induced ferroptosis, unlike glutathione depletion, is ERK1/2-independent. Together with recent studies, our findings suggest the existence of a novel subtype of neuronal ferroptosis relevant to bleeding in the brain that is 5-lipoxygenase-dependent, ERK-independent, and transcription-independent. Remarkably, our unbiased phosphoproteome analysis revealed dramatic differences in phosphorylation induced by two ferroptosis subtypes. As U0126 also reduced cell death and improved functional recovery after hemorrhagic stroke in male mice, our analysis also provides a template on which to build a search for U0126's effects in a variant of neuronal ferroptosis.SIGNIFICANCE STATEMENT Ferroptosis is an iron-dependent mechanism of regulated necrosis that has been linked to hemorrhagic stroke. Common features of ferroptotic death induced by diverse stimuli are the depletion of the antioxidant glutathione, production of lipoxygenase-dependent reactive lipids, sensitivity to iron chelation, and persistent activation of extracellular signal-regulated kinase (ERK) signaling. Unlike classical ferroptosis induced in neurons or cancer cells, here we show that ferroptosis induced by hemin is ERK-independent. Paradoxically, the canonical MAP kinase kinase (MEK) inhibitor U0126 blocks brain hemorrhage-induced death. Altogether, these data suggest that a variant of ferroptosis is unleashed in hemorrhagic stroke. We present the first, unbiased phosphoproteomic analysis of ferroptosis as a template on which to understand distinct paths to cell death that meet the definition of ferroptosis.

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

ObjectivesN-acetylcysteine (NAC) is a clinically approved thiol-containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an "antioxidant," poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke.MethodsHemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5-lipoxygenase (ALOX5) knockout mice, and viral-gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC.ResultsNAC prevented hemin-induced ferroptosis by neutralizing toxic lipids generated by arachidonate-dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione-dependent enzymes such as glutathione S-transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E2 (PGE2 ).InterpretationNAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854-872.

Dynamic structural color based on tunable optical resonance plays a key role in applications including encryption visualization, camouflage and colorimetric sensing. However, the current design requires either complex growth processes of the high-quality tunable materials or complicated circuit designs. This work makes a humidity-swelling hydrogel layer for metal–insulator–metal (MIM) structure in the dynamic multi-color display. Here, polyvinyl alcohol (PVA) hydrogel structure is patterned through grayscale e-beam lithography and the controlled PVA thickness leads the programmable reflective resonance covering the entire visible range. By varying the ambient humidity between 9.8 and 90.1% RH, the reflective resonance of the structure is tailored across a wavelength range over 100 nm. Our materials platform of humidity-sensitive hydrogel resist presents a novel approach of the stepwise and reversible optical tunability for photonic devices.

In a risk society, the survival and development of humans are facing threats of complex and severe public crisis events. Public participation in collaborative governance (CG) of public crisis events is increasingly recognized as an important direction for the reform of the current and future emergency management system. Previous studies of CG have mainly focused on the macro level and ignored to address micro‐level discussions of the behavioral strategy evolution of stakeholders. From a fresh value perception perspective, this study constructs an evolutionary game model to clarify the evolution mechanism of multi‐level emergency CG. First, the value perception model is built based on Prospect Theory and Mental Accounting to optimize the traditional game matrix. Second, the evolutionary stability is analyzed to solve the system evolution law. Finally, numerical simulation is conducted in the case of Heilongjiang province, a main region of food and energy supply in China. Results showed that (1) the CG game system has a complex evolutionary path; (2) the behavior of game players is affected by perceived incomes and perceived costs; (3) compared with the reference value and the risk aversion coefficient of income accounts, game players are more sensitive to that of cost accounts; (4) enhancing the perceived value of public psychological satisfaction and government reputation is helpful for the long‐term construction of CG. Overall, this study aims to highlight the potential utility of value perception in promoting effective implementations of CG and to provide new insights for the development of CG in China and other countries. [ABSTRACT FROM AUTHOR]

The influence of fluorine on the production wet-process phosphoric acid is described. The principle, application status, advantages and disadvantages of the main defluorination process of wet phosphoric acid are reviewed. The problems existing in the current defluorination process of wet phosphoric acid are pointed out, and the future development direction is put forward in order to provide reference for the comprehensive utilization of fluorine resources in wet phosphoric acid in our country. [ABSTRACT FROM AUTHOR]