Background and Purpose: Isoleucine is a branched-chain amino acid serving as an essential nutrient resource and metabolic. However， its role in cerebral ischemic stroke remains unknown. Experimental Approach: Middle cerebral artery occlusion (MCAO) was used to mimic in vivo model of stroke. Oxygen-glucose deprivation insult (OGD) was used to injure cultured cortical neurons. High-Performance Liquid Chromatography (HPLC) was used to measure the level of isoleucine. A western blot assay and immunofluorescent staining were used to measure the level of CBFB and PTEN. TTC staining was used to measure the infarct size. Cell death and viability were assessed by LDH and CCK8 assays. DCS was used to stimulate cortical neurons. tDCS was used to stimulate the cortex. Key Results: Extraneuronal isoleucine is decreased and intraneuronal isoleucine is increased after rat cerebral I/R injury. Reducing intraneuronal isoleucine via inhibition of its transporter, LAT1 promotes neuronal survival whereas supplementing isoleucine aggravates neuronal damage. Isoleucine downregulates the expression of CBFB, and that acts upstream of PTEN to mediate isoleucine-induced neuronal damage after OGD insult. To identify the therapeutic approach that suppresses the ischemia-induced increase of intraneuronal isoleucine, we tested the effect of tDCS on isoleucine. Our data suggest that Cathodal tDCS can reduce cerebral infarct size. And such neuroprotection is mediated through reducing LAT1-dependent increase of intraneuronal isoleucine. Conclusions and Implications: This study identifies LAT1- dependent increase of intraneuronal isoleucine promotes neuronal death after rat cerebral I/R injury. Our results indicate that tDCS protects against rat cerebral I/R injury through regulating LAT1-isoleucine-CBFB-PTEN signaling.
Abstract Isoleucine is a branched chain amino acid. The role of isoleucine in cerebral ischemia–reperfusion injury remains unclear. Here, we show that the concentration of isoleucine is decreased in cerebrospinal fluid in a rat model of cerebral ischemia–reperfusion injury, the rat middle cerebral artery occlusion (MCAO). To our surprise, the level of intraneuronal isoleucine is increased in an in vitro model of cerebral ischemia injury, the oxygen–glucose deprivation (OGD). We found that the increased activity of LAT1, an L‐type amino acid transporter 1, leads to the elevation of intraneuronal isoleucine after OGD insult. Reducing the level of intraneuronal isoleucine promotes cell survival after cerebral ischemia–reperfusion injury, but supplementing isoleucine aggravates the neuronal damage. To understand how isoleucine promotes ischemia‐induced neuronal death, we reveal that isoleucine acts upstream to reduce the expression of CBFB (core binding factor β, a transcript factor involved in cell development and growth) and that the phosphatase PTEN acts downstream of CBFB to mediate isoleucine‐induced neuronal damage after OGD insult. Interestingly, we demonstrate that direct‐current stimulation reduces the level of intraneuronal isoleucine in cortical cultures subjected to OGD and that transcranial direct‐current stimulation (tDCS) decreases the cerebral infarct volume of MCAO rat through reducing LAT1‐depencent increase of intraneuronal isoleucine. Together, these results lead us to conclude that LAT1 over activation‐dependent isoleucine‐CBFB‐PTEN signal transduction pathway may mediate ischemic neuronal injury and that tDCS exerts its neuroprotective effect by suppressing LAT1 over activation‐dependent signalling after cerebral ischemia–reperfusion injury.
Inverse hysteresis model with magnetic flux density and magnetic field intensity as input and output, respectively, is more preferred, compared with the forward one, for resolving the electromagnetic issues of electrical equipment in terms of magnetic vector potential or with voltage sources. And an inverse hysteresis model with high accuracy and high computation speed has a broader range of applications. However, the well-known classical Preisach hysteresis model is formulated with the forward form, and has the double integration of its distribution function, making it inconvenient and impractical in electrical engineering. In this article, an analytical inverse Preisach model is proposed for the first time. First, the analytical expressions of permeability of the initial magnetization curve, descending and ascending branches of the hysteresis loop are derived using one closed form of the Everett integral function. Subsequently, the analytical inverse Preisach model is derived by the difference method, considering the reversible magnetization component that the classical Preisach model cannot simulate with an odd function analytically. The experiment of one grain-oriented silicon steel sample and one non-oriented silicon steel sample, under different magnetic excitation levels, is conducted, and the accuracy and efficiency of the proposed analytical inverse Preisach model are confirmed by comparing its simulated hysteresis loops with the experimental ones and that computed with the widely used inverse Jiles–Atherton (J–A) hysteresis model.
Inverse hysteresis model with magnetic flux density and magnetic field intensity as input and output respectively is more preferred, compared with the forward one, for resolving the electromagnetic problems of the electrical equipment in terms of magnetic vector potential, or for analyzing the electromagnetic issues of electrical equipment with voltage sources. And an inverse hysteresis model with high accuracy and high computation speed both has broader range of applications. However, the classical Preisach hysteresis model that is well known is formulated with the forward form, and involves the double integration of its distribution function, making it inconvenient and unpractical in the electrical engineering. In this paper, an analytical inverse Preisach model is proposed in this paper for the first time. To derive it, the analytical expressions of permeability for the initial magnetization curve, descending and ascending branches of hysteresis loop are derived using one closed form of Everett integral function. Subsequently the analytical inverse Preisach model is derived by the difference method, considering the reversible magnetization component that classical Preisach model cannot simulate with an odd function analytically. The experiment of one grain oriented silicon steel sample and one non-oriented silicon steel sample, under different magnetic excitation levels is conducted, and the accuracy and efficiency of the proposed analytical inverse Preisach model are confirmed by comparing its simulated hysteresis loops with the experimental ones and that computed with widely used inverse Jiles-Atherton hysteresis model.
Hypoxia, induced by inadequate oxygen supply, is a key indication of various major illnesses, which necessitates the need to develop new nanoprobes capable of sensing hypoxia environments for the targeted system monitoring and drug delivery. Herein, we report a hypoxia-responsive, periodic mesoporous organosilica (PMO) nanocarrier for repairing hypoxia damage. β-cyclodextrin (β-CD) capped azobenzene functionalization on the PMO surface could be effectively cleaved by azoreductase under a hypoxia environment. Moreover, the nanosystem is equipped with fluorescence resonance energy transfer (FRET) pair (tetrastyrene derivative (TPE) covalently attached to the PMO framework as the donor and Rhodamine B (RhB) in the mesopores as the receptor) for intracellular visualization and tracking of drug release in real-time. The design of intelligent nanocarriers capable of simultaneous reporting and treating of hypoxia conditions highlights a great potential in the biomedical domain.
Compound Amino Acid injection (CAA) is a clinically drug by intravenous drip for hepatic disease, kidney disease, and traumatic disease, but there is no effective CAA for brain disease because of the blood-brain barrier. Proline, which is one of main components in CAA, is a nonessential amino acid that has been shown to exhibit neuroprotective effect in the CNS. But its underlying mechanisms in the cerebral ischemia-reperfusion (I/R) injury remain unclear. We showed that the level of proline was decreased in the ischemic brain tissues in the I/R mice. Supplementing proline protected against ischemic neuronal death both in vivo and in vitro. These data suggest that proline may be developed as a potential neuroprotectant in ischemic stroke. What’s more, our data indicate that proline has low permeability to BBB in mice. To develop an approach to deliver proline into the injured brain, we prepared chitosan nanoparticles loaded with proline by using the method of ion cross-linking. We found that the proline-loaded chitosan nanoparticles efficiently passed through BBB and delivered proline into the injured brain to confer neuroprotection. Our results further demonstrated that proline upregulated the level of annexin A6 (ANX6)/β1 integrin, which in turn increased the phosphorylation of cell-survival promoting kinase Akt thereby promoting neuronal survival after I/R injury. This study developed a novel neuroprotection approach by which low BBB-permeable proline is delivered by chitosan nanoparticles into the ischemic brain . Our results reveal that proline protects against ischemic neuronal injury through regulating ANX6/β1 integrin/Akt signal transduction pathway.
Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form of cell death and RSL3 is a well-known inducer of cell ferroptosis. Here, we aimed to investigate the effects of RSL3 in neuroinflammation and sensitivity of different type of microglia and macrophage to ferroptosis.Here, we used quantitative RT-PCR analysis and ELISA analysis to analyze the production of proinflammatory cytokine production of microglia and macrophages after lipopolysaccharides (LPS) stimulation. We used CCK8, LDH, and flow cytometry analysis to evaluate the sensitivity of different microglia and macrophages to RSL3-induced ferroptosis. Western blot was used to test the activation of inflammatory signaling pathway and knockdown efficiency. SiRNA-mediated interference was conducted to knockdown GPX4 or Nrf2 in BV2 microglia. Intraperitoneal injection of LPS was performed to evaluate systemic inflammation and neuroinflammation severity in in vivo conditions.We found that ferroptosis inducer RSL3 inhibited lipopolysaccharides (LPS)-induced inflammation of microglia and peritoneal macrophages (PMs) in a cell ferroptosis-independent manner, whereas cell ferroptosis-conditioned medium significantly triggered inflammation of microglia and PMs. Different type of microglia and macrophages showed varied sensitivity to RSL3-induced ferroptosis. Mechanistically, RSL3 induced Nrf2 protein expression to inhibit RNA Polymerase II recruitment to transcription start site of proinflammatory cytokine genes to repress cytokine transcription, and protect cells from ferroptosis. Furthermore, simultaneously injection of RSL3 and Fer-1 ameliorated LPS-induced neuroinflammation in in vivo conditions.These data revealed the proinflammatory role of ferroptosis in microglia and macrophages, identified RSL3 as a novel inhibitor of LPS-induced inflammation, and uncovered the molecular regulation of microglia and macrophage sensitivity to ferroptosis. Thus, targeting ferroptosis in diseases by using RSL3 should consider both the pro-ferroptosis effect and the anti-inflammation effect to achieve optimal outcome.
Textile-based energy storage is an important energy supply element of the microelectronic signal collection system for flexible wearable textiles. This article summarizes the recent research progress of flexible supercapacitors from multiple perspectives of fibers, yarns and fabrics, and states the preparation methods, advantages and disadvantages of supercapacitors of different matrix types. Focusing on the technological characteristics of textile supercapacitors, analysis the method that should be adopted to improve the performance of materials. Finally, an explanation for the presence of textile-based supercapacitor development and the key work of future which need to overcome is given an analysis and outlook.
Propionic acid (PPA) is a critical metabolite involved in microbial fermentation, which functions to reduce fat production, inhibit inflammation, and reduce serum cholesterol levels. The role of PPA in the context of cerebral ischemia-reperfusion (I/R) injury has yet to be clarified. Increasing evidence indicate that transcranial direct-current stimulation (tDCS) is a safe approach that confers neuroprotection in cerebral ischemia injury. Here, we show that the levels of PPA were reduced in the ischemic brain following a rat cerebral I/R injury and in the cultured rat cortical neurons after oxygen-glucose deprivation (OGD), an in vitro model of ischemic injury. We found that the decreased levels of transporter protein monocarboxylate transporter-1 (MCT1) were responsible for the OGD-induced reduction of PPA. Supplementing PPA reduced ischemia-induced neuronal death after I/R. Moreover, our results revealed that the neuroprotective effect of PPA is mediated through downregulation of phosphatase PTEN and subsequent upregulation of Lon protease 1 (LONP1). We demonstrated that direct-current stimulation (DCS) increased MCT1 expression and PPA level in OGD-insulted neurons, while tDCS decreased the brain infarct volume in the MCAO rats via increasing the levels of MCT1 expression and PPA. This study supports a potential application of tDCS in ischemic stroke.
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