Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis.

Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/ß-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl4-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg-1·d-1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.

Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation.

Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high­throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride­induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin­3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC­LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF­ß1­induced expression of α­smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.

Implementation of Dropout Neuronal Units Based on Stochastic Memristive Devices in Neural Networks with High Classification Accuracy.

Neural networks based on memristive devices have achieved great progress recently. However, memristive synapses with nonlinearity and asymmetry seriously limit the classification accuracy. Moreover, insufficient number of training samples in many cases also have negative effect on the classification accuracy of neural networks due to overfitting. In this work, dropout neuronal units are developed based on stochastic volatile memristive devices of Ag/Ta2O5:Ag/Pt. The memristive neural network using the dropout neuronal units effectively solves the problem of overfitting and mitigates the negative effects of the nonideality of memristive synapses, eventually achieves a classification accuracy comparable to the theoretical limit. The stochastic and volatile switching performances of the Ag/Ta2O5:Ag/Pt device are attributed to the stochastical rupture of the Ag filament under high electrical stress in the Ta2O5 layer, according to the TEM observation and the kinetic Monte Carlo simulation.

Multi-gate memristive synapses realized with the lateral heterostructure of 2D WSe2 and WO3.

The development of novel synaptic device architectures with a high order of synaptic plasticity can provide a breakthrough toward neuromorphic computing. Herein, through the thermal oxidation of two-dimensional (2D) WSe2, unique memristive synapses based on the lateral heterostructure of 2D WSe2 and WO3, with multi-gate modulation characteristics, are firstly demonstrated. An intermediate transition layer in the heterostructure is observed through transmission electron microscopy. Raman spectroscopy and detailed electrical measurements provide insights into the mechanism of memristive behavior, revealing that the protons injected into/removed from the intermediate transition layer account for the memristive behavior. This novel memristive synapse can be used to emulate two neuron-based synaptic functions, like post-synaptic current, short-term plasticity and long-term plasticity, with remarkable linearity, symmetry, and an ultralow energy consumption of ∼2.7 pJ per spike. More importantly, the synaptic plasticity between the drain and source electrodes can be effectively modulated by the gate voltage and visible light in a four-terminal configuration. Such multi-gate tuning of the synaptic plasticity cannot be accomplished by any previously reported multi-gate synaptic devices that only mimic two neuron-based synapses. This new synaptic architecture with electrical and optical modulation enables a realistic emulation of biological synapses whose synaptic plasticity can be additionally regulated by the surrounding astrocytes, greatly improving the recognition accuracy and processing capacity of artificial neuristors, and paving a new way for highly efficient neuromorphic computation devices.

Structure and magnetic properties of highly oriented LaBaCo2O5+δ films deposited on Si wafers with Pt/Ti buffer layer.

Fabrication of highly crystalline oxide films onto silicon wafers has long been a critical obstacle for integrating multi-functional oxides into silicon-based technology. Herein, Pt/Ti is used as a buffer layer for the integration of highly oriented crystalline LaBaCo2O5+δ (LBCO) thin films onto silicon via pulsed laser deposition. LBCO films are highly (00l) oriented with smooth and sharp LBCO/Pt interfaces. The highly oriented LBCO films exhibit a high magnetic transition temperature (TC) and large coercive field (HC) with superparamagnetism over those deposited on single crystal substrates. What is more, the metallic-like behavior with enhanced magnetoresistance is also observed. The opportunity of using a Pt/Ti buffer layer as the growth template opens an alternative route for integrating functional transition metal oxides with tunable magnetic properties into Si-based technology.

Identification of biomarkers in macrophages of atherosclerosis by microarray analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) refers to a series of diseases caused by atherosclerosis (AS). It is one of the most important causes of death worldwide. According to the inflammatory response theory, macrophages play a critical role in AS. However, the potential targets associated with macrophages in the development of AS are still obscure. This study aimed to use bioinformatics tools for screening and identifying molecular targets in AS macrophages. METHODS: Two expression profiling datasets (GSE7074 and GSE9874) were obtained from the Gene Expression Omnibus dataset, and differentially expressed genes (DEGs) between non-AS macrophages and AS macrophages were identified. Functional annotation of the DEGs was performed by analyzing the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. STRING and Cytoscape were employed for constructing a protein-protein interaction network and analyzing hub genes. RESULTS: A total of 98 DEGs were distinguished between non-AS macrophages and AS macrophages. The functional variations in DEGs were mainly enriched in response to hypoxia, respiratory gaseous exchange, protein binding, and intracellular, ciliary tip, early endosome membrane, and Lys63-specific deubiquitinase activities. Three genes were identified as hub genes, including KDELR3, CD55, and DYNC2H1. CONCLUSION: Hub genes and DEGs identified by using microarray techniques can be used as diagnostic and therapeutic biomarkers for AS.

Electric field control of resistive switching and magnetization in epitaxial LaBaCo2O5+δ thin films.

The low operating temperature and volatile characteristics of the magnetization change are the main obstacles for the practical applications of spintronic and magnetic memories. In this work, both the resistive switching and magnetization switching are realized in Pt/LaBaCo2O5+δ (LBCO)/Nb-doped SrTiO3 (Nb-STO) devices at room temperature through an electric field. Unlike the traditional approach of an external stress inducing a volatile magnetization change, the magnetization in the Pt/LBCO/Nb-STO device is modulated by an electrical field, along with the resistive switching. The resistive and magnetization switching can be attributed to the variation of the depletion layer width at the LBCO/Nb-STO interface via oxygen vacancy migration and the increase/decrease of the Co-O-Co bond length, respectively. The present device with the synchronous manipulation of both resistance and magnetization at room temperature can be applied in nonvolatile resistive memories and novel magnetic multifunctional devices.

Quasi-Hodgkin-Huxley Neurons with Leaky Integrate-and-Fire Functions Physically Realized with Memristive Devices.

Artificial neurons with functions such as leaky integrate-and-fire (LIF) and spike output are essential for brain-inspired computation with high efficiency. However, previously implemented artificial neurons, e.g., Hodgkin-Huxley (HH) neurons, integrate-and-fire (IF) neurons, and LIF neurons, only achieve partial functionality of a biological neuron. In this work, quasi-HH neurons with leaky integrate-and-fire functions are physically demonstrated with a volatile memristive device, W/WO3 /poly(3,4-ethylenedioxythiophene): polystyrene sulfonate/Pt. The resistive switching behavior of the device can be attributed to the migration of protons, unlike the migration of oxygen ions normally involved in oxide-based memristors. With multifunctions similar to their biological counterparts, quasi-HH neurons are advantageous over the reported HH and LIF neurons, demonstrating their potential for neuromorphic computing applications.

Ionic Conduction in Composite Polymer Electrolytes: Case of PEO:Ga-LLZO Composites.

By dispersing Li6.25Ga0.25La3Zr2O12 (Ga-LLZO) nanoparticles in poly(ethylene oxide) (PEO) matrix, PEO:Ga-LLZO composite polymer electrolytes are synthesized. The PEO: Ga-LLZO composite with 16 vol % Ga-LLZO nanoparticles shows a conductivity of 7.2 × 10-5 S cm-1 at 30 °C, about 4 orders of magnitude higher than the conductivity of PEO. The enhancement of the ionic conductivity is closely related to the space charge region (∼3 nm) formed at the interface between the PEO matrix and the Ga-LLZO nanoparticles. The space charge region is observed by transmission electron microscope (TEM) and corroborated by the phase-field simulation. Using the random resistor model, the lithium-ion transport in the composite polymer electrolyte is simulated by the Monte Carlo simulation, demonstrating that the enhanced ionic conductivity can be ascribed to the ionic conduction in the space charge regions and the percolation of the space charge regions.

Photonic Potentiation and Electric Habituation in Ultrathin Memristive Synapses Based on Monolayer MoS2.

Monolayer of 2D transition metal dichalcogenides, with a thickness of less than 1 nm, paves a feasible path to the development of ultrathin memristive synapses, to fulfill the requirements for constructing large-scale high density 3D stacking neuromorphic chips. Herein, memristive devices based on monolayer n-MoS2 on p-Si substrate with a large self-rectification ratio, exhibiting photonic potentiation and electric habituation, are successfully fabricated. Versatile synaptic neuromorphic functions, such as potentiation/habituation, short-term/long-term plasticity, and paired-pulse facilitation, are successfully mimicked based on the inherent persistent photoconductivity performance and the volatile resistive switching behavior. These findings demonstrate the potential applications of ultrathin transition metal dichalcogenides for memristive synapses. These memristive synapses with the combination of photonic and electric neuromorphic functions have prospective in the applications of synthetic retinas and optoelectronic interfaces for integrated photonic circuits based on mixed-mode electro-optical operation.

Effects of prostaglandin E1 infused via the superior mesenteric artery on partially resected, dearterialized canine liver.

This study was performed to determine whether the infusion of prostaglandin E1 (PGE1) via the superior mesenteric artery (SMA) lessens hypoxic hepatic injury in beagle dogs subjected to major hepatectomy and dearterialization. Changes in systemic and hepatic hemodynamics by infusion of PGE1 were measured in intact and dearterialized dogs. The effects of infusion at 0.02 microg/kg/min were also studied in dogs that underwent resection of 55% of the liver and complete dearterialization. PGE1 infusion significantly increased portal vein flow and hepatic oxygen delivery. Hepatic dearterialization remarkably decreased delivery, but infusion at 0.02 microg/kg/min significantly restored it to 88% of the pre-dearterialized value. In hepatectomized animals, complete dearterialization provoked fatal hepatic damage, but infusion remarkably improved hepatic parenchymal and non-parenchymal injury. PGE1 through SMA might be useful for patients who have undergone major hepatectomy and combined arterial resection without reconstruction.