Background and Aims
Mitochondrial double‐stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol‐associated liver ...disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll‐like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)‐17A (IL‐17A) production in ALD.
Approach and Results
Following binge ethanol (EtOH) drinking, IL‐17A production primarily increased in γδ T cells of wild‐type (WT) mice, whereas the production of IL‐17A was mainly facilitated by CD4+ T cells in acute‐on‐chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell–depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA‐restricting enzyme, was significantly decreased in EtOH‐exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH‐treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small‐sized RNAs were enriched in EtOH‐treated Exos (EtOH‐Exos) rather than EtOH‐treated microvesicles in hepatocytes of WT mice and humans. Quantitative real‐time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH‐Exos from mice and humans. After direct treatment with EtOH‐Exos, IL‐1β expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL‐17A production of γδ T cells in mice and humans.
Conclusions
EtOH‐mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL‐1β expression in Kupffer cells triggers IL‐17A production in γδ T cells at the early stage that may accelerate IL‐17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.
Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains ...unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA-treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH.
Background and Aims
The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the ...glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon‐γ (IFN‐γ) production in both mice and humans.
Approach and Results
Following 2‐week injection of carbon tetrachloride (CCl4) or 5‐week methionine‐deficient and choline‐deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild‐type mice. Consistently, NK cell–specific mGluR5 knockout mice had aggravated CCl4‐induced liver fibrosis with decreased production of IFN‐γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti‐fibrosis‐related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN‐γ through the mitogen‐activated extracellular signal‐regulated kinase/extracellular signal‐related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl4‐induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells.
Conclusions
mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis.
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor ...4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b
F4/80
hepatic infiltrating macrophages, but not CD11b
F4/80
Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68
CD14
macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.
In the quest for renewable and highly efficient energy storage devices, all-lignin-based flexible supercapacitors are fabricated by integrating chemically cross-linked lignin hydrogel electrolytes ...with electrospun lignin/polyacrylonitrile nanofiber electrodes. The cross-linked networks of lignin-based hydrogel electrolytes show high ionic conductivity and mechanical integrity, whereas the free-standing flexible composite electrode achieves outstanding charge storage capability and kinetics arising from interconnected porous channels. The resulting devices demonstrate a high capacitance of 129.23 F g
−1
and capacitance retention of 95% over 10 000 cycles as well as flexibility and durability under diverse bending angles. Moreover, these renewable flexible supercapacitors deliver a maximum energy and power density of 4.49 W h kg
−1
and 2.63 kW kg
−1
, respectively.
In the quest for renewable and highly efficient energy storage devices, all-lignin-based flexible supercapacitors are fabricated by integrating cross-linked lignin hydrogel electrolytes with electrospun lignin/polyacrylonitrile nanofiber electrodes.
A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to ...physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.
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•The bioactive scaffolds were fabricated by a 3D bio-printing method to construct microstructures of abalone shell particles (ASP) containing bioactive factors.•ASP is thermally ...embedded on the printed scaffold, and can load heat resistant particles onto the surface and simple control the roughness of the surface.•The ASP scaffold showed increased viability, proliferation, and differentiation of osteoblast like cells.•This study shows the possibility of applying bioactive scaffolds to the natural organisms for bon tissue engineering.
Abalone shells, which contain both organic and inorganic matter, can facilitate bone remodeling and have been used to fabricate three-dimensional (3D)-printed scaffolds for bone regeneration. Herein, polycaprolactone (PCL) scaffolds were fabricated using 3D printing with abalone shell particles (ASPs) used in high-temperature processing. ASPs were heated to approximately the melting point of PCL and thermally embedded in 3D-printed PCL using a relatively simple process. The morphology and roughness of the composite scaffold changed according to the weight of ASPs used. The scaffolds were grouped as follows: ASP25 (25 mg), ASP50 (50 mg), and ASP100 (100 mg). The ASP25 group exhibited optimum cell viability and proliferation because of the direct influence of roughness and rapid pH changes. The ASP25 and ASP100 groups showed the highest alkaline phosphatase activity. This could be attributed to the effect of the alkaline environment, dissolution of calcium ions, and presence of bioactive molecules in the ASPs that could support bone regeneration. Therefore, the ASP25 group was the most suitable for fabricating bone scaffolds. This study revealed the potential applicability of ASP-embedded scaffolds in bone tissue engineering involving natural bio-organisms that self-mineralize in a process similar to human bone formation.
Design and fabrication of a 1-MW inductive power transfer (IPT) system that supplies power to the vehicle in real time without any battery charge is proposed for a high-speed train. The IPT system ...consists of a 1-MW resonant inverter, a 128-m transmitter, four pickups, including rectifiers, and a wireless feedback network to maintain a constant output voltage of the pickups. The operating frequency of the system is 60 kHz to achieve efficient power transfer with a large air gap. The measured efficiency of the IPT system at the 818-kW output power of the pickups for the 5-cm air gap is 82.7%. The electromagnetic field and the induced voltage at the rail are also measured for safety evaluation. The fabricated IPT system was adapted to the high-speed train, and the train successfully accelerates to a speed of 10 km/h according to startup procedures.
Multi‐valued logic (MVL) technology that utilizes more than two logic states has recently been reconsidered because of the demand for greater power saving in current binary logic systems. Extensive ...efforts have been invested in developing MVL devices with multiple threshold voltages by adopting negative differential transconductance and resistance. In this study, a reconfigurable, multiple negative‐differential‐resistance (m‐NDR) device with an electric‐field‐induced tunability of multiple threshold voltages is reported, which comprises a BP/ReS2 heterojunction and a ReS2/h‐BN/metal capacitor. Tunability for the m‐NDR phenomenon is achieved via the resistance modulation of the ReS2 layer by electrical pulses applied to the capacitor region. Reconfigurability is verified in terms of the function of an MVL circuit composed of a reconfigurable m‐NDR device and a load transistor, wherein staggered‐type and broken‐type double peak‐NDR device operations are adopted for ternary inverter and latch circuits, respectively.
A reconfigurable, multiple negative‐differential‐resistance device with an electric‐field‐induced tunability of multiple threshold voltages is proposed. Following the successful verification of the tunability of multiple negative‐differential‐resistance phenomenon, the reconfigurability in terms of the function of multi‐valued logic circuits, from ternary inverter to latch circuit, is demonstrated.
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