In the adult hippocampus, synapses are constantly formed and eliminated
. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we ...show that astrocytic phagocytosis
is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.
Recent findings demonstrate that cellulose, a highly abundant, versatile, sustainable, and inexpensive material, can be used in the preparation of very stable and flexible electrochemical energy ...storage devices with high energy and power densities by using electrodes with high mass loadings, composed of conducting composites with high surface areas and thin layers of electroactive material, as well as cellulose‐based current collectors and functional separators. Close attention should, however, be paid to the properties of the cellulose (e.g., porosity, pore distribution, pore‐size distribution, and crystallinity). The manufacturing of cellulose‐based electrodes and all‐cellulose devices is also well‐suited for large‐scale production since it can be made using straightforward filtration‐based techniques or paper‐making approaches, as well as utilizing various printing techniques. Herein, the recent development and possibilities associated with the use of cellulose are discussed, regarding the manufacturing of electrochemical energy storage devices comprising electrodes with high energy and power densities and lightweight current collectors and functional separators.
The recent progress of cellulose, as an appealing natural material that can outperform traditional synthetic materials, for use in energy‐storage devices is described. Cellulose can bring benefits in the fabrication and properties of energy‐storage materials and devices, eventually enabling significant improvements in electrochemical performance, mechanical flexibility, cost competitiveness, and form factors, which are difficult to achieve with conventional power source technologies.
Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic ...radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear.
By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts.
Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation.
Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.
Here, an electrode comprising a Zn hexagonal pyramid array (HPA) coated with a functionalized ZnO layer (Zn@ZnO HPA) is prepared using a periodic anodizing technique. The HPA structure markedly ...increases the electroactive surface area of Zn anode, thus decreasing the local current density. Furthermore, the functionalized ZnO coating layer has a gradient thickness that plays an important role in the selective deposition of Zn ions and the mitigation of side reactions at the interface. The electrochemical stability of the Zn@ZnO HPA electrode, which is closely related to the electroactive surface area and charge transfer resistance, is determined by the “split” value, i.e., ratio of current‐off to current‐on time, a parameter of the periodic anodizing process. Compared with the pristine Zn‐based symmetric cell, the Zn@ZnO HPA‐based symmetric cell is safely operated in the investigated experimental range with the 10‐fold improved running life and 25‐fold enhanced current density without Zn dendrite growth. Moreover, the Zn@ZnO HPA/MnO2 battery exhibits outstanding long‐term cyclability (nearly 100%) with greater than 99% Coulombic efficiency after 1000 cycles at a current density of 9 A g−1. This periodic anodizing technique for ultrastable Zn metal anodes is expected to contribute to the development of inherently safe energy storage systems.
A Zn hexagonal pyramid array coated with a functionalized ZnO layer (Zn@ZnO HPA) prepared via a periodic anodizing process acts as a Zn metal electrode for inherently safe Zn ion aqueous batteries. The unique Zn@ZnO HPA anode shows improved stability without dendrite formation owing to the large surface area and guided Zn ion plating.
Chemotherapy, one of the principal approaches for cancer patients, plays a crucial role in controlling tumor progression. Clinically, tumors reveal a satisfactory response following the first ...exposure to the chemotherapeutic drugs in treatment. However, most tumors sooner or later become resistant to even chemically unrelated anticancer agents after repeated treatment. The reduced drug accumulation in tumor cells is considered one of the significant mechanisms by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell membrane. The mechanisms of treatment failure of chemotherapeutic drugs have been investigated, including drug efflux, which is mediated by extracellular vesicles (EVs). Exosomes, a subset of EVs with a size range of 40–150 nm and a lipid bilayer membrane, can be released by all cell types. They mediate specific cell‐to‐cell interactions and activate signaling pathways in cells they either fuse with or interact with, including cancer cells. Exosomal RNAs are heterogeneous in size but enriched in small RNAs, such as miRNAs. In the primary tumor microenvironment, cancer‐secreted exosomes and miRNAs can be internalized by other cell types. MiRNAs loaded in these exosomes might be transferred to recipient niche cells to exert genome‐wide regulation of gene expression. How exosomal miRNAs contribute to the development of drug resistance in the context of the tumor microenvironment has not been fully described. In this review, we will highlight recent studies regarding EV‐mediated microRNA delivery in formatting drug resistance. We also suggest the use of EVs as an advancing method in antiresistance treatment.
Phthalate esters (PEs) are the most commonly used plasticizers and one of the endocrine disrupting chemicals (EDCs) which are extensively present in various environment. Therefore, it is important to ...examine the levels and distribution of phthalates in multimedia environment. This study investigated the seasonal and spatial variation of 14 PEs in air, water, sediments, and fish in the Asan Lake. Asan Lake is one of the largest artificial lakes in Korea, and is surrounded by industrial complex and farmlands. The PEs were found to be present throughout the study area. The mean concentration of total PEs (∑14 PEs) was 3.92–33.09 ng/m3 in air, not detected (n.d.)-2.29 μg/L in water, 3.6–8973 μg/kg dry weight (dw) in sediment, and n.d.-1081 μg/kg dw in fish, respectively. The most frequently detected phthalate in the samples was di(2-ethylhexyl) phthalate (DEHP), and followed by di-n-butyl phthalate (DBP). The concentrations of PEs in water and sediment samples tended to decrease moving downstream of Asan Lake. Bioaccumulation of PEs showed that benthic feeding fish such as crucian carp or skygager contained higher levels of DEHP. Partitioning of DEHP and DBP between water and sediment was calculated using paired sediment/water samples and fugacity fraction (ff). High ff value (ff = 0.89 ± 0.1) of DBP and low ff value of DEHP (ff = 0.24 ± 0.1) confirmed that DEHP is the most abundant PEs in the sediment, and DBP is the second most abundant PEs except DEHP in water. Our results can provide important information of the distribution and behavior of PEs in the lake environment.
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•14 phthalates were measured in air, water, sediment, and fish in Asan lake areas.•Among phthalates, 2. DEHP and DBP were most frequently detected in all media.•Phthalate levels in water and sediment increased moving downstream of the lake.•Benthic feeding fish such as crucian carp or skygazer contained high level of DEHP.•Sediment was a sink of DEHP and the potential secondary source of DBP in the lake.
Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate ...hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.
Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).
HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of
but not
was higher in mouse models and patients with NASH. FC in hepatocytes induced
expression, and
knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of
prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but
knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.
SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.
Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in ...cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, we engineered liposomal indocyanine green (ICG) to maximize its photothermal effects while maintaining the fluorescence intensity. Various liposomal formulations of ICG were prepared ...by varying the lipid composition and the molar ratio between total lipid and ICG, and their photothermal characteristics were evaluated under near-infrared irradiation. We showed that the ICG dispersity in the liposomal membrane and its physical interaction with phospholipids were the main factors determining the photothermal conversion efficiency. In phototherapeutic studies, the optimized formulation of liposomal ICG showed greater anticancer effects in a mouse tumor model compared with other liposomal formulations and the free form of ICG. Furthermore, we utilized liposomal ICG to visualize the metastatic lymph node around the primary tumor under fluorescence imaging guidance and ablate the lymph node with the enhanced photothermal effect, indicating the potential for selective treatment of metastatic lymph node.
It has been established that nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological ...inhibition of NF‐κB is required for tumor necrosis factor (TNF)‐induced hepatocyte apoptosis. In this study, we demonstrate that this pro‐survival pathway is switched to pro‐apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)‐deficient conditions. PDK4‐deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c‐Jun N‐terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein‐protein interaction. Disruption of PDK4‐p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF‐TNFR1 apoptotic pathway. Pdk4−/− livers were sensitized to Jo2 and D‐(+)‐Galactosamine /Lipopolysaccharide (GalN/LPS)‐mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro‐survival activity of TNF was shifted, which was switched to a pro‐apoptotic activity in Pdk4−/− hepatocytes as a result of impaired activation of pro‐survival NF‐κB targets. Conclusion: PDK4 is indispensable to dictate the fate of TNF/NF‐κB‐mediated hepatocyte apoptosis. (Hepatology 2018).
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