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.
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.
The ability to image pressure distribution over complex three-dimensional surfaces would significantly augment the potential applications of electronic skin. However, existing methods show poor ...spatial and temporal fidelity due to their limited pixel density, low sensitivity, or low conformability. Here, we report an ultraflexible and transparent electroluminescent skin that autonomously displays super-resolution images of pressure distribution in real time. The device comprises a transparent pressure-sensing film with a solution-processable cellulose/nanowire nanohybrid network featuring ultrahigh sensor sensitivity (>5000 kPa
) and a fast response time (<1 ms), and a quantum dot-based electroluminescent film. The two ultrathin films conform to each contact object and transduce spatial pressure into conductivity distribution in a continuous domain, resulting in super-resolution (>1000 dpi) pressure imaging without the need for pixel structures. Our approach provides a new framework for visualizing accurate stimulus distribution with potential applications in skin prosthesis, robotics, and advanced human-machine interfaces.
Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD ...using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.
Main Points
Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules ...(SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs.
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•We performed BioID on 119 human proteins involved in various facets of mRNA biology•Proximal relationships reveal the spatial organization of RNA regulatory structures•Prey-based analysis identifies 144 protein components of cytosolic RNA granules•UBAP2L, CSDE1, and PRRC2C are required for efficient formation of stress granules
Youn et al. performed proximity-based proteomics on 119 human proteins involved in the mRNA life cycle, focusing on cytosolic RNA granule components that are important for mRNA regulation. Systematic analysis of the proximal interactome revealed 144 core components of cytosolic RNA granules and illuminated the spatial organization of RNA regulatory structures.
Based on the base module of Universal Robotics, this paper deals with a 16-pole, 18-slot fractional-slot concentrated-winding permanent magnet synchronous machine (PMSM) for articulated robot ...applications considering several pole-slot combinations and using an optimum design. The selected PMSM considering the pole-slot combination is optimized and compared both analytically and experimentally. The experimental results confirmed that the proposed PMSM can achieve improved performance at the rated state. Repeatability test results of the proposed smart actuator with a link-attached sphere-mounted retroreflector sensor met the goal of within <inline-formula> <tex-math notation="LaTeX">100~\mu \text{m} </tex-math></inline-formula> according to a laser tracker. The analysis results are in good agreement with the experimental results within the maximum 2.5% error in terms of the efficiency. The design, analysis, and experiment with the PMSM for articulated robot applications were conducted successfully.
Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively ...expressed channelrhodopsin‐2 (ChR2), a light‐sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole‐cell patch‐clamp recordings in two functionally distinct types of VLPO neurons: sleep‐promoting GABAergic projection neurons and non‐sleep‐promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non‐sleep‐promoting neurons and excitation of sleep‐promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue‐nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin‐negative VLPO neurons, but not in galanin‐positive sleep‐promoting projection neurons. Taken together, these results suggest that astrocyte‐derived ATP is converted into adenosine by TNAP in non‐sleep‐promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep‐promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte‐neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep‐promoting VLPO neurons, and thus decreases neuronal excitability in arousal‐related areas of the brain.
Main Points
Astrocyte‐derived adenosine decreased the excitability of local GABAergic neurons, and indirectly excited sleep‐promoting neurons within the VLPO.
The present results provide a novel mechanism of astrocyte‐neuron interactions in sleep regulation.
Background Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. Methods To ...investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. Results Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. Conclusions ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value. Keywords: AMPK, Metformin, mTORC1, REDD1, Sestrin2
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