The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
The purpose of the present study was to investigate whether catalpol exhibited neuroprotective effects in chronic unpredictable mild stress (CUMS) mice through oxidative stress-mediated ...nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3 (NLRP3) inflammasome and neuroinflammation. Deficits in behavioral tests, including open field test (OFT), forced swim test (FST), and elevated plus-maze test (EPM), were ameliorated following catalpol administration. To study the potential mechanism, western blots, quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence imaging were performed on the hippocampus samples. We found that the defects of behavioral tests induced by CUMS could be reversed by the absence of NLRP3 and NLRP3 inflammasome might be involved in the antidepressant effects of catalpol on CUMS mice. Similar to the NLRP3 inflammasome, the expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and inducible nitride oxide synthase (iNOS) were increased after CUMS. The current study demonstrated that catalpol possessed anti-inflammatory effect on CUMS mice and inhibited microglial polarization to the M1 phenotype. In addition, the activity of mitochondrial oxidative stress might be involved in the NLRP3 activation, which was proved by the downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved IL-1β, after the administration of mitochondrion-targeted antioxidant peptide SS31. Taken together, we provided evidence that catalpol exhibited antidepressive effects on CUMS mice possibly via the oxidative stress-mediated regulation of NLRP3 and neuroinflammation.
Detecting epileptic seizure from EEG signals constitutes a challenging problem of significant importance. Combining adaptive optimal kernel time-frequency representation and visibility graph, we ...develop a novel method for detecting epileptic seizure from EEG signals. We construct complex networks from EEG signals recorded from healthy subjects and epilepsy patients. Then we employ clustering coefficient, clustering coefficient entropy and average degree to characterize the topological structure of the networks generated from different brain states. In addition, we combine energy deviation and network measures to recognize healthy subjects and epilepsy patients, and further distinguish brain states during seizure free interval and epileptic seizures. Three different experiments are designed to evaluate the performance of our method. The results suggest that our method allows a high-accurate classification of epileptiform EEG signals.
The role of physical exercise in the prevention of Alzheimer's disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) ...is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear.
Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, 18F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia.
Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5
/IBA1
microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2'-deoxyuridine (BrdU)
/IBA1
microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice.
Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.
Energy storage materials and their applications have attracted attention among both academic and industrial communities. Over the past few decades, extensive efforts have been put on the development ...of lead-free high-performance dielectric capacitors. In this review, we comprehensively summarize the research progress of lead-free dielectric ceramics for energy storage, including ferroelectric ceramics, composite ceramics, and multilayer capacitors. The results indicate that dielectric capacitors with both high energy density and high efficiency are feasible using the materials providing high breakdown electric field and a slim hysteresis loop. This article also lists the factors affecting the fabrication cost of dielectric capacitors, such as sintering temperature, raw material costs, and types of internal electrodes, to promote the industrial application of ceramic energy storage capacitors.
Typical lead-free energy storage systems and their performances for dielectric and multilayer capacitors over the last decade.
Abstract
Although chirality is an ever-present characteristic in biology and some artificial molecules, controlling the chirality and demystifying the chirality origin of complex assemblies remain ...challenging. Herein, we report two homochiral Ag
14
nanoclusters with inherent chirality originated from identical rotation of six square faces on a Ag
8
cube driven by intra-cluster π···π stacking interaction between pntp
−
(Hpntp =
p-
nitrothiophenol) ligands. The spontaneous resolution of the racemic (SD/
rac
-Ag14a) to homochiral nanoclusters (SD/
L
-Ag14 and SD/
R
-Ag14) can be realized by re-crystallizing SD/
rac
-Ag14a in acetonitrile, which promotes the homochiral crystallization in solid state by forming C–H···O/N hydrogen bonds with nitro oxygen atoms in pntp
−
or aromatic hydrogen atoms in dpph (dpph = 1,6-bis(diphenylphosphino)hexane) on Ag
14
nanocluster. This work not only provides strategic guidance for the syntheses of chiral silver nanoclusters in an all-achiral environment, but also deciphers the origin of chirality at molecular level by identifying the special effects of intra- and inter-cluster supramolecular interactions.
The elaborate selection of capping ligands is of great importance in the synthesis of atomically precise metal nanoclusters. Organic thiolates, alkynyls, phosphines, and/or their combinations are the ...ligands most widely utilized to protect metal nanoclusters, while inorganic oxo anions have been almost neglected in this field. Herein, the first CrO4 2–/ t BuCC– co-capped Ag48 nanocluster (SD/Ag48, SD = SunDi) was synthesized and structurally characterized by single-crystal X-ray diffraction. The pseudo-5-fold symmetric metal skeleton of SD/Ag48 shows a core–shell structure composed of a Ag23 cylinder encircled by an outer Ag25 shell. Unprecedentedly, coexistence of inorganic (CrO4 2–) and organic ( t BuCC–) ligands was observed on the surface of SD/Ag48. The inorganic CrO4 2– anion plays three important roles in the construction of silver nanoclusters: (i) passivating the Ag23 kernel; (ii) connecting the core and shell; and (iii) protecting the Ag25 shell. This nanocluster belongs to a 14e superatom system and exhibits successive molecule-like absorption bands from the visible to the ultraviolet region. This work not only establishes a fresh inorganic ligand strategy in the synthesis of silver nanoclusters but also provides a new insight into the important surface coordination chemistry of CrO4 2– in the shape control of silver nanoclusters.
MOF (metal organic framework) materials have been used as functional materials in a number of fields due to their diverse spatial tunability, which produces rich porous structures with stable and ...continuous pores and a high specific surface area. A triboelectric nanogenerator can convert trace mechanical energy into electrical energy, and the application of MOF materials to triboelectric nanogenerators has been intensively studied. In this work, we report on two MOFs with similar spatial structures, and the modulation of the end microstructures was achieved using the difference in F content. The output performance of friction power generation increases with the increase in F content, and the obtained polyacidic ligand materials can be used to construct self-powered corrosion protection systems, which can effectively protect metallic materials from corrosion.
Carboxylation with carbon dioxide (CO2) represents one notable methodology to produce carboxylic acids. In contrast to carbon–heteroatom bonds, carbon–carbon bond cleavage for carboxylation with CO2 ...is far more challenging due to their inherent and less favorable orbital directionality for interacting with transition metals. Here we report a photocatalytic protocol for the deconstructive carboxylation of alkenes with CO2 to generate carboxylic acids in the absence of transition metals. It is emphasized that our protocol provides carboxylic acids with obviously unchanged carbon numbers when terminal alkenes were used. To show the power of this strategy, a variety of pharmaceutically relevant applications including the modular synthesis of propionate nonsteroidal anti‐inflammatory drugs and the late‐stage carboxylation of bioactive molecule derivatives are demonstrated.
A novel metal‐free photochemical method for the deconstructive carboxylation of alkenes with CO2 is reported for the first time. The power of this strategy is demonstrated for the late‐stage carboxylation of bioactive molecule derivatives and the synthesis of propionate nonsteroidal anti‐inflammatory drugs.
A series of (
)-1-phenyl-3,4-dihydroisoquinoline-2(1
)-carboxamide derivatives was synthesized and evaluated for inhibitory activity against monoamine oxidase (MAO)-A and-B, acetylcholine esterase ...(AChE), and butyrylcholine esterase (BChE). Four compounds (
,
,
, and
) showed good inhibitory activity against both MAO-A and MAO-B, and two compounds (
and
) showed selective inhibitory activity against MAO-A, with IC
values of 1.38 and 2.48 µM, respectively. None of the compounds showed inhibitory activity against AChE; however, 12 compounds showed inhibitory activity against BChE. None of the active compounds showed cytotoxicity against L929cells. Molecular docking revealed several important interactions between the active analogs and amino acid residues of the protein receptors. This research paves the way for further study aimed at designing MAO and ChE inhibitors for the treatment of depression and neurodegenerative disorders.
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![[Ag48(CC t Bu)20(CrO4)7]: ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0002-7863/small "[Ag48(CC t Bu)20(CrO4)7]: An Atomically Precise Silver Nanocluster Co-protected by Inorganic and Organic Ligands")
