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Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer's disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer's disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.

Vanadium compounds have been reported to mimic the anti-diabetes effects of insulin on rodent models, but their effects on Alzheimer’s disease (AD) have rarely been explored. In this paper, 9-month-old triple transgenic AD model mice (3×Tg-AD) received bis(ethylmaltolato)oxidovanadium(iv) (BEOV) at doses of 0.2 mmol L−1 (68.4 μg mL−1) and 1.0 mmol L−1 (342 μg mL−1) for 3 months. BEOV at both doses was found to improve contextual memory and spatial learning in AD mice. It also improved glucose metabolism and protected neuronal synapses in the AD brain, as evidenced respectively by 18F-labeled fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) scanning and by transmission electron microscopy. Inhibitory effects of BEOV on β-amyloid (Aβ) plaques and neuronal impairment in the cortex and hippocampus of fluorescent AD mice were visualized three-dimensionally by applying optical clearing technology to brain slices before confocal laser scanning microscopy. Western blot analysis semi-quantitatively revealed the altered levels of Aβ42 in the brains of wildtype, AD, and AD treated with 0.2 and 1.0 mmol L−1 BEOV mice (70.3%, 100%, 83.2% and 56.8% in the hippocampus; 82.4%, 100%, 66.9% and 42% in the cortex, respectively). The mechanism study showed that BEOV increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) (140%, 100%, 142% and 160% in the hippocampus; 167%, 100%, 124% and 133% in the cortex) to inactivate the JAK2/STAT3/SOCS-1 pathway and to block the amyloidogenesis cascade, thus attenuating Aβ-induced insulin resistance in AD models. BEOV also reduced protein tyrosine phosphatase 1B (PTP1B) expression (74.8%, 100%, 76.5% and 53.8% in the hippocampus; 71.8%, 100%, 94.2% and 81.8% in cortex) to promote insulin sensitivity and to stimulate the PI3K/Akt/GSK3β pathway, subsequently reducing tau hyperphosphorylation (phosphorylated tau396 levels were 51.1%, 100%, 56.1% and 50.2% in the hippocampus; 22.2%, 100%, 36.1%, and 24% in the cortex). Our results suggested that BEOV reduced the pathological hallmarks of AD by targeting the pathways of PPARγ and PTP1B in 3×Tg AD mice.

Anisotropy and inhomogeneity are ubiquitous in spark plasma sintered thermoelectric devices. However, the origin of inhomogeneity in thermoelectric nanocomposites has rarely been investigated so far. Herein, we systematically study the impact of inhomogeneity in spark plasma sintered bismuth antimony telluride (BiSbTe) thermoelectric nanocomposites fabricated from solution-synthesized nanoplates. The figure of merit can reach 1.18, which, however, can be overestimated to 1.88 without considering the inhomogeneity. Our study reveals that the inhomogeneity in thermoelectric properties is attributed to the non-uniformity of porosity, textures and elemental distribution from electron backscatter diffraction and energy-dispersive spectroscopy characterizations. This finding suggests that the optimization of bulk material homogeneity should also be actively pursued in any future thermoelectric material research.

The proper orientation of centrosome and spindle is essential for genome stability; however, the mechanism that governs these processes remains elusive. Here, we demonstrated that polo-like kinase 1 (Plk1), a key mitotic kinase, phosphorylates residue Thr76 in VCP/p97 (an AAA-ATPase), at the centrosome from prophase to anaphase. This phosphorylation process recruits VCP to the centrosome and in this way, it regulates centrosome orientation. VCP exhibits strong co-localization with Eg5 (a mitotic kinesin motor), at the mitotic spindle, and the dephosphorylation of Thr76 in VCP is required for the enrichment of both VCP and Eg5 at the spindle, thus ensuring proper spindle architecture and chromosome segregation. We also showed that the phosphatase, PTEN, is responsible for the dephosphorylation of Thr76 in VCP; when PTEN was knocked down, the normal spread of VCP from the centrosome to the spindle was abolished. Cryo-EM structures of VCP

Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer's disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer's disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.

Alzheimer’s disease (AD) patients often exhibit perturbed circadian rhythm with fragmented sleep before disease onset. This study was designed to evaluate the effect of a 40-Hz light flicker on circadian rhythm in an AD mouse model (APP/PS1). Locomotor rhythms recordings were conducted to examine the circadian clock rhythm in APP/PS1 mice. Molecular biology analyses, including western blot and real-time qPCR assays, were conducted to assess the changes in circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like protein-1 (BMAL1), and period 2 (PER2). In addition to determining the direct effect of a 40-Hz light flicker on hypothalamic central clock, whole-cell voltage-clamp electrophysiology was employed to record individual neurons of suprachiasmatic nucleus (SCN) sections. The results reported herein demonstrate that a 40-Hz light flicker relieves circadian rhythm disorders in APP/PS1 mice and returns the expression levels of key players in the central circadian clock, including Clock, Bmal1, and Per2, to baseline. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in SCN neurons is significantly lower in APP/PS1 mice than in the control, and the amplitude of sIPSCs is decreased. Exposure to a 40-Hz light flicker significantly increases the sIPSC frequency in SCN neurons of APP/PS1 mice, with little effect on the amplitude. However, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) are both unaffected by a 40-Hz light flicker. The data suggest that a 40-Hz light flicker can ameliorate AD-associated circadian rhythm disorders, presenting a new type of therapeutic treatment for rhythm disorders caused by AD.

Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/β-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3×Tg-AD) had been treated with sodium selenate in drinking water for 10month before the detection of hippocampal pathology. Increased Aβ generation, tau hyperphosphorylation and neuronal apoptosis were found in the hippocampus of AD model mouse. Down-regulation of Wnt/β-catenin signaling is closely associated with the alteration of AD pathology. Treatment with sodium selenate significantly promoted the activity of protein phosphatases of type 2A (PP2A) and repressed the hallmarks of AD. Activation of PP2A by sodium selenate could increase active β-catenin level and inhibit GSK3β activity in the hippocampal tissue and primarily cultured neurons of AD model mouse, leading to activation of Wnt/β-catenin signaling and transactivation of target genes, including positively-regulated genes c-myc, survivin, TXNRD2 and negatively-regulated gene BACE1. Meanwhile, APP phosphorylation was also reduced on the Thr668 residue after selenate treatment, causing the decreases of APP cleavage and Aβ generation. These findings reveal that the Wnt/β-catenin signaling is a potential target for prevention of AD and sodium selenate may be developed as a new drug for AD treatment.

Correction for ‘Bis(ethylmaltolato)oxidovanadium(iv) inhibited the pathogenesis of Alzheimer's disease in triple transgenic model mice’ by Zhijun He et al., Metallomics, 2020, DOI: 10.1039/c9mt00271e.

Synaptic neurodegeneration of retinal ganglion cells (RGCs) is the earliest event in the pathogenesis of diabetic retinopathy. Our previous study proposed that impairment of mitochondrial trafficking by hyperphosphorylated tau is a potential contributor to RGCs synapse degeneration. However, other molecular mechanisms underlying mitochondrial defect in diabetic retinal neurodegeneration remain to be elucidated. Here, using a high-fat diet (HFD)-induced diabetic mouse model, we showed for the first time that downregulation of active β-catenin due to abnormal GSK3β activation caused synaptic neurodegeneration of RGCs by inhibiting ROS scavenging enzymes, thus triggering oxidative stress-driven mitochondrial impairment in HFD-induced diabetes. Rescue of β-catenin via ectopic expression of β-catenin with a recombinant adenoviral vector, or via GSK3β inhibition by a targeted si-GSK3β, through intravitreal administration, abrogated the oxidative stress-derived mitochondrial defect and synaptic neurodegeneration in diabetic RGCs. By contrast, ablation of β-catenin by si-β-catenin abolished the protective effect of GSK3β inhibition on diabetic RGCs by suppression of antioxidant scavengers and augmentation of oxidative stress-driven mitochondrial lesion. Thus, our data identify β-catenin as a part of an endogenous protective system in diabetic RGCs and a promising target to develop intervention strategies that protect RGCs from neurodegeneration at early onset of diabetic retinopathy.

Alzheimer’s disease (AD) is a widely distributed neurodegenerative disease characterized clinically by cognitive deficits and pathologically by formation of amyloid-β (Aβ) plaque and neurofibrillary tangles (NFTs) in the brain. Vanadium is a biological trace element that has a function to mimic insulin for diabetes. Bis(ethylmaltolato) oxidovanadium (IV) (BEOV) has been reported to have a hypoglycemic property, but its effect on AD remains unclear. In this study, BEOV was supplemented at doses of 0.2 and 1.0 mmol/L to the AD model mice APPSwe/PS1dE9 for 3 months. The results showed that BEOV substantially ameliorated glucose metabolic disorder as well as synaptic and behavioral deficits of the AD mice. Further investigation revealed that BEOV significantly reduced Aβ generation by increasing the expression of peroxisome proliferator-activated receptor gamma and insulin-degrading enzyme and by decreasing β-secretase 1 in the hippocampus and cortex of AD mice. BEOV also reduced tau hyperphosphorylation by inhibiting protein tyrosine phosphatase-1B and regulating the pathway of insulin receptor/insulin receptor substrate-1/protein kinase B/glycogen synthase kinase 3 beta. Furthermore, BEOV could enhance autophagolysosomal fusion and restore autophagic flux to increase the clearance of Aβ deposits and phosphorylated tau in the brains of AD mice. Collectively, the present study provides solid data for revealing the function and mechanism of BEOV on AD pathology.

We synthesized Cu3.8Ni/CoO and Cu3.8Ni/MnO nanoparticles via an easy and scalable solution synthesis. The synthesized Cu3.8Ni/CoO and Cu3.8Ni/MnO nanoparticles were annealed to remove the organic surfactants without phase transitions or side reactions. Electrons can be transferred via metallic Cu3.8Ni, which will not react with lithium ions. The heterogeneous structures of Cu3.8Ni/CoO and Cu3.8Ni/MnO nanoparticles could enhance the lithium ion mobility and improve the life cycle, and these materials are therefore promising candidates as high-power-density and high-energy-density anode materials for lithium-ion batteries in diverse applications, such as electrical vehicles.

We demonstrate an easy and scalable low-temperature process to convert porous ternary complex metal oxide nanoparticles from solution-synthesized core/shell metal oxide nanoparticles by thermal annealing. The final products demonstrate superior electrochemical properties with a large capacity and high stability during fast charging/discharging cycles for potential applications as advanced lithium-ion battery (LIB) electrode materials. In addition, a new breakdown mechanism was observed on these novel electrode materials.

Background Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. Methods To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. Results We demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner. Conclusions Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities. Electronic supplementary material The online version of this article (10.1186/s13024-018-0295-z) contains supplementary material, which is available to authorized users.

Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer’s disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti-oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment.

For the first time, we demonstrate the use of a microemulsion reaction to synthesize different nanostructures of LiCoO2 cathode material. By varying the annealing temperature and time, porous nanowires and nanoparticles of LiCoO2 are obtained. The electrochemical performances of these different nanostructures obtained under the respective annealing conditions are evaluated. It is shown that nanoparticles formed under the annealing condition of 700 °C, 1.5 h perform the best, delivering an initial capacity of around 135 mA h g(-1), which is close to the theoretical capacity of LiCoO2, 140 mA h g(-1). They also exhibit a capacity retention of around 93% by 100 cycles at 0.1 C. Comparisons are made between our LiCoO2 material obtained under different annealing conditions and those in the literature.

Oil/water emulsion is treated with polyvinylidenefluoride(PVDF) tubular ultrafiltration membrane. The flux of PVDF tubular ultrafiltration membrane is tested by varying the operation pressure(from 0.06Mpa to 0.25Mpa), membrane surface velocity of flow(from 1.47m/s to 3.69m/s) and system running time (from 1h to 20h). The average membrane flux is up to 108.2 L/(m2.h) in proper experiment conditions. Then some cleaning methods are studied and the chemical cleaning has the best effect, the flux restoration rate is more than 92%. Oil concentration in permeate water was less than 10 mg/L. The rejection rate of oil was more than 90%, The cleaning periods were 24h. Using PVDF tubular ultrafiltration membrane to treat oil/water emulsion is a feasible and economical method.