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We report a facile fabrication of a host-metal-guest coordination-bonding system in a mesostructured Fe3O4/chitosan nanoparticle that can act as a pH-responsive drug-delivery system. The mesostructured Fe3O4/chitosan was synthesized by a solvothermal approach with iron(III) chloride hexahydrate as a precursor, ethylene glycol as a reducing agent, ammonium acetate as a porogen, and chitosan as a surface-modification agent. Subsequently, doxorubicin (DOX), acting as a model drug (guest), was loaded onto the mesostructured Fe3O4/chitosan nanoparticles, with chitosan acting as a host molecule to form the NH2ZnIIDOX coordination architecture. The release of DOX can be achieved through the cleavage of coordination bonds that are sensitive to variations in external pH under weakly acidic conditions. The pH-responsive nature of the nanoparticles was confirmed by in vitro releases and cell assay tests. Furthermore, the relaxation efficiency of the nanoparticles as high-performance magnetic resonance imaging contrast agents was also investigated. Experimental results confirm that the synthesized mesostructured Fe3O4/chitosan is a smart nanovehicle for drug delivery owing to both its pH-responsive nature and relaxation efficiency. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 beta (GSK-3β) dysfunction may play an essential role in the pathogenesis of psychiatric, metabolic, neurodegenerative diseases, in which oxidative stress exists concurrently. Some studies have shown that GSK-3β activity is up-regulated under oxidative stress. This study evaluated how oxidative stress regulates GSK-3β activity in human embryonic kidney 293 (HEK293)/Tau cells treated with hydrogen peroxide (H2O2). Here, we show that H2O2 induced an obvious increase of GSK-3β activity. Surprisingly, H2O2 dramatically increased phosphorylation of GSK-3β at Ser9, an inactive form of GSK-3β,while there were no changes of phosphorylation of GSK-3β at Tyr216. Moreover, H2O2 led to a transient [Ca2+]i elevation, and simultaneously increased the truncation of GSK-3β into two fragments of 40 kDa and 30 kDa, whereas inhibition of calpain decreased the truncation and recovered the activity of GSK-3β. Furthermore, tau was hyperphosphorylated at Ser396, Ser404, and Thr231, three most common GSK-3β targeted sites after 100 μM H2O2 administration in HEK293/Tau cells, whereas inhibition of calpain blocked the tau phosphorylation. In addition, we found that there were no obvious changes of Cyclin-dependent kinase 5 (CDK5) expression (responsible for tau phosphorylation) and of p35 cleavage, the regulatory subunit of CDK5 in H2O2-treated HEK293/Tau cells. In conclusion, Ca2+-dependent calpain activation leads to GSK-3β truncation, which counteracts the inhibitory effect of Ser9 phosphorylation, up-regulates GSK-3β activity, and phosphorylates tau in H2O2-treated HEK293/Tau cells. [ABSTRACT FROM AUTHOR]

Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2′ measurements. Fifteen patients with AD, 15 age- and sex-matched healthy controls, and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2* mapping for the measurement of transverse relaxation rate R2′ (R2′=R2*−R2). We statistically analyzed the R2′ and iron concentrations of bilateral hippocampus (HP), parietal cortex (PC), frontal white matter (FWM), putamen (PU), caudate nucleus (CN), thalamus (TH), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) of the cerebellum for the correlation with the severity of dementia. Two-tailed t-test, Student-Newman-Keuls test (ANOVA) and linear correlation test were used for statistical analysis. In 30 healthy volunteers, the R2′ values of bilateral SN, RN, PU, CN, globus pallidus (GP), TH, and FWM were measured. The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2′ and brain iron concentration. The iron concentration of regions of interest (ROI) in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed. Regional R2′ was positively correlated with regional brain iron concentration in normal adults ( r=0.977, P<0.01). Iron concentrations in bilateral HP, PC, PU, CN, and DN of patients with AD were significantly higher than those of the controls ( P<0.05); Moreover, the brain iron concentrations, especially in parietal cortex and hippocampus at the early stage of AD, were positively correlated with the severity of patients' cognitive impairment ( P<0.05). The higher the R2′ and iron concentrations were, the more severe the cognitive impairment was. Regional R2′ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients' cognitive impairment, indicating that it may be used as a biomarker to evaluate the progression of AD. [ABSTRACT FROM AUTHOR]

Developing high-performance nonprecious-metal electrocatalysts for the oxygen evolution reaction (OER) is crucial for efficient water splitting. Therefore, the reasonable design principle of catalyst, leading to high activity catalytic center and improving the accessibility of active sites, is undoubtedly crucial. Here, we used a kind of Prussian blue analogue (CoFe-PBA) nanoparticles to anchor the nitrogen-carbon doped CoFe 2 O 4 (CoFe 2 O 4 @NC) species to reduced graphene oxide aerogels as OER catalysts. The strong interaction between nanosized CoFe 2 O 4 @NC and the graphitic carbon shell led to synergistic effects in the OER, and the protection of the carbon shell guaranteed stability of the catalyst. As a result, the aerogel electrocatalyst exhibits more excellent activity and stability than the most advanced RuO 2 catalyst in OER under the same mass load in alkaline medium. It shows smaller overpotential of 250 mV to afford a current density of 10 mA cm−2 in a continuous working time of more than 70 hours. [Display omitted] • The catalyst has highly exposed active surface, multi-dimensional mass transfer pathway and good charge transfer ability. • The in-situ formation of nitrogen-carbon doped structure can greatly improve the catalytic activity and stability. • The binary active sites on the conductive GA network reduce the interfacial resistance and enhance catalytic activity. • The "Plum Pudding Model" structure integrates multiple requirements for catalyst design strategies. [ABSTRACT FROM AUTHOR]

Countering the problem of expediting the peroxymonosulfate oxidation, porous carbon nanofibers loaded with copper-cobalt bimetallic particles (CuCo@ CNF) were synthesized by a three-step process, including electrospinning, solvothermal reaction and carbonization. The well-crystallized copper-cobalt nanoparticles with an average particle size of 322 nm, which were evenly decorated on the surface of the porous carbon nanofibers with a relatively high specific surface area (average value=161.281 m2 g−1), as examined by XRD, SEM, TEM, and BET. The saturation magnetization of CuCo@CNF measured by VSM is 26.5 emu g−1, suggesting its easy separation due to magnetic property. In CuCo@CNF-PMS system, the removal rate of Acid Red 1 (AR1) as a model pollutant can achieved 99.0% and 98.1% in the 1st and 7th run, respectively. Metal leaching after reaction were reduced for CuCo@CNF when compared with the respective CNF supported Co or Cu catalysts. In addition, the catalytic degradation mechanism of AR1 was elucidated by detecting reactive oxygen species (ROS: SO• 4 -, •OH and 1O 2) alongside the reaction. AR1 can even be mineralized through CuCo@CNF-PMS, evidenced by TOC removal rate of 55.5% within 20 min. These results suggest that the as-synthesized catalyst is an attractive candidate for the treatment of wastewater with recalcitrant organic pollutants. [Display omitted] • CuCo@CNF was synthesized by a three-step process, including electrospinning, solvothermal reaction and carbonization. • CuCo bimetallic nanoparticles with heterostructure was almost uniformly embedded in CNF. • Magnetic CuCo@CNF possesses mesoporous structure. • Reduced metal leaching and improved catalytic performance for PMS activation was achieved on CuCo@CNF. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the effect of tyrosine kinase Src on Tyrosine 307(Y307) phosphorylation, protein phosphatase 2A (PP2A) activity, and on tau phosphorylation. Specific Src siRNA was transfected into cultured mouse neuroblastoma N2a cells to inhibit the expression of Src protein, and the phosphorylation levels of PP2A Y307 and tau at different sites, as well as PP2A activity were detected at different time points after siRNA transfection. Twelve hours after siRNA transfection, the protein level of Src was dramatically decreased, with decreased PP2A Y307 phosphorylation. However, the total PP2A protein level was also decreased, together with a decreased PP2A activity. Tau was hyperphosphorylated at the Ser198/199/202 sites. Multiple factors may be involved in the cellular regulation of PP2A activity. Inhibiting Src expression could induce inactivation of PP2A and tau hyperphosphorylation. [ABSTRACT FROM AUTHOR]

We previously reported that the injection of okadaic acid (OA) into the Meynert nucleus basalis of rats induced spatial memory deficits. The present study was designed to further explore the underlying mechanisms. We found that the level of acetylcholine (Ach) in the hippocampus significantly decreased 24 h after injection of OA into the Meynert nucleus basalis of rats. Simultaneously, spatial memory deficit, PP-2A inhibition and tau hyperphosphorylation at Ser-198/Ser-199/Ser-202 (Tau-1 epitope) and Ser-396/Ser-404 (PHF-1 epitope) were observed. With the restoration of hippocampus Ach to normal levels at 48 and 72 h after the injection, the spatial memory deficits, PP-2A inhibition and tau hyperphosphorylation were reversed. It is suggested that injection of OA into the Meynert nucleus basalis of rats may impair the hippocampus-dependent spatial memory through damaging the cholinergic projection between the Meynert nucleus basalis and the hippocampus and the selective inhibition of PP-2A and tau hyperphosphorylation may be at least part of the underlying mechanisms. [ABSTRACT FROM AUTHOR]

One of the neuropathological features of Alzheimer’s disease (AD) is the deposition of senile plaques containing β-amyloid (Aβ). There is limited evidence for the treatment to arrest Aβ pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on Aβ in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16–17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg−1 day−1) partially attenuated Aβ overproduction and intracellular Aβ deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote Aβ42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD. [ABSTRACT FROM AUTHOR]

Abstract: The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment. [Copyright &y& Elsevier]

In Alzheimer’s disease (AD), hyperphosphorylation of tau may be the underlying mechanism for the cytoskeletal abnormalities and neuronal death. It was reported that cyclin-dependent kinase5 (cdk-5) could phosphorylate tau at most AD-related epitopes in vitro. In this study, we investigated the effect of cdk-5 overexpression on tau phosphorylation and spatial memory in rat. We demonstrated that 24 h after transfection into rat hippocampus, cdk-5 was overexpressed and induced a reduced staining with antibody tau-1 and an enhanced staining with antibodies 12e8 and PHF-1, suggesting hyperphosphorylation of tau at Ser199/202, Ser262/356 and Ser396/404 sites. Additionally, the cdk-5 transfected rats showed long latency to find the hidden platform in Morris water maze compared to the control rat. 48 h after transfection, the level of cdk-5 was decreased significantly, and the latency of rats to find the hidden platform was prolonged. It implies that in vivo overexpression of cdk-5 leads to impairment of spatial memory in rat and tau hyperphosphorylation may be the underlying mechanism. [ABSTRACT FROM AUTHOR]

Investigates the association between abnormal phosphorylation sites found in Alzheimer disease and the inhibition of its biological activity. Techniques used to prepare and phosphorylate human recombinant; Effect of different kinases on microtubule binding activity; Inhibition of microtubule binding activity.

Low-cost and earth-rich electrocatalysts with excellent catalytic activity in the electrochemical hydrogen evolution reaction (HER) are essential for large-scale renewable energy storage. Herein, we report a new type of core-shell Ni 2 P@CoP nanoarrays supported on nickel foam (NF) (Ni 2 P@CoP/NF) with large specific surface area, serving as an efficient cathode for hydrogen evolution reaction (HER). Plenty of tiny Ni 2 P nanosheets were tightly wrapped on the CoP nanowires, forming a rich heterostructure interface, which can provide more active sites and improve conductivity, thereby increasing their catalytic performance. What's more, the synergistic effect between Ni 2 P and CoP can promote the rapid electron transfer and improve the catalytic efficiency. The obtained Ni 2 P@CoP/NF NAs exhibited excellent HER activity with a low overpotential of 61 mV at 10 mA cm−2 and good durability in the alkaline media. The core-shell nanoarray structure of Ni 2 P@CoP/NF provides a novel method for the preparation of other heterojunction metal phosphides, which can be used to develop high performance HER electrocatalysts. [Display omitted] • Designed a new type of core-shell Ni 2 P@CoP nanoarrays supported on nickel foam. • The catalyst has a large specific surface area and rich heterostructure interfaces, which can provide more active sites. • The synergistic effect between Ni 2 P and CoP can promote the rapid electron transfer. • The obtained catalyst exhibits remarkable enhanced HER activities compared to pure Ni 2 P and CoP nanostructures. [ABSTRACT FROM AUTHOR]

Background: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. Methods: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. Results: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). Conclusions: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] Covalent organic frameworks (COFs) with controlled porosity, high crystallinity, diverse designability and excellent stability are very attractive in metal-free heterogeneous photocatalysis of volatile organic compounds (VOCs) degradation. In order to construct the high optimal performance COFs under feasible and universal conditions, herein, the visible light-driven hollow COF TAPB-PDA (H-COF TAPB-PDA) microcapsule was designed by a facile dual-ligand regulated sacrificial template method. The H-COF TAPB-PDA microcapsule possesses improved surface area, high crystallinity, broad absorption range and high stability, which enables enhanced substrates and visible light adsorption, photogenerated electrons-holes separation and transfer, and facilitate the generation of reactive radicals. Importantly, it was found to be a highly efficient photocatalyst for toluene degradation under visible-light irradiation compared with the solid COF TAPB-PDA , and the degradation efficiency of toluene reached 91.8 % within 180 min with the conversion rate of CO 2 was 68.9 %. Additionally, the H-COF TAPB-PDA presented good recyclability and long-term stability after multiple photocatalytic reuses. Furthermore, the active sites of H-COF TAPB-PDA in photocatalytic degradation of toluene was proposed by XPS and DFT calculations, and the degradation pathway and mechanism was proposed and analyzed. The result presented great prospect of morphologic design of hollow COFs in metal-free heterogeneous photocatalysis for VOCs degradation. [ABSTRACT FROM AUTHOR]

Designing ultrahigh energy density and mass-loading of electrocatalysts for hydrogen evolution is highly desirable but remains a great challenge. Herein, a 3D high-rise architectural structure consisting of dense Ni(OH) 2 nanoparticles on CuMoO 4 nanocube heterostructure arrays on Ni foam (Ni(OH) 2 /CuMoO 4 /NF) is developed via a hydrothermal reaction, calcination and electrodeposition method. Benefitting from the optimized electronic configuration, hierarchical high-rise architecture, and large specific surface area and mesoporous, the Ni(OH) 2 /CuMoO 4 /NF exhibits superior hydrogen evolution reaction (HER) activity in 1.0 M KOH solution. Ni(OH) 2 /CuMoO 4 /NF only requires low overpotential of 70 mV achieving a current density of 10 mA cm−2 with a low Tafel slope of 80 mV dec−1, and superior long-term stability toward HER. This work provides a new structural design to high-rise architectural structures for efficient catalytic application. [Display omitted] • A highly topological nickel hydroxide doped copper molybdate oxide composite was synthesized. • The high-topology structure with a heterogeneous interface enhances the conductivity. • The typical structure and proper components contribute to the electrochemical activity. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule‐associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. Methods: The levels of nucleotide‐binding oligomerisation domain (NOD)‐like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme‐linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test‐tube acetylation assay, co‐immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau‐overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno‐associated virus injection. The cognitive functions of Tau‐overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba‐1 IF staining and [18F]‐DPA‐714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau–NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. Results: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg‐AD mice, microtubule‐associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated‐Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau–K18 domain acetyltransferase activity‐dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV‐2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau–NLRP3‐binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. Conclusions: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies. [ABSTRACT FROM AUTHOR]