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Reducing the amount of precious metal Pt in proton exchange membrane fuel cells while improving its electrocatalytic activity is one of the core problems in this field. The formation of stable ultrafine Pt nanoparticles is one of the effective methods for improving the utilization rate of Pt and indirectly reducing the amount of Pt. The traditional carbon support has carbon corrosion phenomenon, and the exploration of suitable catalyst support can also improve the utilization rate of the Pt unit and indirectly reduce its consumption. In this paper, ultrafine Pt nanoparticles (2 nm) have been loaded on white carbon black (WCB) in situ by a simple hydrothermal reaction. When the Pt mass load is 40%, the Pt particles are highly dispersed on the WCB, but when the load is increased to 60%, the Pt particles will agglomerate significantly. Due to its high dispersion and ultrafine particle size, 40%Pt/SiO2 catalyst shows enhanced methanol oxidation reaction (MOR) performance in acidic electrolyte. The maximum oxidation peak current density (163.3mA mg−1Pt) of the MOR is superior to that of the commercial carbon-supported Pt catalyst. This study not only describes the design of a highly dispersed, ultrafine particle size of Pt-based catalyst, but also provides a new choice for a new catalyst carrier. [ABSTRACT FROM AUTHOR]

Precious metal Pt‐based electrocatalysts have been widely used in the methanol catalytic oxidation anodes in direct methanol fuel cells. However, decreasing their cost and improving their efficiency and durability have still been challenging. Herein, ternary PtPdCu nanocatalysts are synthesized through a facile one‐step hydrothermal synthesis method. When KI is present with a suitable amount in the synthesis, PtPdCu nanospheres with surface‐embedded CuI clusters (CuI/PtPdCu) are fabricated. However, without KI, the prepared PtPdCu catalysts show a distinct hollow structure (h‐PtPtCu). CuI/PtPdCu displays the highest specific activity with enhancement 4 times higher than commercial Pt/C for the methanol oxidation reaction in an alkaline medium. The superior activity can be attributed to two aspects: 1) the electronic effect originating from the highly alloyed PtPdCu; 2) the synergetic effect resulting from surface inlaid CuI clusters, which can promote the CO intermediate removal. Furthermore, because of the stable Pt–Pd‐rich surface and its special linked hollow structure, the h‐PtPtCu catalyst exhibits good durability with only a 3.6% decay in the specific activity. [ABSTRACT FROM AUTHOR]

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Proton exchange membrane fuel cell is a clean energy system that can effectively reduce carbon emissions. At present, precious metal Pt is an irreplaceable catalyst for fuel cells. How to reduce the amount of Pt and improve its electrocatalytic performance is one of the difficulties in this field. In this paper, two kinds CoPtPd nanocatalysts have been prepared and the surface structure of the catalyst could be reconstructed by means of electrochemical dealloying method. The electrocatalytic methanol oxidation reaction (MOR) performance before and after dealloying have been investigated. The results show that the active sites on the surface of the alloy increased after alloying, but the MOR properties do not improve significantly. With the increase of dealloying degree, the stability decay of the catalyst is accelerated. It may be that the alloying effect between Co and PtPd is weakened by the process of dealloying. [ABSTRACT FROM AUTHOR]

Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) develop insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylate lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reverse F-K1057/1079 and counteract the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients are positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizes insulin signaling and relieves T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation. Whether amino acids act on cellular insulin signaling remains unclear. Here, the authors find that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake and positively correlated with T2D onset. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role. Chuanxiong Rhizoma (CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis–based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski's rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis–related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD. [ABSTRACT FROM AUTHOR]

Presently, the treatment options for ischemic stroke (IS) are limited due to the complicated pathological process of the disease. Chuanxiong Rhizome (CR), also known as Conioselinum anthriscoides "Chuanxiong" (rhizome), is the most widely used traditional Chinese medicine for treating stroke. This study aimed to uncover the key phytochemicals and biological functions of CR against IS through a network pharmacology approach combining with IS pathophysiology analysis. We employed permanent unilateral common carotid artery ligation to construct a mouse model of global cerebral ischemia and found that cerebral ischemia injuries were improved after 7 days of gavage treatment of CR (1,300 mg/kg/day). CR exerts protective effects on neurons mainly by acting on targets related to synaptic structure, synaptic function, neuronal survival and neuronal growth. A total of 18 phytochemicals from CR based on UHPLC-MS/MS that corresponded to 85 anti-IS targets. Coniferyl ferulate, neocnidilide and ferulic acid were identified as the key phytochemicals of CR against IS. Its brain protective effects involve anti-inflammatory, anti-oxidative stress, and anti-cell death activities and improves blood circulation. Additionally, the two most important synergistic effects of CR phytochemicals in treating IS are prevention of infection and regulation of blood pressure. In brain samples of Sham mice, L-tryptophan and vanillin were detected, while L-tryptophan, gallic acid, vanillin and cryptochlorogenic acid were detected in IS mice by UHPLC–MS/MS. Our findings provide a pathophysiology relevant pharmacological basis for further researches on IS therapeutic drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, but its underlying mechanism is still unclear and the identities of drugs for AD also lack. Tau acetylation has become potentially important post-translational modification of tau. Levels of tau acetylation are significantly enhanced in AD patients and transgenic mouse models of AD, but the underlying mechanism and roles of tau hyperacetylation in AD onset maintain elusive. In the current study, we found that tau acetylation is obviously enhanced and the activities of AMP-activated protein kinase (AMPK) and sirtuin1 (Sirt1) are significantly decreased in APP/PS1 and streptozotocin (STZ) mice and high glucose (HG)-treated cells. Moreover, we demonstrated that activation of AMPK reduces the level of tau acetylation and ameliorates memory impairment, and its mechanism is associated with activation of Sirt1. Taken together, AMPK might be a crucial upstream molecular to regulate acetylation of tau and become a new target for AD therapy in the future. [ABSTRACT FROM AUTHOR]

The studies have shown that 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is involved in Alzheimer's disease (AD) pathology, but the effects of AMPK on AD-like Tau abnormal phosphorylation and its underlying mechanism remains unclear. Herein, we found that the mRNA expression and activity of AMPK are significantly decreased in the brains of the aging C57 mice and 3 × Tg AD mice when compared with their respective control. Moreover, when downregulation of AMPK with AAV-siAMPK-eGFP in the hippocampus CA3 of 3-month-old C57 mice, the mice display AD-like Tau hyperphosphorylation, fear memory impairment, and glycogen synthase kinase-3β (GSK3β) activity increased. On the other hand, there are also AD-like Tau hyperphosphorylation, impairment of fear memory, and AMPK activity decreased in streptozotocin (STZ) mice. Interestingly, AMPK overexpression could efficiently rescue AD-like Tau phosphorylation and brain impairment in STZ mice. Moreover, the activity of GSK3β and the level of Tau phosphorylation (Ser396 and Thr231 sites) were significantly decreased in HEK293 Tau cells transfected by AMPK plasmid or treated with agonists salicylate (SS), but GSK3β agonists Wortmannin (Wort) could ablate AMPK-mediated Tau dephosphorylation. Taken together, the study indicated that AMPK reduces Tau phosphorylation and improves brain function and inhibits GSK3β in AD-like model. These findings proved that AMPK might be a new target for AD in the future. [ABSTRACT FROM AUTHOR]

Acidosis, a common feature of cerebral ischaemia and hypoxia, plays a key role in these pathological processes by aggravating the ischaemic and hypoxic injuries. To explore the mechanisms, in this research, we cultured primary neurons in an acidic environment (potential of hydrogen [pH]6.2, 24 hours) to mimic the acidosis. By proteomic analysis, 69 differentially expressed proteins in the acidic neurons were found, mainly related to stress and cell death, synaptic plasticity and gene transcription. And, the acidotic neurons developed obvious alterations including increased neuronal death, reduced dendritic length and complexity, reduced synaptic proteins, tau hyperphosphorylation, endoplasmic reticulum (ER) stress activation, abnormal lysosome‐related signals, imbalanced oxidative stress/anti‐oxidative stress and decreased Golgi matrix proteins. Then, melatonin (1 × 10−4 mol/L) was used to pre‐treat the cultured primary neurons before acidic treatment (pH6.2). The results showed that melatonin partially reversed the acidosis‐induced neuronal death, abnormal dendritic complexity, reductions of synaptic proteins, tau hyperphosphorylation and imbalance of kinase/phosphatase. In addition, acidosis related the activations of glycogen synthase kinase‐3β and nuclear factor‐κB signals, ER stress and Golgi stress, and the abnormal autophagy‐lysosome signals were completely reversed by melatonin. These data indicate that melatonin is beneficial for neurons against acidosis‐induced injuries. [ABSTRACT FROM AUTHOR]

Background Hyperhomocysteinemia is an independent risk factor for dementia, including Alzheimer's disease. Lowering homocysteine levels with folic acid treatment with or without vitamin B12 has shown few clinical benefits on cognition. Methods To verify the effect of emodin, a naturally active compound from Rheum officinale, on hyperhomocysteinemia-induced dementia, rats were treated with homocysteine injection (HCY, 400 μg/kg/d, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations for 2 weeks: 0 (HCY-E0), 20 (HCY-E20), 40 (HCY-E40), and 80 mg/kg/d (HCY-E80). Results β-Amyloid overproduction, tau hyperphosphorylation, and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioral performance. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/d) reduced the levels of β-amyloid and tau phosphorylation, decreased the levels of β-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins, and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased. In addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6, and tumor necrosis factor α were also observed. Lastly, hyperhomocysteinemia-induced microangiopathic alterations, oxidative stress, and elevated DNA methyltransferases 1 and 3β were rescued by emodin. Conclusions Emodin represents a novel potential candidate agent for hyperhomocysteinemia-induced dementia and Alzheimer's disease-like features. [ABSTRACT FROM AUTHOR]

Abstract: Menopause, a risk factor for brain dysfunction in women, is characterized by neuropsychological symptoms including depression and dementia, which are closely related to alterations in different brain regions after menopause. However, little is known about the variability in pathophysiologic changes associated with menopause in the brain. Here, we observed that menopause in rats induced by bilateral ovariectomy (OVX) showed depressive and dementia‐related behaviors along with neuronal loss in the prefrontal cortex (PFC), hippocampus (HIP), hypothalamus (HYP), and amygdala (AMY) by Nissl staining. Meanwhile, by immunohistochemical staining, increased microglia in the HIP and AMY and increased astrocytes in the PFC, HYP, and AMY were shown. Using quantitative proteomics, we identified 146 differentially expressed proteins in the brains of OVX rats, for example, 20 in the PFC, 41 in the HIP, 17 in the HYP, and 79 in the AMY, and performed further detection by western blotting. A link between neuronal loss and apoptosis was suggested, as evidenced by increases in adenylate kinase 2 (AK2), B‐cell lymphoma 2 associated X (Bax), cleaved caspase 3, and phosphorylated p53 and decreases in Huntingtin‐interacting protein K, hexokinase, and phosphorylated B‐cell lymphoma 2 (Bcl‐2), and apoptosis might be triggered by endoplasmic reticulum stress (probed by increased glucose‐regulated protein 78 (GRP78), cleaved caspase 12, phosphorylated protein kinase R (PKR)‐like endoplasmic reticulum kinase, inositol‐requiring enzyme‐1 and activating transcription factor 6), and mitochondrial dysfunction (probed by increased cytochrome c and cleaved caspase 3 and decreased sideroflexin‐1 (SFXN1) and NADH dehydrogenase (ubiquinone) 1 α subcomplex 11 (NDUFA11)). Activation of autophagy was also indicated by increased autophagy‐related 7, γ‐aminobutyric acid (GABA) receptor‐associated protein‐like 2, and oxysterol‐binding protein‐related protein 1 and confirmed by increased microtubule‐associated protein light chain 3 (LC3II/I), autophagy‐related 5, and Beclin1 in the HIP and AMY. In the AMY, which is important in emotion, higher GABA transporter 3 and lower vesicular glutamate transporter 1 levels indicated an imbalance between excitatory and inhibitory neurotransmission, and the increased calretinin and decreased calbindin levels suggested an adjustment of GABAergic transmission after OVX. In addition, cytoskeletal abnormalities including tau hyperphosphorylation, dysregulated Ca²+ signals, and glutamic synaptic impairments were observed in the brains of OVX rats. Collectively, our study showed the changes in different brain regions related to depression and dementia during menopause. [ABSTRACT FROM AUTHOR]

Abstract: Endoplasmic reticulum (ER) stress is involved in Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we injected tunicamycin (TM), a recognized ER stress inducer, into the brain ventricle of Sprague‐Dawley (SD) rats to induce the unfolded protein response (UPR), demonstrated by the enhanced phosphorylation of pancreatic ER kinase (PERK), inositol‐requiring enzyme‐1 (IRE‐1) and activating transcription factor‐6 (ATF‐6). We observed that UPR induced spatial memory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK‐3β was activated and phosphorylation of cAMP response element binding protein at Ser129 (pS129‐CREB) was increased with an increased nuclear co‐localization of pY126‐GSK‐3β and pS129‐CREB. Simultaneous inhibition of GSK‐3β by hippocampal infusion of SB216763 (SB) attenuated TM‐induced UPR and spatial memory impairment with restoration of pS129‐CREB and synaptic plasticity. We concluded that UPR induces AD‐like spatial memory deficits with mechanisms involving GSK‐3β/pS129‐CREB pathway. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1 - 42 mice compared with that of WT-Aβ1 - 42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1 - 42 mice than that in WT-Aβ1 - 42 mice. CB2R activation could decrease Aβ1 - 40 and Aβ1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer’s disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R−/− mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R−/− mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R−/− mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3β activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3β disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3β pathway. These findings proved that CB2R/AMPK/GSK3β pathway can be a promising new drug target for AD. [ABSTRACT FROM AUTHOR]

Clinical data have shown women are more susceptible to depression. This study was performed to identify differentially regulated proteins from hippocampus in chronic unpredicted mild stress (CUMS)-exposed male and female young rats. After 7 weeks of CUMS, depressed male (M-D) and female rats (F-D) and unstressed male (M-C) and female controls (F-C) were studied. By proteomics analysis, 74 differential proteins in F-C/M-C, 79 in F-D/M-D, 77 in F-D/F-C, and 32 in M-D/M-C were found. Further, the synapse-related proteins, cytoskeleton protein tau, and stress-related kinases in hippocampus were assayed by Western blotting. F-C rats were found to have lower levels of metabotropic glutamate receptor 1 (mGluR1) and mGluR2 and higher levels of N-methyl-d-aspartate receptor 2B (NR2B), synapsin1, total tau, and dephosphorylated tau than M-C rats. Both F-D and M-D rats had lower levels of glutamate transporter SLC1α2, mGluR1, and mGluR2, and higher levels of total tau and phosphorylated tau than their controls. Compared with their controls, M-D rats had lower NR1 and higher NR2B, and F-D rats had lower NR2A, NR2B, PSD95, and synapsin1. F-C rats had higher JNK and lower phosphorylation levels of ERK at Thr202/Thr204, JNK at Thr183/Thr185, and GSK-3β at Ser9 than M-C ones. Both M-D and F-D rats had decreased phosphorylation of ERK at Thr202/Thr204 and GSK-3β at Ser9, and increased JNK phosphorylation at Thr183/Thr185 compared with their controls. All these data illustrate the biochemical complexity behind the genders, and may also aid in the development of more accurate treatment strategies for depression. [ABSTRACT FROM AUTHOR]

Helicobacter pylori ( H.pylori) infection is a recognized risk factor of dementia, while its role and mechanism in Alzheimer disease (AD) remained unclarified. Our previous study has identified that injection of soluble H.pylori filtrate could induce AD-like pathologic changes and cognitive impairment in SD rats. In the present study, we further explored the effect of long-term stomach colonization of H.pylori bacteria on the brains of SD rats. The results showed that H.pylori bacteria gavage induced an efficient colonization of H.pylori in the stomach after four weeks. However, there was no significant change of tau phosphorylation at Thr205 (pT205), Thr231 (pT231), Ser396 (pS396) and Ser404 (pS404) sites in the hippocampus and cerebral cortex. The H.pylori-infected rats also showed no cognitive impairment. These observations may result from inefficient release of bacterial pathogenic factors or the overall lack of host inflammatory responses. We conclude that SD rat with long-term H.pylori colonization in the stomach is not a suitable animal model for exploring the effects of H.pylori infection on brain function in human beings; administration of bacterial filtrates may better reveal the systemic pathologic changes induced by bacterial infection in animals which show a negative host response to bacterial colonization. [ABSTRACT FROM AUTHOR]

Synaptic activity increases the resistance of neurons to diverse apoptotic insults; however, the underlying mechanisms remain less well understood. Zinc promotes cell survival under varied conditions, but the role of synaptically released zinc in the activity-dependent anti-apoptotic effect is unknown. Using cultured hippocampal slices and primary neurons we show that a typical apoptosis inducer–staurosporine (STP) was able to cause concentration-dependent apoptotic cell death in brain slices; Enhanced synaptic activity by bicuculline (Bic)/4-Aminopyridine (AP) treatment effectively prevented neurons from STP-induced cell apoptosis, as indicated by increased cell survival and suppressed caspase-3 activity. Application of Ca-EDTA, a cell membrane-impermeable zinc chelator which can efficiently capture the synaptically released zinc, completely blocked the neuronal activity-dependent anti-apoptotic effect. Same results were also observed in cultured primary hippocampal neurons. Therefore, our results indicate that synaptic activity improves neuronal resistance to apoptosis via synaptically released zinc. [ABSTRACT FROM AUTHOR]

Transient receptor potential-canonical 1 (TRPC1) plays a crucial role in neuronal survival, nerve regeneration, and protects neurons from neurotoxic injury, but it is not reported whether or how TRPC1 may affect learning and memory. Here, we found that TRPC1 knockout did not significantly affect the spatial learning and memory ability when the mice were housed in standard cages (SC). Interestingly, after the mice were exposed to environmental enrichment (EE) for 4 weeks, TRPC1 knockout abolished the EE-induced spatial memory enhancement, LTP induction, and neurogenesis in hippocampal DG subset. By stereotaxic infusion of the recombinant adeno-associated viruses (rAAV)-TRPC1 into the hippocampal DG subsets bilaterally, we observed that the EE-associated neurogenesis, LTP induction and the cognitive enhancement were efficiently rescued in TRPC1 knockout mice. EE increased the phosphorylation levels of ERK, p38, and cyclic AMP response element-binding protein (CREB) in wild-type mice, whereas the activation of ERK and CREB was not seen in TRPC1 knockout mice, and the phosphorylation of p38 was same in EE-TRPC1 and WT-EE. Finally, EE increased TRPC1 expression and overexpression of TRPC1 increased neurogenesis and activated ERK/CREB pathway in the wild-type mice. These findings suggest that TRPC1 is indispensable for the EE-induced hippocampal neurogenesis and cognitive enhancement. [ABSTRACT FROM AUTHOR]

Mononuclear molybdenum(VI) citrates with variable degrees of protonation, (NH4)2[MoO2(H2cit)2]·H2O (1), (NH4)3[MoO2(H2cit)(Hcit)]·H2O (2) and (NH4)5[MoO2(Hcit)(cit)]·2.5H2O (3) (H4cit = citric acid), have been well characterized, where the citrate ligands in1–3coordinate bidentate with Mo, while the free carboxylates form very strong hydrogen bonds with α-alkoxy and β-carboxylic acid groups. The chelation of α-alkoxy and α-carboxy groups in citrate are compared with that of FeMo-cofactor inNifV–Klebsiella pneumoniaenitrogenase. Solution13C NMR spectra show that1–3dissociated partly in D2O. The equilibria are calculated based on1H NMR spectra in solution. [ABSTRACT FROM AUTHOR]

For decades, Ni based cermet anodes for solid oxide fuel cells (SOFCs) have been suffering from poisoning from sulfur in fuel and carbon deposition while operating on hydrocarbon fuel. Using perovskite as an alternative can effectively alleviate these problems. However, its performance is unsatisfying. In this work, a lanthanum strontium titanate based perovskite oxide with facile modification of Ni and Ce (LSCNT) was fabricated by a modified sol–gel method. The exsolution of Ni surrounded by uniformly dispersed Ce species in the perovskite lattice could only be obtained by sintering the material in consecutive atmospheres of air and 10% H2/Ar. The solid oxide fuel cell (SOFC) equipped with an LSCNT anode exhibited desirable electrochemical performance and stability with 5000 pm H2S/H2 and dry methane fuel. The presence of exsolved metallic Ni provided strong active sites for the fuel oxidation reaction and simultaneously the Ce species with a redox couple provided Ni with abundant oxygen ions. The synergetic effect between Ce and Ni facilitates the electrochemical reaction and promotes the removal of carbon deposition. All these features make LSCNT a promising sulfur and carbon-deposition tolerant anode material for SOFCs. [ABSTRACT FROM AUTHOR]

CoPd nanocatalysts were synthesized by a successive reduction using poly(vinylpyrrolidone) as stabilizer. The structure, morphology, and composition of CoPd nanocatalysts were characterized by transmission electron microscopy (TEM), high-resolution TEM, X-ray powder diffraction (XRD), energy dispersive X-ray spectroscopy (EDS), and inductively coupled plasma mass spectrometry (ICP-MS). The CoPd nanocatalysts showed electrocatalytic performance for methanol oxidation in alkaline medium. The electrocatalytic performance was weakened after dealloying process in acidic solution. The balance of the dealloying effect and the alloying effect should be accentuated in this field in the future. [ABSTRACT FROM AUTHOR]

Collecting evidence has shown that type 2 diabetes mellitus is a high risk factor of late-onset Alzheimer's disease (AD); the energy metabolic dysfunction is thought to be a convergent point of the two diseases. However, the underlying mechanisms of diabetes-associated AD are still unclear. In the current study, we investigated the roles of AMPK in diabetes-related AD-like pathologic features in models of intracerebroventricular-streptozotocin (ICV-STZ) animals. Rats infused with STZ (3 mg/kg, once) were followed by injection of AICAR (AMPK activator) or vehicle via ICV. We found that the level of p-AMPK (active type of AMPK) and SIRT1 activity were decreased and the level of phosphorylated tau was increased at Ser396 and Thr231 sites in ICV-STZ rats when compared with control rats. Mitochondria from ICV-STZ rats displayed a significant decrease in mitochondrial membrane potential, complex I activity, ATP level, and superoxide dismutase activity as well as an increase of reactive oxygen species production when compared with that from control rats. Meanwhile the number of apoptotic cell confirmed by cleaved caspase-3 (active type of caspase-3) staining was also stronger in ICV-STZ rats than control rats. All pathological changes including biochemistry and cognitive function could be mitigated through rescuing AMPK activity with its specific activator (AICAR) in ICV-STZ rats. Taken together, these results suggested that AMPK activation improves AD-like pathological changes via repairing mitochondrial functions in ICV-STZ rats. [ABSTRACT FROM AUTHOR]

Tetranuclear zinc(II) citrates with N-heterocycle ligand, [Zn4(Hcit)2(phen)4(H2O)4]·2NO3·10H2O (1) and [Zn4(Hcit)2(bpy)4(H2O)6]·2NO3·12H2O (2) (H4cit?=?citric acid, phen?=?1,10-phenanthroline, bpy?=?2,2?-bipyridine), were synthesized from aqueous solution and characterized by Infrared, Powder X-ray diffraction, fluorescence spectra, and X-ray structural analyses. Complexes1and2are centrosymmetric tetranuclear species with two crystallographically independent Zn(II) ions, which display different coordination geometries, while the citrate ligand shows similar coordination modes and bridges three different Zn ions. In1, the Zn1 is five-coordinate by three oxygens from two citrates and two nitrogens from phen. There exist weak interactions between Zn1 and O4a atom of ?-carboxy group of citrate (Zn1?O4a?=?2.895?Å). Zn2 is six-coordinate by two oxygens from one citrate, two nitrogens from phen, and two water molecules. Zn1 and Zn2 are bridged by one citrate to form a dinuclear unit, which is further extended to a tetranuclear unit. In2, two citrates bridge two pairs of symmetry-related Zn(II) ions into a tetranuclear unit. The structural analyses of1and2indicate that different tetranuclear species are caused by arrangement of citrates with different steric hindrance of N-chelates.1H and13C NMR spectra indicate that2remains coordinated in D2O. Moreover, both1and2show strong fluorescent emission in dilute solution and solid state. Two tetranuclear zinc(II) citrates with N-heterocycle ligand, [Zn4(Hcit)2(phen)4(H2O)4]·2NO3·10H2O (1) and [Zn4(Hcit)2(bpy)4(H2O)6]·2NO3·12H2O (2) (H4cit?=?citric acid, phen?=?1,10-phenanthroline, bpy?=?2,2?-bipyridine), were synthesized from aqueous solution and characterized by Infrared, Powder X-ray diffraction, fluorescence spectra and X-ray structural analyses.1and2show strong fluorescent emission in dilute solution and solid state. [ABSTRACT FROM PUBLISHER]

Recent studies have reported a correlation between dementia and low blood pressure. How hypotension is associated with the increased risk of Alzheimer's disease (AD) remains unclear. Here we show that one month treatment of losartan, an angiotensin II type 1 (AT1) receptor antagonist, causes chronic and sustained hypotension, along with oxidative stress in adult male Sprague-Dawley rats. Furthermore, we show that losartan treatment increases the level of inactivated protein phosphatase 2A (PP2A) and the hyperphosphorylation of tau at Ser 199 and Ser 396. Rats treated with losartan present memory deficits and decreases in spine-density. These findings suggest that losartan-induced hypotension may increase the risk of AD-like pathological alteration and behavioral impairment through oxidative stress which leads to tau hyperphosphorylation and loss of dendritic spines. [ABSTRACT FROM AUTHOR]

The paper considers to construct an experimental teaching team in the course of medical functional science to cultivate medical talents. According to the goal of training medical talents in colleges, based on the syllabus, the experimental teaching content and methods in different subjects, by breaking the boundaries in these courses, redesigning experiment contents which were relatively independent of the curriculum system, and integrating the experimental resources, we established a teaching team that can adapt to high professional medical experiment teaching in the 21st century. Through the construction of experimental teaching team, on the one hand, the value of the lab in college as an important place for the student to consolidate their foundation, broad their knowledge, upgrade their ability and enhance their quality had been effectively practiced. On the other hand, the goals of experimental teaching not only to instruct medical students with knowledge and skills, cultivate their problem-analyzing, problem-solving and manipulative abilities, but also to affect their view of the world, way of thinking and academic style, had been achieved. A high-quality teaching team is the key point to promote the level of laboratory construction and management in colleges, and to adapt the demand of reform and development of higher education under the new situation. [ABSTRACT FROM AUTHOR]

Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity. [ABSTRACT FROM AUTHOR]

This article compares the effects of Co doping on phase structures and stability of lanthanum strontium titanate (LST) anodes and electrochemical measurements in solid oxide fuel cells (SOFCs) employing H2S-containing H2 as fuel. The Co-doped LST (LSCT) with a perovskite structure was synthesized via a solid state approach, achieving excellent phase purity and refined particle size. The catalytic activity and electrochemical performance are significantly improved by introducing Co. A maximum power density of 300 mW cm−2 was achieved at 900 °C with 5000 ppm H2S–H2 in a fuel cell having a 300 μm thick YSZ electrolyte. Trace amounts of metallic Co nanoparticles with sizes typically no larger than 10 nm in diameter were detected on the LSCT surface after reduction in H2 at 900 °C. The nano-sized Co clusters could reduce the anode polarization resistance, as well as improve the cell performance, compared with undoped LST anodes. The LSCT anode catalyst was electrochemically stable in 5000 ppm H2S–H2 during the test time at high operating temperature. The LSCT anode catalyst also had relatively high redox stability in reversible oxidation–reduction cycles. [ABSTRACT FROM AUTHOR]

The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies. [ABSTRACT FROM AUTHOR]

Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS-induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS-induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD. [ABSTRACT FROM AUTHOR]

The hyperphosphorylated tau is a major protein component of neurofibrillary tangle, which is one of hallmarks of Alzheimer's disease (AD). While the level of methylglyoxal (MG) is significantly increased in the AD brains, the role of MG in tau phosphorylation is still not reported. Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE). Glycogen synthesis kinase-3β (GSK-3β) and p38 MAPK were activated, whereas the level and activity of JNK, Erk1/2, cdk5, and PP2A were not altered after MG treatment. Simultaneous inhibition of GSK-3β or p38 attenuated the MG-induced tau hyperphosphorylation. Aminoguanidine, a blocker of AGEs formation, could effectively reverse the MG-induced tau hyperphosphorylation. These data suggest that MG induces AD-like tau hyperphosphorylation through AGEs formation involving RAGE up-regulation and GSK-3β activation and p38 activation is also partially involved in MG-induced tau hyperphosphorylation. Thus, targeting MG may be a promising therapeutic strategy to prevent AD-like tau hyperphosphorylation. [ABSTRACT FROM AUTHOR]

Overproduction and accumulation of amyloid-β (Aβ) have been proposed to be an initiating factor of neuron loss in Alzheimer's disease (AD). AKT is a pivotal molecule in regulating neuronal survival, however, it is still not known whether upregulation of AKT can protect the cells from the Aβ-induced apoptosis. By using cell viability assay and flow cytometry, we demonstrated in the present study that overexpression of AKT could significantly attenuate the cell apoptosis induced by Aβ1-42, whereas simultaneous inhibition of PI3 K, the immediate upstream stimulator of AKT, abolished the protective effect of AKT in HEK293 cells. Upregulation of AKT restored the Aβ-induced alterations of the mitochondria-related Bcl-2 family members (including Bcl-xL, Bcl-w, Bad, and Bax) and suppressed the activation of caspase-3 and JNK. Our data suggest that upregulation of AKT could be a promising therapeutic strategy for arresting Aβ toxicity in AD patients. [ABSTRACT FROM AUTHOR]

Zinc(II) coordination polymers, [Zn(Hmal)(im)(H2O)]n · 2nH2O (1) and [Zn(Hmal)(bpy)]n · 3nH2O (2) (H3mal = malic acid, im = imidazole, bpy = 2,2'-bipyridine), were synthesized from aqueous solution and characterized by elemental analyses, infrared and fluorescence spectra, thermogravimetric analyses, and single-crystal X-ray structural analyses. In 1, zinc is coordinated by imidazole, water, and tridentate malate in octahedral geometry. The β-carboxy group of malate further bridges with the other zinc forming 1-D polymeric chains. A pair of 1-D chains self-assemble to generate a double chain by strong hydrogen bonds between imidazole and malate. Furthermore, neighboring pairs of double chains are extended to form the final 3-D framework through intermolecular hydrogen bonds. In 2, the malates link Zn in a bidentate-monodentate fashion to form spiral-shaped chains that extend into a 3-D supramolecular structure by π-π stacking interactions and intermolecular hydrogen bonds. Complex 1 exhibits strong fluorescence at room temperature. [ABSTRACT FROM AUTHOR]

In this study, we investigated how tau phosphorylation is regulated by protein kinase glycogen synthase kinase 3beta (GSK3 beta), protein kinase B (PKB), and protein phosphatase 2A (PP2A) in mouse N2a neuroblastoma cells. Results showed that GSK3 beta overexpression significantly increased PKB phosphorylation at the S473 site but not the T308 site. Neither GSK3 beta nor PKB overexpression could reduce the PP2AC phosphorylation at the Y307 site. In contrast, either PKB or GSK3 beta knockdown could increase PP2A phosphorylation at the Y307 site. PP2AC knockdown increased GSK3 beta phosphorylation at the S9 site but not at the Y216 site, and PKB phosphorylation at the T308 site but not at the S473 site. Tau phosphorylation at the S396 site was increased by GSK3 beta or PKB overexpression. Tau phosphorylation at the S214 site was only induced by PKB overexpression in the study. While GSK3 beta knockdown decreased tau phosphorylation at the S396 site, PKB knockdown increased tau phosphorylation at both the S396 and S214 sites. PP2AC knockdown decreased tau phosphorylation at the S396 and S214 sites. These findings suggest that tau phosphorylation at the S396 and S214 sites is differentially regulated by GSK3 beta, PKB, and PP2A in N2a cells. The final phosphorylation state of tau is possibly caused by the synergic action of the three enzymes. [ABSTRACT FROM AUTHOR]

Abstract: This study set out to search for a link between overproduction of Aβ and p70S6 kinase (p70S6K) phosphorylation/activation. Results showed that levels of p-p70S6K at T421/S424 and T389 are significantly increased in mouse N2a neuroblastoma cells carrying human APP with Swedish mutation (APPswe), and in transgenic APPswe/PS1 (A246E) mice as compared with respective controls, corresponding to the increase of tau phosphorylation at S262. This parallel increase in p70S6K activation and tau phosphorylation could be demonstrated by treating wild-type N2a cells with Aβ25–35. Our results suggest that the Aβ deposition in senile plaques in Alzheimer disease brains might be a primary event that activates p70S6K and phosphorylates tau at S262, resulting in microtubule disruption. [Copyright &y& Elsevier]

Abstract: Currently, we found that the 70-kDa p70 S6 kinase (p70S6K) directly phosphorylates tau at S262, S214, and T212 sites in vitro. By immunoprecipitation, p-p70S6K (T421/S424) showed a close association with p-tau (S262 and S396/404). Zinc-induced p70S6K activation could only upregulate translation of total S6 and tau but not global proteins in SH-SY5Y cells. The requirement of p70S6K activation was confirmed in the SH-SY5Y cells that overexpress wild-type htau40. Level of p-p70S6K (T421/S424) was only significantly correlated with p-tau at S262, S214, and T212, but not T212/S214, in Alzheimer’s disease (AD) brains. These suggested that p70S6K might contribute to tau related pathologies in AD brains. [Copyright &y& Elsevier]

Correction for ‘An ingenious Ni/Ce co-doped titanate based perovskite as a coking-tolerant anode material for direct hydrocarbon solid oxide fuel cells’ by Yi-Fei Sun et al., J. Mater. Chem. A, 2015, 3, 22830–22838. [ABSTRACT FROM AUTHOR]