Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.

Toxic amyloid beta (Aß) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aß production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aß and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aß production and memory impairment under hypoxia.

SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions.

The enzyme γ-secretase generates ß-amyloid (Aß) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aß generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aß production. Moreover, SERP1 abundance, γ-secretase assembly, and Aß production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aß production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.

Utility of the immature granulocyte percentage for diagnosing acute appendicitis among clinically suspected appendicitis in adult.

BACKGROUND: Acute appendicitis is the most common cause of abdominal surgical emergencies that present at the emergency department (ED). Although early phase of acute appendicitis cannot induce systemic inflammatory responses, it may induce proliferation immature granulocyte before leukocytosis is occurred. Based on this, we hypothesized that IG% may be beneficial for detecting appendicitis, in addition to classic inflammatory markers including the WBC count, a left shift in neutrophils, and CRP, at no additional cost. METHODS: A retrospective observational study was conducted in a tertiary-care, university-affiliated hospital emergency department in adults (>18 years old) with suspected appendicitis from January 1, 2015 to December 31, 2016. The diagnostic performance of IG% and other inflammatory markers, namely white blood cell (WBC) count, proportion of neutrophils, and C-reactive protein (CRP), for acute appendicitis was evaluated. RESULTS: Of 403 patients, 204 (50.6%) were diagnosed with acute appendicitis and 45 (22.0%) had complicated appendicitis. All inflammatory markers, including WBC count, proportion of neutrophils, IG%, and CRP, were statistically different between the appendicitis and nonappendicitis group (P < .01). However, IG% was not clinically useful because the median IG% was the same (0.3 vs 0.3) between the appendicitis and nonappendicitis group. Moreover, the area under the curve for IG% was smaller than for other inflammatory markers (0.57, 0.51-0.63, P < .02). CONCLUSION: The diagnostic ability of IG% for appendicitis is insufficient, and it brings no additional benefit over other inflammatory markers.

Effect of Mn in Li3V2-xMnx(PO4)3 as High Capacity Cathodes for Lithium Batteries.

Li3V2-xMnx(PO4)3 (x = 0, 0.05) cathode materials, which allow extraction of 3 mol of Li from the formula unit, were investigated to achieve a high energy density utilizing multielectron reactions, activated by the V3+/5+ redox reaction. Structural investigation demonstrates that V3+ was replaced by equivalent Mn3+, as confirmed by Rietveld refinement of the X-ray diffraction data and X-ray absorption near edge spectroscopy. The substitution simultaneously lowered the band gap energy from 3.4 to 3.2 eV, according to a density functional theory calculation. In addition to the effect of Mn doping, surface carbonization of Li3V2-xMnx(PO4)3 (x = 0, 0.05) dramatically increased the electric conductivity up to 10-3 S cm-1. As a result, the carbon-coated Li3V2-xMnx(PO4)3 (x = 0.05) delivered a high discharge (reduction) capacity of approximately 180 mAh g-1 at a current of 20 mA g-1 (0.1 C rate) with excellent retention, delivering approximately 163 mAh g-1 at the 200th cycle. Even at 50 C (10 A g-1), the electrode afforded a discharge capacity of 68 mAh g-1 and delivered approximately 104 mAh g-1 (1 C) at -10 °C with the help of Mn doping and carbon coating. The synergetic effects such as a lowered band gap energy by Mn doping and high electric conductivity associated with carbon coating are responsible for the superior electrode performances, including thermal properties with extremely low exothermic heat generation (<0.4 J g-1 for Li0.02V1.95Mn0.05(PO4)3), which is compatible with the layered high energy density of LiNi0.8Co0.15Al0.05O2 and LiNi0.8Co0.1Mn0.1O2 materials.

Synthesis and Electrochemical Reaction of Tin Oxalate-Reduced Graphene Oxide Composite Anode for Rechargeable Lithium Batteries.

Unlike for SnO2, few studies have reported on the use of SnC2O4 as an anode material for rechargeable lithium batteries. Here, we first introduce a SnC2O4-reduced graphene oxide composite produced via hydrothermal reactions followed by a layer-by-layer self-assembly process. The addition of rGO increased the electric conductivity up to ∼10-3 S cm-1. As a result, the SnC2O4-reduced graphene oxide electrode exhibited a high charge (oxidation) capacity of ∼1166 mAh g-1 at a current of 100 mA g-1 (0.1 C-rate) with a good retention delivering approximately 620 mAh g-1 at the 200th cycle. Even at a rate of 10 C (10 A g-1), the composite electrode was able to obtain a charge capacity of 467 mAh g-1. In contrast, the bare SnC2O4 had inferior electrochemical properties relative to those of the SnC2O4-reduced graphene oxide composite: ∼643 mAh g-1 at the first charge, retaining 192 mAh g-1 at the 200th cycle and 289 mAh g-1 at 10 C. This improvement in electrochemical properties is most likely due to the improvement in electric conductivity, which enables facile electron transfer via simultaneous conversion above 0.75 V and de/alloy reactions below 0.75 V: SnC2O4 + 2Li+ + 2e- → Sn + Li2C2O4 + xLi+ + xe- → LixSn on discharge (reduction) and vice versa on charge. This was confirmed by systematic studies of ex situ X-ray diffraction, transmission electron microscopy, and time-of-flight secondary-ion mass spectroscopy.

Synthesis of LiVOPO4 by Emulsion Drying Method for Use as an Anode Material for Rechargeable Lithium Batteries.

Highly crystalline ß-LiVOPO4 was synthesized from a water-in-oil emulsion. At 400 °C in ambient air, removal of the oil phase from the emulsion precipitates resulted in a poorly crystalline intermediate compound. On increasing the temperature to 750 °C under Ar, a single phase was formed. Rietveld refinement of the X-ray diffraction (XRD) data obtained from the product heated at 750 °C indicated that the product has an orthorhombic ß-LiVOPO4 olivine structure with no impurities. Although the ß-LiVOPO4 had an irreversible capacity in the first cycle, the electrode exhibited stable cyclability for 100 cycles, maintaining approximately 85.5% (573 mAh g-1) of the first charge capacity (670 mAh g-1). In addition, the ß-LiVOPO4 electrode had a high capacity even at high rates: 601 mAh g-1 at 1C rate (670 mA g-1) and 373 mAh g-1 at 30C rates (20.1 A g-1). Consolidating the results from XRD, X-ray photoelectron spectroscopy, and time-of-flight secondary mass spectroscopy, we suggest that the electrochemical activity of the ß-LiVOPO4 arises from the conversion reaction accompanied by the formation of Li2O and Li3PO4. In addition, the ion-conducting Li3PO4 contributes to high capacity delivery at high rates up to a C-rate of 30.

Dual-specificity phosphatase 26 (DUSP26) stimulates Aß42 generation by promoting amyloid precursor protein axonal transport during hypoxia.

Amyloid beta peptide (Aß) is a pathological hallmark of Alzheimer's disease (AD) and is generated through the sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases. Hypoxia is a known risk factor for AD and stimulates Aß generation by γ-secretase; however, the underlying mechanisms remain unclear. In this study, we showed that dual-specificity phosphatase 26 (DUSP26) regulates Aß generation through changes in subcellular localization of the γ-secretase complex and its substrate C99 under hypoxic conditions. DUSP26 was identified as a novel γ-secretase regulator from a genome-wide functional screen using a cDNA expression library. The phosphatase activity of DUSP26 was required for the increase in Aß42 generation through γ-secretase, but this regulation did not affect the amount of the γ-secretase complex. Interestingly, DUSP26 induced the accumulation of C99 in the axons by stimulating anterograde transport of C99-positive vesicles. Additionally, DUSP26 induced c-Jun N-terminal kinase (JNK) activation for APP processing and axonal transport of C99. Under hypoxic conditions, DUSP26 expression levels were elevated together with JNK activation, and treatment with JNK inhibitor SP600125, or the DUSP26 inhibitor NSC-87877, reduced hypoxia-induced Aß generation by diminishing vesicle trafficking of C99 to the axons. Finally, we observed enhanced DUSP26 expression and JNK activation in the hippocampus of AD patients. Our results suggest that DUSP26 mediates hypoxia-induced Aß generation through JNK activation, revealing a new regulator of γ-secretase-mediated APP processing under hypoxic conditions. We propose the role of phosphatase dual-specificity phosphatase 26 (DUSP26) in the selective regulation of Aß42 production in neuronal cells under hypoxic stress. Induction of DUSP26 causes JNK-dependent shift in the subcellular localization of γ-secretase and C99 from the cell body to axons for Aß42 generation. These findings provide a new strategy for developing new therapeutic targets to arrest AD progression.

SIRT1 modulates high-mobility group box 1-induced osteoclastogenic cytokines in human periodontal ligament cells.

Bone resorptive cytokines contribute to bone loss in periodontal disease. However, the involvement of SIRT1 in high-mobility group box 1 (HMGB1)-induced osteoclastic cytokine production remains unknown. The aim of this study was to investigate the role of SIRT1 in the responses of human periodontal ligament cells to HMGB1 and to identify the underlying mechanisms. The effect of HMGB1 on osteoclastic cytokine expression and secretion, and the regulatory mechanisms involved were studied by ELISA, reverse transcription-polymerase chain reaction, and Western blot analysis. HMGB1 upregulated the mRNA expression levels of the osteoclastic cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-11, and IL-17. In addition, HMGB1 upregulated RANKL mRNA expression, and SIRT1 mRNA and protein expression. The upregulation of these cytokines by HMGB1 was attenuated by pretreatment with inhibitors of p38 mitogen-activated protein kinase and NF-κB, as well as neutralizing antibodies against Toll-like receptors 2 and 4. Inhibition of SIRT1 by sirtinol or SIRT1 siRNA blocked the HMGB1-stimulated expression of RANKL and cytokines. These results suggest that the inhibition of SIRT1 may attenuate HMGB1-mediated periodontal bone resorption through the modulation of osteoclastogenic cytokine levels in human periodontal ligament cells.

Endoplasmic reticulum stress is involved in hydrogen peroxide induced apoptosis in immortalized and malignant human oral keratinocytes.

BACKGROUND: Although hydrogen peroxide may play an important role in the development of cancer, it can be an efficient inducer of apoptosis in cancer cells; the exact mechanism by which this action occurs is not completely understood in oral cancer cells. METHOD: In this study, the mechanisms by which H(2)O(2) inhibited growth and induced apoptosis were differentially investigated using HPV-immortalized human oral keratinocytes (IHOK) and oral cancer cells (HN4). RESULTS: H(2)O(2) treatment sensitively and dose-dependently induced growth inhibition and typical apoptosis in IHOK and HN4 cells, as demonstrated by a decreased level of cell viability, an increased population of cells in the sub-G(0)/G(1) phase, ladder formation of the genomic DNA, chromatin condensation and accumulation of Annexin V(+)/PI(+) cells. Furthermore, the expression of Bax, p53 and p21(WAF1/CIP1) increased, whereas the expression of Bcl-2 decreased in immortalized and malignant keratinocytes that were treated with H(2)O(2). In addition, cytochrome-c from the mitochondria was observed in H(2)O(2)-treated IHOK and oral cancer cells, and this was accompanied by the activation of caspase-3 and -9. Additionally, H(2)O(2) treatment induced upregulation of CHOP, GRP78 and several representative endoplasmic reticulum (ER) stress-responsive proteins, including heme oxygenase-1. CONCLUSION: Overall, these results suggest that H(2)O(2) triggers apoptosis via the mitochondrial and ER stress pathway in IHOK and HN4 cells, and that increasing the cellular levels of H(2)O(2) sufficiently may lead to selective killing of oral cancer cells and therefore be therapeutically useful.