SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.

ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Two new species of Antrodia (Polyporales, Basidiomycota) in western China.

Two new species of Antrodia, A. aridula and A. variispora, are described from western China. Phylogeny based on a six-gene dataset (ITS + nLSU + nSSU + mtSSU + TEF1 + RPB2) demonstrates that samples of the two species form two independent lineages within the clade of Antrodia s.s. and are different in morphology from the existing species of Antrodia. Antrodia aridula is characterized by its annual and resupinate basidiocarps with angular to irregular pores of 2-3 mm each and oblong ellipsoid to cylindrical basidiospores measuring 9-12 × 4.2-5.3 µm, growing on gymnosperm wood in a dry environment. Antrodia variispora is characterized by its annual and resupinate basidiocarps with sinuous or dentate pores with a size of 1-1.5 mm each and oblong ellipsoid, fusiform, pyriform, or cylindrical basidiospores measuring 11.5-16 × 4.5-5.5 µm, growing on the wood of Picea. The differences between the new species and morphologically similar species are discussed in this article.

HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24.

BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-ß protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation. METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or ß-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Sulfuretin exerts diversified functions in the processing of amyloid precursor protein.

Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation. In this study, we investigated the role of sulfuretin in the processing of amyloid precursor protein (APP), in association with the two catalytic enzymes the α-secretase a disintegrin and metalloproteinase (ADAM10), and the beta-site APP cleaving enzyme 1 (BACE1) that play important roles in the generation of ß amyloid protein (Aß) in Alzheimer's disease (AD). We found that sulfuretin increased the levels of the immature but not the mature form of ADAM10 protein. The enhanced ADAM10 transcription by sulfuretin was mediated by the nucleotides -444 to -300 in the promoter region, and was attenuated by silencing or mutation of transcription factor retinoid X receptor (RXR) and by GW6471, a specific inhibitor of peroxisome proliferator-activated receptor α (PPAR-α). We further found that sulfuretin preferentially increased protein levels of the immature form of APP (im-APP) but significantly reduced those of BACE1, sAPPß and ß-CTF, whereas Aß1-42 levels were slightly increased. Finally, the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine, respectively. Taken together, (1) RXR/PPAR-α signaling was involved in sulfuretin-mediated ADAM10 transcription. (2) Alteration of Aß protein level by sulfuretin was not consistent with that of ADAM10 and BACE1 protein levels, but was consistent with the elevated level of im-APP protein, suggesting that im-APP, an isoform mainly localized to trans-Golgi network, plays an important role in Aß generation.

TUFM is involved in Alzheimer's disease-like pathologies that are associated with ROS.

Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) is part of the mitochondrial translation machinery. It is reported that TUFM expression is reduced in the brain of Alzheimer's disease (AD), suggesting that TUFM might play a role in the pathophysiology. In this study, we found that TUFM protein level was decreased in the hippocampus and cortex especially in the aged APP/PS1 mice, an animal model of AD. In HEK cells that stably express full-length human amyloid-ß precursor protein (HEK-APP), TUFM knockdown or overexpression increased or reduced the protein levels of ß-amyloid protein (Aß) and ß-amyloid converting enzyme 1 (BACE1), respectively. TUFM-mediated reduction of BACE1 was attenuated by translation inhibitor cycloheximide (CHX) or α-[2-[4-(3,4-Dichlorophenyl)-2-thiazolyl]hydrazinylidene]-2-nitro-benzenepropanoic acid (4EGI1), and in cells overexpressing BACE1 constructs deleting the 5' untranslated region (5'UTR). TUFM silencing increased the half-life of BACE1 mRNA, suggesting that RNA stability was affected by TUFM. In support, transcription inhibitor Actinomycin D (ActD) and silencing of nuclear factor κB (NFκB) failed to abolish TUFM-mediated regulation of BACE1 protein and mRNA. We further found that the mitochondria-targeted antioxidant TEMPO diminished the effects of TUFM on BACE1, suggesting that reactive oxygen species (ROS) played an important role. Indeed, cellular ROS levels were affected by TUFM knockdown or overexpression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation at selective sites was attenuated by TEMPO. Collectively, TUFM protein levels were decreased in APP/PS1 mice. TUFM is involved in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role.

Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression.

Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-ß precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, ß-amyloid protein (Aß) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline. Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.

[Effects of seed size and drought stress on the growth and physiological characteristics of Quercus wutaishanica seedlings]. / ç§å­å¤§å°å’Œå¹²æ—±èƒè¿«å¯¹è¾½ä¸œæ Žå¹¼è‹—ç”Ÿé•¿å’Œç”Ÿç†ç‰¹æ€§çš„å½±å“.

The effects of seed size and drought stress on the growth and physiological characteristics of Quercus wutaishanica seedlings were investigated under shading conditions of a pot experiment in greenhouse. There were four treatments, including 80% field water content (FWC), 60% FWC, 40% FWC, and 20% FWC [CK, light drought stress (LDS), medium drought stress (MDS), and high drought stress (HDS), respectively]. The results showed that leaf area per plant, total dry mass, and root-shoot ratio of Q. wutaishanica seedlings regenerated from large seeds (3.05±0.38 g) were significantly higher than those from small seeds (1.46±0.27 g) in all four treatments. Shoot height, basal stem diameter, leaf number, specific leaf area, relative growth rate, and net assimilation rate of the seedlings from large seeds were higher than those of seedlings from small seeds under the treatments of LDS, MDS and HDS. Activities of peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) in large-seeded seedlings were higher than those of small-seeded seedlings under all treatments, while the contents of MDA, soluble protein, free proline, and total chlorophyll of large-seeded seedlings were higher than those of small-seeded seedlings only under some drought stress treatments. All growth parameters except the root-shoot ratio decreased with the increases of drought stress. The HDS treatment resulted in 19.4% and 20.0% decline in total dry mass of large- and small-seeded seedlings respectively, compared with those of CK. With increasing drought stress, the activities of POD, CAT, and SOD decreased after an initial increase. POD activity of large- and small-seeded seedling under MDS treatment was 126.7% and 142.1% higher than CK, while CAT was 170.0% and 151.9% higher than CK, respectively. However, the MDA content of seedlings from large and small seeds under HDS treatment was 86.5% and 68.9% higher than that of CK, respectively. The contents of soluble protein, free proline, and total chlorophyll rose at first and then fell with increasing drought stress, and soluble protein content in large- and small-seeded seedlings experienced MDS enhanced 320.7% and 352.7%, respectively. Those results indicated that large-seeded seedlings of Q. wutaishanica had stronger drought tolerance than small-seeded seedlings due to their growth and physiology advantages. Large-seeded seedlings with stronger resistance to drought stress should be applied to artificial regeneration of the degraded secondary Q. wutaishanica plantations.

Ubiquitination status does not affect Vps34 degradation.

Vps34 (vacuolar protein-sorting 34) plays important role in autophagy and endosomal trafficking. These processes are closely associated protein ubiquitination and degradation. We have hypothesized that Vps34 ubiquitination status would also control its degradation. Here, we report that our results did not support this assumption. In cells transiently transfected with ubiquitin (UB) constructs contained different lysine residues (Ks), Vps34 ubiquitination could occur regardless of the presence of any Ks in UB. However, Vps34 protein levels were not significantly altered in cells transiently transfected with these UB mutants. We further found that Vps34 protein was altered by pharmacological manipulation of E2/E3 activity; yet this effect was not significantly affected by UB overexpression. In vivo experiments revealed that in APP/PS1 mice, an animal model of Alzheimer's disease (AD), although ubiquitination of Vps34 was significantly reduced, Vps34 protein levels remained unchanged. Vps34 indeed was subjected to proteasomal or lysosomal degradation, as prolonged treatment of proteasomal inhibitor MG132 or lysosomal inhibitor chloroquine elevated Vps34 protein levels. We conclude that unlike most of other proteins, Vps34 ubiquitination is not closely associated with its degradation.

Age- and Nicotine-Associated Gene Expression Changes in the Hippocampus of APP/PS1 Mice.

The etiology of Alzheimer's disease (AD) has been intensively studied. However, little is known about the molecular alterations in early-stage and late-stage AD. Hence, we performed RNA sequencing and assessed differentially expressed genes (DEGs) in the hippocampus of 18-month and 7-month-old APP/PS1 mice. Moreover, the DEGs induced by treatment with nicotine, the nicotinic acetylcholine receptor agonist that is known to improve cognition in AD, were also analyzed in old and young APP/PS1 mice. When comparing old APP/PS1 mice with their younger littermates, we found an upregulation in genes associated with calcium overload, immune response, cancer, and synaptic function; the transcripts of 14 calcium ion channel subtypes were significantly increased in aged mice. In contrast, the downregulated genes in aged mice were associated with ribosomal components, mitochondrial respiratory chain complex, and metabolism. Through comparison with DEGs in normal aging from previous reports, we found that changes in calcium channel genes remained one of the prominent features in aged APP/PS1 mice. Nicotine treatment also induced changes in gene expression. Indeed, nicotine augmented glycerolipid metabolism, but inhibited PI3K and MAPK signaling in young mice. In contrast, nicotine affected genes associated with cell senescence and death in old mice. Our study suggests a potential network connection between calcium overload and cellular signaling, in which additional nicotinic activation might not be beneficial in late-stage AD.

Author Correction: Identification of TC2N as a novel promising suppressor of PI3K-AKT signaling in breast cancer.

After publication of this article, it came to the attention of the authors that their names had been reordered. Professor. Jia Cao and Prof. Jin-yi Liu are the co-corresponding authors, and Prof. Jin-yi Liu should be the last author.

Identification of TC2N as a novel promising suppressor of PI3K-AKT signaling in breast cancer.

Although TC2N has proven to be an oncogene in lung cancer, its biological function and molecular mechanisms in other cancer still remains unclear. Here, we investigate in breast cancer that TC2N expression is sharply overexpressed in breast cancer specimens compared with normal breast specimens, and the low TC2N expression was associated with advanced stage, lymphatic metastasis, larger tumors and shorter survival time. Upregulation of TC2N significantly restrains breast cancer cell proliferation in vitro and tumor growth in vivo. Mechanistically, TC2N blocks AKT signaling in a PI3K dependent and independent way through weakening the interaction between ALK and p55γ or inhibiting the binding of EBP1 and AKT. To sum up, these results unmask an ambivalent role of TC2N in cancer, providing a promising inhibitor for PI3K-AKT signaling.

Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology.

Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cell from oxidative stress. The antioxidant activity suggests that MSRB2 may play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, MSRB2 protein levels were decreased in the hippocampus at both young (6 mon) and old (18 mon) age, and in the cortex only at an old age, respectively. In HEK293 cells that stably express human full-length ß-amyloid precursor protein (APP, HEK/APP), MSRB2 reduced the protein and mRNA levels of APP and ß-amyloid converting enzyme 1 (BACE1), and the consequent amyloid beta peptide (Aß) 1-40 and Aß1-42 levels. MSRB2 overexpression or knockdown also oppositely affected Tau phosphorylation at selective sites, with the concomitant alteration of the phosphorylated extracellular signal regulated kinase (p-ERK) and AMP-activated protein kinase (p-AMPK) levels. Moreover, in cells treated with long-term (24 h) hydrogen peroxide, the alterations of APP processing and Tau phosphorylation were reversed by MSRB2 overexpression. We further found that MSRB2-mediated regulation of APP transcription involved JNK and ERK signaling, as MSRB2 also reduced the levels of phosphorylated JNK (p-JNK), and JNK or ERK inhibitor attenuated the effect of MSRB2 on APP proteins and transcripts. Finally, MSRB2 reduced apoptosis-related proteins Bax and caspase3 and enhanced the anti-apoptotic protein Bcl2. These results indicated that the role for MSRB2 in AD-like pathology was closely associated with its antioxidant activity. By attenuating both amyloidogenesis and Tau phosphorylation, MSRB2 may serve as a potential therapeutic target for AD.

Estrogen receptor α promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP/PS1 mice.

Cav1.2 is the pore-forming subunit of L-type voltage-gated calcium channel (LTCC) that plays an important role in calcium overload and cell death in Alzheimer's disease. LTCC activity can be regulated by estrogen, a sex steroid hormone that is neuroprotective. Here, we investigated the potential mechanisms in estrogen-mediated regulation of Cav1.2 protein. We found that in cultured primary neurons, 17ß-estradiol (E2) reduced Cav1.2 protein through estrogen receptor α (ERα). This effect was offset by a proteasomal inhibitor MG132, indicating that ubiquitin-proteasome system was involved. Consistently, the ubiquitin (UB) mutant at lysine 29 (K29R) or the K29-deubiquitinating enzyme TRAF-binding protein domain (TRABID) attenuated the effect of ERα on Cav1.2. We further identified that the E3 ligase Mdm2 (double minute 2 protein) and the PEST sequence in Cav1.2 protein played a role, as Mdm2 overexpression and the membrane-permeable PEST peptides prevented ERα-mediated Cav1.2 reduction, and Mdm2 overexpression led to the reduced Cav1.2 protein and the increased colocalization of Cav1.2 with ubiquitin in cortical neurons in vivo. In ovariectomized (OVX) APP/PS1 mice, administration of ERα agonist PPT reduced cerebral Cav1.2 protein, increased Cav1.2 ubiquitination, and improved cognitive performances. Taken together, ERα-induced Cav1.2 degradation involved K29-linked UB chains and the E3 ligase Mdm2, which might play a role in cognitive improvement in OVX APP/PS1 mice.

Functional characterization of short-type peptidoglycan recognition proteins (PGRPs) from silkworm Bombyx mori in innate immunity.

Peptidoglycan recognition proteins (PGRPs) are members of an important class of pattern recognition receptors in insects that can specifically recognize peptidoglycan (PGN) in bacterial cell walls and participate in immune regulation and bacterial clearance. Although the role of PGRPs in regulating the innate immune response in Drosophila melanogaster has been studied, little is known regarding PGRPs in Lepidoptera species. In this study, five short (S)-type Bombyx mori PGRPs (BmPGRPs) were cloned, expressed, and evaluated for their function in innate immunity. B. mori larvae that were injected with the gram-positive bacterium Bacillus megaterium or the gram-negative bacterium Escherichia coli exhibited a rapid and significant upregulation in S-type BmPGRP expression. The results showed that the five evaluated BmPGRPs have significant agglutination activity toward E. coli and B. megaterium and more notable amidase activity toward meso-diaminopimelic acid peptidoglycan (DAP-PGN). Furthermore, only in the presence of BmPGRP-S5 did B. mori larval hemocytes exhibit significant phagocytosis against E. coli and B. megaterium.

MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation.

MMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer's disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5' untranslated region (5'UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5'UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer's disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-ß precursor protein processing, amyloid-ß load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer's disease, via the translational regulation of BACE1.

Pilomatricoma (calcifying epithelioma): MDCT and MR imaging findings in 31 patients with radiological-pathological correlation.

PURPOSE: To describe the radiological characteristics of pilomatricomas on multi-detector computed tomography (MDCT) and magnetic resonance imaging (MRI), and to correlate the radiological findings and pathological features. MATERIALS AND METHODS: The radiological findings of 41 pilomatricomas in 31 patients were retrospectively reviewed. The images were evaluated with emphasis on calcifications, reticular and ring-like appearances, enhancement patterns, circular target sign and peritumoral fat stranding, and correlating these with pathological features. RESULTS: Of the 31 lesions evaluated by MDCT, 25(80.6%) showed different patterns of calcifications which included single in 12(38.7%) lesions and multiple in 13(41.9%) lesions, but peritumoral fat stranding was observed only in 2(6.5%) lesions. MRI scans were performed in 11 patients with 21 lesions, homogeneous and inhomogeneous hypointensities on T1-weighted (T1W) images were showed respectively in 14(66.7%) and 7(33.3%) lesions. On fat-suppressed (FS) T2-weighted (T2W) images, a ring-like hyperintensity was observed in all 21(100%) lesions, reticular hyperintensity, circular target sign, peritumoral fat stranding and secondary anetoderma were seen in 7(33.3%), 4(19%), 4(19%) and 1(4.8%) lesions, respectively; and a significant difference (P < 0.05) was found when comparing the maximum diameter of tumors with (2.3 ± 1.4 mm) and without (1.1 ± 0.3 mm) reticular hyperintensity. On contrast-enhanced T1W images, all 21(100%) lesions were found to have ring-like enhancement and 7(33.3%) of them showed reticular enhancement. The reticular and ring-like appearances on MR images respectively corresponded to the pathological edematous stroma and connective tissue capsule, and the four-layer structures of the circular target sign on FS T2W images also corresponded to pathological calcifications, shadow cells, epithelial cells and connective tissue capsule, respectively. CONCLUSIONS: The characteristic radiological findings associated with pilomatricomas include different patterns of calcifications on MDCT images and ring-like, reticular appearances and circular target sign on MR images. Radiological findings are well correlated with pathological nature.

An ML protein from the silkworm Bombyx mori may function as a key accessory protein for lipopolysaccharide signaling.

Lipopolysaccharide (LPS) is a common component of the outermost cell wall in Gram-negative bacteria. In mammals, LPS serves as an endotoxin that can be recognized by a receptor complex of TLR4 (Toll-like receptor 4) and MD-2 (myeloid differentiation-2) and subsequently induce a strong immune response to signal the release of tumor necrosis factor (TNF). In Drosophila melanogaster, no receptors for LPS have been identified, and LPS cannot activate immune responses. Here, we report a protein, BmEsr16, which contains an ML (MD-2-related lipid-recognition) domain, may function as an LPS receptor in the silkworm Bombyx mori. We showed that antibacterial activity in the hemolymph of B. mori larvae was induced by Escherichia coli, peptidoglycan (PGN) and LPS and that the expression of antimicrobial peptide genes was also induced by LPS. Furthermore, both the expression of BmEsr16 mRNA in the fat body and the expression of BmEsr16 protein in the hemolymph were induced by LPS. Recombinant BmEsr16 bound to LPS and lipid A, as well as to PGN, lipoteichoic acid, but not to laminarin or mannan. More importantly, LPS-induced immune responses in the hemolymph of B. mori larvae were blocked when the endogenous BmEsr16 protein was neutralized by polyclonal antibody specific to BmEsr16. Our results suggest that BmEsr16 may function as a key accessory protein for LPS signaling in B. mori.

Cosmosiin Increases ADAM10 Expression via Mechanisms Involving 5'UTR and PI3K Signaling.

The α-secretase "a disintegrin and metalloproteinase domain-containing protein" (ADAM10) is involved in the processing of amyloid precursor protein (APP). Upregulation of ADAM10 precludes the generation of neurotoxic ß-amyloid protein (Aß) and represents a plausible therapeutic strategy for Alzheimer's disease (AD). In this study, we explored compounds that can potentially promote the expression of ADAM10. Therefore, we performed high-throughput small-molecule screening in SH-SY5Y (human neuroblastoma) cells that stably express a luciferase reporter gene driven by the ADAM10 promoter, including a portion of its 5'-untranslated region (5'UTR). This has led to the discovery of cosmosiin (apigenin 7-O-ß-glucoside). Here, we report that in human cell lines (SH-SY5Y and HEK293), cosmosiin proportionally increased the levels of the immature and mature forms of the ADAM10 protein without altering its mRNA level. This effect was attenuated by translation inhibitors or by deleting the 5'UTR of ADAM10, suggesting that a translational mechanism was responsible for the increased levels of ADAM10. Luciferase deletion assays revealed that the first 144 nucleotides of the 5'UTR were necessary for mediating the cosmosiin-induced enhancement of ADAM10 expression in SH-SY5Y cells. Cosmosiin failed to increase the levels of the ADAM10 protein in murine cells, which lack native expression of the ADAM10 transcript containing the identified 5'UTR element. The potential signaling pathway may involve phosphatidylinositide 3-kinase (PI3K) because pharmacological inhibition of PI3K attenuated the effect of cosmosiin on the expression of the ADAM10 protein. Finally, cosmosiin attenuated Aß generation because the levels of Aß40/42 in HEK-APP cells were significantly reduced after cosmosiin treatment. Collectively, we found that the first 144 nucleotides of the ADAM10 5'UTR, and PI3K signaling, are involved in cosmosiin-induced enhancement of the expression of ADAM10 protein. These results suggest that cosmosiin may be a potential therapeutic agent in the treatment of AD.

Estrogen-related receptor alpha is involved in Alzheimer's disease-like pathology.

Estrogen-related receptor alpha (ERRα) is a transcriptional factor associated with mitochondrial biogenesis and energy metabolism. However, little is known about the role of ERRα in Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, ERRα protein and mRNA were decreased in a region- and age-dependent manner. In HEK293 cells that stably express human full-length ß-amyloid precursor protein (APP), overexpression of ERRα inhibited the amyloidogenic processing of APP and consequently reduced Aß1-40/1-42 level. ERRα overexpression also attenuated Tau phosphorylation at selective sites, with the concomitant reduction of glycogen synthase kinase 3ß (GSK3ß) activity. Interestingly, alterations of APP processing and Tau phosphorylation induced by hydrogen peroxide were reversed by ERRα overexpression in HEK/APP cells. These results indicated that ERRα plays a functional role in AD pathology. By attenuating both amyloidogenesis and Tau phosphorylation, ERRα may serve as a potential therapeutic target for AD.