Dual modification of phosphate toward improving electrochemical performance of LiNiO2 cathode materials.

Lithium nickel oxide (LiNiO2) cathode materials are featured with high capacity and low cost for rechargeable lithium-ion batteries but suffer from severe structure and interface instability. Bulk doping together with surface coating has been proven to be an efficient approach to improve the inner structure and interfacial stability of the LiNiO2 cathode material. Nevertheless, the role of anion doping seems to be quite different from that of cation doping, and a deep insight will be desirable for the structure design of the LiNiO2 cathode material. In this paper, PO43--doped and Li3PO4-coating of dual modification of LiNiO2 are achieved via a facile approach. It is demonstrated that the PO43- anions are doped into the tetrahedron vacant sites of the crystal structure, alleviating the phase transition and improving the reversibility of crystal structure. Besides, the Li3PO4 coating layer ameliorates the interface stability to restrain the side reactions. Therefore, the dual modification enhances overall structural stability of the material to provide excellent performance. Moreover, the consumption of the Li residues by the formation of Li3PO4 coating layer, and the enlarged interlayer spacing of the crystal structure by PO43- doping can facilitate the Li+ ions diffusion, resulting in a superior rate capability.

Identification of Cytochrome P450 2E1 as a Novel Target in Glioma and Development of Its Inhibitor as an Anti-Tumor Agent.

Glioblastoma (GBM) is a devastating inflammation-related cancer for which novel therapeutic targets are urgently required. Previous studies of the authors indicate Cytochrome P450 2E1 (CYP2E1) as a novel inflammatory target and develop a specific inhibitor Q11. Here it is demonstrated that CYP2E1 overexpression is closely related to higher malignancy in GBM patients. CYP2E1 activity is positively correlated with tumor weight in GBM rats. Significantly higher CYP2E1 expression accompanied by increased inflammation is detected in a mouse GBM model. Q11, 1-(4-methyl-5-thialzolyl) ethenone, a newly developed specific inhibitor of CYP2E1 here remarkably attenuates tumor growth and prolongs survival in vivo. Q11 does not directly affect tumor cells but blocks the tumor-promoting effect of microglia/macrophage (M/Mφ) in the tumor microenvironment through PPARγ-mediated activation of the STAT-1 and NF-κB pathways and inhibition of the STAT-3 and STAT-6 pathways. The effectiveness and safety of targeting CYP2E1 in GBM are further supported by studies with Cyp2e1 knockout rodents. In conclusion, a pro-GBM mechanism in which CYP2E1-PPARγ-STAT-1/NF-κB/STAT-3/STAT-6 axis fueled tumorigenesis by reprogramming M/Mφ and Q11 as a promising anti-inflammatory agent for GBM treatment is uncovered.

Luminescent Materials for Volumetric Three-Dimensional Displays Based on Photoactivated Phosphorescence.

True three-dimensional (3D) displays are the best display technologies and their breakthrough is primarily due to advancements in display media. In this paper, we propose two luminescent materials for a static volumetric 3D display based on photoactivated phosphorescence. The luminescent materials include (1) dimethyl sulfoxide (DMSO)/1-methyl-2-pyrrolidinone (NMP) or tetramethylene sulfoxide (TMSO) as the solvent and photochemically-deoxygenating reagent; (2) a metal phthalocyanine complex as the sensitizer; (3) a phosphorescent platinum complex as the emitter. The metal phthalocyanine complex, PdPrPc (PdBuPc), absorbs the light beam of 635 nm and the solvent scavenges the sensitized singlet oxygen. Light beams pass through a deoxygenated zone. The phosphorescent emitter, PtNI, absorbs the 440 nm light beam and phosphoresces only in the deoxygenated zone generated by the sensitizer. Phosphorescent voxels and high-contrast 3D images are well-defined at the intersection of 635 and 440 nm light beams.

The proteomic characterization of the peritumor microenvironment in human hepatocellular carcinoma.

The tumor microenvironment (TME) was usually studied in tumor tissue and in relation to only tumor progression, with little involved in occurrence, recurrence and metastasis of tumor. Thus, a new concept "peritumor microenvironment (PME)" was proposed in the proteomic characterization of peritumor liver tissues in human hepatocellular carcinoma (HCC). The PME for occurrence (PME-O) and progression (PME-P) were almost totally different at proteome composition and function. Proteins for occurrence and progression rarely overlapped and crossed. Immunity played a central role in PME-O, whereas inflammation, angiogenesis and metabolism were critical in PME-P. Proteome profiling identified three PME subtypes with different features of HCC. Thymidine phosphorylase (TYMP) was validated as an antiangiogenic target in an orthotopic HCC mouse model. Overall, the proteomic characterization of the PME revealed that the entire processes of HCC occurrence and progression differ substantially. These findings could enable advances in cancer biology, diagnostics and therapeutics.

The POR rs10954732 polymorphism decreases susceptibility to hepatocellular carcinoma and hepsin as a prognostic biomarker correlated with immune infiltration based on proteomics.

The effect of the cytochrome P450 oxidoreductase (POR) rs10954732 (G > A) polymorphism on hepatocellular carcinoma (HCC) susceptibility is unknown. Here we found that A allele carriers showed a 69% decrease in susceptibility to HCC with overall survival (OS) prolonged to 199%, accompanied by lower activity for cytochrome P450 2E1. A total of 222 differentially expressed proteins were mainly enriched in neutrophil and T cell activation and involved in the immune and inflammatory responses, constituting the altered immune tumor microenvironment related with A allele by proteomics analysis. Hepsin (HPN) showed significant down-regulation in HCC and up-regulation in A allele carriers. A lower HPN level was associated with increased susceptibility to HCC and a worse prognosis. Moreover, HPN is a potential independent prognostic biomarker for HCC and is strongly associated with clinicopathological features, tumor-infiltrating status of immune cells both in our discovery cohort and database surveys. Our findings provide a new potential mechanism by which HPN may play an important role in the susceptibility of rs10954732 A allele carriers to HCC and their prognosis through tumor immune infiltration, thus offering potential insights for future studies on tumor immunotherapy.

Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker.

BACKGROUND: Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. METHODS: Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. RESULTS: We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. CONCLUSIONS: The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.

Jak-STAT Inhibition Mediates Romidepsin and Mechlorethamine Synergism in Cutaneous T-Cell Lymphoma.

Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. In this study, we show synergistic antilymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in cutaneous T-cell lymphoma cell lines and primary samples with strong antitumor effects in an in vivo model of Sézary syndrome. Mechanistically, gene expression profiling points to abrogation of Jak/signal transducer and activator of transcription (STAT) signaling as an important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary Sézary syndrome samples, but not in romidepsin-resistant tumors. Moreover, in further support of Jak/STAT signaling as a modulator of romidepsin activity in cutaneous T-cell lymphoma, treatment with romidepsin in combination with Jak inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of cutaneous T-cell lymphoma and uncover a previously unrecognized role for Jak/STAT signaling in the response to romidepsin and romidepsin-based combination therapies in Sézary syndrome.

Impacts of bio-carriers on the characteristics of soluble microbial products in a hybrid membrane bioreactor for treating mariculture wastewater.

To gain greater insights into impacts of bio-carriers on the fate and characteristics of soluble microbial products (SMPs) for mariculture wastewater treatment, the hybrid membrane bioreactor (HMBR) and conventional membrane bioreactor (CMBR) were investigated. Both protein and polysaccharide exhibited lower level in HMBR (8.95 ± 0.28 mg/L and 20.49 ± 1.3 mg/L for anoxic stage, 5.16 ± 0.22 mg/L and 17.85 ± 0.92 mg/L for aerobic stage) than CMBR (14.6 ± 0.68 mg/L and 28.3 ± 2.99 mg/L for anoxic stage, 10.53 ± 0.68 and 26.04 ± 3.15 mg/L for aerobic stage). Three-dimensional fluorescence excitation emission matrix (EEM) revealed bio-carriers reduced the production of aromatic protein-like components in anoxic and aerobic supernatant and caused a blue-shift of soluble microbial product in aerobic stage. Molecular weight (Mw) distribution indicated that bio-carriers ameliorated the excretion of biopolymer (Mw > 500 kDa) in anoxic supernatant and intermediate Mw fractions (20-500 kDa) in aerobic supernatant. Moreover, little changes were observed in SMPs with Mw < 3 kDa down the whole treatment process of both systems. Gas chromatography-mass spectrometry (GC-MS) demonstrated that the major SMPs were long-chain alkanes and aromatics in all units of both systems and fewer aromatics were detected in HMBR. For anoxic stage, more peaks were identified in the HMBR (138) than CMBR (115), while for aerobic stage, more compounds were observed in the CMBR (94) than HMBR (70). Over 50% of the compounds in the anoxic supernatant for the HMBR were the same as in the CMBR. And 27 compounds were the same in aerobic supernatant for the HMBR and CMBR. Fewer compounds in the HMBR effluent (52) was observed, compared to CMBR effluent (80). Approximately 25.7% of compounds in the aerobic stage of the HMBR were rejected by membrane, while this value decreased to 14.9% in the CMBR.

A Review of Primary Cutaneous CD30+ Lymphoproliferative Disorders.

Primary cutaneous CD30+ lymphoproliferative diseases (LPDs) comprise a range of diseases (LyP, pcALCL, and borderline lesions) with broad histologic and phenotypical characteristics, although they all share the common feature of a favorable prognosis notwithstanding histology suggestive of a high-grade lymphoma. Given their cytomorphologic similarities, accurate diagnosis and workup are needed to differentiate these distinct entities in order to best use novel biologic therapies and avoid aggressive overtreatment. Moreover, although CD30+ LPDs have a favorable prognosis, secondary malignancies should be considered as part of the initial evaluation, and patients should have ongoing surveillance.

Concurrence of autophagy with apoptosis in alveolar epithelial cells contributes to chronic pulmonary toxicity induced by methamphetamine.

OBJECTIVES: Methamphetamine (MA) abuse evokes pulmonary toxicity. The aim of our study is to investigate if autophagy is induced by MA and if autophagy-initiated apoptosis in alveolar epithelial cells is involved in MA-induced chronic pulmonary toxicity. MATERIALS AND METHODS: The rats in Control group and MA group were tested by Doppler and HE staining. The alveolar epithelial cells were treated with MA, following by western blot, RT-PCR and immunofluorescence assay. RESULTS: Chronic exposure to MA resulted in lower growth ratio of weight and in higher heart rate and peak blood flow velocity of the main pulmonary artery of rats. MA induced infiltration of inflammatory cells in lungs, more compact lung parenchyma, thickened alveolar septum and reduction in the number of alveolar sacs. In alveolar epithelial cells, the autophagy marker LC3 and per cent of cells containing LC3-positive autophagosome were significantly increased. MA dose dependently suppressed the phosphorylation of mTOR to inactivate mTOR, elicited autophagy regulatory proteins LC3 and Beclin-1, accelerated the transformation from LC3 I to LC3 II and initiated apoptosis by decreasing Bcl-2 and increasing Bax, Bax/Bcl-2 and cleaved Caspase 3. The above results suggest that sustained autophagy was induced by long-term exposure to MA and that the increased Beclin-1 autophagy initiated apoptosis in alveolar epithelial cells. CONCLUSIONS: Concurrence of autophagy with apoptosis in alveolar epithelial cells contributes to chronic pulmonary toxicity induced by MA.

Suppression of nuclear factor erythroid­2­related factor 2­mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats.

The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid­2­related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2­mediated antioxidative defense is involved in methamphetamine (MA)­induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate­cysteine ligase catalytic subunit C and heme oxygenase­1), and dose­dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2­mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA­induced chronic lung toxicity.

TBHQ Alleviated Endoplasmic Reticulum Stress-Apoptosis and Oxidative Stress by PERK-Nrf2 Crosstalk in Methamphetamine-Induced Chronic Pulmonary Toxicity.

Methamphetamine (MA) leads to cardiac and pulmonary toxicity expressed as increases in inflammatory responses and oxidative stress. However, some interactions may exist between oxidative stress and endoplasmic reticulum stress (ERS). The current study is designed to investigate if both oxidative stress and ERS are involved in MA-induced chronic pulmonary toxicity and if antioxidant tertiary butylhydroquinone (TBHQ) alleviated ERS-apoptosis and oxidative stress by PERK-Nrf2 crosstalk. In this study, the rats were randomly divided into control group, MA-treated group (MA), and MA plus TBHQ-treated group (MA + TBHQ). Chronic exposure to MA resulted in slower growth of weight and pulmonary toxicity of the rats by increasing the pulmonary arterial pressure, promoting the hypertrophy of right ventricle and the remodeling of pulmonary arteries. MA inhibited the Nrf2-mediated antioxidative stress by downregulation of Nrf2, GCS, and HO-1 and upregulation of SOD2. MA increased GRP78 to induce ERS. Overexpression and phosphorylation of PERK rapidly phosphorylated eIF2α, increased ATF4, CHOP, bax, caspase 3, and caspase 12, and decreased bcl-2. These changes can be reversed by antioxidant TBHQ through upregulating expression of Nrf2. The above results indicated that TBHQ can alleviate MA-induced oxidative stress which can accelerate ERS to initiate PERK-dependent apoptosis and that PERK/Nrf2 is likely to be the key crosstalk between oxidative stress and ERS in MA-induced chronic pulmonary toxicity.

Endoplasmic reticulum stress and apoptosis via PERK-eIF2α-CHOP signaling in the methamphetamine-induced chronic pulmonary injury.

Methamphetamine (MA) leads to multiple organs lesions and apoptosis. The aim of this study is to investigate if endoplasmic reticulum stress (ERS) - initiated apoptosis is involved in the chronic pulmonary injury induced by MA. In this study, rats were divided into a control group, methamphetamine 5mg/kg group and methamphetamine 10mg/kg group. This study found that the protein level of GRP78 is higher in M10 group than in control group. PERK signaling and the relevant apoptosis factors were also activated. Morphological measurements showed that protein BAX and CHOP accumulated in the alveolar epithelium and the alveolar walls with epithelium were damaged and that the number of pulmonary alveoli decreased. The findings showed that ERS and PERK pathway are activated and eventually lead to apoptosis. Severe ERS mediated the apoptosis of alveolar epithelium cells as well as decreasing numbers of pulmonary alveoli.

Fluoxetine protects against methamphetamine­induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.

Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA­induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine­treated groups. Rats in the MA and the two fluoxetine­treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine­treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin­6 and tumor necrosis factor­α in rat lungs. Fluoxetine inhibited MA­induced increases in the expression levels of serotonin transporter (SERT) and p­p38 mitogen­activated protein kinase (MAPK), and reversed the MA­induced decrease in nuclear Nrf2 and human heme oxygenase­1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA­induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.

An intergenic non-coding rRNA correlated with expression of the rRNA and frequency of an rRNA single nucleotide polymorphism in lung cancer cells.

BACKGROUND: Ribosomal RNA (rRNA) is a central regulator of cell growth and may control cancer development. A cis noncoding rRNA (nc-rRNA) upstream from the 45S rRNA transcription start site has recently been implicated in control of rRNA transcription in mouse fibroblasts. We investigated whether a similar nc-rRNA might be expressed in human cancer epithelial cells, and related to any genomic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative rRNA measurement, we demonstrated that a nc-rRNA is transcribed in human lung epithelial and lung cancer cells, starting from approximately -1000 nucleotides upstream of the rRNA transcription start site (+1) and extending at least to +203. This nc-rRNA was significantly more abundant in the majority of lung cancer cell lines, relative to a nontransformed lung epithelial cell line. Its abundance correlated negatively with total 45S rRNA in 12 of 13 cell lines (P = 0.014). During sequence analysis from -388 to +306, we observed diverse, frequent intercopy single nucleotide polymorphisms (SNPs) in rRNA, with a frequency greater than predicted by chance at 12 sites. A SNP at +139 (U/C) in the 5' leader sequence varied among the cell lines and correlated negatively with level of the nc-rRNA (P = 0.014). Modelling of the secondary structure of the rRNA 5'-leader sequence indicated a small increase in structural stability due to the +139 U/C SNP and a minor shift in local configuration occurrences. CONCLUSIONS/SIGNIFICANCE: The results demonstrate occurrence of a sense nc-rRNA in human lung epithelial and cancer cells, and imply a role in regulation of the rRNA gene, which may be affected by a +139 SNP in the 5' leader sequence of the primary rRNA transcript.