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Human herpesvirus 6 (HHV-6) is neurophilic, and its relationship with Alzheimer's disease (AD) remains controversial. This study aimed to examine the relationships between HHV-6 and cognitive abilities in elderly people aged 60 years or above from communities in Shenzhen.We recruited participants from 10 community health service centers in Shenzhen. Participants were divided into case and control groups according to Mini-Mental State Examination (MMSE) scale standards and were included in this study with 1:1 matching based on sex and age (± 3 years). The HHV-6 gene was detected by real-time fluorescent quantitative PCR, and the HHV-6 copy number was quantified.A total of 580 participants (cases, n = 290; controls, n = 290), matched for gender and age was included in this study. A positive HHV-6 test was not associated with a significant difference in global cognitive performance (ORHHV-6 infection significantly associated with orientation, attention and calculation, and language in elderly individuals.

SUMMARY The ocean is the primary source of seismic ambient noise. Therefore, seismic recordings at seafloor stations should reveal noise characteristics more directly than land stations. However, due to a lack of broad-band seismic instrumentation, seafloor noise studies using seafloor stations have been inadequate compared to land-based instrumentation. In this study, we use seismic data collected at the South China Sea (SCS) seafloor by newly developed ocean bottom seismographs (OBSs) to analyze the ambient noise features in this marginal sea. The broad-band OBS, dubbed ‘Pankun’, has unique shielding to isolate its sensor from the influences of bottom currents. A side-by-side land test between the OBS sensor unit and a standalone seismometer showed that the self-noise caused by the gimbal and the pressure case is insignificant. The recordings on the SCS seafloor have distinct noise spectra. The double frequency microseisms (DFMs) have a single instead of double peak like that seen for Pacific stations. The peak appears in a lower period range (1–5 s) than in the global noise model, indicating that the primary source region for the DFM is the SCS itself. The high-frequency content of the DFM is attenuated more as it propagates from its source region (seafloor) to land stations. The single frequency microseism (SFM) peak on the spectrum is weak, reflecting that SFMs, generated in shallow water along the coast, have difficulties propagating back into the deep ocean due to the substantial increase in seafloor depth. A long-period Earth's hum signal is also identifiable on the vertical component at periods greater than 50 s, probably due to the anti-current design of the OBS. Although the seasonal sea state mainly affects the noise level, extreme events such as typhoons can produce short-term abnormally high DFMs in the basin. However, the DFM highs caused by such events exhibit complex patterns, depending on the wind speed, duration, and area covered by the events.

This paper presents a new broadband ocean bottom seismograph (OBS) developed by the SUSTech OBS lab for passive-source seafloor seismic observations. This instrument, called Pankun, has several key features that set it apart from traditional OBS instruments. Besides the seismometer-separated scheme, these features include a unique shielding structure to minimize current-induced noise, a compact gimbal for accurate leveling, and low power consumption for extended operation on the seafloor. The design and testing of Pankun's primary components are thoroughly described in the paper. The instrument has been successfully tested in the South China Sea, demonstrating its ability to record high-quality seismic data. The anti-current shielding structure of Pankun OBS has the potential to improve low-frequency signals, particularly on the horizontal components, in seafloor seismic data.

Trichloroethylene (TCE) is a major ground water pollutant which causes severe hepatic toxicity. Previously, we have identified histone chaperon, SET as a key mediator of TCE-induced liver cell apoptosis. DNA damage with p53 suppression and reduced tri-methylation at histone H3K79 (H3K79me3) were also found under the treatment of TCE. However, epigenetic mechanisms in TCE-associated DNA damage response still remain largely unknown. In this study, we evaluated TCE-induced DNA damage of hepatic cells in the absence of SET, analyzed levels of H3K79me3 and p53 in hepatic cells and in mice livers with carcinogenesis. Results suggested that SET partially suppressed H3K79me3 and interfering with DNA response via mediating down-regulation of p53 under treatment of TCE. To further figure out the regulatory cascade, DoT1L (regulator of H3K79me3) and p53 were knocked down in L-02 cells respectively. Additionally, extent of DNA damage along with alterations of H3K79me3 and p53 were also evaluated. Results indicated that reduced H3K79me3 could lead to down-regulation of p53 which further exacerbated TCE-induced DNA injury. These findings demonstrated that SET-H3K79me3-p53 served as an epigenetic regulatory axis involved in TCE-induced DNA damage response.

The wide application of organophosphorus flame retardants (OPFRs) in consumer products leads to their ubiquitous occurrence. The neurotoxicity of OPFRs has been raised, whereas evidence from the elderly population were rather scarce. Hence, a case-control study was conducted based on the Shenzhen Aging-related Disorder Cohort. A total of 184 cases [Mini-mental State Examination (MMSE)24] and 795 participants as controls (MMSE ≥24) were recruited. Eight metabolites of OPFRs (m-OPFRs) in urine samples were measured, including bis(2-butoxyethyl) phosphate (BBOEP), bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCIPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), dibutyl phosphate (DBP), di-o-cresyl phosphate (DOCP), di-p-cresyl phosphate (DPCP) and diphenyl phosphate (DPHP). The detection frequencies of m-OPFRs ranged from 88.8 % to 95.4 %. BCEP had the highest median concentration (0.93 μg/L), followed by BCIPP (0.32 μg/L), DPHP (0.27 μg/L) and DBP (0.20 μg/L). Significant correlations were found between all pairs of urinary m-OPFRs with correlation coefficients ranging from 0.22 to 0.71 (p0.05). Logistic regression models showed that urinary concentrations of BDCIPP (adjusted odds ratio [OR]: 1.25, 95 % confidential interval [CI]: 1.04-1.50) and DBP (adjusted OR: 1.10, 95 % CI: 1.01-1.20) were positively associated with lower cognitive functions. Furthermore, a nonlinear dose-response relationship was found between urinary BDCIPP concentration and cognitive decline. To our knowledge, this is the first report on OPFR exposure and cognitive impairment among elderly population. Further toxicological tests of BDCIPP and DBP are needed to illustrate these results.

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles accompanied by progressive neurite loss. Mitochondria play pivotal roles in AD development. PRDX3 is a mitochondrial peroxide reductase critical for H

Higher static magnetic field (SMF) enables higher imaging capability in magnetic resonance imaging (MRI), which encourages the development of ultra-high field MRIs above 20 T with a prerequisite for safety issues. However, animal tests of ≥ 20 T SMF exposure are very limited. The objective of the current study is to evaluate mice behaviour consequences of 3.5-23.0 T SMF exposure.We systematically examined 112 mice for their short- and long-term behaviour responses to a 2-h exposure of 3.5-23.0 T SMFs. Locomotor activity and cognitive functions were measured by five behaviour tests, including balance beam, open field, elevated plus maze, three-chamber social recognition, and Morris water maze tests.Besides the transient short-term impairment of the sense of balance and locomotor activity, the 3.5-23.0 T SMFs did not have long-term negative effects on mice locomotion, anxiety level, social behaviour, or memory. In contrast, we observed anxiolytic effects and positive effects on social and spatial memory of SMFs, which is likely correlated with the significantly increased CaMKII level in the hippocampus region of high SMF-treated mice.Our study showed that the short exposures to high-field SMFs up to 23.0 T have negligible side effects on healthy mice and may even have beneficial outcomes in mice mood and memory, which is pertinent to the future medical application of ultra-high field SMFs in MRIs and beyond.• Short-term exposure to magnetic fields up to 23.0 T is safe for mice. • High-field static magnetic field exposure transiently reduced mice locomotion. • High-field static magnetic field enhances memory while reduces the anxiety level.

During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.

Neuroendocrine tumors (NETs) are often misdiagnosed because they can involve any part of the body and have non-specific symptoms. Here, we report a case of a 39-year-old man with rectal neuroendocrine tumor (RNET) and hepatic metastases treated with a combination of radical surgery and Everolimus therapy. The patient complained of abdominal distension, pain, and constipation of one month duration. Enhanced CT scan of the abdomen, colonoscopy and Biopsy findings confirmed the diagnosis of rectal neuroendocrine tumor. As the anatomical structures were clear and the masses seemed to be resectable, we decided to initiate treatment with radical operation and Everolimus therapy. The patient has responded well to the treatment with no evidence of recurrence after 4 years of follow-up. This case is interesting because of the rarity of this neoplasm and its initial misdiagnosis as a giant hepatic carcinoma (hepatoma). It also demonstrates that a combination of curative surgical resection and Everolimus is a good option in a patient with large colorectal neuroendocrine tumors and massive hepatic metastases.

The combination of network communication and medical education gave birth to distance medical education (DME). Now the fifth generation of mobile communication technology (5G) with high data rate, low delay, save energy, reduce cost and other advantages to the telemedicine education has provided a substantial change. It can make the utilization of excellent resources have sufficiency and high efficiency, which equalize educational resources. Teachers can stay face-to-face with students, even if they are in different places. It makes the teaching content is updated in time and so on. This paper reviews the development history of distance medicine education and looks forward to the prospect brought by the combination of 5G communication technology. How to guide clinical practice and improve the learning efficiency and interest.

Hexavalent chromium (Cr(VI)) is a well-established human carcinogen with DNA damaging effects. Recently we established a Cr(VI)-induced malignant transformation model from a human bronchial epithelial (16HBE) cell line, and in the transformed (16HBE-T) cells reduced levels of 53BP1 (critical for DNA repair) and the acetylated histone H3K18/27 (H3K18/27ac) were observed. In 16HBE-T cells SET (a multifunctional protein) was elevated by Cr(VI) through quantitative proteomics analysis. In the present study, we further explore the involvement of SET in the H3K18/27ac/53BP1 cascade in the 16HBE-T model, primarily by knockdown of SET. Bioinformatic analysis of the differentially expressed proteins indicated enrichment in histone modifications, in which SET was a major regulator. In 16HBE cells SET expression was enhanced by Cr(VI) in a concentration- and exposure duration-dependent manner. In 16HBE-T cells, SET knockdown showed the following effects: reversal of H3K18/27ac and 53BP1 levels, enhanced enrichment H3K18/27ac in 53BP1's promotor region, increase rate of apoptosis and cell cycle G0/G1 arrest (with or without Cr(VI) treatment), and reduced colony-forming efficiency. Finally, In comparison with benzo(a)pyrene-transformed (malignant, 16HBE-B) cells from 16HBE where no changes in H3K18/27ac, 53BP1 or SET were observed, while the H3K18/27ac/53BP1 cascade was downregulated and SET upregulated in 16HBE-T cells, as compared with the parental 16HBE cells; thus the changes in 16HBE-T might be a specific effect of Cr(VI). In conclusion, our results suggest that SET may be involved in the malignant cell transformation, through inhibiting the H3K18/27ac/53BP1 cascade, at least in the 16HBE cell model.

Introduction Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by chronic pain in pelvic area and lower urinary tract symptoms (LUTS). Previous neuroimaging studies demonstrated that chronic pain was associated with altered brain activity. However, the pathological mechanisms associated with altered brain control of CP/CPPS is not well understood. Therefore, we sought to investigate the topological properties of white matter brain networks in patients with CP/CPPS and whether the topological configuration of frontal-parietal control network was disrupted. Methods We collected 19 patients with CP/CPPS and 32 matched healthy controls (HCs). Diffusion tensor imaging data of all participates were used to map the white matter structural networks. Graph theoretical method was applied to investigate the alterations of topological properties of brain network in patients. Moreover, the associations between the alerted brain regions of patients and clinical measurements were analysised by using Pearson correlation analyses. Results Both CP/CPPS patients and HCs exhibited a 'small-world' behaviour or economical small-world architecture of the white matter brain networks. In addition, CP/CPPS had a lower global efficiency in the right middle frontal gyrus (orbital part) and a higher global efficiency in the left middle cingulate and paracingulate gyri. CP/CPPS also showed decreased local efficiency in the left middle cingulate and paracingulate gyri and paracentral lobule. Moreover, the local efficiency of the left middle cingulate gyrus was positively correlated with the scores of the influence of symptoms on the quality of life. The local efficiency of the left precuneus and right supplementary motor area were positively correlated with the total scores of NIH-CPSI and the scores of pain and discomfort symptoms, respectively. Conclusion Together, we found that patients with CP/CPPS had alterations of connections within the frontal-parietal control network, which suggested that the altered connectivity involved in the executive control processing procedures might contribute to the pathogenesis of the pelvic pain and LUTS in CP/CPPS. Thus these results providing new insights into the understanding of CP/CPPS.

Trichloroethylene (TCE) was widely used as an industrial solvent which could cause severe liver damage. The histone chaperone SET have been identified as an important mediator of TCE-induced hepatic cytotoxicity in our previous study; however, the underlying regulatory mechanisms remain poorly understood. In this study, we found a total of 136 histone acetylation sites involved in TCE-induced hepatic cytotoxicity with the technique of Triton-acid-urea polyacrylamide gel electrophoresis (TAU-PAGE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Importantly, 17 histone acetylation sites were revealed to be mediated by SET in TCE-induced cytotoxicity. The acetylation of histone H2AK9 (H2AK9ac) was further validated by Western-blot analysis. The data showed that TCE treatment increased the acetylation of H2AK9 in hepatic L-02 cell and decreased the one in SET-knockdown L-02 cells. Besides, levels of the histone deacetylases (HDACs, including HDAC1, HDAC2, and HDAC3) was also analyzed. Interestingly, the level of HDAC1 was aberrantly suppressed in TCE-treated L-02 cells while enhanced in SET-knockdown L-02 cells. To further explore the potential role of HDAC1 in SET-mediated hepatic cytotoxicity of TCE, we employed RNA interference (RNAi) to knockdown HDAC1 in both wide type L-02 and SET-knockdown cells. The results showed that the siRNA inhibition of HDAC1 increased the acetylation of H2AK9. Taken together, our data suggested that SET promoted the acetylation of H2AK9 via suppressing the level of HDAC1, which was involved in SET-mediated hepatic cytotoxicity of TCE.

The potent neurotoxin saxitoxin produced by both marine and freshwater phytoplankton causes paralytic shellfish poisoning syndrome. The toxicity and mode of action of the acute exposure of high-dose saxitoxin have been intensively studied for decades; however, the potential risk of exposure of low-dose saxitoxin remained to be uncovered. Here we present a proteomics study of murine neuroblastoma N2A cell with low-dose saxitoxin exposure (1 nM and 10 nM, 24-h intoxication). Differential proteins were profiled by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). A total of 9 proteins, including 14-3-3 beta (1433B), alpha enolase (ENO1) and cofilin 2 (CFL2), were altered by the low-dose saxitoxin exposure. We further validated the expressions of 1433B, ENO1 and CFL2 by Western blot analysis and the enzyme-linked immunosorbent assay. These 9 proteins involve cell apoptotic pathways, cell skeleton maintenance, membrane potentials and mitochondrial functions. Modulation of these 9 proteins by low-dose saxitoxin exposure could correlate to the reports on genotoxicity and neurotoxicity induced by saxitoxin. This study also suggested other potential risks of saxitoxin.

Methyl tert-butyl ether (MTBE) is widely used as an oxygenating agent in gasoline to reduce harmful emissions. However, previous studies have demonstrated that MTBE is a cytotoxic substance that has harmful effects in vivo and in vitro. Although remarkable progress has been made in elucidating the mechanisms underlying the MTBE-induced reproductive toxicological effect in different cell lines, the precise mechanisms remain far from understood. The present study aimed to evaluate whether mammalian ovary cells were sensitive to MTBE exposure in vitro by assessing cell viability, lactate dehydrogenase (LDH) leakage, malondialdehyde (MDA) content and antioxidant enzyme activities. In addition, the effect of MTBE exposure on differential protein expression profiles was examined by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. MTBE exposure induced significant effects on cell viability, LDH leakage, plasma membrane damage and the activity of antioxidant enzymes. In the proteomic analysis, 24 proteins were demonstrated to be significantly affected by MTBE exposure. Functional analysis indicated that these proteins were involved in catalytic activity, binding, structural molecule activity, metabolic processes, cellular processes and localization, highlighting the fact that the cytotoxic mechanisms resulting from MTBE exposure are complex and diverse. The altered expression levels of two representative proteins, heat shock protein family A (Hsp70) members 8 and 9, were further confirmed by western blot analysis. The results revealed that MTBE exposure affects protein expression in Chinese hamster ovary cells and that oxidative stress and altered protein levels constitute the mechanisms underlying MTBE-induced cytotoxicity. These findings provided novel insights into the biochemical mechanisms involved in MTBE-induced cytotoxicity in the reproductive system.

Aim: The aim of our study was to explore the role of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) on the exposure of SiO2 nanoparticles (NPs) and its influence. Materials & methods: To understand the mechanism of NP-induced oxidative stress, the involvement of oxidative-stress-responding transcription factors and the Nrf2/antioxidant reactive element (ARE) signaling pathway in the toxicity of SiO2 NPs’ exposure was investigated via in vivo and in vitro models. Results: A549 cells showed a significant cytotoxic effect while A549-shNrf2 cells showed decreased cell viability after nm-SiO2 exposure. SiO2 NPs’ exposure activated the Nrf2/ARE signaling pathway. Nrf2−/− exposed mice showed increased reactive oxygen species, 8-hydroxyl deoxyguanosine level and decreased total antioxidant capacity. Nrf2/ARE signaling pathway activation disrupted, leading inhibition of heme oxygenase-1 and upregulation of PKR-like endoplasmic-reticulum-regulated kinase. Conclusion: Our findings suggested that Nrf2 could protect against oxidative stress induced by SiO2 NPs, and the Nrf2/ARE pathway might be involved in mild-to-moderate SiO2 NP-induced oxidative stress that was evident from dampened activity of Nrf2.

Alzheimer's disease (AD) is a devastating neurodegenerative disease accompanied by neuropsychiatric symptoms, such as anxiety and depression. The levels of melatonin decrease in brains of AD patients. The potential effect of melatonin on anxiety and depression behaviors in AD and the underlying mechanisms remain unclear. In this study, we treated 10-month-old triple transgenic mice of AD (3xTg-AD) with melatonin (10 mg/kg body weight/day) for 1 month and explored the effects of melatonin on anxiety and depression-like behaviors in 3xTg-AD mice and the protein expression of hippocampal tissues. The behavioral test showed that melatonin ameliorated anxiety and depression-like behaviors of 3xTg-AD mice as measured by open field test, elevated plus maze test, forced swimming test, and tail suspension test. By carrying out two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 46 differentially expressed proteins in hippocampus between the wild-type (WT) mice and non-treated 3xTg-AD mice. A total of 21 differentially expressed proteins were revealed in hippocampus between melatonin-treated and non-treated 3xTg-AD mice. Among these differentially expressed proteins, glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) were significantly down-regulated in hippocampus of 3xTg-AD mice compared with the WT mice. The expression of these two proteins was modulated by melatonin treatment. Our study suggested that melatonin could be used as a potential candidate drug to improve the neuropsychiatric behaviors in AD via modulating the expression of the proteins (i.e. GSTP1 and CPLX1) involved in anxiety and depression behaviors. © 2017 BioFactors, 43(4):593-611, 2017.

// Xiaohu Ren 1, 2 , Xinfeng Huang 1 , Xifei Yang 1 , Yungang Liu 2 , Wei Liu 1 , Haiyan Huang 1 , Desheng Wu 1 , Fei Zou 2 and Jianjun Liu 1 1 Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China 2 School of Public Health, Southern Medical University, Guangzhou, 510515, China Correspondence to: Jianjun Liu, email: bio-research@hotmail.com , junii8@126.com Fei Zou, email: zoufei616@163.com Keywords: trichloroethylene, nucleolin, SET, hepatic cytotoxicity, proteomics Received: August 26, 2016 Accepted: February 12, 2017 Published: April 03, 2017 ABSTRACT Trichloroethylene (TCE) is an occupational and environmental chemical that can cause severe hepatotoxicity. While our previous studies showed that the phosphatase inhibitor SET is a key mediator of TCE-induced liver cell apoptosis, the molecular mechanisms remain elusive. Using quantitative phosphoproteomic analysis, we report here that nucleolin is a SET-regulated phosphoprotein in human liver HL-7702 cells. Functional analysis suggested that SET promoted dephosphorylation of nucleolin, decreased its binding to its transcriptional activator, c-myc, and upregulated nucleolin expression in TCE-treated cells. Importantly, TCE-induced hepatocyte apoptosis was significantly attenuated when nucleolin was downregulated with specific siRNAs. These findings indicate that TCE may induce hepatocyte apoptosis via SET-mediated dephosphorylation and overexpression of nucleolin.

Effective treatment to prevent or arrest the advance of Alzheimer disease (AD) has yet to be discovered. We investigated whether OligonolR, an FDA-approved flavanol-rich extract prepared from lychee fruit and green tea, exerted beneficial effects relevant to AD in a triple transgenic male mouse model of AD (3×Tg-AD). At 9 months of age, untreated 3×Tg-AD mice vs. wild-type (WT) controls displayed cognitive deficits in behavioral assays and, at 12 months, elevated levels of hippocampal amyloid beta-protein (Aβ), amyloid precursor protein (APP), tau phosphorylation, and pro-inflammatory cytokines. 3×Tg-AD mice given Oligonol showed fewer cognitive deficits and attenuated pathological indices at 12 months. Oligonol treatment of 3×Tg-AD mice modulated expression of some critical brain proteins that involve multiple pathways relevant to mitochondrial dysfunction, proteasomal failure, endoplasmic reticulum (ER) stress and synaptic impairment. Together, these results demonstrate that continuous Oligonol treatment attenuates AD-like pathology and cognitive impairment of 3×Tg-AD mice and set the stage for clinical trials of this flavanol-rich plant extract in patients with early AD.

Trichloroethylene (TCE) is a ubiquitous toxicant widespread in our environment. Exposure to TCE can cause severe liver damage. In previous studies, we detected an abnormal elevation of SET (a protein encoded by the SETgene in humans) which was observed in human HL-7702 cells (L-02 hepatocytes) under the treatment of TCE. Moreover, further study indicated that SET acts as an important mediator in TCE-induced hepatocyte apoptosis. The major functions of SET have been elucidated, while the regulatory mechanism responsible for modulation of SET remains unclear. In this study, four major microRNA-related databases were used to screen and identify 6 candidate microRNAs involved in the regulation of SET. Subsequent verification indicated that miR-21 and miR-199b-5p were decreased in TCE-treated L-02 cells, suggesting that miR-21 and miR-199b-5p (miR199b for short) miR199b potentially regulate SET expression. Additionally, the dual-luciferase system revealed that only miR199b could directly bind to untranslated region (3'-UTR) of the SETgene. Modulation of SET by miR199b was verified through overexpression and knockdown of miR199b in L-02 cells. Assessment of apoptosis indicated that elevated miR199b attenuated TCE-induced apoptosis, while reduced miR199b enhanced it. In summary, this study suggests that in cultured hepatocytes, TCE-induced suppression of miR199b drives SET induction, which further mediates the response to TCE.

// Lingling Zhang 1, 2, 3, 4 , Huanan Wang 1, 5 , Wei Li 2, 6 , Juchang Zhong 1 , Rongcheng Yu 1 , Xinfeng Huang 1 , Honghui Wang 1 , Zhikai Tan 1 , Jiangang Wang 3, Yingjie Zhang 1, 7 1 College of Biology, Hunan University, Changsha, China 2 Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China 3 Department of Internal Medicine, The Third Xiangya Hospital, Central South University, Changsha, China 4 School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China 5 Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China 6 Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China 7 Shenzhen Institute, Hunan University, Shenzhen, China Correspondence to: Yingjie Zhang, email: yingjiezhang@hnu.edu.cn Jiangang Wang, email: wangzigangcsu@hotmail.com Keywords: colon cancer, PUMA, apoptosis, Akt, p53 Abbreviations: PUMA, p53 up-regulated modulator of apoptosis; Bax, Bcl-2-associated X protein; CCK-8, Cell Counting Kit-8; CRC, colorectal cancer Received: February 20, 2016 Accepted: October 19, 2016 Published: December 01, 2016 ABSTRACT Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo . Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.

Trichloroethylene (TCE), a halogenated organic solvent widely used in industries, is known to cause severe hepatotoxicity. However, the mechanisms underlying TCE hepatotoxicity are still not well understood. It is predicted that membrane proteins are responsible for key biological functions, and recent studies have revealed that TCE exposure can induce abnormal levels of membrane proteins in body fluids and cultured cells. The aim of this study is to investigate the TCE-induced alterations of membrane proteins profiles in human hepatic L-02 liver cells. A comparative membrane proteomics analysis was performed in combination with two-dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. A total of 15 proteins were identified as differentially expressed (4 upregulated and 11 downregulated) between TCE-treated cells and normal controls. Among this, 14 of them are suggested as membrane-associated proteins by their transmembrane domain and/or subcellular location. Furthermore, the differential expression of β subunit of adenosine triphosphate synthase (ATP5B) and prolyl 4-hydroxylase, β polypeptide (P4HB) were verified by Western blot analysis in TCE-treated L-02 cells. Our work not only reveals the association between TCE exposure and altered expression of membrane proteins but also provides a novel strategy to discover membrane biomarkers and elucidate the potential mechanisms involving with membrane proteins response to chemical-induced toxic effect.

Some issues concerning expansions of functions in Fourier–Legendre series is considered in L2[−1, 1]. In particular, the rate of their convergence in the classes of functions characterized by the generalized modulus of continuity are estimated, and estimates of the remainder terms are obtained.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD.

Alzheimer’s disease (AD), the most common neurodegenerative disease, has no effective treatment. Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, reportedly has neuroprotective effects in cerebral ischemia. Here, we investigated the effects of DAU on N2a cells stably transfected with Swedish mutant amyloid precursor protein (N2a/APP), an AD-like cell model. ELISA and Western blot analysis revealed that DAU inhibited APP processing and reduced Aβ accumulation. In addition, DAU ameliorated tau hyperphosphorylation via PP2A, p35/25, and CDK5 pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by DAU was also validated in HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis revealed 85 differentially expressed proteins in the lysates between the wild-type N2a cells (N2a/WT) and the N2a/APP cells in the presence or absence of DAU; these were classified into 6 main categories according to their functions: endoplasmic reticulum (ER) stress-associated proteins, oxidative stress-associated proteins, cytoskeleton proteins, molecular chaperones, mitochondrial respiration and metabolism-related proteins, and signaling proteins. Taken together, we demonstrated that DAU treatment reduces AD-like pathology, thereby suggesting that DAU has potential therapeutic utility in AD.

The aim of our study was to explore the role of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) on the exposure of SiOTo understand the mechanism of NP-induced oxidative stress, the involvement of oxidative-stress-responding transcription factors and the Nrf2/antioxidant reactive element (ARE) signaling pathway in the toxicity of SiOA549 cells showed a significant cytotoxic effect while A549-shNrf2 cells showed decreased cell viability after nm-SiOOur findings suggested that Nrf2 could protect against oxidative stress induced by SiO

Breast cancer is the most malignant tumor for women, however, the mechanisms underlying this devastating disease remain unclear. SET is an endogenous inhibitor of protein phosphatase 2A (PP2A) and involved in many physiological and pathological processes. SET could promote the occurrence of tumor through inhibiting PP2A. In this study, we explore the role of SET in the migration and invasion of breast cancer cells MDA-MB-231 and ZR-75-30. The stable suppression of SET expression through lentivirus-mediated RNA interference (RNAi) was shown to inhibit the growth, migration and invasion of breast cancer cells. Knockdown of SET increases the activity and expression of PP2Ac and decrease the expression of matrix metalloproteinase 9 (MMP-9). These data demonstrate that SET may be involved in the pathogenic processes of breast cancer, indicating that SET can serve as a potential therapeutic target for the treatment of breast cancer.

Muscle atrophy is a disease that is usually caused by denervation. The aim of the present study was to determine whether electrical stimulation by semi-implantable electrodes is capable of decreasing the levels of specific proteins associated with sciatic nerve injury-induced muscle atrophy. Male Sprague Dawley (SD) rats with damaged sciatic nerves were maintained on a 12‑h light/dark cycle. Thirty-two SD rats were randomly allocated into 4 groups (each group, n=8). The rats in group C received no electrical stimulation; the rats in groups D, N and DN received electrical stimulation by semi-implantable electrodes during the daytime alone, nighttime alone and both the daytime and nighttime, respectively. Immunoblot assays were performed to detect the expression of cellular proteins associated with muscle atrophy. The number of muscle satellite cells was determined using a microscope, indicating that electrical stimulation increased the number of muscle satellite cells. Immunoblot assay results showed that electrical stimulation reduced the expression levels of cathepsin L, calpain 1 and the ubiquitinated muscle ring finger‑1 (MuRF-1) protein. In conclusion, electrical stimulation by semi-implantable electrodes constitutes a potential method for the treatment of sciatic nerve injury-induced muscle atrophy. The decreased expression levels of the cellular proteins cathepsin L and calpain 1, as well as the ubiquitinated protein MuRF-1, are associated with the attenuation of sciatic nerve injury-induced muscle atrophy.

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, so far, there are no effective measures to prevent and cure this deadly condition. Ginsenoside Rg1 (Rg1) was shown to improve behavioral abnormalities in AD; however, the potential mechanisms remain unclear. In this study, we pretreated 7-month-old 3xTg-AD mice for 6 weeks with Rg1 and evaluated the effects of Rg1 on the behaviors and the protein expression of hippocampal tissues. The behavioral tests showed that Rg1 could improve the memory impairment and ameliorate the depression-like behaviors of 3xTg-AD mice. Proteomic results revealed a total of 28 differentially expressed hippocampal proteins between Rg1-treated and nontreated 3xTg-AD mice. Among these proteins, complexin-2 (CPLX2), synapsin-2 (SYN2), and synaptosomal-associated protein 25 (SNP25) were significantly downregulated in the hippocampus of 3xTg-AD mice compared with the WT mice, and the treatment of Rg1 modulated the expression of CPLX2 and SNP25 in the hippocampus of 3xTg-AD mice. The expression of CPLX2, SYN2, and SNP25 was further validated by Western blot analysis. Taken together, we concluded that Rg1 could be a potential candidate drug to improve the behavioral deficits in AD via modulating the expression of the proteins (i.e., CPLX2, SYN2, and SNP25).

Evaluating competition for individual tree growth simulation is significant to forest management. However, few existing software were developed for practical use. To analyze the competition of spruce-fir conifer and broadleaf mixed forests in Changbai Mountain, China, an algorithm for Influence-zone overlap competition indices was developed. Firstly, based on different positions of subjected tree crown and competition tree crown, the overlap area and length were calculated separately in their related equations. Subsequently, a drawing flow chart, the user interface and fields of sheet were produced to construct concept models. Finally, the contribution of competition indices to individual tree basal area growth were tested by non-linear extra sum of squares method. Keyword: Competition Indices, Competitor Selection, Excel VBA

Alzheimer's disease (AD) is a devastating neurodegenerative disease accompanied by neuropsychiatric symptoms, such as anxiety and depression. The levels of melatonin decrease in brains of AD patients. The potential effect of melatonin on anxiety and depression behaviors in AD and the underlying mechanisms remain unclear. In this study, we treated 10-month-old triple transgenic mice of AD (3xTg-AD) with melatonin (10 mg/kg body weight/day) for 1 month and explored the effects of melatonin on anxiety and depression-like behaviors in 3xTg-AD mice and the protein expression of hippocampal tissues. The behavioral test showed that melatonin ameliorated anxiety and depression-like behaviors of 3xTg-AD mice as measured by open field test, elevated plus maze test, forced swimming test, and tail suspension test. By carrying out two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 46 differentially expressed proteins in hippocampus between the wild-type (WT) mice and non-treated 3xTg-AD mice. A total of 21 differentially expressed proteins were revealed in hippocampus between melatonin-treated and non-treated 3xTg-AD mice. Among these differentially expressed proteins, glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) were significantly down-regulated in hippocampus of 3xTg-AD mice compared with the WT mice. The expression of these two proteins was modulated by melatonin treatment. Our study suggested that melatonin could be used as a potential candidate drug to improve the neuropsychiatric behaviors in AD via modulating the expression of the proteins (i.e. GSTP1 and CPLX1) involved in anxiety and depression behaviors. © 2017 BioFactors, 43(4):593-611, 2017.