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2.  RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy 
Autophagy  2015;11(7):975-994.
Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM- or TG-induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM- or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM- or TG-induced ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIPK1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress.
doi:10.1080/15548627.2015.1049800
PMCID: PMC4590596  PMID: 26018731
autophagy; cell death; endoplasmic reticulum stress; melanoma; RIPK1
3.  Transcriptional profiling analysis of Spodoptera litura larvae challenged with Vip3Aa toxin and possible involvement of trypsin in the toxin activation 
Scientific Reports  2016;6:23861.
Vip proteins, a new group of insecticidal toxins produced by Bacillus thuringiensis, are effective against specific pests including Spodoptera litura. Here, we report construction of a transcriptome database of S. litura by de novo assembly along with detection of the transcriptional response of S. litura larvae to Vip3Aa toxin. In total, 56,498 unigenes with an N50 value of 1,853 bp were obtained. Results of transcriptome abundance showed that Vip3Aa toxin provoked a wide transcriptional response of the S. litura midgut. The differentially expressed genes were enriched for immunity-related, metabolic-related and Bt-related genes. Twenty-nine immunity-related genes, 102 metabolic-related genes and 62 Bt-related genes with differential expression were found. On the basis of transcriptional profiling analysis, we focus on the functional validation of trypsin which potentially participated in the activation of Vip3Aa protoxin. Zymogram analysis indicated that the presence of many proteases, including trypsin, in S. litura larvae midgut. Results of enzymolysis in vitro of Vip3Aa by trypsin, and bioassay and histopathology of the trypsin-digested Vip3Aa toxin showed that trypsin was possibly involved in the Vip3Aa activation. This study provides a transcriptome foundation for the identification and functional validation of the differentially expressed genes in an agricultural important pest, S. litura.
doi:10.1038/srep23861
PMCID: PMC4812304  PMID: 27025647
4.  Bioinformatics analysis of differentially expressed proteins in prostate cancer based on proteomics data 
OncoTargets and therapy  2016;9:1545-1557.
We mined the literature for proteomics data to examine the occurrence and metastasis of prostate cancer (PCa) through a bioinformatics analysis. We divided the differentially expressed proteins (DEPs) into two groups: the group consisting of PCa and benign tissues (P&b) and the group presenting both high and low PCa metastatic tendencies (H&L). In the P&b group, we found 320 DEPs, 20 of which were reported more than three times, and DES was the most commonly reported. Among these DEPs, the expression levels of FGG, GSN, SERPINC1, TPM1, and TUBB4B have not yet been correlated with PCa. In the H&L group, we identified 353 DEPs, 13 of which were reported more than three times. Among these DEPs, MDH2 and MYH9 have not yet been correlated with PCa metastasis. We further confirmed that DES was differentially expressed between 30 cancer and 30 benign tissues. In addition, DEPs associated with protein transport, regulation of actin cytoskeleton, and the extracellular matrix (ECM)–receptor interaction pathway were prevalent in the H&L group and have not yet been studied in detail in this context. Proteins related to homeostasis, the wound-healing response, focal adhesions, and the complement and coagulation pathways were overrepresented in both groups. Our findings suggest that the repeatedly reported DEPs in the two groups may function as potential biomarkers for detecting PCa and predicting its aggressiveness. Furthermore, the implicated biological processes and signaling pathways may help elucidate the molecular mechanisms of PCa carcinogenesis and metastasis and provide new targets for clinical treatment.
doi:10.2147/OTT.S98807
PMCID: PMC4803245  PMID: 27051295
bioinformatics analysis; differentially expressed proteins; occurrence; literature mining; metastasis; prostate cancer; proteomics
5.  Safety and Efficacy Studies of Vertebroplasty, Kyphoplasty, and Mesh-Container-Plasty for the Treatment of Vertebral Compression Fractures: Preliminary Report 
PLoS ONE  2016;11(3):e0151492.
To evaluate the clinical safety and efficacies of percutaneous vertebroplasty (PVP), percutaneous kyphoplasty (PKP), and percutaneous mesh-container-plasty (PMCP) for the treatment of vertebral compression fractures (VCFs), a retrospective study of 90 patients with VCFs who had been treated by PVP (n = 30), PKP (n = 30), and PMCP (n = 30) was conducted. The clinical efficacies of these three treatments were evaluated by comparing their PMMA cement leakages, cement patterns, height restoration percentages, wedge angles, visual analogue scales (VAS), and oswestry disability index (ODI) at the pre- and post-operative time points. 6.67%, 3.33%, and 0% of patients had PMMA leakage in PVP, PKP, and PMCP groups, respectively. Three (solid, trabecular, and mixed patterns), two (solid and mixed patterns), and one (mixed patterns) types of cement patterns were observed in PVP, PKP, and PMCP groups, respectively. PKP and PMCP treatments had better height restoration ability than PVP treatment. PVP, PKP, and PMCP treatments had significant and similar ability in pain relief and functional recovery ability for the treatment of VCFs. These results indicate minimally invasive techniques were effective methods for the treatment of VCFs. Moreover, these initial outcomes suggest PMCP treatment may be better than both PVP treatment and PKP treatment.
doi:10.1371/journal.pone.0151492
PMCID: PMC4786194  PMID: 26963808
6.  NADPH Oxidase Inhibitor Apocynin Attenuates PCB153-Induced Thyroid Injury in Rats 
PCBs, widespread endocrine disruptors, cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. However, the exact mechanism of thyroid dysfunction caused by PCBs is still unknown. In order to clarify the hypotheses that NADPH oxidase (NOX) and subsequent NF-κB pathway may play roles in thyroid dysfunction, sixty Sprague-Dawley rats were randomly divided into four groups: control group, PCB153 treated (PCB) group, received apocynin with PCB153 treatment (APO + PCB) group, and drug control (APO) group. Serum thyroid hormone levels were evaluated. The morphological change of thyroid tissue was analyzed under the light and transmission electron microscopy. NOX2, 8-OHdG, and NF-κB expression in the thyroid tissue was evaluated by immune-histochemical staining. Oxidative stress and inflammatory cytokines were detected. The following results were reduced after apocynin treatment: (1) serum thyroid hormone, (2) thyroid pathological injuries, (3) thyroid MDA, (4) thyroid ultrastructural change, (5) serum inflammatory cytokines, and (6) thyroid expression of NOX2, 8-OHdG, and NF-κB. These results suggested that NOX inhibition attenuates thyroid dysfunction induced by PCB in rats, presumably because of its role in preventing ROS generation and inhibiting the activation of NF-κB pathway. Our findings may provide new therapeutic targets for PCBs induced thyroid dysfunction.
doi:10.1155/2016/8354745
PMCID: PMC4800090  PMID: 27047545
7.  Water distribution in dentin matrices: bound vs. unbound water 
Objectives
This work measured the amount of bound versus unbound water in completely-demineralized dentin.
Methods
Dentin beams prepared from extracted human teeth were completely demineralized, rinsed and dried to constant mass. They were rehydrated in 41% relative humidity (RH), while gravimetrically measuring their mass increase until the first plateau was reached at 0.064 (vacuum) or 0.116 g H2O/g dry mass (Drierite). The specimens were then exposed to 60% RH until attaining the second plateau at 0.220 (vacuum) or 0.191 g H2O/g dry mass (Drierite), and subsequently exposed to 99% RH until attaining the third plateau at 0.493 (vacuum) or 0.401 g H2O/g dry mass (Drierite).
Results
Exposure of the first layer of bound water to 0% RH for 5 min produced a −0.3% loss of bound water; in the second layer of bound water it caused a −3.3% loss of bound water; in the third layer it caused a −6% loss of bound water. Immersion in 100% ethanol or acetone for 5 min produced a 2.8 and 1.9% loss of bound water from the first layer, respectively; it caused a −4 and −7% loss of bound water in the second layer, respectively; and a −17 and −23% loss of bound water in the third layer.. Bound water represented 21–25% of total dentin water. Chemical dehydration of water-saturated dentin with ethanol/acetone for 1 min only removed between 25 to 35% of unbound water, respectively.
Significance
Attempts to remove bound water by evaporation were not very successful. Chemical dehydration with 100% acetone was more successful than 100% ethanol especially the third layer of bound water. Since unbound water represents between 75–79% of total matrix water, the more such water can be removed, the more resin can be infiltrated.
doi:10.1016/j.dental.2014.12.007
PMCID: PMC4332395  PMID: 25612786
Adhesive dentistry; Bound water; Bulk water; Collagen; dentin; Hydrogen bonding
8.  Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II 
Cardiovascular Research  2015;105(3):304-317.
Aims
Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process.
Methods and results
Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (αMHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in α-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-γ activation, reduced oxidative stress, reduced NF-κB p65 nuclear translocation, and inhibition of TGF-β1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-γ antagonist GW9662. In in vitro studies, 11,12-EET(1 μmol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-β1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-κB pathway via PPAR-γ activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-β1/smad pathway.
Conclusion
Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-κBp65 nuclear translocation via PPAR-γ activation.
doi:10.1093/cvr/cvv018
PMCID: PMC4351370  PMID: 25618409
Epoxyeicosatrienoic acids; Cardiac hypertrophy; CYP2J2; Cardiac remodelling; Oxidative stress
9.  Epigenetic modification of PKMζ rescues aging-related cognitive impairment 
Scientific Reports  2016;6:22096.
Cognition is impacted by aging. However, the mechanisms that underlie aging-associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mζ (PKMζ) in the prelimbic cortex (PrL). PKMζ is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMζ in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMζ and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMζ DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMζ DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMζ and restored cognitive performance in aged rats. Inactivation of PKMζ prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMζ might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue.
doi:10.1038/srep22096
PMCID: PMC4772003  PMID: 26926225
10.  Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity 
Acta Pharmacologica Sinica  2016;37(3):415-424.
Aim:
Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo.
Methods:
The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg·kg−1·d−1, ig) for 4 weeks, their blood samples were analyzed.
Results:
A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg−1·d−1) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg−1·d−1, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats.
Conclusion:
Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.
doi:10.1038/aps.2015.157
PMCID: PMC4775851  PMID: 26806301
leflunomide; hepatotoxicity; CYPs; teriflunomide; aminobenzotriazole; proadifen; NTCP; cholestasis
11.  Hexarelin Protects Rodent Pancreatic Β-Cells Function from Cytotoxic Effects of Streptozotocin Involving Mitochondrial Signalling Pathways In Vivo and In Vitro 
PLoS ONE  2016;11(2):e0149730.
Mitochondrial functions are crucial for pancreatic β-cell survival and glucose-induced insulin secretion. Hexarelin (Hex) is a synthetic small peptide ghrelin analogue, which has been shown to protect cardiomyocytes from the ischemia-reperfusion process. In this study, we used in vitro and in vivo models of streptozotocin (STZ)-induced β-cell damage to study the protective effect of Hex and the associated mechanisms. We found that STZ produced a cytotoxic effect in a dose- and time-dependent manner in MIN6 cells (a mouse β-cell line). Hex (1.0 μM) decreased the STZ-induced damage in β-cells. Rhodamine 123 assay and superoxide DHE production assay revealed that Hex ameliorated STZ-induced mitochondrial damage and excessive superoxide activity in β-cells. In addition, Hex significantly reduced STZ-induced expression of cleaved Caspases-3, Caspases-9 and the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 in MIN6 cells. We further examined the in vivo effect of Hex in a rat model of type 1 diabetes induced by STZ injection. Hex ameliorated STZ-induced decrease in plasma insulin and protected the structure of islets from STZ-induced disruption. Hex also ameliorated STZ-induced expression of cleaved Caspase-9 and the Bax in β-cells. In conclusion, our data indicate that Hex is able to protects β-cell mass from STZ-caused cytotoxic effects involving mitochondrial pathways in vitro and in vivo. Hex may serve as a potential protective agent for the management of diabetes.
doi:10.1371/journal.pone.0149730
PMCID: PMC4769129  PMID: 26918825
12.  CD36 is a co-receptor for hepatitis C virus E1 protein attachment 
Scientific Reports  2016;6:21808.
The cluster of differentiation 36 (CD36) is a membrane protein related to lipid metabolism. We show that HCV infection in vitro increased CD36 expression in either surface or soluble form. HCV attachment was facilitated through a direct interaction between CD36 and HCV E1 protein, causing enhanced entry and replication. The HCV co-receptor effect of CD36 was independent of that of SR-BI. CD36 monoclonal antibodies neutralized the effect of CD36 and reduced HCV replication. CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), which directly bound CD36 but not SR-BI, significantly interrupted HCV entry, and therefore inhibited HCV replication. SSO’s antiviral effect was seen only in HCV but not in other viruses. SSO in combination with known anti-HCV drugs showed additional inhibition against HCV. SSO was considerably safe in mice. Conclusively, CD36 interacts with HCV E1 and might be a co-receptor specific for HCV entry; thus, CD36 could be a potential drug target against HCV.
doi:10.1038/srep21808
PMCID: PMC4761891  PMID: 26898231
13.  Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy 
Scientific Reports  2016;6:21587.
Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.
doi:10.1038/srep21587
PMCID: PMC4759604  PMID: 26892229
14.  “APEC Blue”: Secondary Aerosol Reductions from Emission Controls in Beijing 
Scientific Reports  2016;6:20668.
China implemented strict emission control measures in Beijing and surrounding regions to ensure good air quality during the 2014 Asia-Pacific Economic Cooperation (APEC) summit. We conducted synchronous aerosol particle measurements with two aerosol mass spectrometers at different heights on a meteorological tower in urban Beijing to investigate the variations in particulate composition, sources and size distributions in response to emission controls. Our results show consistently large reductions in secondary inorganic aerosol (SIA) of 61–67% and 51–57%, and in secondary organic aerosol (SOA) of 55% and 37%, at 260 m and ground level, respectively, during the APEC summit. These changes were mainly caused by large reductions in accumulation mode particles and by suppression of the growth of SIA and SOA by a factor of 2–3, which led to blue sky days during APEC commonly referred to as “APEC Blue”. We propose a conceptual framework for the evolution of primary and secondary species and highlight the importance of regional atmospheric transport in the formation of severe pollution episodes in Beijing. Our results indicate that reducing the precursors of secondary aerosol over regional scales is crucial and effective in suppressing the formation of secondary particulates and mitigating PM pollution.
doi:10.1038/srep20668
PMCID: PMC4758222  PMID: 26891104
15.  Antibacterial effect and shear bond strength of an orthodontic adhesive cement containing Galla chinensis extract 
Biomedical Reports  2016;4(4):507-511.
Galla chinensis extract (GCE), a naturally-derived agent, has a significant inhibitory effect on cariogenic bacteria. The present study aims to evaluate the antibacterial effect and shear bond strength of an orthodontic adhesive cement containing GCE. A resin-modified glass ionomer cement incorporated GCE at five mass fractions (0, 0.1, 0.2, 0.4, and 0.8%) to prepare GCE-containing cement for analysis. For the agar diffusion test, cement specimens were placed on agar disk inoculated with Streptococcus mutans (strain ATCC 25175). Following 48 h incubation, the inhibition halo diameter was measured. To assess bacteria colonization susceptibility, S. mutans adhesion to cement specimens was detected by scanning electron microscopy (SEM) following 48 h incubation. To evaluate bond strength, a total of 50 metal brackets were bonded on premolar surfaces by using cement (10 teeth/group). Following immersion in an artificial saliva for 3 days, shear bond strength (SBS) was measured. The results demonstrated that GCE-containing samples exhibited a larger bacterial inhibition halo than control, and the inhibition zone increased as the GCE mass fraction increased. SEM analysis demonstrated that S. mutans presented a weaker adherent capacity to all GCE-containing cements compared with control, but the difference between each GCE-containing group was not significant. SBS values of each GCE-containing group exhibited no difference compared with the control. In conclusion, GCE-containing adhesive cement exhibits a promising inhibitory effect on S. mutans growth and adhesion. Without compromising bond strength, adding GCE in adhesive cement may be an attractive option for preventing white spot lesions during orthodontic treatment.
doi:10.3892/br.2016.603
PMCID: PMC4812524  PMID: 27073642
white spot lesions; Galla chinensis extract; adhesive cement; antibacterial effect; bond strength
16.  High-Contrast Gratings based Spoof Surface Plasmons 
Scientific Reports  2016;6:21199.
In this work, we explore the existence of spoof surface plasmons (SSPs) supported by deep-subwavelength high-contrast gratings (HCGs) on a perfect electric conductor plane. The dispersion relation of the HCGs-based SSPs is derived analyt- ically by combining multimode network theory with rigorous mode matching method, which has nearly the same form with and can be degenerated into that of the SSPs arising from deep-subwavelength metallic gratings (MGs). Numerical simula- tions validate the analytical dispersion relation and an effective medium approximation is also presented to obtain the same analytical dispersion formula. This work sets up a unified theoretical framework for SSPs and opens up new vistas in surface plasmon optics.
doi:10.1038/srep21199
PMCID: PMC4754736  PMID: 26879637
17.  APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis 
Objective
We aimed to examine the association of apolipoprotein E (APOE) ε4 genotype with neuroimaging markers of Alzheimer’s disease: hippocampal volume, brain amyloid deposition and cerebral metabolism.
Methods
We performed a systematic review and meta-analysis of 14 cross-sectional studies identified in Pubmed from 1996 to 2014 (n=1628). The pooled standard mean difference (SMD) was used to estimate the association between APOE and hippocampal volume and amyloid deposition. Meta-analysis was performed using effect size signed differential mapping using coordinates extracted from clusters with statistically significant difference in cerebral metabolic rate for glucose between APOE ε4+ and ε4− groups.
Results
APOE ε4 carrier status was associated with atrophic hippocampal volume (pooled SMD: −0.47; 95% CI −0.82 to −0.13; p=0.007) and increased cerebral amyloid positron emission tomography tracer (pooled SMD: 0.62, 95% CI 0.27 to 0.98, p=0.0006). APOE ε4 was also associated with decreased cerebral metabolism, especially in right middle frontal gyrus.
Conclusions
APOE ε4 was associated with atrophic hippocampal volume in MRI markers, increased cerebral amyloid deposition and cerebral hypometabolism. Theses associations may indicate the potential role of the APOE gene in the pathophysiology of Alzheimer’s disease.
doi:10.1136/jnnp-2014-307719
PMCID: PMC4331076  PMID: 24838911
18.  Loop replacements with gut-binding peptides in Cry1Ab domain II enhanced toxicity against the brown planthopper, Nilaparvata lugens (Stål) 
Scientific Reports  2016;6:20106.
Bacillus thuringiensis (Bt) Cry toxins have been used widely in pest managements. However, Cry toxins are not effective against sap-sucking insects (Hemiptera), which limits the application of Bt for pest management. In order to extend the insecticidal spectrum of Bt toxins to the rice brown planthopper (BPH), Nilaparvata lugens, we modified Cry1Ab putative receptor binding domains with selected BPH gut-binding peptides (GBPs). Three surface exposed loops in the domain II of Cry1Ab were replaced with two GBPs (P2S and P1Z) respectively. Bioassay results showed that toxicity of modified toxin L2-P2S increased significantly (~9 folds) against BPH nymphs. In addition, damage of midgut cells was observed from the nymphs fed with L2-P2S. Our results indicate that modifying Cry toxins based on the toxin-gut interactions can broaden the insecticidal spectrum of Bt toxin. This method provides another approach for the development of transgenic crops with novel insecticidal activity against hemipteran insects and insect populations resistant to current Bt transgenic crops.
doi:10.1038/srep20106
PMCID: PMC4735585  PMID: 26830331
19.  bmo-miR-0001 and bmo-miR-0015 down-regulate expression of Bombyx mori fibroin light chain gene in vitro*  
Based on bioinformatic analysis, we selected two novel microRNAs (miRNAs), bmo-miR-0001 and bmo-miR-0015, from high-throughput sequencing of the Bombyx mori larval posterior silk gland (PSG). Firstly, we examined the expression of bmo-miR-0001 and bmo-miR-0015 in 12 different tissues of the 5th instar Day-3 larvae of the silkworm. The results showed that the expression levels of both bmo-miR-0001 and bmo-miR-0015 were obviously higher in the PSG than in other tissues, implying there is a spatio-temporal condition for bmo-miR-0001 and bmo-miR-0015 to regulate the expression of BmFib-L. To test this hypothesis, we constructed pri-bmo-miR-0001 expressing the plasmid pcDNA3.0 [ie1-egfp-pri-bmo-miR-0001-SV40] and pri-bmo-miR-0015 expressing the plasmid pcDNA3.0 [ie1-egfp-pri-bmo-miR-0015-SV40]. Finally, the BmN cells were harvested and luciferase activity was detected. The results showed that luciferase activity was reduced significantly (P<0.05) in BmN cells co-transfected by pcDNA3.0 [ie1-egfp-pri-bmo-miR-0001-SV40] or pcDNA3.0 [ie1-egfp-pri-bmo-miR-0015-SV40] with pGL3.0 [A3-luc-Fib-L-3'UTR-SV40], suggesting that both bmo-miR-0001 and bmo-miR-0015 can down-regulate the expression of BmFib-L in vitro.
doi:10.1631/jzus.B1500078
PMCID: PMC4757582  PMID: 26834013
Bombyx mori; MicroRNA; bmo-miR-0001; bmo-miR-0015; BmFib-L; Regulation of expression
20.  Exploring Metabolic Profile Differences between Colorectal Polyp Patients and Controls Using Seemingly Unrelated Regression 
Journal of proteome research  2015;14(6):2492-2499.
Despite the fact that colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world, the development of improved and robust biomarkers to enable screening, surveillance, and therapy monitoring of CRC continues to be evasive. In particular, patients with colon polyps are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients suffer from poor performance. In consideration of the challenges involved in identifying metabolite biomarkers in individuals with high risk for colon cancer, we have investigated NMR-based metabolite profiling in combination with numerous demographic parameters to investigate the ability of serum metabolites to differentiate polyp patients from healthy subjects. We also investigated the effect of disease risk on different groups of biologically related metabolites. A powerful statistical approach, seemingly unrelated regression (SUR), was used to model the correlated levels of metabolites in the same biological group. The metabolites were found to be significantly affected by demographic covariates such as gender, BMI, BMI2, and smoking status. After accounting for the effects of the confounding factors, we then investigated potential of metabolites from serum to differentiate patients with polyps and age matched healthy controls. Our results showed that while only valine was slightly associated, individually, with polyp patients, a number of biologically related groups of metabolites were significantly associated with polyps. These results may explain some of the challenges and promise a novel avenue for future metabolite profiling methodologies.
doi:10.1021/acs.jproteome.5b00059
PMCID: PMC4729298  PMID: 25919433
seemingly unrelated regression; colorectal polyp; NMR spectroscopy; metabolic profiling; metabolomics
21.  Heart Rate Variability Is Associated with Exercise Capacity in Patients with Cardiac Syndrome X 
PLoS ONE  2016;11(1):e0144935.
Heart rate variability (HRV) reflects the healthiness of autonomic nervous system, which is associated with exercise capacity. We therefore investigated whether HRV could predict the exercise capacity in the adults with cardiac syndrome X (CSX). A total of 238 subjects (57±12 years, 67.8% men), who were diagnosed as CSX by the positive exercise stress test and nearly normal coronary angiogram were enrolled. Power spectrum from the 24-hour recording of heart rate was analyzed in frequency domain using total power (TP) and spectral components of the very low frequency (VLF), low frequency (LF) and high frequency (HF) ranges. Among the study population, 129 subjects with impaired exercise capacity during the treadmill test had significantly lower HRV indices than those with preserved exercise capacity (≥90% of the age predicted maximal heart rate). After accounting for age, sex, and baseline SBP and heart rate, VLF (odds ratio per 1SD and 95% CI: 2.02, 1.19–3.42), LF (1.67, 1.10–2.55), and TP (1.82, 1.17–2.83) remained significantly associated with preserved exercise capacity. In addition, increased HRV indices were also associated with increased exercise duration, rate-pressure product, and heart rate recovery, independent of age, body mass index, and baseline SBP and heart rate. In subgroup analysis, HRV indices demonstrated similar predictive values related to exercise capacity across various subpopulations, especially in the young. In patients with CSX, HRV was independently associated with exercise capacity, especially in young subjects. The healthiness of autonomic nervous system may have a role in modulating the exercise capacity in patients with CSX.
doi:10.1371/journal.pone.0144935
PMCID: PMC4727925  PMID: 26812652
22.  B7-H3 and B7-H4 are independent predictors of a poor prognosis in patients with pancreatic cancer 
Oncology Letters  2016;11(3):1841-1846.
B7-H3 and B7-H4 belong to the peripheral membrane protein B7 family and are hypothesized to regulate immunity. These proteins are expressed in human pancreatic cancer (PC), but their prognostic significance is poorly understood. The present study examined the association between B7-H3 and B7-H4 expression and the overall survival time in patients with PC that underwent surgery at the Second Affiliated Hospital to Zhengzhou University between April 2000 and January 2009. Immunohistochemical analysis demonstrated that B7-H3 and B7-H4 were expressed in 35 (88%) and 30 (75%) tumor tissue samples, respectively, which were obtained from 40 patients with PC. Statistical analysis revealed that B7-H3 expression was associated with an early tumor-node-metastasis stage (stage I and II; P<0.01), and B7-H4 expression was associated with tumors located in the body and tail of the pancreas (P<0.01) and lymph node metastasis (P=0.02). In addition, using Spearman's rank correlation coefficient, the present study demonstrated a positive correlation between B7-H3 expression and B7-H4 expression (r=0.37; P=0.02) in tumor samples. B7-H4 expression (P=0.01), tumors located in the pancreatic body and tail (P<0.01), lymph node metastasis (P=0.02) and combined B7-H3 and B7-H4 expression (P<0.01) were indicators of a poor overall survival time. However, solitary B7-H4 expression (P=0.03) and combined B7-H3 and B7-H4 expression (P=0.04) remained significant prognostic factors following adjustment for other prognostic factors in a multivariate Cox's proportional hazards regression model. Therefore, the present results indicate that solitary B7-H4 expression and a combination of B7-H3 and B7-H4 expression are independent predictors of a poor prognosis in patients with PC.
doi:10.3892/ol.2016.4128
PMCID: PMC4774460  PMID: 26998087
B7-H3; B7-H4; pancreatic cancer; prognosis; immunohistochemistry
23.  Alcohol drinking as an unfavorable prognostic factor for male patients with nasopharyngeal carcinoma 
Scientific Reports  2016;6:19290.
The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan–Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05–1.81, P = 0.022; HR = 1.38, 95% CI 1.09–1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.
doi:10.1038/srep19290
PMCID: PMC4725964  PMID: 26776301
24.  The Protective Effects of Buzui on Acute Alcoholism in Mice 
This study was designed to investigate the role of a traditional buzui recipe in anti-inebriation treatment. Buzui consists of Fructus Schisandrae Chinensis, Fructus Chebulae, Fructus Mume, Fructus Crataegi, Endothelium Corneum Gigeriae Galli, and Excrementum Bombycis. The buzui mixture was delivered by gavage, and ethanol was delivered subsequent to the final treatment. The effects of buzui on the righting reflex, inebriation rates, and the survival curve are depicted. Blood alcohol concentrations, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, and alkaline phosphatase (ALP) levels were recorded. The activities of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and superoxide dismutase (SOD), as well as malonaldehyde (MDA) levels, were also measured. Our results demonstrated that a traditional buzui recipe showed significant effects on promoting wakefulness and the prevention of acute alcohol intoxication, accelerating the metabolism of alcohol in the liver and reducing the oxidative damage caused by acute alcoholism.
doi:10.1155/2016/3539748
PMCID: PMC4739222  PMID: 26884793
25.  Sputum endothelin-1 level is associated with active pulmonary tuberculosis and effectiveness of anti-tuberculosis chemotherapy 
Pulmonary tuberculosis (TB) is a major global health problem. Endothelin (ET)-1 is an important pro-inflammatory factor in the airways, which acts as a chemoattractant and an upregulator of other inflammatory mediators. In the present study, the association of the sputum ET-1 level with active pulmonary TB and the effectiveness of anti-TB chemotherapy was explored for the first time. A total of 56 newly diagnosed patients with active pulmonary TB, 56 age- and gender-matched TB-free controls, and 43 subjects with latent TB were recruited to the study. Patients in the active TB group received standard anti-TB chemotherapy. Sputum samples were collected from all study subjects at baseline (day 0) and on days 1, 2, 4, 6, 10 and 14 of treatment for the active TB group and the ET-1 level was determined by enzyme-linked immunosorbent assay. The sputum ET-1 level in the active TB group was significantly higher than those in the latent TB and the non-TB groups at baseline. Following adjustment for confounders such as age, gender, severity of clinical presentation, plasma ET-1 level and comorbidities that might affect the sputum ET-1 level, multivariate logistic regression analysis revealed that sputum ET-1 level was an independent indicator for active pulmonary TB. In the active TB group during anti-TB chemotherapy, decrements in the sputum ET-1 level were in significant correlation with decrements in the number of colony-forming units and increments in the time to positivity in a Mycobacteria Growth Indicator Tube assay. In conclusion, this study indicates that an elevated sputum ET-1 level is an independent indicator of active pulmonary TB and suggests that decrements in the sputum ET-1 level could reflect the effectiveness of anti-TB chemotherapy.
doi:10.3892/etm.2016.2980
PMCID: PMC4774540  PMID: 26998044
endothelin-1; tuberculosis; pulmonary tuberculosis; sputum; biomarker

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