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1.  RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation 
Scientific Reports  2015;5:14298.
p38 mitogen-activated protein kinase (MAPK) activity has been reported to either promote or suppress cell death, which depends on cell type and stimulus. Our previous report indicates that p38 exerts a protective role in tumor necrosis factor (TNF)-α-induced cell death in L929 fibroblastoma cells. However, key molecules regulating p38 activation remain unclear. Here, we show that ectopic expression of scaffold protein receptor for activated C kinase 1 (RACK1) suppressed TNF-α-induced cell death in L929 cells, which was associated with enhanced p38 activation. Knockdown of endogenous RACK1 expression exhibited opposite effects. The protective role of RACK1 in TNF-α-induced cell death diminished upon blockade of p38 activation. Therefore, RACK1 antagonizes TNF-α-induced cell death through, at least partially, augmenting p38 activation. Further exploration revealed that RACK1 directly bound to MKK3/6 and enhanced the kinase activity of MKK3/6 without affecting MKK3/6 phosphorylation. Similar effects of RACK1 were also observed in primary murine hepatocytes, another cell type sensitive to TNF-α-induced cell death. Taken together, our data suggest that RACK1 is a key factor involved in p38 activation as well as TNF-α-induced cell death.
doi:10.1038/srep14298
PMCID: PMC4585558  PMID: 26381936
2.  Modulation of Brain Electroencephalography Oscillations by Electroacupuncture in a Rat Model of Postincisional Pain 
The present study aimed to investigate how ongoing brain rhythmical oscillations changed during the postoperative pain and whether electroacupuncture (EA) regulated these brain oscillations when it relieved pain. We established a postincisional pain model of rats with plantar incision to mimic the clinical pathological pain state, tested the analgesic effects of EA, and recorded electroencephalography (EEG) activities before and after the EA application. By analysis of power spectrum and bicoherence of EEG, we found that in rats with postincisional pain, ongoing activities at the delta-frequency band decreased, while activities at theta-, alpha-, and beta-frequency bands increased. EA treatment on these postincisional pain rats decreased the power at high-frequency bands especially at the beta-frequency band and reversed the enhancement of the cross-frequency coupling strength between the beta band and low-frequency bands. After searching for the PubMed, our study is the first time to describe that brain oscillations are correlated with the processing of spontaneous pain information in postincisional pain model of rats, and EA could regulate these brain rhythmical frequency oscillations, including the power and cross-frequency couplings.
doi:10.1155/2013/160357
PMCID: PMC3655616  PMID: 23710210
3.  The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice 
Background
Alzheimer’s disease (AD) is characterized by extracellular β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms.
Methods
After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of Aβ and phosphorylation of tau was quantified by ELISA and western blot.
Results
Inhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, Aβ production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3β in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice.
Conclusions
Taken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0522-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0522-x
PMCID: PMC4776389  PMID: 26939570
Nogo; NgR; AD; Microglia; Neuron; Aβ; Tau; Neuroinflammation
4.  Review, Evaluation, and Discussion of the Challenges of Missing Value Imputation for Mass Spectrometry-Based Label-Free Global Proteomics 
Journal of proteome research  2015;14(5):1993-2001.
In this review, we apply selected imputation strategies to label-free liquid chromatography–mass spectrometry (LC–MS) proteomics datasets to evaluate the accuracy with respect to metrics of variance and classification. We evaluate several commonly used imputation approaches for individual merits and discuss the caveats of each approach with respect to the example LC–MS proteomics data. In general, local similarity-based approaches, such as the regularized expectation maximization and least-squares adaptive algorithms, yield the best overall performances with respect to metrics of accuracy and robustness. However, no single algorithm consistently outperforms the remaining approaches, and in some cases, performing classification without imputation sometimes yielded the most accurate classification. Thus, because of the complex mechanisms of missing data in proteomics, which also vary from peptide to protein, no individual method is a single solution for imputation. On the basis of the observations in this review, the goal for imputation in the field of computational proteomics should be to develop new approaches that work generically for this data type and new strategies to guide users in the selection of the best imputation for their dataset and analysis objectives.
Graphical abstract
doi:10.1021/pr501138h
PMCID: PMC4776766  PMID: 25855118
Imputation; label free; peak intensity; accuracy; mean-square error; classification
5.  2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation 
Retrovirology  2016;13:13.
Backgroud
BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface.
Results
Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination.
Conclusion
Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-016-0247-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12977-016-0247-z
PMCID: PMC4776379  PMID: 26935098
HIV-1; BST-2; Vpu; Membrane protein; 2-thio-6-azauridine; β-TrCP2; Ubiquitination
6.  Immunization with Recombinant SFTSV/NSs Protein Does Not Promote Virus Clearance in SFTSV-Infected C57BL/6J Mice 
Viral Immunology  2015;28(2):113-122.
Abstract
The severe fever with thrombocytopenia syndrome (SFTS), caused by a novel Phlebovirus in the Bunyaviridae family named SFTS virus (SFTSV), is an emerging hemorrhagic fever with a wide distribution and high case-fatality rate. Neither effective treatment nor vaccines are available to treat and prevent this disease to date. It was recently reported that SFTSV nonstructural protein in S segment (SFTSV/NSs) functioned as the interferon (IFN) antagonist targeting for suppressing host's innate immunity. This study was designed to investigate the potential of recombinant SFTSV (rSFTSV)/NSs protein for inducing anti-NSs antibodies by pre-exposure vaccination to block SFTSV/NSs in the SFTSV-infected C57BL/6J mice. All mice in the rSFTSV/NSs-vaccinated group, negative control group, and blank control group survived with no visible clinical abnormities throughout the experiment, except for their sacrifice for sampling at each observation point. However, unexpectedly, a negative effect on the bodyweight of rSFTSV/NSs-vaccinated mice was observed after 21 days postinoculation. Pre-exposure vaccination with rSFTSV/NSs did not accelerate virus removal in mice though high titer of anti-NSs antibodies and elevated IFN-γ were detected in sera. Before virus challenge, the rSFTSV/NSs-vaccinated mice and negative control mice had a larger amount of platelets (PLT) than the blank control mice, which indicated that Freund's adjuvants could stimulate PLT production. In the aspect of cytokines, the rSFTSV/NSs-vaccinated mice had a 5- to 10-fold increase in interleukin (IL)-2, IL-5, IL-6, IFN-γ, and tumor necrosis factor-α, which probably just had a negative effect on the bodyweight of mice. In general, therefore, previous vaccination with rSFTSV/NSs did not accelerate virus clearance in the SFTSV-infected mice.
doi:10.1089/vim.2014.0100
PMCID: PMC4334103  PMID: 25594805
7.  Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation 
Cell Stress & Chaperones  2015;20(5):787-792.
Cellular senescence of endothelial cells is a damage and stress response which induces pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotypes. Donepezil is a drug used for the treatment of mild to moderate dementia of the Alzheimer’s disease (AD). The aim of the present study was to investigate the attenuation of endothelial cell senescence by donepezil and to explore the mechanisms underlying the anti-aging effects of donepezil. Our results indicated that high glucose (HG) markedly decreased cell viability of human umbilical vein endothelial cells (HUVECs), and this phenomenon was reversed by treatment with donepezil. Importantly, our results displayed that the frequency of senescent (SA-ß-gal-positive) cells and the expression level of senescence genes (PAI-1 and p21) were significantly higher in the HG group compared with the normal glucose (NG) group, and these changes were blocked by treatment with donepezil. Also, our results showed that donepezil inhibits the generation of reactive oxygen species (ROS), which promotes cellular senescence. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with donepezil. Indeed, our results indicated that donepezil increased the SIRT1 enzyme activity. Therefore, these results show that donepezil delays cellular senescence that is promoted under HG condition via activation of SIRT1.
doi:10.1007/s12192-015-0601-4
PMCID: PMC4529865  PMID: 26194321
Alzheimer’s disease; Donepezil; Senescence; SIRT1
8.  Trends in Radical Surgical Treatment Methods for Breast Malignancies in China: A Multicenter 10-Year Retrospective Study 
The Oncologist  2015;20(9):1036-1043.
The purpose of this study was to describe Chinese trends in radical surgical modalities and influential imaging and demographic factors for breast malignancies. Rates of mastectomy in the People’s Republic of China remain elevated due to diagnosis at higher stages; however, because of increased use of diagnostic imaging, improvement of biopsy methods, and patient education, rates of less invasive lumpectomy are increasing and rates of mastectomy have decreased in China.
Background.
Incidence rates of breast cancer continue to rise in the People’s Republic of China. The purpose of this study was to describe Chinese trends in radical surgical modalities and influential imaging and demographic factors for breast malignancies.
Materials and Methods.
This study was a hospital-based, multicenter, 10-year (1999–2008), retrospective study. Descriptive statistical tests were used to illustrate information regarding radical surgical trends for the treatment of breast malignancies. Chi-square tests were used to assess effect of demographic factors in addition to imaging and pathological data on the specific surgical method.
Results.
A total of 4,211 patients were enrolled in the survey. Among them, 3,335 patients with stage 0 to stage III disease undergoing mastectomy or breast-conserving surgery (BCS) were included in the final analysis. The rate of BCS increased from 1.53% in 1999 to 11.88% in 2008. The rate of mastectomy declined over this time period, from 98.47% in 1999 to 88.12% in 2008, with increasing use of diagnostic imaging methods and pathological biopsies. A significantly greater percentage of patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy.
Conclusion.
Rates of mastectomy in China remain elevated due to diagnosis at higher stages; however, because of increased use of diagnostic imaging, improvement of biopsy methods, and patient education, rates of less invasive lumpectomy are increasing and rates of mastectomy have decreased in China.
Implications for Practice:
In this study, 4,211 cases were collected from 1999 to 2008 through a multicenter retrospective study of varying geographic and socioeconomic areas to illustrate trends of surgeries in the People’s Republic of China. The correlations between demographic and tumor characteristics and among methods of surgical treatment were explored. This study shows that the rate of breast-conserving surgery (BCS) increased and the rate of mastectomy declined over this time period with increasing use of diagnostic imaging methods and pathological biopsies. Patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy in China.
doi:10.1634/theoncologist.2014-0281
PMCID: PMC4571796  PMID: 26253559
Breast neoplasms; Surgical; Imaging; Diagnosis
9.  Curcumin modulates TLR4/NF-κB inflammatory signaling pathway following traumatic spinal cord injury in rats 
Background
Curcumin, a polyphenolic compound extracted from the plant turmeric, has protective effects on spinal cord injury (SCI) through attenuation of inflammatory response. This study was designed to detect whether curcumin modulates toll-like receptor 4 (TLR4) and the nuclear factor-kappa B (NF-κB) inflammatory signaling pathway in the injured rat spinal cord following SCI.
Methods
Adult male Sprague–Dawley rats were subjected to laminectomy at T8–T9 and compression with a vascular clip. There were three groups: (a) sham group; (b) SCI group; and (g) SCI + curcumin group. We measured TLR4 gene and protein expression by real-time polymerase chain reaction and western blot analysis; NF-κB activity by electrophoretic mobility shift assay, inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels by enzyme-linked immunosorbent assay, hindlimb locomotion function by Basso, Beattie, and Bresnahan rating, spinal cord edema by wet/dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis.
Results
The results showed that SCI induced the up-regulation of TLR4, NF-κB, and inflammatory cytokines in the injured rat spinal cord. Treatment with curcumin following SCI markedly down-regulated the levels of these agents related to the TLR4/NF-κB inflammatory signaling pathway. Administration of curcumin also significantly ameliorated SCI induced hind limb locomotion deficits, spinal cord edema, and apoptosis.
Conclusions
Post-SCI curcumin administration attenuates the TLR4/NF-κB inflammatory signaling pathway in the injured spinal cord, and this may be a mechanism whereby curcumin improves the outcome following SCI.
doi:10.1179/2045772313Y.0000000179
PMCID: PMC4397202  PMID: 24621048
Curcumin; Toll-like receptor 4; Nuclear factor-kappa B; Inflammation; Spinal cord injury
10.  The role of Card9 overexpression in peripheral blood mononuclear cells from patients with aseptic acute pancreatitis 
Abstract
Activated mononuclear cells are an early event in the course of severe acute pancreatitis (SAP). To date, the molecular mechanism triggering peripheral blood mononuclear cells (PBMCs) is poorly understood. The aim of this paper was to determine the potential role of Card9 in SAP. We collected data from 72 subjects between January 2013 and June 2014. Subsequently, PBMCs were isolated on day 1, 3 and 5 of pancreatitis. Immunofluorescence staining, quantitative real‐time PCR, Western blotting, immunoprecipitation and ELISA were used to determine the role of Card9 in SAP. Microbial culture showed that SAP patients at the early period did not develop any bacteria and fungi infection. Card9 expression in SAP patients was higher than that in mild acute pancreatitis and volunteer healthy controls, up to the peak on day 1. The monocyte‐derived cytokines interleukin (IL)‐17, IL‐1β, IL‐6 and tumour necrosis factor‐α mediated by the induction of Card9 markedly increased in SAP patients compared with the control group. Furthermore, the inducible formation of Card9‐Bcl10 complex was found in PBMCs, which may be involved in nuclear factor kappa B (NF‐κB) and p38 activation in SAP. Receiver operating characteristic curve indicated that Card9 levels had a high sensitivity of 87.5% and specificity of 67.7%, showing the close correlation with SAP patients. Card9 overexpression was firstly found in aseptic SAP, which may be played an important role in NF‐κB and p38 activation in PBMCs. It also provided the new insights into therapeutic interventions by targeting monocytes activation in SAP patients.
doi:10.1111/jcmm.12738
PMCID: PMC4759462  PMID: 26893103
Card9 overexpression; peripheral blood mononuclear cells; acute pancreatitis; non‐infection inflammation
11.  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
12.  MLIF Alleviates SH-SY5Y Neuroblastoma Injury Induced by Oxygen-Glucose Deprivation by Targeting Eukaryotic Translation Elongation Factor 1A2 
PLoS ONE  2016;11(2):e0149965.
Monocyte locomotion inhibitory factor (MLIF), a heat-stable pentapeptide, has been shown to exert potent anti-inflammatory effects in ischemic brain injury. In this study, we investigated the neuroprotective action of MLIF against oxygen-glucose deprivation (OGD)-induced injury in human neuroblastoma SH-SY5Y cells. MTT assay was used to assess cell viability, and flow cytometry assay and Hoechst staining were used to evaluate apoptosis. LDH assay was used to exam necrosis. The release of inflammatory cytokines was detected by ELISA. Levels of the apoptosis associated proteins were measured by western blot analysis. To identify the protein target of MLIF, pull-down assay and mass spectrometry were performed. We observed that MLIF enhanced cell survival and inhibited apoptosis and necrosis by inhibiting p-JNK, p53, c-caspase9 and c-caspase3 expression. In the microglia, OGD-induced secretion of inflammatory cytokines was markedly reduced in the presence of MLIF. Furthermore, we found that eukaryotic translation elongation factor 1A2 (eEF1A2) is a downstream target of MLIF. Knockdown eEF1A2 using short interfering RNA (siRNA) almost completely abrogated the anti-apoptotic effect of MLIF in SH-SY5Y cells subjected to OGD, with an associated decrease in cell survival and an increase in expression of p-JNK and p53. These results indicate that MLIF ameliorates OGD-induced SH-SY5Y neuroblastoma injury by inhibiting the p-JNK/p53 apoptotic signaling pathway via eEF1A2. Our findings suggest that eEF1A2 may be a new therapeutic target for ischemic brain injury.
doi:10.1371/journal.pone.0149965
PMCID: PMC4769291  PMID: 26918757
13.  Deterioration of eggshell quality in laying hens experimentally infected with H9N2 avian influenza virus 
Veterinary Research  2016;47:35.
This study aimed to determine the mechanism by which H9N2 avian influenza virus (AIV) affects eggshell quality. Thirty-week-old specific pathogen free egg-laying hens were inoculated with the chicken-origin H9N2 AIV strain (A/Chicken/shaanxi/01/2011) or with inoculating media without virus by combined intraocular and intranasal routes. The time course for the appearance of viral antigen and tissue lesions in the oviduct was coincident with the adverse changes in egg production in the infected hens. The viral loads of AIV have a close correlation with the changes in the uterus CaBP-D28k mRNA expression as well as the Ca concentrations in the eggshells in the infected hens from 1 to 7 days post inoculation (dpi). Ultrastructural examination of eggshells showed significantly decreased shell thickness in the infected hens from 1 to 5 dpi (P < 0.05). Furthermore, obvious changes in the structure of the external shell surface and shell membrane were detected in the infected hens from 1 to 5 dpi as compared with the control hens. In conclusion, this study confirmed that H9N2 AIV strain (A/Chicken/shaanxi/01/2011) infection is associated with severe lesions of the uterus and abnormal expression of CaBP-D28k mRNA in the uteri of the infected hens. The change of CaBP-D28k mRNA expression may contribute to the deterioration of the eggshell quality of the laying hens infected with AIV. It is noteworthy that the pathogenicity of H9N2 AIV strains may vary depending on the virus strain and host preference.
doi:10.1186/s13567-016-0322-4
PMCID: PMC4766683  PMID: 26915662
14.  miR-155 acts as an anti-inflammatory factor in atherosclerosis-associated foam cell formation by repressing calcium-regulated heat stable protein 1 
Scientific Reports  2016;6:21789.
Atherosclerosis (AS) is chronic inflammation in response to lipid accumulation. MicroRNA-155 (miR-155) is being increasingly studied to evaluate its potential as diagnostic biomarkers and therapeutic targets in many diseases. However, delineating the role of miR-155 in AS remains difficult. Here, we detected constitutive expression of several microRNAs (miRNAs) possibly associated with cardiovascular disease in foam cells and clinical specimens from patients with AS. Among them, we found that the level of miR-155 in foam cells was the most significantly elevated in a dose- and time-dependent manner. In addition, the expression of miR-155 was elevated in the plasma and plaque of patients with AS. We also reported for the first time that miR-155 targets calcium-regulated heat stable protein 1 (CARHSP1), which regulates the stability of tumor necrosis factor alpha (TNF-α) mRNA. Furthermore, we investigated the mechanism by which the miR-155 level is elevated. miR-155 upregulation is due to transcriptional regulation by nuclear factor (NF)-κB, which is activated by the inflammatory factor TNF-α. In summary, increased miR-155 relieves chronic inflammation by a negative feedback loop and plays a protective role during atherosclerosis-associated foam cell formation by signaling through the miR-155–CARHSP1–TNF-α pathway.
doi:10.1038/srep21789
PMCID: PMC4761895  PMID: 26899994
15.  Assessment of Vascularity in Hepatic Alveolar Echinococcosis: Comparison of Quantified Dual-Energy CT with Histopathologic Parameters 
PLoS ONE  2016;11(2):e0149440.
Purpose
To investigate whether dual-energy computer tomography(DECT) could determine the angiographic vascularity of alveolar echinococcosis lesions by comparing the quantitative iodine concentration (IC) with the microvascular density (MVD).
Material and Methods
Twenty-five patients (16 men, 9 women; mean age, 40.9 ± 13.8 years) with confirmed hepatic alveolar echinococcosis (HAE) underwent DECT of the abdomen, consisting of arterial phase (AP), portal venous phase (PVP), and delayed phase (DP) scanning, in dual-source mode (100 kV/140 kV). Image data were processed with a DECT software algorithm that was designed for the evaluation of iodine distribution in the different layers (marginal zone, solid and cystic) of the lesions. The CT patterns of HAE lesions were classified into three types: solid type, pseudocystic type and ‘geographic map’ (mixed) type. The IC measurements in different layers and different types of lesions were statistically compared. MVD was examined using CD34 immunohistochemical staining of the resected HAE tissue and scored based on the percentage of positively stained cells and their intensity. Pearson’s correlation analysis was used to evaluate the potential correlation between DECT parameters and MVD.
Results
A total of 27 HAE lesions were evaluated, of which 9 were solid type, 3 were pseudocystic type and 15 were mixed type. The mean lesion size was 100.7 ± 47.3 mm. There was a significant difference in the IC measurements between different layers of HAE lesions during each scan phase (p < 0.001). The IC in the marginal zone was significantly higher than in the solid and cystic components in AP (2.15 mg/mL vs. 0.17 or 0.01 mg/mL), PVP (3.08 mg/mL vs. 0.1 or 0.02 mg/mL), and DP (2.93 mg/mL vs. 0.04 or 0.02 mg/mL). No significant difference was found among the different CT patterns of HAE lesions. Positive expression of CD34 in the marginal zones surrounding HAE lesions was found in 92.5% (25/27) of lesions, of which 18.5% (5/27) were strongly positive, 62.7% (17/27) were moderately positive, and 11.1% (3/27) were weakly positive. In contrast, 7.4% (2/27) of the lesions were negative for CD34. There was a positive correlation between IC measurements and MVD in the marginal zone of HAE lesions (r = 0.73, p < 0.05).
Conclusions
The DECT quantitative iodine concentration was significantly correlated with MVD in the marginal zones surrounding HAE lesions. Dual-energy CT using a quantitative analytic methodology can be used to evaluate the vascularity of AE.
doi:10.1371/journal.pone.0149440
PMCID: PMC4762698  PMID: 26901164
16.  Preventive obesity agent montmorillonite adsorbs dietary lipids and enhances lipid excretion from the digestive tract 
Scientific Reports  2016;6:19659.
Western diets are typically high in fat and are associated with long-term complications such as obesity and hepatic steatosis. Because of the enjoyable taste of high-fat diets (HFDs), we are interested in determining how to decrease lipid absorption and enhance lipid excretion from the digestive tract after the consumption of eating fatty foods. Montmorillonite was initially characterized as a gastrointestinal mucosal barrier protective agent for the treatment of diarrhoea. Dietary lipid adsorbent- montmorillonite (DLA-M) was isolated and purified from Xinjiang montmorillonite clay via the water extraction method. Here, we show that DLA-M has an unexpected role in preventing obesity, hyperlipidaemia and hepatic steatosis in HFD-fed rats. Interestingly, combined application of polarized light microscopy and lipid staining analyses, showed that DLA-M crystals have dietary lipid-adsorbing ability in vitro and in vivo, which enhances lipid excretion via bowel movements. In summary, our results indicate that DLA-M prevent HFD-induced obesity. This novel dietary lipid-adsorbing agent can help prevent obesity and its comorbidities.
doi:10.1038/srep19659
PMCID: PMC4759552  PMID: 26891902
17.  Characterization of intraocular pressure pattern and changes of retinal ganglion cells in DBA2J glaucoma mice 
AIM
To characterize the pattern of intraocular pressure (IOP) change and the deficit of retinal ganglion cells (RGCs) in DBA2J, which is most well-characterized chronic glaucoma mouse model and wild type (WT) C57bl/6 mice, and to study the relationship between IOP change and RGCs deficit.
METHODS
IOP was monitored with a rebound tonometer in WT C57bl/6 and DBA2J mice from 3 to 15-month-old. Retinal function was evaluated by dark-adapted electroretinogram (ERG) in DBA2J and WT mice of 15-month-old. A dye (Neurobiotin) was applied to optic nerve stump to retrograde label RGCs. TO-PRO-3 visualized all nuclei of cells in the RGC layer.
RESULTS
The IOP in WT mice was 9.03±0.6 mm Hg on average and did not increase significantly as aging. The IOP in DBA2J mice, arranging from 7.2 to 28 mm Hg, was increasing significantly as aging, and it was normal at 3-month-old compared with WT mice, slightly increased from 7-month-old and increased in 50% animals at 11-month-old and in 38% animals at 15-month-old. The RGCs density in DBA2J mice started reducing by 7-month-old, continuously decreased until reached about 20% of RGC in WT retina by 15-month-old. RGC density was not linearly correlated with IOP in 15-month-old DBA2J mice. The amplitude of positive scotopic threshold response, and negative scotopic threshold response of ERG were significantly reduced in DBA2J mice of 15-month-old than that in age-paired WT mice.
CONCLUSION
The present study found that DBA2J mice display pathological and functional deficits of the retina that was not linearly correlated with IOP.
doi:10.18240/ijo.2016.02.05
PMCID: PMC4761729  PMID: 26949637
retinal ganglion cell; glaucoma; intraocular pressure; retina; mouse
18.  Posterior scleral reinforcement combined with vitrectomy for myopic foveoschisis 
AIM
To investigate the effects of posterior scleral reinforcement (PSR) combined with vitrectomy for myopic foveoschisis.
METHODS
Thirty-nine highly myopic eyes of 39 patients with myopic foveoschisis underwent PSR combined with vitrectomy. Best corrected visual acuity (BCVA), refraction error, and the foveal thickness by optical coherence tomography (OCT) were recorded before and after the surgery, and complications were noted.
RESULTS
The follow-up period was 12mo, and the main focus was on the results of the 12-month follow-up visit. The mean preoperative BCVA was 0.96±0.43 logMAR. At the final follow-up visit, the mean BCVA was 0.46±0.28 logMAR, which significantly improved compared with the preoperative one (P=0.003). The BCVA improved in 33 eyes (84.62%), and unchanged in 6 eyes (15.38%). At the end of follow-up, the mean refractive error was -15.13±2.55 D, and the improvement was significantly compared with the preoperative one (-17.53±4.51 D) (P=0.002). Twelve months after surgery, OCT showed complete resolution of the myopic foveoschisis and a reat-tachment of the fovea in 37 eyes (94.87%) and partial resolution in the remained two eyes (5.13%). The foveal thickness was obviously reduced at 12-month follow-up visit (196.45±36.35 µm) compared with the preoperative one (389.32±75.56 µm) (P=0.002). There were no serious complications during the 12mo follow-up period.
CONCLUSION
PSR combined with vitrectomy is a safe and effective procedure for myopic foveoschisis with both visual and anatomic improvement.
doi:10.18240/ijo.2016.02.14
PMCID: PMC4761738  PMID: 26949646
high myopia; myopic foveoschisis; posterior scleral reinforcement; vitrectomy
19.  Microphthalmia-associated transcription factor regulates the visual cycle genes Rlbp1 and Rdh5 in the retinal pigment epithelium 
Scientific Reports  2016;6:21208.
Regeneration of the visual pigment by cells of the retinal pigment epithelium (RPE) is fundamental to vision. Here we show that the microphthalmia-associated transcription factor, MITF, which plays a central role in the development and function of RPE cells, regulates the expression of two visual cycle genes, Rlbp1 which encodes retinaldehyde binding protein-1 (RLBP1), and Rdh5, which encodes retinol dehydrogenase-5 (RDH5). First, we found that Rlbp1 and Rdh5 are downregulated in optic cups and presumptive RPEs of Mitf-deficient mouse embryos. Second, experimental manipulation of MITF levels in human RPE cells in culture leads to corresponding modulations of the endogenous levels of RLBP1 and RDH5. Third, the retinal degeneration associated with the disruption of the visual cycle in Mitf-deficient mice can be partially corrected both structurally and functionally by an exogenous supply of 9-cis-retinal. We conclude that the expression of Rlbp1 and Rdh5 critically depends on functional Mitf in the RPE and suggest that MITF has an important role in controlling retinoid processing in the RPE.
doi:10.1038/srep21208
PMCID: PMC4753414  PMID: 26876013
20.  Quantitative profiling of sphingolipids in wild Cordyceps and its mycelia by using UHPLC-MS 
Scientific Reports  2016;6:20870.
In the present study, 101 sphingolipids in wild Cordyceps and its five mycelia were quantitatively profiled by using a fully validated UHPLC-MS method. The results revealed that a general rank order for the abundance of different classes of sphingolipids in wild Cordyceps and its mycelia is sphingoid bases/ceramides > phosphosphingolipids > glycosphingolipids. However, remarkable sphingolipid differences between wild Cordyceps and its mycelia were observed. One is that sphingoid base is the dominant sphingolipid in wild Cordyceps, whereas ceramide is the major sphingolipid in mycelia. Another difference is that the abundance of sphingomyelins in wild Cordyceps is almost 10-folds higher than those in most mycelia. The third one is that mycelia contain more inositol phosphorylceramides and glycosphingolipids than wild Cordyceps. Multivariate analysis was further employed to visualize the difference among wild Cordyceps and different mycelia, leading to the identification of respective sphingolipids as potential chemical markers for the differentiation of wild Cordyceps and its related mycelia. This study represents the first report on the quantitative profiling of sphingolipids in wild Cordyceps and its related mycelia, which provided comprehensive chemical evidence for the quality control and rational utilization of wild Cordyceps and its mycelia.
doi:10.1038/srep20870
PMCID: PMC4751452  PMID: 26868933
21.  GDP (Gemcitabine, Dexamethasone, and Cisplatin) Is Highly Effective and Well-Tolerated for Newly Diagnosed Stage IV and Relapsed/Refractory Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type 
Medicine  2016;95(6):e2787.
Abstract
This study was conducted to evaluate the effectiveness and tolerance of GDP (gemcitabine, dexamethasone, and cisplatin) regimen in patients with newly diagnosed stage IV and relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKTL).
The study enrolled 41 ENKTL patients who received GDP regimen at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2008 and January 2015.
The disease status was newly diagnosed stage IV in 15 patients and relapsed/refractory in 26 patients. The median number of cycles of chemotherapy per patient was 6 (range, 2–8 cycles). The overall response rate and complete-remission rate were 83.0% (34/41) and 41.5% (17/41), respectively. After a median follow-up of 16.2 months, 1-year progression-free survival rate and 1-year overall survival rate for the whole cohort were 54.5% and 72.7%. Grade 3 to 4 adverse events included neutropenia (34.1%), thrombocytopenia (19.5%), and anemia (14.6%).
Our study has suggested high efficacy and low toxicity profile of GDP regimen in patients with newly diagnosed stage IV and relapsed/refractory ENKTL.
doi:10.1097/MD.0000000000002787
PMCID: PMC4753932  PMID: 26871836
22.  Transformation-optical Fan-beam Synthesis 
Scientific Reports  2016;6:20530.
Gradient-index dielectric lenses are generated based on the coordinate transformation by compressing the homogeneous air spaces quasi-conformally towards and outwards the primary source. The three-dimensional modeling is then performed through revolving the prescribed transformational media 180 degrees around the focal point to reach the architecture of barrel-vaults. It is found that all these two- and three-dimensional transformation-optical designs are capable of producing fan-beams efficiently over a broad frequency range with their main lobes possessing the narrow beamwidth in one dimension and the wide beamwidth in the other, while having the great ability of the wide angular scanning. Finally, we propose to construct such four types of fan-beam lenses through multiple-layered dielectrics with non-uniformed perforations and experimentally demonstrate their excellent performances in the fan-beam synthesis.
doi:10.1038/srep20530
PMCID: PMC4742821  PMID: 26847048
23.  Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations 
PLoS ONE  2016;11(2):e0148521.
MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD.
doi:10.1371/journal.pone.0148521
PMCID: PMC4743935  PMID: 26849207
24.  Immunity Elicited by an Experimental Vaccine Based on Recombinant Flagellin-Porcine Circovirus Type 2 Cap Fusion Protein in Piglets 
PLoS ONE  2016;11(2):e0147432.
In a recent study, we reported that a recombinant protein from fusion expression of flagellin to porcine circovirus type 2 (PCV2) Cap induced robust humoral and cell-mediated immunity that afforded full protection for PCV2 infection using BALB/c mice. Here, we further evaluated the immunogenicity and protection of the recombinant protein using specific pathogen free (SPF) pigs. Twenty-five 3-week-old piglets without passively acquired immunity were divided into 5 groups. All piglets except negative controls were challenged with a virulent PCV2 at 21 days after booster vaccination and necropsied at 21 days post-challenge. Vaccination of piglets with the recombinant protein without adjuvant induced strong humoral and cellular immune responses as observed by high levels of PCV2-specific IgG antibodies and neutralizing antibodies, as well as frequencies of PCV2-specific IFN-γ-secreting cells that conferred good protection against PCV2 challenge, with significant reduced PCV2 viremia, mild lesions, low PCV2 antigen-positive cells, as well as improved body weight gain, comparable to piglets vaccinated with a commercial PCV2 subunit vaccine. These results further demonstrated that the recombinant flagellin-Cap fusion protein is capable of inducing solid protective humoral and cellular immunity when administered to pigs, thereby becoming an effective PCV2 vaccine candidate for control of PCV2 infection.
doi:10.1371/journal.pone.0147432
PMCID: PMC4746120  PMID: 26848967
25.  Lipid and lipoprotein measurements and the risk of ischemic vascular events 
Neurology  2015;84(5):472-479.
Objectives:
To examine the relationship between plasma lipid measurements and incident ischemic vascular events (ischemic stroke [IS], and as a positive control, myocardial infarction [MI]) in a community cohort.
Methods:
In 6,276 stroke-free Framingham participants (aged 64 ± 10 years, 56% female), we related plasma lipid levels (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TC/HDL-C ratio) measured at the original cohort 15th (1977–1979) and 20th examination cycles (1986–1990) and (TC, HDL-C, TC/HDL-C ratio, triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) measured at the offspring fourth examination (1995–1998), to 10-year risk of incident IS and MI. Utilizing genome-wide genotyping in the same subjects, we used mendelian randomization methods to assess whether observed associations were incidental or causal.
Results:
During a mean follow-up of 9 years, 301 participants experienced incident IS. In multivariable-adjusted analyses, HDL-C ≤40 mg/dL and TC/HDL ratio ≥5 were associated with increased risk of IS (hazard ratio [95% confidence interval]: 1.59 [1.23–2.05], p < 0.001 and 1.47 [1.15–1.87], p < 0.001), but not TC or LDL-C. In adjusted analysis, a strong association between TG and IS was diminished. In the MI-free sample (n = 5,875, aged 64 ± 10 years, 58% female; 403 MI events), all lipid markers were associated with MI risk. A genetic risk score comprising 47 known determinants of circulating HDL-C was not associated with IS.
Conclusions:
In a middle-aged to elderly community sample, we observed that low HDL-C and high TC/HDL-C ratio, but not LDL-C or TG were associated with risk of incident IS. We observed the usual associations between lipids and risk of MI. Our findings suggest an important, but less likely causal, role of HDL-C over other lipid biomarkers for optimal stroke risk stratification.
doi:10.1212/WNL.0000000000001202
PMCID: PMC4336066  PMID: 25568296

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