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1.  A Suppressor of Cytokine Signaling 1 Antagonist Enhances Antigen-Presenting Capacity and Tumor Cell Antigen-Specific Cytotoxic T Lymphocyte Responses by Human Monocyte-Derived Dendritic Cells 
The suppressor of cytokine signaling 1 (SOCS1) has emerged as a critical inhibitory molecule for controlling the cytokine response and antigen presentation by dendritic cells (DCs), thereby regulating the magnitude of both innate and adaptive immunity. The aim of this study was to investigate whether the SOCS1 antagonist pJAK2(1001-1013) peptide can weaken or block the inhibition function of SOCS1 in DCs by evaluating the phenotype and cytokine production, antigen-presenting, and specific T-cell-activating capacities of DCs electroporated with human gastric cancer cell total RNA. Furthermore, STAT1 activation of the JAK/STAT signal pathway mediated by SOCS1 was analyzed by Western blotting. The results demonstrate that the SOCS1 antagonist pJAK2(1001-1013) peptide upregulated the expression of the maturation marker (CD83) and costimulatory molecule (CD86) of RNA-electroporated human monocyte-derived mature DCs (mDCs), potentiated the capacity of mDCs to induce T-cell proliferation, stimulated the secretion of proinflammatory cytokines, and enhanced the cytotoxicity of tumor cell antigen-specific CTLs activated by human gastric cancer cell total RNA-electroporated mDCs. Data from Western blot analysis indicate that STAT1 was further activated in pJAK2(1001-1013) peptide-loaded mDCs. These results imply that the SOCS1 antagonist pJAK2(1001-1013) peptide is an effective reagent for the enhancement of antigen-specific antitumor immunity by DCs.
doi:10.1128/CVI.00130-13
PMCID: PMC3889590  PMID: 23885028
2.  Key structure of Brij for overcoming multidrug resistance in cancer 
Biomacromolecules  2013;14(2):424-430.
Multidrug resistance (MDR) is a major barrier to the chemotherapy treatment of many cancers. However, some non-ionic surfactants, for example Brij, have been shown to restore the sensitivity of MDR cells to such drugs. The aim of this study was to explore the reversal effect of Brij on MDR tumor cells and elucidate its potential mechanism. Our data indicate that the structure of Brij surfactants plays an important role in overcoming MDR in cancer, i.e. modified hydrophilic-lipophilic balance (MHLB, the ratio of the number (n) of hydrophilic repeating units of ethylene oxide (EO) to the number (m) of carbons in the hydrophobic tail (CH2).). Cell viability of cells treated with paclitaxel (PTX) nanocrystals (NCs) formulated with Brij showed positive correlations with MHLB (R2 = 0.8195); the higher the ratio of Brij to PTX in NCs, the higher cytotoxicity induced by the PTX NCs. Significant increases in intracellular accumulation of 3H-PTX (P-gp substrate) were observed in an MDR cell line (H460/taxR cells) treated with Brij 78 (MHLB=1.11) and Brij 97 (MHLB=0.6). After treatments with Brij 78 and Brij 97, the levels of intracellular ATP were decreased and verapamil induced ATPase activities of P-gp were inhibited in multidrug resistant cells. The responses of the cells to Brij 78 and Brij 97 in ATP depletion studies correlated with the cell viability induced by PTX/Brij NCs and intracellular accumulation of 3H-PTX. Brij 78 and Brij 97 could not alter the levels of P-gp expression detected by western blotting. These findings may provide some insight into the likelihood of further development of more potent P-gp inhibitors for the treatment of MDR in cancer.
doi:10.1021/bm301661w
PMCID: PMC3574583  PMID: 23311629
Brij; multidrug resistance (MDR); Nanocrystals; paclitaxel; P-glycoprotein
3.  Association between Statin Use and Short-Term Outcome Based on Severity of Ischemic Stroke: A Cohort Study 
PLoS ONE  2014;9(1):e84389.
Background
Statins reportedly improve clinical outcomes for ischemic stroke patients. However, it is unclear whether the contribution of statin treatment varies depending on the severity of stroke. We sought to investigate the relationship between statin use and the outcome of acute first-ever ischemic stroke patients stratified by stroke severity.
Methods
A total of 7,455 acute first-ever ischemic stroke patients without statin treatment before onset were eligible from the China National Stroke Registry. A National Institutes of Health Stroke Scale (NIHSS) score of 0 to 4 was defined as minor stroke, and a NIHSS score of >4 was defined as non-minor stroke. We analyzed the association between statin use during hospitalization and mortality as well as functional outcome (measured by a modified Rankin Scale score of 0–5) at 3 months after onset using multivariable logistic regression models.
Results
A total of 3,231 (43.3%) patients received statin treatment during hospitalization. Multivariable analysis showed that statin use during hospitalization decreased mortality of ischemic stroke patients (OR, 0.51; 95%CI, 0.38–0.67), but did not improve poor functional outcomes (OR, 0.95; 95CI%, 0.81–1.11) at 3 months. The interaction between statin use and stroke severity was significant both in dependence and death outcome (P = 0.04 for dependence outcome, P = 0.03 for death outcome). After stratification by stroke severity, statin use during hospitalization decreased the mortality of stroke (OR, 0.44; 95%CI, 0.31–0.62) and poor functional outcome (OR, 0.73; 95%CI, 0.57–0.92) at 3 months in the non-minor stroke group.
Conclusions
Statin use during hospitalization may improve the clinical outcome of acute first-ever ischemic stroke depending on the severity of stroke. Non-minor stroke patients may obtain benefit from statin treatment with improvements in poor functional outcomes and mortality.
doi:10.1371/journal.pone.0084389
PMCID: PMC3897364  PMID: 24465409
4.  Trps1 Differentially Modulates the Bone Mineral Density between Male and Female Mice and Its Polymorphism Associates with BMD Differently between Women and Men 
PLoS ONE  2014;9(1):e84485.
The objective of our study was to identify genetic factors that regulate bone mineral density (BMD) in mice using well defined recombinant inbred strains. For this purpose we chose the BXD recombinant inbred (RI) strains derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains. We sampled both male and female mice (∼4 each) of 46 strains at 3 months-of-age, measured their BMD, and conducted QTL mapping. The data were analyzed to identify candidates genes contained within the most significant quantitative trait locus (QTL). Evaluation of candidate genes included functional assessment, single nucleotide polymorphism (SNP) genotyping and direct sequencing. We established that there was a QTL for BMD in males on chromosome 15 that has the impact larger than QTLs on all other chromosomes. The QTL on chromosome 15 was narrowed to a genomic region between 38 Mbp and 52 Mbp. By examining transcripts within this region, we found an important candidate gene: trichorhinophalangeal syndrome, type I (Trps1). SNP analysis identified a nonsynonymous SNP (rs32398060) in Trps1 that co-segregated with bone mineral density. Analysis of association between this SNP within TRPS1 and BMD in a human population confirmed its significance.
doi:10.1371/journal.pone.0084485
PMCID: PMC3885592  PMID: 24416236
5.  Altered Topological Organization of Cortical Network in Adolescent Girls with Idiopathic Scoliosis 
PLoS ONE  2013;8(12):e83767.
Adolescent idiopathic scoliosis (AIS) is a multifactorial disease affecting approximately 1–4% of teenagers especially girls at the age of 10–16, but its etiopathogenesis remains uncertain. Previous study has revealed that the cortical thickness in AIS patients is different from that in normal controls. Cortical thickness measurements are known to be strongly correlated between regions that are axonally connected. Hence, a hypothesis is proposed to study the possibility to demonstrate abnormal structural network revealed by cortical thickness in AIS patients. The aim of the study is to investigate abnormalities in the organization of the brain cortical network in AIS patients. This study included 42 girls with severe idiopathic scoliosis (14.7±1.3 years old) and 41 age-matched normal controls (NC, 14.6±1.4 years old). The brain cortex was partitioned into 154 cortical regions based on gyral and sulcal structure. The interregional connectivity was measured as the statistical correlations between the regional mean thicknesses across the subjects. We employed the graph theoretic analysis to examine the alteration in interregional correlation, small-world efficiency, hub distribution, and regional nodal characteristics in AIS patients. We demonstrated that the cortical network of AIS patients fully preserved the small-world architecture and organization, and further verified the hemispheric asymmetry of AIS brain. Our results indicated increased central role of temporal and occipital cortex and decreased central role of limbic cortex in AIS patients compared with controls. Furthermore, decreased structural connectivity between hemispheres and increased connectivity in several cortical regions were observed. The findings of the study reveal the pattern of structural network alteration in AIS brain, and would help in understanding the mechanism and etiopathogenesis of AIS.
doi:10.1371/journal.pone.0083767
PMCID: PMC3869815  PMID: 24376742
6.  Abnormal Organization of White Matter Network in Patients with No Dementia after Ischemic Stroke 
PLoS ONE  2013;8(12):e81388.
Structural changes after ischemic stroke could affect information communication extensively in the brain network. It is likely that the defects in the white matter (WM) network play a key role in information interchange. In this study, we used graph theoretical analysis to examine potential organization alteration in the WM network architecture derived from diffusion tensor images from subjects with no dementia and experienced stroke in the past 5.4–14.8 months (N = 47, Mini-Mental Screening Examination, MMSE range 18–30), compared with a normal control group with 44 age and gender-matched healthy volunteers (MMSE range 26–30). Region-wise connectivity was derived from fiber connection density of 90 different cortical and subcortical parcellations across the whole brain. Both normal controls and patients with chronic stroke exhibited efficient small-world properties in their WM structural networks. Compared with normal controls, topological efficiency was basically unaltered in the patients with chronic stroke, as reflected by unchanged local and global clustering coefficient, characteristic path length, and regional efficiency. No significant difference in hub distribution was found between normal control and patient groups. Patients with chronic stroke, however, were found to have reduced betweenness centrality and predominantly located in the orbitofrontal cortex, whereas increased betweenness centrality and vulnerability were observed in parietal-occipital cortex. The National Institutes of Health Stroke Scale (NIHSS) score of patient is correlated with the betweenness centrality of right pallidum and local clustering coefficient of left superior occipital gyrus. Our findings suggest that patients with chronic stroke still exhibit efficient small-world organization and unaltered topological efficiency, with altered topology at orbitofrontal cortex and parietal-occipital cortex in the overall structural network. Findings from this study could help in understanding the mechanism of cognitive impairment and functional compensation occurred in patients with chronic stroke.
doi:10.1371/journal.pone.0081388
PMCID: PMC3862493  PMID: 24349063
7.  Magnetic Resonance Angiography Signal Intensity as a Marker of Hemodynamic Impairment in Intracranial Arterial Stenosis 
PLoS ONE  2013;8(11):e80124.
Background
Intracranial arterial stenosis (ICAS) is the predominant cause of ischemic stroke and transient ischemic attack in Asia. Change of signal intensities (SI) across an ICAS on magnetic resonance angiography (MRA) may reflect its hemodynamic severity.
Methods
In-patients with a symptomatic single ICAS detected on 3D time-of-flight MRA were recruited from 2 hospitals. Baseline and 1-year follow-up data were collected. Signal intensity ratio (SIR) [ =  (mean post-stenotic SI -mean background SI)/(mean pre-stenotic SI - mean background SI)] was evaluated on baseline MRA to represent change of SIs across an ICAS. Acute infarct volume was measured on baseline diffusion-weighted images (DWI). Relationships between SIR and baseline characteristics as well as 1y outcomes were evaluated.
Results
Thirty-six subjects (86.1% males, mean age 55.0) were recruited. Overall, mean SIR was 0.84±0.23. Mean SIRs were not significantly different between the 23 (63.9%) anatomically severe stenoses and the 13 (36.1%) anatomically moderate stenoses (0.80±0.23 versus 0.92±0.21, p = 0.126). SIR was significantly, linearly and negatively correlated to acute infarct volume on DWI (Spearman correlation coefficient −0.471, p = 0.011). Two patients (5.6%) had recurrent ischemic strokes at 1y, not related to SIR values.
Conclusions
Change of signal intensities across an ICAS on MRA may reflect its hemodynamic and functional severity. Future studies are warranted to further verify the relationships between this index and prognosis of patients with symptomatic ICAS.
doi:10.1371/journal.pone.0080124
PMCID: PMC3841201  PMID: 24302997
8.  Glycated Hemoglobin Independently Predicts Stroke Recurrence within One Year after Acute First-Ever Non-Cardioembolic Strokes Onset in A Chinese Cohort Study 
PLoS ONE  2013;8(11):e80690.
Objective
Hyperglycemia is related to stroke. Glycated hemoglobin (HbA1c) can reflect pre-stroke glycaemia status. However, the information on the direct association between HbA1c and recurrence after non-cardioembolic acute ischemic strokes is rare and there is no consistent conclusion.
Methods
The ACROSS-China database comprised of 2186 consecutive first-ever acute ischemic stroke patients with baseline HbA1c values. After excluding patients who died from non-stroke recurrence and patients lost to follow up, 1817 and 1540 were eligible for 3-month and 1-year analyses, respectively. Multivariate Cox regression was performed to evaluate the associations between HbA1c and 3-month and 1-year stroke recurrence.
Results
The HbA1c values at admission were divided into 4 levels by quartiles: Q1 (<5.5%); Q2 (5.5 to <6.1%); Q3 (6.1% to <7.2%); and Q4 (≥7.2%). The cumulative recurrence rates were 8.3% and 11.0% for 3 months and 1 year, respectively. In multivariate analyses, when compared with Q1, the adjusted hazard ratios (AHRs) were 2.83 (95% confidence interval (CI) 1.28-6.26) in Q3 and 3.71(95% CI 1.68-8.21) in Q4 for 3-month stroke recurrence; 3.30 (95% CI 1.31-8.34) in Q3 and 3.35 (95% CI 1.36-8.21) in Q4 for 1-year stroke recurrence. Adding fasting plasma glucose in the multivariate analyses did not modify the association: AHRs were 2.75 (95% CI 1.24-6.11) in Q3 and 3.67 (95% CI 1.59-8.53) in Q4 for 3-month analysis; AHRs were 3.08 (95% CI 1.10-8.64) in Q3 and 3.31(95% CI 1.35-8.14) in Q4 for 1-year analysis.
Conclusions
A higher “normal” HbA1c level reflecting pre-stroke glycaemia status independently predicts stroke recurrence within one year after non-cardioembolic acute ischemic stroke onset. HbA1c is recommended as a routine test in acute ischemic stroke patients.
doi:10.1371/journal.pone.0080690
PMCID: PMC3827473  PMID: 24236195
9.  Assessment of Dynamic Cerebral Autoregulation in Patients with Basilar Artery Stenosis 
PLoS ONE  2013;8(10):e77802.
Background and Aims
Previous studies have shown impaired cerebral autoregulation (CA) in carotid and middle cerebral artery (MCA) stenosis/occlusion. Little is known about CA in patients with basilar artery (BA) stenosis. We therefore investigated dynamic CA patterns in BA stenosis using transfer function analysis (TFA).
Methods
We measured spontaneous oscillations of blood flow velocity (CBFV) in the right posterior cerebral artery (PCA), and left MCA and mean arterial pressure (ABP) continuously in 25 patients with BA stenosis (moderate n=16 with 50-69% occlusion and severe n=9 with ≥70% occlusion) and 22 healthy volunteers in supine position during 6 circles per minute deep breath. Analysis was based on the ‘black-box’ model of transfer function deriving phase and gain in both PCA and MCA.
Results
Though changes of phase shift and gain between the patients and healthy controls were observed in MCA, the differences are however not significant. Phase shift in PCA was significantly decreased in severe stenosis when comparing with healthy controls and moderate stenosis (4.2±34.2° VS 41.1±40.4°, 4.2±34.2° VS 34.2±27.2°, both p<0.05), whilst the gain in PCA is increased for moderate BA stenosis and decreased for severe BA stenosis. Furthermore, we found that phase shift were almost abolished in patients with ischemic stroke who developed unfavorable clinical outcome (mRs>2) on the 90 days after stroke onset.
Conclusion
Dynamic CA in PCA reduces in patients with severe BA stenosis and those with ischemic stroke who present poor outcome in 90 days after stroke onset. Phase shift might be a sensitive index prompting impaired CA in posterior circulation.
doi:10.1371/journal.pone.0077802
PMCID: PMC3790759  PMID: 24124620
10.  Runx1 Is Critical for PTH-induced Onset of Mesenchymal Progenitor Cell Chondrogenic Differentiation 
PLoS ONE  2013;8(9):e74255.
Parathyroid hormone (PTH) plays a critical role in the regulation of chondrogenesis. In this study, we have found for the first time that Runt-related transcription factor 1 (Runx1) contributes to PTH-induced chondrogenesis. Upon PTH treatment, limb bud mesenchymal progenitor cells in micromass culture showed an enhanced chondrogenesis, which was associated with a significant increase of chondrogenic marker gene expression, such as type II collagen and type X collagen. Runx1 was also exclusively expressed in cells treated with PTH at the onset stage of chondrogenesis. Knockdown of Runx1 completely blunted PTH-mediated chondrogenesis. Furthermore, PTH induced Runx1 expression and chondrogenesis were markedly reduced by inhibition of protein kinase A (PKA) signaling. Taken together, our present study indicates that chondrogenesis induced by PTH in mesenchymal progenitor cells is mediated by Runx1, which involves the activation of PKA. These data provide a novel insight into understanding the molecular mechanisms behind PTH-enhanced cartilage regeneration.
doi:10.1371/journal.pone.0074255
PMCID: PMC3776859  PMID: 24058535
11.  Correction: A Neuropeptide Y Variant (rs16139) Associated with Major Depressive Disorder in Replicate Samples from Chinese Han Population 
PLoS ONE  2013;8(9):10.1371/annotation/f3ebdce9-783e-4e59-a3e8-d28369434fa5.
doi:10.1371/annotation/f3ebdce9-783e-4e59-a3e8-d28369434fa5
PMCID: PMC3776885  PMID: 24058435
12.  Prognostic Value of Inflammatory Mediators in 1-Year Outcome of Acute Ischemic Stroke with Middle Cerebral Artery Stenosis 
Mediators of Inflammation  2013;2013:850714.
Background and Purpose. Inflammation exists in inception, progression, and reperfusion of acute ischemic stroke. Insightful understanding of correlation in inflammatory mediators and stroke severity with intracranial artery stenosis may improve rational stroke therapy. Methods. We prospectively recruited 977 patients with acute noncardioembolic ischemic stroke with MCA stenosis by MRA as none to mild (<50%), moderate (50–69%), severe (70–99%), or occlusive (100%). The peripheral levels of WBC, homocysteine (HCY), and high sensitivity C-reactive protein (hs-CRP) were recorded. All patients were assessed of 1-year outcome by mRS as favorable (0–2) or poor (3–6). Results. The levels of WBC, HCY, and hs-CRP had no significant differences in patients with categorized MCA stenosis (all P > 0.05). Higher levels of WBC, HCY, and hs-CRP were found in patients with 1-year poor outcome (all P < 0.05), but only hs-CRP is an independent predictor (OR 1.06, 95% CI 1.027–1.093, P = 0.0003). The combination of any two of increased hs-CRP (>3 mg/L), WBC (>6.91 × 109/L), and HCY (>15 μmol/L) had higher power in predicting 1-year poor outcome than the single elevated mediator. Conclusions. Elevated hs-CRP independently predicts 1-year poor outcome in acute stroke. The combination of increased hs-CRP, WBC, or HCY had a stronger predictive value in poor outcome than individual elevated mediator.
doi:10.1155/2013/850714
PMCID: PMC3760102  PMID: 24023414
13.  Conditional Activation of β-Catenin Signaling Leads to Severe Defects in Intervertebral Disc Tissue 
Arthritis and rheumatism  2012;64(8):2611-2623.
Objective
The incidence of low back pain is extremely high and is often linked to intervertebral disc (IVD) degeneration. The mechanism of this disease is currently unknown. In this study, we have investigated the role of β-catenin signaling in IVD tissue function.
Methods
β-catenin protein levels were measured in disc samples derived from patients with disc degeneration and normal subjects by immunohistochemistry (IHC). To generate β-catenin conditional activation (cAct) mice, Col2a1-CreERT2 transgenic mice were bred with β-cateninfx(Ex3)/fx(Ex3) mice. Changes in disc tissue morphology and function were analyzed by micro-CT, histology and real-time PCR assays.
Results
We found that β-catenin protein was up-regulated in disc tissues from patients with disc degeneration. To assess the effects of increased β-catenin on disc tissue we generated β-catenin cAct mice. Overexpression of β-catenin in disc cells led to extensive osteophyte formation in 3- and 6-month-old β-catenin cAct mice which were associated with significant changes in the cells and extracellular matrix of disc tissues and growth plate. Gene expression analysis demonstrated that activation of β-catenin could enhance Runx2-dependent Mmp13 and Adamts5 expression. Moreover, genetic ablation of the Mmp13 or Adamts5 under β-catenin cAct background, or treatment of β-catenin cAct mice with a specific MMP13 inhibitor, ameliorated the mutant phenotype.
Conclusions
β-catenin signaling pathway plays a critical role in disc tissue function.
doi:10.1002/art.34469
PMCID: PMC3632450  PMID: 22422036
14.  Multifunctional Nanoparticles Based on a Single-Molecule Modification for the Treatment of Drug-Resistant Cancer 
Molecular pharmaceutics  2013;10(4):1465-1469.
Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Tocopheryl polyethylene glycol 1000 succinate (TPGS) has been extensively explored for the treatment of MDR in cancer because of its ability to inhibit P-glycoprotein. Here, we have established multifunctional nanoparticles (MFNPs) using a single-molecule modification of TPGS, which can deliver a hydrophobic drug, paclitaxel (PTX), and a hydrophilic drug, fluorouracil (5-FU), and overcome MDR in cancer. Our data indicated that, when delivered into a PTX-resistant cell line using MFNPs, the combination of PTX and 5-FU was more cytotoxic than each agent individually.
doi:10.1021/mp400022h
PMCID: PMC3685192  PMID: 23473373
multidrug resistance; TPGS; paclitaxel; multifunctional nanoparticles
15.  Impact of a Better Persistence with Antihypertensive Agents on Ischemic Stroke Outcomes for Secondary Prevention 
PLoS ONE  2013;8(6):e65233.
Background
The efficacy of antihypertensive (AH) treatment after stroke has been investigated in several randomized clinical trials. However, non-adherence to AH medication is common for stroke patients in “real world” setting. The purpose of this study was to assess the impact of persistence with AH agents on ischemic stroke (IS) outcomes.
Methods and Results
Using the China National Stroke Registry, we analyzed data from 8409 IS patients with hypertension. Persistence with AH therapy (high persistence ≥75%, low persistence <75%) was measured by patient self-report at 3, 6, and 12 months after stroke. Multivariate logistic regression model was used to assess the relationship between persistence and IS outcomes (stroke recurrence, combined vascular events and death) at 12 months. Of the 8409 patients in this study, 40.0% were female and the mean age at study entry was 66.7 years. 31.6% of patients had high persistence with AH drugs, and 68.4% had low persistence during 1 year after stroke onset. High persistence with AH drugs significantly decreased the risk of stroke recurrence (odds ratio, 0.78; 95% CI, 0.68 to 0.89), combined vascular events (0.71; 0.63–0.81) and death (0.44; 0.36–0.53) compared with low persistence.
Conclusions
Our study reinforces the benefits of AH medications in routine clinical practice and highlights the importance of persistence with AH therapy among IS patients known to be hypertensive within the first year of an event.
doi:10.1371/journal.pone.0065233
PMCID: PMC3679119  PMID: 23776454
16.  Draft Genome Sequence of Rahnella aquatilis Strain HX2, a Plant Growth-Promoting Rhizobacterium Isolated from Vineyard Soil in Beijing, China 
Journal of Bacteriology  2012;194(23):6646-6647.
Rahnella aquatilis strain HX2 is a plant growth-promoting, disease-suppressive rhizobacterium that was isolated from a vineyard soil in Beijing, China. Here, we report the genome sequence of this strain, which provides a valuable resource for future research examining the mechanisms of traits associated with plant growth promotion and biocontrol.
doi:10.1128/JB.01769-12
PMCID: PMC3497517  PMID: 23144397
17.  Tumor Necrosis Factor-induced Toxic Liver Injury Results from JNK2-dependent Activation of Caspase-8 and the Mitochondrial Death Pathway* 
The Journal of biological chemistry  2006;281(22):15258-15267.
In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-α (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1−/− mice but markedly decreased in jnk2−/− mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2−/− mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2−/− mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1−/− mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity.
doi:10.1074/jbc.M512953200
PMCID: PMC3668334  PMID: 16571730
18.  Low HDL-C Level Is Associated with the Development of Intracranial Artery Stenosis: Analysis from the Chinese IntraCranial AtheroSclerosis (CICAS) Study 
PLoS ONE  2013;8(5):e64395.
Background
Intracranial atherosclerotic stenosis (ICAS) is an important cause of ischemic stroke worldwide. The role of high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) in the development of ICAS remains to be elucidated. In the current study, we investigated the relationship of HDL-C level and the risk of developing ICAS in Chinese patients with acute ischemic stroke.
Methods
From October 2007 to June 2009, a total of 1,984 consecutive ischemic stroke patients were evaluated for the presence of symptomatic ICAS by magnetic resonance angiography (MRA). Patients were classified into two groups: intracranial steno-occlusion (ICAS group, n = 888) and non-intracranial stenosis (NICAS group, n = 1096). Serum lipid profiles were analyzed and compared between the ICAS and NICAS group.
Results
Significantly more patients in ICAS group had low HDL-C level (51.6%) than in the NICAS group (42.9%, P<0.001). The observed association remained significant after adjustment for conventional risk factors [(adjusted OR 1.36; 95%CI (1.13–1.63)]. Such predictive value of low level HDL-C persisted even when LDL-C was at very low level(<1.8 mmol/L). Patients in the lowest serum HDL-C quartile (<0.96 mmol/L) had the highest risk of developing ICAS [adjusted OR 1.52; 95%CI (1.17–1.98)] compared to patients in the highest serum HDL-C quartile (≥1.32 mmol/L) after adjustments for the covariates.
Conclusions
Low HDL-C level is strongly associated with the development of ICAS. There was an inverse relationship between the level of HDL-C and the risk of developing ICAS.
doi:10.1371/journal.pone.0064395
PMCID: PMC3656851  PMID: 23691210
19.  Over-expression of Sox2 in C3H10T1/2 cells inhibits osteoblast differentiation through Wnt and MAPK signalling pathways 
International Orthopaedics  2011;36(5):1087-1094.
Purpose
Many Sox proteins play important roles both in mesoderm and ectoderm development. It is reported that Sox2, a member of this family, is essential for the maintenance of the self-renewal of embryonic stem cells (ES) and neural stem cells (NSCs). To investigate whether Sox2 participates in mesoderm development besides ectoderm, Sox2 was introduced into C3H10T1/2 cells.
Methods
We produced recombinant retrovirus expressing Sox2 in GP2-293t cells and infected the virus into C3H10T1/2 cells. Growth property, alkaline phosphatase (ALP) staining, mineralized nodules, osteogenic gene expression and related signal pathways were analysed and compared between Sox2-expressing cells and control cells.
Results
Sox2 over-expression led to increased proliferation of C3H10T1/2 cells, activation of Wnt/β-catenin and p38MAPK pathways. When cultured in osteogenic differentiation medium, ALP and mineralized nodules formation were inhibited in Sox2 over-expressing cells with down-regulation of osteogenic gene expression as well as inhibition of Wnt/β-catenin and p38MAPK pathways.
Conclusions
All these data suggested that over-expression of Sox2 promoted proliferation and inhibited osteoblast differentiation of C3H10T1/2 cells.
doi:10.1007/s00264-011-1368-6
PMCID: PMC3337101  PMID: 22012572
Medicine & Public Health; Orthopedics
20.  The Cloning and Characterization of the Enolase2 Gene of Gekko japonicus and Its Polyclonal Antibody Preparation 
The enolase2 gene is usually expressed in mature neurons and also named neuron specific enolase (NSE). In the present study, we first obtained the NSE gene cDNA sequence by using the RACE method based on the expressed sequence tag (EST) fragment from the cDNA library of Gekko japonicus and identified one transcript of about 2.2 kb in central nervous system of Gekko japonicus by Northern blotting. The open reading frame of NSE is 1305 bp, which encodes a 435 amino-acid protein. We further investigated the multi-tissue expression pattern of NSE by RT-PCR and found that the expression of NSE mRNA was very high in brain, spinal cord and low in heart, while it was not detectable in other tissues. The real-time quantitative PCR was used to investigate the time-dependent change in the expression of the NSE mRNA level after gecko spinal cord transection and found it significantly increased at one day, reaching its highest level three days post-injury and then decreasing at the seventh day of the experiment. The recombinant plasmid of pET-32a-NSE was constructed and induced to express His fused NSE protein. The purified NSE protein was used to immunize rabbits to generate polyclonal antisera. The titer of the antiserum was more than 1:65536 determined by ELISA. Western blotting showed that the prepared antibody could specifically recognize the recombinant and endogenous NSE protein. The result of immunohistochemistry revealed that positive signals were present in neurons of the brain and the spinal cord. This study provided the tools of cDNA and polyclonal antibody for studying NSE function in Gekko japonicus.
doi:10.3390/ijms14058787
PMCID: PMC3676756  PMID: 23615470
Gekko japonicus; Molecular cloning; Neuron specific enolase (NSE); polyclonal antibody
21.  Genome-Wide Gene Expression Profiles in Antioxidant Pathways and Their Potential Sex Differences and Connections to Vitamin C in Mice 
Vitamin C (VC) is well known as an antioxidant in humans, primates and guinea pigs. Studies have suggested gender differences in VC requirements in humans, and gender differences in oxidant injury vulnerability in early life may represent a biological mechanism contributing to gender disparity in later life. Using spontaneous bone fracture (sfx) mice, which lack the gene for L-Gulonolactone oxidase (Gulo), we studied the potential sex difference in expression profiles of oxidative genes at the whole-genome level. Then, we analyzed data of gene expressions in a mouse population of recombinant inbred (RI) strains originally derived by crossing C57BL/6J (B6) and DBA/2J (D2) mice. Our data indicated that there were sex differences in the regulation of pre- and pro-oxidative genes in sfx mice. The associations of expression levels among Gulo, its partner genes and oxidative genes in the BXD (B6 × D2) RI strains showed a sex difference. Transcriptome mapping suggests that Gulo was regulated differently between female and male mice in BXD RI strains. Our study indicates the importance of investigating sex differences in Gulo and its oxidative function by using available mouse models.
doi:10.3390/ijms140510042
PMCID: PMC3676827  PMID: 23665904
L-Gulonolactone oxidase; mouse; oxidative; vitamin C; sex
22.  Beneficial Effects of Trypsin Inhibitors Derived from a Spider Venom Peptide in L-Arginine-Induced Severe Acute Pancreatitis in Mice 
PLoS ONE  2013;8(4):e61049.
HWTI is a 55-residue protein isolated from the venom of the spider Ornithoctonus huwena. It is a potent trypsin inhibitor and a moderate voltage-gated potassium channel blocker. Here, we designed and expressed two HWTI mutants, HWTI-mut1 and HWTI-mut2, in which the potassium channel inhibitory activity was reduced while the trypsin inhibitory activity of the wild type form (approximately 5 EPU/mg) was retained. Animal studies showed that these mutants were less toxic than HWTI. The effects of HWTI and HWTI-mut1 were examined in a mouse model of acute pancreatitis induced by intraperitoneal injection of a large dose of L-arginine (4 mg/kg, twice). Serum amylase and serum lipase activities were assessed, and pathological sections of the pancreas were examined. Treatment with HWTI and HWTI-mut1 significantly reduced serum amylase and lipase levels in a dose dependent manner. Compared with the control group, at 4 mg/kg, HWTI significantly reduced serum amylase level by 47% and serum lipase level by 73%, while HWTI-mut1 significantly reduced serum amylase level by 59% and serum lipase level by 72%. Moreover, HWTI and HWTI-mut1 effectively protected the pancreas from acinar cell damage and inflammatory cell infiltration. The trypsin inhibitory potency and lower neurotoxicity of HWTI-mut1 suggest that it could potentially be developed as a drug for the treatment of acute pancreatitis with few side effects.
doi:10.1371/journal.pone.0061049
PMCID: PMC3626702  PMID: 23613780
23.  Correction: Gender Differences in 1-Year Clinical Characteristics and Outcomes after Stroke: Results from the China National Stroke Registry 
PLoS ONE  2013;8(3):10.1371/annotation/3ff065bf-8100-4ddd-be5b-88f81ffcfe04.
doi:10.1371/annotation/3ff065bf-8100-4ddd-be5b-88f81ffcfe04
PMCID: PMC3609721
24.  A Neuropeptide Y Variant (rs16139) Associated with Major Depressive Disorder in Replicate Samples from Chinese Han Population 
PLoS ONE  2013;8(2):e57042.
Objective
This study aimed to investigate the single nucleotide polymorphisms (SNPs) of neuropeptide Y (NPY) and major depressive disorder (MDD) in Chinese Han population.
Design
Prospective and randomized studies were carried out.
Patients
A total of 700 patients (324 male and 376 female; mean age = 40±14.9 years) with depression who met the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 673 healthy controls (313 male and 360 female; mean age = 41.9±17.2 years) were used to investigate the relationship between SNPs of NPY and the pathogenesis of MDD. A total of 417 patients (195 male and 202 female; mean age = 36±14.2 years) diagnosed with MDD and 314 healthy controls (153 male and 161 female; mean age = 37.9±14.2 years) from Chinese Han population were used to verify the relationship between SNPs of NPY and the pathogenesis of MDD.
Intervention and outcome
Ligase detection reactions were performed to detect the SNP sites of NPY. A series of statistical methods was carried out to investigate the correlation between the NPY gene SNP and MDD.
Results
Statistical analysis showed a significant correlation between the SNP sites rs16139 in NPY and the morbidity of depression. Patients with MDD have a lower frequency of A-allele in rs16139 in replicate samples from Chinese Han population. However, the frequency varied between male and female patients.
Conclusion
The gene polymorphism loci rs16139 was closely related to MDD in Chinese Han population.
doi:10.1371/journal.pone.0057042
PMCID: PMC3584142  PMID: 23468908
25.  Differential Gene Expression Profiling and Biological Process Analysis in Proximal Nerve Segments after Sciatic Nerve Transection 
PLoS ONE  2013;8(2):e57000.
After traumatic injury, peripheral nerves can spontaneously regenerate through highly sophisticated and dynamic processes that are regulated by multiple cellular elements and molecular factors. Despite evidence of morphological changes and of expression changes of a few regulatory genes, global knowledge of gene expression changes and related biological processes during peripheral nerve injury and regeneration is still lacking. Here we aimed to profile global mRNA expression changes in proximal nerve segments of adult rats after sciatic nerve transection. According to DNA microarray analysis, the huge number of genes was differentially expressed at different time points (0.5 h–14 d) post nerve transection, exhibiting multiple distinct temporal expression patterns. The expression changes of several genes were further validated by quantitative real-time RT-PCR analysis. The gene ontology enrichment analysis was performed to decipher the biological processes involving the differentially expressed genes. Collectively, our results highlighted the dynamic change of the important biological processes and the time-dependent expression of key regulatory genes after peripheral nerve injury. Interestingly, we, for the first time, reported the presence of olfactory receptors in sciatic nerves. Hopefully, this study may provide a useful platform for deeply studying peripheral nerve injury and regeneration from a molecular-level perspective.
doi:10.1371/journal.pone.0057000
PMCID: PMC3578805  PMID: 23437294

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