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1.  Low magnitude of tensile stress represses the inflammatory response at intervertebral disc in rats 
Objective
This study aims to determine if the involvement of tensile stress affects the expressions of inflammatory cytokines interleukin-17(IL-17), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) at intervertebral discs in vivo.
Material and method
Sixty-four female Sprague–Dawley rats were randomly divided into four groups: sham, tail-suspended (TS), tail-suspended with needle puncture (TSNP), and single-needle puncture (SNP) groups. A tail-suspension device provides low magnitude of tensile stress (2.45 Newton (N)), and aseptic needle puncture on the tail disc induces inflammatory response. After 4 weeks, the treated discs were harvested for histologic analysis, quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA).
Result
Pathological examination demonstrated that compared to the sham group, the morphologies of nucleus pulposus (NP) and anulus fibrosus (AF) in TS, SNP, and TSNP groups displayed degenerative changes in varying degrees. Results from RT-qPCR showed that IL-17 and iNOS mRNA expression levels were significantly higher in both TSNP and SNP groups than those in the sham groups. Expression of IL-17 and iNOS are not significantly different between the sham and TS groups (P > 0.05). Compared with the SNP group, the mRNA expression of IL-17 and iNOS in the TSNP groups were markedly decreased (P < 0.05). The regulation of IL-1β and IL-17 detected by ELISA was coincident with the qRT-PCR results.
Conclusion
The results from this study suggested that relatively low magnitude tensile stress might play an essential role in the anti-inflammatory process and the relief of low-back pain (LBP).
doi:10.1186/s13018-015-0159-y
PMCID: PMC4333165
Mechanical stress; Tail suspension; Anti-inflammation; Interleukin-17; Interleukin-1β; Inducible nitric oxide synthase
2.  GeneChip Expression Profiling Reveals the Alterations of Energy Metabolism Related Genes in Osteocytes under Large Gradient High Magnetic Fields 
PLoS ONE  2015;10(1):e0116359.
The diamagnetic levitation as a novel ground-based model for simulating a reduced gravity environment has recently been applied in life science research. In this study a specially designed superconducting magnet with a large gradient high magnetic field (LG-HMF), which can provide three apparent gravity levels (μ-g, 1-g, and 2-g), was used to simulate a space-like gravity environment. Osteocyte, as the most important mechanosensor in bone, takes a pivotal position in mediating the mechano-induced bone remodeling. In this study, the effects of LG-HMF on gene expression profiling of osteocyte-like cell line MLO-Y4 were investigated by Affymetrix DNA microarray. LG-HMF affected osteocyte gene expression profiling. Differentially expressed genes (DEGs) and data mining were further analyzed by using bioinfomatic tools, such as DAVID, iReport. 12 energy metabolism related genes (PFKL, AK4, ALDOC, COX7A1, STC1, ADM, CA9, CA12, P4HA1, APLN, GPR35 and GPR84) were further confirmed by real-time PCR. An integrated gene interaction network of 12 DEGs was constructed. Bio-data mining showed that genes involved in glucose metabolic process and apoptosis changed notablly. Our results demostrated that LG-HMF affected the expression of energy metabolism related genes in osteocyte. The identification of sensitive genes to special environments may provide some potential targets for preventing and treating bone loss or osteoporosis.
doi:10.1371/journal.pone.0116359
PMCID: PMC4312085  PMID: 25635858
3.  Therapeutic Effects of PPARα on Neuronal Death and Microvascular Impairment 
PPAR Research  2015;2015:595426.
Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARα has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα's effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARα agonist in diabetic microvascular complications.
doi:10.1155/2015/595426
PMCID: PMC4326216
4.  AtPHT4;4 is a chloroplast-localized ascorbate transporter in Arabidopsis 
Nature Communications  2015;6:5928.
Ascorbate is an antioxidant and coenzyme for various metabolic reactions in vivo. In plant chloroplasts, high ascorbate levels are required to overcome photoinhibition caused by strong light. However, ascorbate is synthesized in the mitochondria and the molecular mechanisms underlying ascorbate transport into chloroplasts are unknown. Here we show that AtPHT4;4, a member of the phosphate transporter 4 family of Arabidopsis thaliana, functions as an ascorbate transporter. In vitro analysis shows that proteoliposomes containing the purified AtPHT4;4 protein exhibit membrane potential- and Cl−-dependent ascorbate uptake. The AtPHT4;4 protein is abundantly expressed in the chloroplast envelope membrane. Knockout of AtPHT4;4 results in decreased levels of the reduced form of ascorbate in the leaves and the heat dissipation process of excessive energy during photosynthesis is compromised. Taken together, these observations indicate that the AtPHT4;4 protein is an ascorbate transporter at the chloroplast envelope membrane, which may be required for tolerance to strong light stress.
In plants, ascorbate is synthesized in the mitochondria yet plays essential roles as an antioxidant in the chloroplast. Here, Miyaji et al. show that AtPHT4;4 is a chloroplast envelope ascorbate transporter and suggest it is required for dissipation of excess energy under light stress.
doi:10.1038/ncomms6928
PMCID: PMC4308718  PMID: 25557369
5.  Glucose and TGF β2 Modulate the Viability of Cultured Human Retinal Pericytes and Their VEGF Release 
Current eye research  2008;33(11):984-993.
Purpose
Determine the effects of glucose and exogenous TGFβ2 on viability and VEGF release by human retinal pericytes (HRP).
Methods
Human retinal pericytes (HRP) were cultured in 5 mM (physiologic) or high (18 mM) glucose with or without added TGFβ2. Viable cells were counted; TGFβ2 and VEGF in the conditioned media (CM) were measured by ELISA.
Results
High glucose significantly reduced viable cell number and increased the levels of TGFβ2 and VEGF. TGFβ2 caused a significant dose-dependent effect on viable cell number and on the level of VEGF secreted into the CM by HRP in physiologic glucose, decreasing viable cell number, and increasing VEGF release per 1000 cells at a low concentration (0.1 ng/ml) and increasing viable cell number and decreasing VEGF release per 1000 cells at higher concentrations (1.0 and 10 ng/ml). TGFβ2 affected neither parameter in high glucose.
Conclusions
Elevated glucose decreased HRP viability and modulated changes in TGFβ2 and VEGF release. This suggests a novel mechanism for HRP dropout in diabetic retinopathy.
doi:10.1080/02713680802450976
PMCID: PMC4308732  PMID: 19085381
diabetic retinopathy; human retinal pericytes; hyperglycemia; TGFβ2; VEGF
6.  Protective and Antioxidant Effects of PPARα in the Ischemic Retina 
Purpose.
Previous studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPARα) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARα's protective effects in the ischemic retina, and to delineate its molecular mechanism of action.
Methods.
For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARα knockout (PPARα−/−) mice were exposed to 75% O2 from postnatal day 7 (P7) to P12 and treated with the PPARα agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling.
Results.
Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARα−/− OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARα overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-α (HIF-1α) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARα−/− mice.
Conclusions.
Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1α/Nox 4 and consequently alleviation of oxidative stress.
Activation and over-expression of PPARα protected retinal cells against ischemia-induced apoptosis. Further, PPARα ablation exacerbated ischemia-induced retinal glial activation and cell death. PPARα alleviated oxidative stress under ischemia via down-regulation of NADPH Oxidase 4 expression.
doi:10.1167/iovs.13-13127
PMCID: PMC4109406  PMID: 24825105
apoptosis; diabetic retinopathy; HIF-1; hypoxia; ischemia; neurodegeneration; OIR
7.  Discontinuation of antiviral prophylaxis correlates with high prevalence of hepatitis B virus (HBV) reactivation in rheumatoid arthritis patients with HBV carrier state: a real-world clinical practice 
Background
To investigate the risk of hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with HBV carrier state during treatment of disease-modifying antirheumatic drugs (DMARDs) and the use of antiviral prophylaxis in real-world clinical practice.
Methods
Consecutive RA patients with HBV carrier state were included. Clinical data including liver evaluation, HBV infection evaluation and the use of antiviral prophylaxis were recorded.
Results
Fifty-three RA patients with HBV carrier state were screened and 36 patients were qualified for analysis. Thirty-six percentage of patients developed HBV reactivation and 17% developed HBV hepatitis together with reactivation, one of which developed decompensate cirrhosis. Only 50% of patients accepted lamivudine although all patients were recommended antiviral prophylaxis with entecavir or tenofovir and only 31% continued during DMARDs therapy. Seventy-one percentage of patients who discontinued antiviral prophylaxis developed HBV reactivation 3 ~ 21 months after discontinuation. Logistic regression analyses showed discontinuation of antiviral prophylaxis (OR: 66, p = 0.027), leflunomide (OR: 64, p = 0.011) and past history of hepatitis (OR: 56, p = 0.013) were risk factors of HBV reactivation. Past history of hepatitis (OR: 10, p = 0.021) was also risk factor of HBV hepatitis together with reactivation.
Conclusion
Our results suggest poor patient acceptance and discontinuation of antiviral prophylaxis should not be ignored for Chinese RA patients with HBV carrier state in real-world clinical practice. Discontinuation of antiviral prophylaxis, past history of hepatitis and LEF might increase risk of HBV reactivation for RA patients with HBV carrier state during DMARDs therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-449) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2474-15-449
PMCID: PMC4320507  PMID: 25532827
Rheumatoid arthritis; Hepatitis B virus; Disease-modifying antirheumatic drugs
8.  Induction of H2AX phosphorylation in tumor cells by gossypol acetic acid is mediated by phosphatidylinositol 3-kinase (PI3K) family 
Cancer Cell International  2014;14(1):141.
Background
H2AX is phosphorylated (γH2AX) by members of the phosphatidylinositol 3-kinase (PI3K) family, including Ataxia telangiectasia-mutated (ATM), ATM- and Rad3-related (ATR) and DNA-PK in response to DNA damage. Our study shows that gossypol acetic acid (GAA) alone can induce γH2AX in Human mucoepidermoid carcinoma cell line (MEC-1) in vitro. Thus, we further examined the possible mechanisms of GAA to induce γH2AX in tumor cells.
Materials and methods
The PI3K inhibitors caffeine and wortmannin were used in an effort to identify the kinase(s) responsible for GAA -induced γH2AX in MEC-1 cells. DNA dependent protein kinase (DNA-PK) - proficient and –deficient cells, human glioma cell lines M059K and M059J, were also used to evaluate the kinases responsible for GAA induced H2AX phosphorylation. γH2AX expression was detected by immunofluorescent microscopy. Flow cytometry assay was used to assay γH2AX and cell cycle.
Results
GAA induced H2AX phosphorylation in a cell cycle-dependent manner and a significant G0/G1 phase arrest in MEC-1 cells was shown. Caffeine and wortmannin significantly inhibited GAA-induced H2AX phosphorylation in MEC-1 cells. GAA induced H2AX phosphorylation in M059K, but not in M059J. Taken together, these data suggested that GAA treatment alone could induce H2AX phosphorylation in a cell cycle dependent manner in MEC-1 and M059K, but not in M059J cells. A significant G0/G1 phase arrest was shown in MEC-1.
Conclusions
The member of PI3K family, DNA-PK, ATM and ATR are involved in the H2AX phosphorylation of MEC-1 cells.
doi:10.1186/s12935-014-0141-5
PMCID: PMC4272777  PMID: 25530717
Gossypol acetic acid; H2AX phosphorylation; DNA-PK; ATM; ATR
9.  Promoter Methylation of Protocadherin8 is an Independent Prognostic Factor for Biochemical Recurrence of Early-Stage Prostate Cancer 
Background
Protocadherin8 has been demonstrated to play critical roles in initiation and progression of several human cancers. It is frequently inactivated by promoter methylation in cancers and may be used as a potential biomarker. However, the methylation status of protocadherin8 and its clinical significance in prostate cancer remains largely unknown. The purpose of this study was to evaluate the clinical significance of protocadherin8 methylation in early-stage prostate cancer.
Material/Methods
The promoter methylation status of protocadherin8 in 162 prostate cancer tissues and 47 normal prostate tissues was examined using methylation-specific PCR (MSP). Subsequently, the relationships between protocadherin8 methylation and clinicopathological features of prostate cancer patients and biochemical recurrence-free survival of patients were analyzed.
Results
We found that protocadherin8 methylation occurred frequently in prostate cancer tissues but not in normal prostate tissues. Moreover, protocadherin8 methylation was significantly associated with advanced pathologic stage, higher level of preoperative prostate specific antigen (PSA), higher Gleason score, positive lymph node metastasis, and biochemical recurrence. In addition, patients with protocadherin8 methylated have shorter biochemical recurrence-free survival time than patients without. Multivariate Cox regression analysis revealed that protocadherin8 methylation was an independent predictor of biochemical recurrence-free survival in prostate cancer patients.
Conclusions
Promoter methylation of protocadherin8 is a frequent event in prostate cancer, and might be used as an independent prognostic factor for biochemical recurrence-free survival in patients with prostate cancer.
doi:10.12659/MSM.893083
PMCID: PMC4266258  PMID: 25486497
Biological Markers; DNA Methylation; Prostatic Neoplasms
10.  Elevated Serum IgG4 Defines Specific Clinical Phenotype of Rheumatoid Arthritis 
Mediators of Inflammation  2014;2014:635293.
Objectives. To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). Methods. Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. Results. Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (χ2 = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). Conclusions. Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.
doi:10.1155/2014/635293
PMCID: PMC4273547  PMID: 25548435
11.  An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic Retinopathy and Other Microvascular End Points in Patients With Diabetes 
Diabetes  2013;62(12):3968-3975.
The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR) and other diabetes-induced microvascular complications. This interest stems from two recent large, well-designed clinical trials that demonstrated large reductions in the progression of DR and the need for laser intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes. In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline. Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell apoptosis. These factors are believed to be important in the development of DR regardless of the underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further, fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given the results of these preclinical studies, further clinical trials are needed to establish the benefits of fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation into clinical practice should be continually revised as more information becomes available.
doi:10.2337/db13-0800
PMCID: PMC3837039  PMID: 24264394
12.  Antiangiogenic and Antineuroinflammatory Effects of Kallistatin Through Interactions With the Canonical Wnt Pathway 
Diabetes  2013;62(12):4228-4238.
Kallistatin is a member of the serine proteinase inhibitor superfamily. Kallistatin levels have been shown to be decreased in the vitreous while increased in the circulation of patients with diabetic retinopathy (DR). Overactivation of the Wnt pathway is known to play pathogenic roles in DR. To investigate the role of kallistatin in DR and in Wnt pathway activation, we generated kallistatin transgenic (kallistatin-TG) mice overexpressing kallistatin in multiple tissues including the retina. In the oxygen-induced retinopathy (OIR) model, kallistatin overexpression attenuated ischemia-induced retinal neovascularization. In diabetic kallistatin-TG mice, kallistatin overexpression ameliorated retinal vascular leakage, leukostasis, and overexpression of vascular endothelial growth factor and intracellular adhesion molecule. Furthermore, kallistatin overexpression also suppressed Wnt pathway activation in the retinas of the OIR and diabetic models. In diabetic Wnt reporter (BAT-gal) mice, kallistatin overexpression suppressed retinal Wnt reporter activity. In cultured retinal cells, kallistatin blocked Wnt pathway activation induced by high glucose and by Wnt ligand. Coprecipitation and ligand-binding assays both showed that kallistatin binds to a Wnt coreceptor LRP6 with high affinity (Kd = 4.5 nmol/L). These observations suggest that kallistatin is an endogenous antagonist of LRP6 and inhibitor of Wnt signaling. The blockade of Wnt signaling may represent a mechanism for its antiangiogenic and antineuroinflammatory effects.
doi:10.2337/db12-1710
PMCID: PMC3837048  PMID: 23884893
13.  Elevated Circulation Levels of an Anti-angiogenic SERPIN in Patients with Diabetic Microvascular Complications Impairs Wound Healing through Suppression of Wnt Signaling 
Wound healing, angiogenesis and hair follicle maintenance are often impaired in the skin of diabetic patients, but the pathogenesis has not been well understood. Here, we report that circulation levels of kallistatin, a member of the serine proteinase inhibitor (SERPIN) superfamily with anti-angiogenic activities, were elevated in Type 2 diabetic patients with diabetic vascular complications. To test the hypothesis that elevated kallistatin levels could contribute to a wound healing deficiency via inhibition of Wnt/β-catenin signaling, we generated kallistatin-transgenic (KS-TG) mice. KS-TG mice had reduced cutaneous hair follicle density, microvascular density, and panniculus adiposus layer thickness as well as altered skin microvascular hemodynamics and delayed cutaneous wound healing. Using Wnt reporter mice, our results showed that Wnt/β-catenin signaling is suppressed in dermal endothelium and hair follicles in KS-TG mice. Lithium, a known activator of β-catenin via inhibition of glycogen synthase kinase-3β, reversed the inhibition of Wnt/β-catenin signaling by kallistatin and rescued the wound healing deficiency in KS-TG mice. These observations suggest that elevated circulating anti-angiogenic serpins in diabetic patients may contribute to impaired wound healing through inhibition of Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling, at a level downstream of Wnt receptors, may ameliorate the wound healing deficiency in diabetic patients.
doi:10.1038/jid.2014.40
PMCID: PMC4065799  PMID: 24463424
14.  PPARα Regulates Mobilization and Homing of Endothelial Progenitor Cells Through the HIF-1α/SDF-1 Pathway 
Purpose.
The mechanism for the antiangiogenic activity of peroxisome proliferator–activated receptor alpha (PPARα) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPARα regulates EPC during retinal NV.
Methods.
Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) or with adenovirus expressing PPARα (Ad-PPARα). Flow cytometry was used to quantify circulating and retinal EPC. Serum stromal cell-derived factor 1 (SDF-1) levels were measured by ELISA. Hypoxia was induced in primary human retinal capillary endothelial cells (HRCEC) and mouse brain endothelial cells (MBEC) by CoCl2. Levels of SDF-1 and hypoxia-inducible factor 1 alpha (HIF-1α) were measured by Western blotting.
Results.
Fenofibric acid and overexpression of PPARα attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPARα knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1α and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPARα inhibited HIF-1α nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPARα−/− mice showed more prominent activation of HIF-1α and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPARα failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1α, suggesting that regulation of SDF-1 by PPARα was through blockade of HIF-1α activation.
Conclusions.
Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1α/SDF-1 pathway. This represents a novel molecular mechanism for PPARα's antiangiogenic effects.
This study identified a novel function of PPARα in regulation of endothelial progenitor cell mobilization and homing in retinal neovascularization.
doi:10.1167/iovs.13-13396
PMCID: PMC4064689  PMID: 24845641
neovascularization; endothelial progenitor cells; PPARα; oxygen-induced retinopathy; retina
15.  Clinical and prognostic significance of high-mobility group box-1 in human gliomas 
The objective of this study was to explore the expression and the clinical and prognostic significance of high-mobility group box-1 (HMGB1) in human gliomas. The expression of HMGB1 in 15 samples of normal brain tissue and 65 samples of different-grade glioma tissue was assayed using immunohistochemistry and western blot analysis. The associations between the differences in expression and pathology grades were analyzed statistically. Uni- and multivariate analyses were performed to investigate the prognostic value of HMGB1 expression and its expression levels. The positive rates of HMGB1 expression in normal brain and glioma tissue were 20.0% (3/15) and 76.9% (50/65), respectively. The expression of HMGB1 in glioma tissue was higher than that in normal tissue (P<0.05). The positive rates of HMGB1 expression in low-grade gliomas (LGGs, grades I and II) and high-grade gliomas (HGGs, grades III and IV) were 63.0% (17/27) and 86.8% (33/38), respectively, and the positive rates in HGG were higher than those in LGG (P=0.024). Western blot analysis showed that HMGB1 was also expressed in normal brain tissue. The expression levels in HGG were significantly higher than those in LGG (P<0.001). HMGB1-positive patients had significantly shorter overall survival times compared with HMGB1-negative patients (P=0.026). Increasing levels of HMGB1 expression significantly correlated with reduced survival times when all patients with glioma were considered (P=0.045). In conclusion, HMGB1 positivity and protein expression levels are of significant clinical and prognostic value in human gliomas. Detecting HMGB1 in human gliomas may be useful for assessing the degree of malignancy, and HMGB1 would appear to be a promising target in the clinical management of patients with glioma.
doi:10.3892/etm.2014.2089
PMCID: PMC4280992  PMID: 25574225
high-mobility group box-1; gliomas; expression; clinical; prognosis
16.  Aberrant Methylation of PCDH8 is a Potential Prognostic Biomarker for Patients with Clear Cell Renal Cell Carcinoma 
Background
PCDH8 is a tumor suppressor that regulates cell adhesin, proliferation, and migration. It is often inactivated by aberrant promoter methylation in several human cancers, including clear cell renal cell carcinoma (CCRCC). The clinical significance of PCDH8 methylation in CCRCC remains unclear. The aim of this study was to investigate the relationship between PCDH8 methylation and clinicopathological characteristics as well as outcome of patients with CCRCC.
Material/Methods
The methylation status of PCDH8 in 153 CCRCC tissues and 97 paired adjacent normal renal tissues were examined using methylation-specific PCR (MSP). Then the relationships between PCDH8 methylation and clinicopathological features as well as progression-free survival of CCRCC patients were evaluated.
Results
PCDH8 methylation was significantly more frequent in CCRCC tissues compared with normal renal tissues. Moreover, PCDH8 methylation was significantly correlated with advanced clinical stage (P=0.0141), higher grade (P=0.0190), and lymph node metastasis (P=0.0098). In addition, multivariate analysis showed that PCDH8 methylation was independently associated with poor progression-free survival (P=0.0316).
Conclusions
PCDH8 methylation is a frequent event in CCRCC and is correlated with unfavorable clinicopathological features. Moreover, PCDH8 methylation may be a useful biomarker to predict the progression of CCRCC.
doi:10.12659/MSM.892433
PMCID: PMC4251547  PMID: 25416427
Cadherins; Carcinoma, Renal Cell; DNA Methylation; Tumor Markers, Biological
17.  Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease 
ACS Chemical Neuroscience  2013;4(11):1430-1438.
Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. Nurr1 may be unable to bind ligands directly, but it forms heterodimers with other NucHRs that do. Using bioluminescence resonance energy transfer (BRET) assays to directly monitor interactions of Nurr1 with other NucHRs, we found the cancer drug bexarotene (Targretin, also LGD1069) displayed biased interactions with Nurr1-RXR heterodimers compared with RXR-RXR homodimers. Remarkably, at doses up to 100-fold lower than those effective in rodent cancer models, bexarotene rescued dopamine neurons and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA) lesioned rats. Compared to the high doses used in cancer therapy, low doses of bexarotene have significantly milder side effects including a reduced increase in plasma triglycerides and less suppression of thyroid function. On the basis of extrapolations from rat to human doses, we hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson’s disease (PD).
doi:10.1021/cn400100f
PMCID: PMC3837375  PMID: 24117438
Bexarotene; Nurr1; retinoid X receptor; dopamine neuron; behavior; Parkinson’s disease
18.  Transcriptome and Allele Specificity Associated with a 3BL Locus for Fusarium Crown Rot Resistance in Bread Wheat 
PLoS ONE  2014;9(11):e113309.
Fusarium pathogens cause two major diseases in cereals, Fusarium crown rot (FCR) and head blight (FHB). A large-effect locus conferring resistance to FCR disease was previously located to chromosome arm 3BL (designated as Qcrs-3B) and several independent sets of near isogenic lines (NILs) have been developed for this locus. In this study, five sets of the NILs were used to examine transcriptional changes associated with the Qcrs-3B locus and to identify genes linked to the resistance locus as a step towards the isolation of the causative gene(s). Of the differentially expressed genes (DEGs) detected between the NILs, 12.7% was located on the single chromosome 3B. Of the expressed genes containing SNP (SNP-EGs) detected, 23.5% was mapped to this chromosome. Several of the DEGs and SNP-EGs are known to be involved in host-pathogen interactions, and a large number of the DEGs were among those detected for FHB in previous studies. Of the DEGs detected, 22 were mapped in the Qcrs-3B interval and they included eight which were detected in the resistant isolines only. The enrichment of DEG, and not necessarily those containing SNPs between the resistant and susceptible isolines, around the Qcrs-3B locus is suggestive of local regulation of this region by the resistance allele. Functions for 13 of these DEGs are known. Of the SNP-EGs, 28 were mapped in the Qcrs-3B interval and biological functions for 16 of them are known. These results provide insights into responses regulated by the 3BL locus and identify a tractable number of target genes for fine mapping and functional testing to identify the causative gene(s) at this QTL.
doi:10.1371/journal.pone.0113309
PMCID: PMC4236173  PMID: 25405461
19.  Association of BRCA2 N372H polymorphism with cancer susceptibility: A comprehensive review and meta-analysis 
Scientific Reports  2014;4:6791.
BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer (dominant model: OR = 1.07, 95% CI = 1.01–1.13; recessive model: OR = 1.12, 95% CI = 1.02–1.23). Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk.
doi:10.1038/srep06791
PMCID: PMC4210867  PMID: 25348552
20.  Extensive Pericentric Rearrangements in the Bread Wheat (Triticum aestivum L.) Genotype “Chinese Spring” Revealed from Chromosome Shotgun Sequence Data 
Genome Biology and Evolution  2014;6(11):3039-3048.
The bread wheat (Triticum aestivum L.) genotype “Chinese Spring” (“CS”) is the reference base in wheat genetics and genomics. Pericentric rearrangements in this genotype were systematically assessed by analyzing homoeoloci for a set of nonredundant genes from Brachypodium distachyon, Triticum urartu, and Aegilops tauschii in the CS chromosome shotgun sequence obtained from individual chromosome arms flow-sorted from CS aneuploid lines. Based on patterns of their homoeologous arm locations, 551 genes indicated the presence of pericentric inversions in at least 10 of the 21 chromosomes. Available data from deletion bin-mapped expressed sequence tags and genetic mapping in wheat indicated that all inversions had breakpoints in the low-recombinant gene-poor pericentromeric regions. The large number of putative intrachromosomal rearrangements suggests the presence of extensive structural differences among the three subgenomes, at least some of which likely occurred during the production of the aneuploid lines of this hexaploid wheat genotype. These differences could have significant implications in wheat genome research where comparative approaches are used such as in ordering and orientating sequence contigs and in gene cloning.
doi:10.1093/gbe/evu237
PMCID: PMC4255769  PMID: 25349265
chromosomal rearrangement; comparative genomics; pericentric inversion; pericentromeric regions; translocation; Chinese Spring
21.  Down-regulating peroxisome proliferator-activated receptor-gamma coactivator-1beta alleviates the proinflammatory effect of rheumatoid arthritis fibroblast-like synoviocytes through inhibiting extracellular signal-regulated kinase, p38 and nuclear factor-kappaB activation 
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1β) is a transcriptional coactivator that plays important roles in regulating multiple aspects of energy metabolism and cytokine signaling pathways. PGC-1β overexpression leads to the attenuation of macrophage-mediated inflammation. In this study, we aimed to determine the expression of PGC-1β in RA synovium and fibroblast-like synoviocytes (FLS), and explore the mechanisms of PGC-1β on both the proinflammatory effects and apoptosis in RA-FLS.
Methods
Synovium was obtained from 31 patients with active RA, as well as 13 osteoarthritis (OA) and 10 orthopedic arthropathies (Orth.A) as “less inflamed” disease controls. FLS were then isolated and cultured. Synovial PGC-1β expression was determined by immunohistochemistry staining, while FLS PGC-1β expression was detected by immunofluorescence staining, quantitative real-time PCR (qPCR) assay and western blot. PGC-1β was depleted by lentivirus sh-RNA, and up-regulated by pcDNA3.1- PGC-1β. The expression of proinflammatory cytokines, matrix metalloproteinases and receptor activator of nuclear factor-kappaB ligand was analyzed by qPCR, cytometric bead array and western blot. The expression of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) was determined by qPCR and western blot. Besides, cell apoptosis was examined using flow cytometry. The interaction between PGC-1β and NF-κB was performed by dual-luciferase reporter gene assays.
Results
(A) Synovial PGC-1β was over-expressed in RA patients compared with OA or Orth.A patients. (B) PGC-1β expression significantly increased in RA-FLS compared with OA-FLS. (C) PGC-1β mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-κB in RA-FLS. (D) PGC-1β mediated NF-κB transcription in RA-FLS, but did not affect ERK and p38.
Conclusion
The results indicate that PGC-1β may play important roles in the proinflammatory effects and apoptosis of RA-FLS.
doi:10.1186/s13075-014-0472-6
PMCID: PMC4237730  PMID: 25367151
22.  The efficacy of a thrombin-based hemostatic agent in primary total knee arthroplasty: a meta-analysis 
Purpose
Total knee arthroplasty (TKA) is a popular procedure in severe osteoarthritis. But perioperative bleeding remains a problem. Floseal® is a mixture of thrombin and bovine gelatin which can benefit a lot on reducing intraoperative and postoperative bleeding. However, there is no enough evidence judging its safety and efficiency. So a meta-analysis is conducted by us to evaluate the efficacy and safety of a thrombin-based hemostatic agent compared with conventional methods in TKA.
Method
Two independent reviewers selected literatures published before August 2014 from MEDLINE, Embase, and The Cochrane Central Register of Controlled Trials. Other internet databases were also performed to identify trials according to the Cochrane Collaboration guidelines. High-quality randomized controlled trials (RCTs), prospective control trials (PCTs), and case controlled trials (CCTs) were selected. The meta-analysis was undertaken using RevMan 5.1 for Windows.
Results
Three RCTs, one PCT, and one CCT met the inclusion criteria. There were significant differences in hemoglobin decline and calculated total blood loss between the Floseal® group and control group. There were no significant differences in postoperative drainage volume, rate of transfusion requirement, incidence of wound infection, deep vein thrombosis (DVT), and pulmonary embolism (PE) between treatment and control groups.
Conclusions
The present meta-analysis indicates that a thrombin-based hemostatic agent can reduce hemoglobin decline and calculated total blood loss after TKA and is not related to adverse reactions or complications such as wound infection, DVT, and PE.
doi:10.1186/s13018-014-0090-7
PMCID: PMC4212119  PMID: 25316253
Floseal®; Thrombin; Arthroplasty; Meta-analysis
23.  SERPINA3K Plays Antioxidant Roles in Cultured Pterygial Epithelial Cells through Regulating ROS System 
PLoS ONE  2014;9(10):e108859.
We recently demonstrated that SERPINA3K, a serine proteinase inhibitor, has antioxidant activity in the cornea. Here we investigated the antioxidant effects of SERPINA3K on the pterygial, which is partially caused by oxidative stress in pathogenesis. The head part of primary pterygial tissue was dissected and then cultured in keratinocyte serum-free defined medium (KSFM). The cultured pterygial epithelial cells (PECs) were treated with SERPINA3K. The cell proliferation and migration of PECs were measured and analyzed. Western blot and quantitative real-time polymerase chain reaction (PCR) assay were performed. It showed that SERPINA3K significantly suppressed the cell proliferation of PECs in a concentration-dependent manner, compared with cultured human conjunctival epithelial cells. SERPINA3K also inhibited the cell migration of PECs. Towards its underlying mechanism, SERPINA3K had antioxidant activities on the PECs by significantly inhibiting NADPH oxidase 4 (NOX4), which is an important enzyme of ROS generation, and by elevating the levels of key antioxidant factors of ROS: such as NAD(P)H dehydrogenase (quinone 1) (NQO1), NF-E2–related factor-2 (NRF2) and superoxide dismutases (SOD2). Meanwhile, SERPINA3K down-regulated the key effectors of Wnt signaling pathway: β-catenin, nonphospho-β-catenin, and low-density lipoprotein receptor-related protein 6 (LRP6). We provided novel evidence that SERPINA3K had inhibitory effects on pterygium and SERPINA3K played antioxidant role via regulating the ROS system and antioxidants.
doi:10.1371/journal.pone.0108859
PMCID: PMC4189792  PMID: 25296038
24.  Anterior versus posterior approach for treatment of thoracolumbar burst fractures: a meta-analysis 
European Spine Journal  2013;22(10):2176-2183.
Purpose
To critically review and summarize the literature comparing the results of surgery via an anterior approach and that via a posterior approach for the treatment of thoracolumbar burst fractures to identify the better approach.
Methods
In this meta-analysis, we conducted electronic searches of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and other databases using the search terms “thoracolumbar fractures”, “anterior”, “posterior”, “controlled clinical trials”. Relevant journals or conference proceedings were also searched manually. Data extraction and quality assessment were in accordance with Cochrane Collaboration guidelines. The analysis was performed on individual patient data from all the trials that met the selection criteria. Sensitivity analysis was performed when there was significant heterogeneity. Results were expressed as risk difference for dichotomous outcomes and mean difference for continuous outcomes with 95 % confidence interval.
Results
Four randomized clinical trials and three controlled clinical trials comparing the results of the anterior versus posterior approach in the treatment of thoracolumbar burst fractures were retrieved; these studies included 179 and 152 patients in the anterior and posterior approach groups, respectively. There were no differences in terms of neurological recovery, return to work, complications and Cobb angle between the two groups. The anterior approach was associated with longer operative time, greater blood loss and higher cost than the posterior approach.
Conclusions
The posterior approach may be more effective than the anterior approach. However, more high-quality, randomized controlled trials are required to compare these approaches and guide clinical decision-making.
Level of Evidence Level II, therapeutic study. See the Guidelines for Authors for a complete description of level of evidence.
doi:10.1007/s00586-013-2987-y
PMCID: PMC3804690  PMID: 24013718
Anterior approach; Posterior approach; Thoracolumbar burst fractures; Meta-analysis
25.  A methodological systematic review of early versus late stabilization of thoracolumbar spine fractures 
European Spine Journal  2012;22(10):2157-2166.
Objective
The optimal timing of stabilization in patients with traumatic thoracolumbar fractures remains controversial. There is currently a lack of consensus on the timing of surgical stabilization, which is limited by the reality that a randomized controlled trial to evaluate early versus late stabilization is difficult to perform. Therefore, the objective of this study was to determine the benefits, safety and costs of early stabilization compared with late stabilization using data available in the current literature.
Methods
An electronic literature search was performed in Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for relevant studies evaluating the timing of surgery in patients with thoracolumbar fractures. Two reviewers independently analyzed and selected each study on the basis of the eligibility criteria. The quality of the included studies was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE). Any disagreements were resolved by consensus.
Results
Ten studies involving 2,512 subjects were identified. These studies demonstrated that early stabilization shortened the hospital length of stay, intensive care unit length of stay, ventilator days and reduced morbidity and hospital expenses for patients with thoracic fractures. However, reduced morbidity and hospital expenses were not observed with stabilization of lumbar fractures. Owing to the very low level of evidence, no conclusion could be made regarding the effect of early stabilization on mortality.
Conclusions
We could adhere to the recommendation that patients with traumatic thoracolumbar fractures should undergo early stabilization, which may reduce the hospital length of stay, intensive care unit length of stay, ventilator days, morbidity and hospital expenses, particularly when the thoracic spine is involved. Individual patient characteristics should be concerned carefully. However, the definite conclusion cannot be made due to the heterogeneity of the included studies and low level of evidence. Further prospective studies are required to confirm whether there are benefits to early stabilization compared with late stabilization.
doi:10.1007/s00586-012-2624-1
PMCID: PMC3804693  PMID: 23263169
Thoracolumbar; Fracture; Spine; Timing of surgery; Systematic review

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