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1.  Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation 
PPARγ (peroxisome proliferator-activated receptor gamma) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Here, we report that PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation is required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating the Dio mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high fat diet induced–insulin resistance. Our data suggest that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for improvement of insulin sensitivity.
PMCID: PMC4391273  PMID: 24982244
type 2 diabetes; insulin sensitivity; metabolic syndrome; adipocytes; adipogenesis; PPARγ; posttranslational modifications; histone deacetylase; HDAC inhibitors; acetylation
2.  Persistent homology analysis of protein structure, flexibility and folding 
Proteins are the most important biomolecules for living organisms. The understanding of protein structure, function, dynamics and transport is one of most challenging tasks in biological science. In the present work, persistent homology is, for the first time, introduced for extracting molecular topological fingerprints (MTFs) based on the persistence of molecular topological invariants. MTFs are utilized for protein characterization, identification and classification. The method of slicing is proposed to track the geometric origin of protein topological invariants. Both all-atom and coarse-grained representations of MTFs are constructed. A new cutoff-like filtration is proposed to shed light on the optimal cutoff distance in elastic network models. Based on the correlation between protein compactness, rigidity and connectivity, we propose an accumulated bar length generated from persistent topological invariants for the quantitative modeling of protein flexibility. To this end, a correlation matrix based filtration is developed. This approach gives rise to an accurate prediction of the optimal characteristic distance used in protein B-factor analysis. Finally, MTFs are employed to characterize protein topological evolution during protein folding and quantitatively predict the protein folding stability. An excellent consistence between our persistent homology prediction and molecular dynamics simulation is found. This work reveals the topology-function relationship of proteins.
PMCID: PMC4131872  PMID: 24902720
persistent homology; molecular topological fingerprint; protein topology-function relationship; protein topological evolution; computational topology
3.  Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors 
Nature communications  2014;5:5807.
Direct reprogramming provides a fundamentally new approach for the generation of patient-specific cells. Here, by screening a pool of candidate transcription factors, we identify that a combination of three factors, MITF, SOX10 and PAX3, directly converts mouse and human fibroblasts to functional melanocytes. Induced melanocytes (iMels) activate melanocyte-specific networks, express components of pigment production and delivery system, and produce melanosomes. Human iMels properly integrate into the dermal-epidermal junction, and produce and deliver melanin pigment to surrounding keratinocytes in a 3D organotypic skin reconstruct. Human iMels generate pigmented epidermis and hair follicles in skin reconstitution assays in vivo. The generation of iMels has important implications for studies of melanocyte lineage commitment, pigmentation disorders and cell replacement therapies.
PMCID: PMC4335710  PMID: 25510211
4.  Spatiotemporal Scan and Age-Period-Cohort Analysis of Hepatitis C Virus in Henan, China: 2005–2012 
PLoS ONE  2015;10(6):e0129746.
Studies have shown that hepatitis C virus (HCV) infection increased during the past decades in China. However, little evidence is available on when, where, and who were infected with HCV. There are gaps in knowledge on the epidemiological burden and evolution of the HCV epidemic in China.
Data on HCV cases were collected by the disease surveillance system from 2005 to 2012 to explore the epidemic in Henan province. Spatiotemporal scan statistics and age-period-cohort (APC) model were used to examine the effects of age, period, birth cohort, and spatiotemporal clustering.
177,171 HCV cases were reported in Henan province between 2005 and 2012. APC modelling showed that the HCV reported rates significantly increased in people aged > 50 years. A moderate increase in HCV reported rates was observed for females aged about 25 years. HCV reported rates increased over the study period. Infection rates were greatest among people born between 1960 and 1980. People born around 1970 had the highest relative risk of HCV infection. Women born between 1960 and 1980 had a five-fold increase in HCV infection rates compared to men, for the same birth cohort. Spatiotemporal mapping showed major clustering of cases in northern Henan, which probably evolved much earlier than other areas in the province.
Spatiotemporal mapping and APC methods are useful to help delineate the evolution of the HCV epidemic. Birth cohort should be part of the criteria screening programmes for HCV in order to identify those at highest risk of infection and unaware of their status. As Henan is unique in the transmission route for HCV, these methods should be used in other high burden provinces to help identify subpopulations at risk.
PMCID: PMC4468242  PMID: 26075599
5.  Effect of radiotherapy on survival of women with locally excised ductal carcinoma in situ of the breast: a Surveillance, Epidemiology, and End Results population-based analysis 
OncoTargets and therapy  2015;8:1407-1418.
Although it has been previously reported that radiotherapy (RT) effectively reduced the incidence of local recurrence of ductal carcinoma in situ (DCIS) following breast-conserving surgery (BCS), little is known about the effect of RT on survival of patients with locally excised DCIS.
Patients and methods
Using Surveillance, Epidemiology, and End Results registry data, we selected 56,968 female DCIS patients treated with BCS between 1998 and 2007. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared among patients who received RT or no RT using the Kaplan–Meier methods and Cox proportional hazards regression models.
Median follow-up was 91 months. In the multivariable model, patients receiving postoperative RT had better OS than those undergoing BCS alone (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.53–0.67, P<0.001). This pattern remained after stratification by estrogen receptor (ER) status and age. In contrast, RT delivery was not significantly associated with improved BCSS (HR 0.71, 95% CI 0.48–1.03, P=0.073). However, after stratifying by the above two variables, RT contributed to better BCSS in ER-negative/borderline patients (HR 0.41, 95% CI 0.19–0.88, P=0.023) and younger patients (≤50 years old; HR 0.37, 95% CI 0.15–0.91, P=0.030).
Our analysis confirms the beneficial effect of RT on OS in women with locally excised DCIS and reveals the specific protective effect of RT on BCSS in ER-negative/borderline and younger patients.
PMCID: PMC4467663  PMID: 26089689
ductal carcinoma in situ; breast cancer; breast-conserving surgery; radiotherapy; survival
6.  Clinical Analysis of the HBV Infection Status of 135 Patients with Diffuse Large B Cell Lymphoma Treated with R-CHOP or CHOP/CHOP-Like Chemotherapy 
PLoS ONE  2015;10(6):e0129064.
This study aimed to determine the HBV infection status of 135 patients with DLBCL (diffuse large B cell lymphoma), to analyze the overall survival (OS) and progression-free survival (PFS) of the different HBV infection status groups, and to discuss the relationship between HBV serological test results and the prognosis of DLBCL patients.
A retrospective analysis was performed of the clinical data, HBV serological test results, and PFS/OS of 135 DLBCL patients who were initially diagnosed and treated with more than 3 cycles of an R-CHOP/CHOP/CHOP-like regimen at our center from January 1, 2008 to December 31, 2012.
The patients in the HBV infection group were older at disease onset (≥60 years old) and were more likely to present with stage 3-4 disease compared with the HBV-free group (P = 0.030 and P = 0.025, respectively). Approximately 50% of the patients with an active HBV infection required a reduction in the chemotherapy dose, and 66.7% of the patients in this group received more than 1 line of therapy; these rates were significantly higher than those in the no infection group (P = 0.003 and P = 0.011, respectively). Although HBV infection had no obvious influence on the outcome of first-line therapy, patients with an inactive infection had a higher relapse/progression rate within 3 months after a CR/PR than patients with an active infection (14/20 vs. 1/12, P = 0.001). The PFS at 1 year, 3 years and OS rates at 1 year, 3 years were significantly lower in the active HBV infection group than in the HBV-free group (P = 0.008, P = 0.002, P = 0.004, and P = 0.002, respectively). The PFS rates at 1 year and 3 year in HBV-free group were higher than those in the HBV infection group (80.5% and 52.9% P = 0.001, 78.1% and 44.4% P = 0.002). The lymphoma-related mortality rates were 2.7% in the no infection group, 19.2% in the HBV infection group (P = 0.004), and 28.6% in the active HBV infection group (P = 0.001). Among the patients treated with MabThera, the PFS in the HBV infection group was 11 months in the HBV infection group and 67 months in the infection-free group (P = 0.000). A Cox regression model of PFS revealed that age ≥60 years and HBV infection were independent prognostic factors (age: P = 0.019, HR = 2.002, 95% CI 1.123-3.567; HBV infection: P = 0.026, HR = 0.494, 95% CI 0.265-0.919).
Compared with the patients in HBV-free group, those in the HBV infection group were older at disease onset, and the active infection patients presented with more advanced disease and had a lower PFS at 1, 3 years as well as a lower OS at 3 years. The patients in the inactive infection group had a higher progression/relapse rate within 3 months after a CR/PR than those in the active infection group. HBV infection was an unfavorable factor for PFS in the MabThera group. An age ≥60 years and HBV infection were independent unfavorable prognostic factors for PFS.
PMCID: PMC4459955  PMID: 26053951
7.  L-citrulline for protection of endothelial function from ADMA–induced injury in porcine coronary artery 
Scientific Reports  2015;5:10987.
Endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. We tested the hypothesis that L-citrulline may ameliorate the endothelial function altered by ADMA in porcine coronary artery (PCA). Myograph study for vasorelaxation, electrochemical measurement for NO, RT-PCR, and Western blot analysis for expression of eNOS, argininosuccinate synthetase (ASS), and p-eNOSser1177 were performed. cGMP was determined by enzyme immunoassay. Superoxide anion (O2.−) production was detected by the lucigenin-enhanced chemiluminescence method. Compare with controls (96.03% ± 6.2%), the maximal relaxation induced by bradykinin was significantly attenuated (61.55% ± 4.8%, p < 0.01), and significantly restored by L-citrulline (82.67 ± 6.4%, p < 0.05) after 24 hours of ADMA exposure. Expression of eNOS, p-eNOSser1177, and ASS in PCA significantly increased after L-citrulline incubation. L-citrulline also markedly restored the NO production, and cGMP level which was reduced by ADMA. The increased O2.− production by ADMA was also inhibited by L-citrulline. L-citrulline restores the endothelial function in preparations treated with ADMA by preservation of NO production and suppression of O2.− generation. Preservation of NO is attributed to the upregulation of eNOS expression along with activation of p-eNOSser1177. L-citrulline improves endothelium-dependent vasodilation through NO/ cGMP pathway.
PMCID: PMC4457144  PMID: 26046576
8.  Protein Phosphatase 2A (PP2A) Regulatory Subunits ParA and PabA Orchestrate Septation and Conidiation and Are Essential for PP2A Activity in Aspergillus nidulans 
Eukaryotic Cell  2014;13(12):1494-1506.
Protein phosphatase 2A (PP2A) is a major intracellular protein phosphatase that regulates multiple aspects of cell growth and metabolism. Different activities of PP2A and subcellular localization are determined by its regulatory subunits. Here we identified and characterized the functions of two protein phosphatase regulatory subunit homologs, ParA and PabA, in Aspergillus nidulans. Our results demonstrate that ParA localizes to the septum site and that deletion of parA causes hyperseptation, while overexpression of parA abolishes septum formation; this suggests that ParA may function as a negative regulator of septation. In comparison, PabA displays a clear colocalization pattern with 4′,6-diamidino-2-phenylindole (DAPI)-stained nuclei, and deletion of pabA induces a remarkable delayed-septation phenotype. Both parA and pabA are required for hyphal growth, conidiation, and self-fertilization, likely to maintain normal levels of PP2A activity. Most interestingly, parA deletion is capable of suppressing septation defects in pabA mutants, suggesting that ParA counteracts PabA during the septation process. In contrast, double mutants of parA and pabA led to synthetic defects in colony growth, indicating that ParA functions synthetically with PabA during hyphal growth. Moreover, unlike the case for PP2A-Par1 and PP2A-Pab1 in yeast (which are negative regulators that inactivate the septation initiation network [SIN]), loss of ParA or PabA fails to suppress defects of temperature-sensitive mutants of the SEPH kinase of the SIN. Thus, our findings support the previously unrealized evidence that the B-family subunits of PP2A have comprehensive functions as partners of heterotrimeric enzyme complexes of PP2A, both spatially and temporally, in A. nidulans.
PMCID: PMC4248680  PMID: 25280816
9.  Structure Elucidation of the Metabolites of 2', 3', 5'-Tri-O-Acetyl-N6-(3-Hydroxyphenyl) Adenosine in Rat Urine by HPLC-DAD, ESI-MS and Off-Line Microprobe NMR 
PLoS ONE  2015;10(6):e0127583.
2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (also known as WS070117) is a new adenosine analog that displays anti-hyperlipidemic activity both in vitro and in vivo experiments as shown in many preliminary studies. Due to its new structure, little is known about the metabolism of WS070117. Hence, the in vivo metabolites of WS070117 in rat urine following oral administration were investigated. Identification of the metabolites was conducted using the combination of high-performance liquid chromatography (HPLC) coupled with diode array detector (DAD), ion trap electrospray ionization-mass spectrometry (ESI-MS), and off-line microprobe nuclear magnetic resonance (NMR) measurements. Seven metabolites were obtained as pure compounds at the sub-milligram to milligram levels. Results of structure elucidation unambiguously revealed that the phase I metabolite, N6-(3-hydroxyphenyl) adenosine (M8), was a hydrolysate of WS070117 by hydrolysis on the three ester groups. N6-(3-hydr-oxyphenyl) adenine (M7), also one of the phase I metabolites, was the derivative of M8 by the loss of ribofuranose. In addition to two phase I metabolites, there were five phase II metabolites of WS070117 found in rat urine. 8-hydroxy-N6-(3-hydroxy-phenyl) adenosine (M6) was the product of M7 by hydrolysis at position 8. The other four were elucidated to be N6-(3-O-β-D-glucuronyphenyl) adenine (M2), N8-hydroxy-N6-(3-O-sulfophenyl) adenine (M3), N6-(3-O-β-D-glucuronyphenyl) adenosine (M4), and N6-(3-O- sulfophenyl) adenosine (M5). Phase II metabolic pathways were proven to consist of hydroxylation, glucuronidation and sulfation. This study provides new and valuable information on the metabolism of WS070117, and also demonstrates the HPLC/MS/off-line microprobe NMR approach as a robust means for rapid identification of metabolites.
PMCID: PMC4451981  PMID: 26029929
10.  Quantification of three-dimensional computed tomography angiography for evaluating coronary luminal stenosis using digital subtraction angiography as the standard of reference 
We sought to evaluate the accuracy of quantitative three-dimensional (3D) CT angiography (CTA) for the assessment of coronary luminal stenosis using digital subtraction angiography (DSA) as the standard of reference.
Twenty-three patients with 54 lesions were referred for CTA followed by DSA. The CTA scans were performed with 256-slice spiral CT. 3D CTA were reconstructed from two-dimensional CTA imaging sequences in order to extract the following quantitative indices: minimal lumen diameter, percent diameter stenosis (%DS), minimal lumen area, and percent area stenosis (%AS). Correlation and limits of agreement were calculated using Pearson correlation and Bland–Altman analysis, respectively. The diagnostic performance and the diagnostic concordance of 3D CTA-derived anatomic parameters (%DS, %AS) for the detection of severe coronary arterial stenosis (as assessed by DSA) were presented as sensitivity, specificity, diagnostic accuracy, and Kappa statistics. Of which vessels with %DS >50% or with %AS >75% were identified as severe coronary arterial lesions.
The correlations of the anatomic parameters between 3D CTA and DSA were significant (r = 0.51–0.74, P < 0.001). Bland–Altman analysis confirmed that the mean differences were small (from −1.11 to 27.39%), whereas the limits of agreement were relatively wide (from ±28.07 to ±138.64%). Otherwise, the diagnostic accuracy (74.1% with 58.3% sensitivity and 86.7% specificity for DS%; 74.1% with 45.8% sensitivity and 96.7% specificity for %AS) and the diagnostic concordance (k = 0.46 for DS%; 0.45 for %AS) of 3D CTA-derived anatomic parameters for the detection of severe stenosis were moderate.
3D advanced imaging reconstruction technique is a helpful tool to promote the use of CTA as an alternative to assess luminal stenosis in clinical practice.
PMCID: PMC4448537  PMID: 26024658
Three-dimensional (3D) CT angiography; Digital subtraction angiography; Coronary luminal stenosis
11.  Development of an HIV-1 Subtype Panel in China: Isolation and Characterization of 30 HIV-1 Primary Strains Circulating in China 
PLoS ONE  2015;10(5):e0127696.
The complex epidemic and significant diversity of HIV-1 strains in China pose serious challenges for surveillance and diagnostic assays, vaccine development and clinical management. There is a lack of HIV-1 isolates in current canonical HIV-1 subtype panels that can represent HIV-1 diversity in China; an HIV-1 subtype panel for China is urgently needed.
Blood samples were collected from HIV-1 infected patients participating in the drug-resistance surveillance program in China. The samples were isolated, cultured and stored as neat culture supernatant. The HIV-1 isolates were fully characterized. The panel was used to compare 2 viral load assays and 2 p24 assays as the examples of how this panel could be used.
An HIV-1 subtype panel for China composed of 30 HIV-1 primary strains of four subtypes (B [including Thai-B], CRF01_AE, CRF07_BC and G) was established. The samples were isolated and cultured to a high-titer (106-109 copies/ml)/high-volume (40ml). The HIV-1 isolates were fully characterized by the final viral load, p24 concentration, gag-pol and envC2V3 sequencing, co-receptor prediction, determination of the four amino acids at the tip of the env V3-loop, glycosylation sites in the V3 loop and the drug-resistance mutations. The comparison of two p24 assays and two viral load assays on the isolates illustrated how this panel may be used for the evaluation of diagnostic assay performance. The Pearson value between p24 assays were 0.938. The viral load results showed excellent concordance and agreement for samples of Thai-B, but lower correlations for samples of CRF01_AE.
The current panel of 30 HIV-1 isolates served as a basis for the development of a comprehensive panel of fully characterized viral isolates, which could reflect the current dynamic and complex HIV-1 epidemic in China. This panel will be available to support HIV-1 research, assay evaluation, vaccine and drug development.
PMCID: PMC4446268  PMID: 26018591
12.  Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for the treatment of advanced intrahepatic cholangiocarcinoma 
OncoTargets and therapy  2015;8:1245-1250.
To retrospectively evaluate the safety and efficacy of ultrasound-guided percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in the treatment of patients with advanced intrahepatic cholangiocarcinoma (ICC).
All patients treated with ultrasound-guided percutaneous MWA combined with simultaneous TACE for advanced ICC at our institution were included. Posttreatment contrast-enhanced computed tomography and/or magnetic resonance imaging were retrieved and reviewed for tumor response to the treatment. Routine laboratory studies, including hematology and liver function tests were collected and analyzed. Procedure-related complications were reviewed and survival rates were analyzed.
From January 2011 to December 2014, a total of 26 advanced ICC patients were treated at our single institute with ultrasound-guided percutaneous MWA combined with simultaneous TACE. There were 15 males and eleven females with an average age of 57.9±10.4 years (range, 43–75 years). Of 26 patients, 20 (76.9%) patients were newly diagnosed advanced ICC without any treatment, and six (23.1%) were recurrent and treated with surgical resection of the original tumor. The complete ablation rate was 92.3% (36/39 lesions) for advanced ICC. There were no major complications observed. There was no death directly from the treatment. Median progression-free survival and overall survival were 6.2 and 19.5 months, respectively. The 6-, 12-, and 24-month survival rates were 88.5%, 69.2%, and 61.5%, respectively.
The study suggests that ultrasound-guided percutaneous MWA combined with simultaneous TACE therapy can be performed safely in all patients with advanced ICC. The complete ablation rate was high and there was no major complication. The overall 24-month survival was 61.5%.
PMCID: PMC4454214  PMID: 26060410
intrahepatic cholangiocarcinoma; interventional radiology; microwave ablation; transarterial chemoembolization
13.  Hearing the light: neural and perceptual encoding of optogenetic stimulation in the central auditory pathway 
Scientific Reports  2015;5:10319.
Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.
PMCID: PMC4441320  PMID: 26000557
14.  The roles of anion channels in Arabidopsis immunity 
Plant Signaling & Behavior  2014;9:e29230.
Anion efflux is one of the most immediate responses of plant cells to pathogen attacks, suggesting that anion channels may play a role in plant defense. Recently we reported that the chloride channel AtCLCd negatively regulates Arabidopsis pathogen-associated molecular pattern-triggered immunity (PTI), probably by affecting trafficking of the pattern recognition receptors (PRRs). Since AtCLCd is localized to the trans-Golgi network, it is not likely to be directly involved in anion flux across the plasma membrane. Here, we used a pharmacological approach to explore further the function of plasma membrane-localized R-type and S-type anion channels in plant immunity. We found that the R-type and S-type anion channels play opposite roles in Arabidopsis innate immunity. Inhibition of the R-type anion channels enhances, whereas inhibition of the S-type channels inhibits PTI and effector-triggered immunity (ETI).
PMCID: PMC4203573  PMID: 25763497
Arabidopsis; anion channel; PAMP-triggered immunity; effector-triggered immunity
15.  The evolution of the gut microbiota in the giant and the red pandas 
Scientific Reports  2015;5:10185.
The independent dietary shift from carnivore to herbivore with over 90% being bamboo in the giant and the red pandas is of great interests to biologists. Although previous studies have shown convergent evolution of the giant and the red pandas at both morphological and molecular level, the evolution of the gut microbiota in these pandas remains largely unknown. The goal of this study was to determine whether the gut microbiota of the pandas converged due to the same diet, or diverged. We characterized the fecal microbiota from these two species by pyrosequencing the 16S V1–V3 hypervariable regions using the 454 GS FLX Titanium platform. We also included fecal samples from Asian black bears, a species phylogenetically closer to the giant panda, in our analyses. By analyzing the microbiota from these 3 species and those from other carnivores reported previously, we found the gut microbiotas of the giant pandas are distinct from those of the red pandas and clustered closer to those of the black bears. Our data suggests the divergent evolution of the gut microbiota in the pandas.
PMCID: PMC4434948  PMID: 25985413
16.  IKK-β/NFκB p65 Mediates p27kip1 Protein Degradation in Arsenite Response 
p27kip1 is a potent inhibitor of the cyclin-dependent kinases that drive G1 to S phase transition. Since deregulation of p27kip1 is found in many malignancies and is associated with the poor prognosis, elucidation of the molecular bases for regulation of p27kip1 expression is of great significance, not only in providing insight into the understanding of biological p27kip1, but also in the development of new cancer therapeutic tactics. We here explored the inhibitory regulation of IKKβ on p27 expression following arsenite exposure. We found that although the basal level of p27 expression in the IKKβ−/− cells is much lower than that in the IKKβ+/+ cells, the deletion of IKKβ in the MEFs led to a marked increase in p27kip1 protein induction due to arsenite exposure in comparison to that in the IKKβ+/+ cells. The IKKβ regulatory effect on p27 expression was also verified in the IKKβ−/− and IKKβ−/− cells with IKKβ reconstitutional expression, IKKβ−/−(IKKβ). Further studies indicated that IKKβ-mediated p27 downregulation occurred at protein degradation level via p65-dependent and p50-independent manner. Moreover, the results obtained from the comparison of arsenite-induced GSK3β activation among transfectants of WT, IKKβ−/− and IKKβ−/−(IKKβ), and the utilization of GSKβ shRNA, demonstrated that IKKβ regulation of p27 protein degradation was mediated by GSK3β following arsenite exposure.
PMCID: PMC4076889  PMID: 24751519
Arsenite; p27kip1 protein degradation; IKKβ; GSK; NFκB
17.  Effects of angiotensin II type 1 receptor antagonist on rats with septic shock 
Aims: To investigate the effects of angiotensin II type 1 receptor (AT1R) antagonist, losartan, on rats with septic shock induced by endotoxin. Methods: Thirty male SD rats were randomly divided into 3 groups (10 for each group): rats were injected with normal saline in C group, lipopolysaccharide (LPS) of 12 mg kg-1 intravenously in LPS group, and losartan of 50 mg kg-1 intraperitoneally followed by LPS of 12 mg kg-1 intravenously in LOS group. The plasma concentrations of nitric oxide (NO), malondialdehyde (MDA), IL-1β and TNF-α were measured 6 h after LPS administration. Then all the rats were sacrificed immediately before the aortas pectoralis were isolated. Inhibitor of NF-κB (IκB) mRNA and its mRNA expressions in aorta were detected. Results: The plasma concentrations of NO, MDA, IL-1β and TNF-α were all significantly elevated in LPS group compared with the control group (P<0.01), which were markedly reduced in LOS group (P<0.01). Both of the mRNA and protein expressions of IκB in aorta were downregulated after injection of LPS when compared with the control group (P<0.01). However, IκB mRNA and protein expressions in aorta in the LOS group were significantly higher than the LPS group (P<0.01). Conclusion: AT1R antagonist, losartan, has a reverse effect at least partly on circulation dysfunction in rats with septic shock induced by endotoxin.
PMCID: PMC4509287  PMID: 26221342
Angiotensin II type 1 receptor; septic shock; losartan
18.  Prognostic role of neutrophil-lymphocyte ratio in operable esophageal squamous cell carcinoma 
AIM: To determine the prognostic significance of preoperative serum neutrophil-lymphocyte ratio (NLR) in esophageal squamous cell carcinoma (ESCC).
METHODS: Data from 371 eligible patients with ESCC who had undergone surgery with curative intent at our institution between October 2000 and May 2007 were retrospectively recruited for analysis. The cutoff value of NLR was 3.0 as determined by the receiver operating characteristic curve, which discriminated between survival and death; the area under the curve was 0.709, and the sensitivity and specificity were 66.1% and 69.1%, respectively, at the cutoff point. The correlation between the NLR and clinicopathological characteristics was analyzed using a χ2 test. The prognostic influence of the NLR and other clinicopathological factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) was studied using the Kaplan-Meier method. To evaluate the independent prognostic value of NLR, multivariate Cox regression models were applied.
RESULTS: The median age of the patients was 57.0 years, and 276/371 (74.4%) patients were male. The NLR was ≤ 3.0 in 80.1% (297/371) of the patients, and the remaining 19.9% (74/371) had an NLR > 3.0. Median postoperative follow-up was 66.0 mo [interquartile range (IQR): 49.0-76.0 mo], with a follow-up rate of 94%. Follow-up was not significantly different between patients with an NLR ≤ and > 3.0 (63.13 ± 1.64 vs 61.52 ± 3.66, P = 0.711). However, higher preoperative serum NLR was associated with significantly increased risks of higher pathological tumor status (P = 0.007). A significant, independent association between high preoperative serum NLR and poor clinical outcome was identified in a multivariate analysis for CSS (HR = 1.591; P = 0.007) and RFS (HR = 1.525; P = 0.013). Moreover, when patients were stratified by pathological tumor-node-metastasis (TNM) staging, the adverse effects of preoperative serum NLR on CSS (HR = 2.294; P = 0.008) and RFS (HR = 2.273; P = 0.008) were greatest in those patients with stage IIIA disease.
CONCLUSION: Preoperative serum NLR is a useful prognostic marker to complement TNM staging for operable ESCC patients, particularly in patients with stage IIIA disease.
PMCID: PMC4427683  PMID: 25987784
Esophageal squamous cell carcinoma; Neutrophil-lymphocyte ratio; Prognosis; Radical esophagectomy
19.  The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential 
Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.
PMCID: PMC4442295  PMID: 26078822
20.  Intestinal Alkaline Phosphatase Inhibits the Translocation of Bacteria of Gut-Origin in Mice with Peritonitis: Mechanism of Action 
PLoS ONE  2015;10(5):e0124835.
Exogenous intestinal alkaline phosphatase (IAP), an enzyme produced endogenously at the brush edge of the intestinal mucosa, may mitigate the increase in aberrant intestinal permeability increased during sepsis. The aim of this study was to test the efficacy of the inhibitory effect of IAP on acute intestinal inflammation and to study the molecular mechanisms underlying IAP in ameliorating intestinal permeability. We used an in vivo imaging method to evaluate disease status and the curative effect of IAP. Two Escherichia coli (E.coli) B21 strains, carrying EGFP labeled enhanced green fluorescent protein (EGFP) and RFP labeled red fluorescent protein (RFP), were constructed as tracer bacteria and were administered orally to C57/B6N mice to generate an injection peritonitis (IP) model. The IP model was established by injecting inflammatory lavage fluid. C57/B6N mice bearing the tracer bacteria were subsequently treated with (IP+IAP group), or without IAP (IP group). IAP was administered to the mice via tail vein injections. The amount of tracer bacteria in the blood, liver, and lungs at 24 h post-injection was analyzed via flow cytometry (FCM), in vivo imaging, and Western blotting. Intestinal barrier function was measured using a flux assay with the macro-molecule fluorescein isothiocyanate dextran, molecular weight 40kD, (FD40). To elucidate the molecular mechanism underlying the effects of IAP, we examined the levels of ERK phosphorylation, and the expression levels of proteins in the ERK-SP1-VEGF and ERK-Cdx-2-Claudin-2 pathways. We observed that IAP inhibited the expression of Claudin-2, a type of cation channel-forming protein, and VEGF, a cytokine that may increase intestinal permeability by reducing the levels of dephosphorylated ERK. In conclusion, exogenous IAP shows a therapeutic effect in an injection peritonitis model. This including inhibition of bacterial translocation. Moreover, we have established an imaging methodology for live-animals can effectively evaluate intestinal permeability and aberrant bacterial translocation in IP models.
PMCID: PMC4422672  PMID: 25946026
21.  Clinical Analysis of 152 Cases of Multiple Primary Malignant Tumors in 15,398 Patients with Malignant Tumors 
PLoS ONE  2015;10(5):e0125754.
In this study, the etiology, clinical characteristics, and prognosis of multiple primary malignant tumors (MPMTs) were investigated. Furthermore, we analyzed the treatment factors associated with MPMTs.
From 15,398 patients with malignant tumors presenting to The First Hospital of Jilin University, China, between January 2010 and December 2013, we identified and analyzed patients with MPMTs. Data were obtained retrospectively from the hospital database.
The prevalence of MPMTs in this study was 0.99% (152/15398): 51 cases were synchronous MPMTs, and 101 cases were metachronous MPMTs. The mean time between the first and second primary cancer was 43.1 months. In this population, MPMTs were observed more frequently in patients with head and neck tumors (5.65%) and urinary tumors (4.19%); the prevalence of MPMTs in these patients was over 4-fold greater than the prevalence of MPMTs in all patients (0.99%). There were no cases of MPMTs in 132 cases of nervous system tumors and 404 cases of multiple myeloma. Nearly 50% (45.4%) of patients with MPMTs did not receive chemotherapy or radiotherapy before the second primary cancer was diagnosed. Eighty-five patients with MPMTs were followed for more than 2 years, and the 2-year cumulative survival rate was 40.8%.
In this study, the prevalence of MPMTs was 0.99% (152/15398), which is consistent with the Chinese literature. Patients with head and neck tumors or urinary tumors are at greater risk of developing MPMTs. In addition to radiotherapy or chemotherapy, this study suggests that other factors may contribute to MPMTs.
PMCID: PMC4422700  PMID: 25945938
22.  Prevalence and characterization of hepatitis B and C virus infections in a needle-sharing population in Northern China 
BMC Public Health  2015;15:460.
The epidemiologies of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in specific populations in certain areas of China are poorly understood. A pilot survey of HCV/HBV infections was carried out in villages in Kuancheng County, Heben Province, where injection of sodium benzoate or amphetamines using shared needles has been a common practice. The aims of this study were to analyze the endemicity and characterize HCV/HBV infections in this population.
Data on demographic characteristics and drug abuse were collected from individuals who signed informed consent forms. Serum HCV antibody (anti-HCV), hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (anti-HBc) were measured in all participants. HCV RNA was measured in samples positive for anti-HCV using real-time polymerase chain reaction.
Among 852 participants from 11 villages, 49.9% had used sodium benzoate or amphetamine at least once, by intravenous injection. The overall prevalence of anti-HCV, HCV RNA, anti-HBc, HBsAg, and HCV/HBV co-infection was 37.1%, 26.6%, 67.7%, 10.7%, and 30.0%, respectively. Two-hundred-twenty-three of 227 (98.2%) participants positive for HCV RNA were aged >40 years. Co-infection was related to sex, age, number of injections, and time from first injection. The rate of spontaneous HCV RNA clearance was 28.2% (89/316), and was related to the number of injections, time from first injection, and HBsAg positivity. However, HBsAg was related to the anti-HBc signal/cut-off ratio rather than to the above parameters. Trend tests demonstrated that the prevalence of anti-HCV, HCV RNA, and anti-HBc was related to the number of injections (P < 0.001), while HBsAg prevalence was not (P = 0.347).
The prevalence of HCV and HBV infection is likely to be high among individuals older than 40 years in areas of needle sharing, and one-time screening for HCV infection should be offered to these populations.
PMCID: PMC4419395  PMID: 25933922
Prevalence; Hepatitis C virus; Hepatitis B virus; Hepatitis; Intravenous drug user
23.  Ku80 cooperates with CBP to promote COX-2 expression and tumor growth 
Oncotarget  2015;6(10):8046-8061.
Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer.
PMCID: PMC4480734  PMID: 25797267
Ku80; CBP; COX-2; lung cancer
24.  mRNA and microRNA expression profiles of radioresistant NCI-H520 non-small cell lung cancer cells 
Molecular Medicine Reports  2015;12(2):1857-1867.
To elucidate the mechanism of radioresistance in non-small cell lung cancer (NSCLC) cells and to identify key molecules conferring radioresistance, the radioresistant subclone NCI-H520/R, derived from the NCI-H520 NSCLC cell line, was established with eight rounds of sublethal irradiation. The radioresistant features were subsequently assessed using a clonogenic assay, analysis of apoptosis and an MTT assay, the gene expression levels were examined using an Agilent Whole Human Genome 4×44 k Oligo microarray and Agilent Human miRCURY™ LNA array, and confirmed by reverse transcription-quantitative polymerase chain reaction. Pathway analysis and Gene Ontology (GO) analysis were performed to determine the biological functions of the subset of differentially expressed genes. miRNA-mRNA correlation analysis between the expression levels of each miRNA and all its predicted target genes was performed to further understand the radioresistance in the NCI-H520 cells. Following eight rounds of sublethal irradiation, a total of 2,862 mRNAs were significantly differentially expressed in the NCI-H520/R cells, including 893 upregulated genes and 1,969 downregulated genes. A total of 162 upregulated miRNAs and 274 downregulated miRNAs were significantly deregulated in the NCI-H520/R cells. Multiple core regulatory processes and signaling pathways were identified as being of likely relevance to radioresistance in NCI-H520/R cells, including the mitogen-activated protein kinase signaling pathway and neurotrophin signaling pathway. The expression of genes associated with radioresistance reflects the complex biological processes involved in clinical cancer cell eradication and requires further investigation for future enhancement of therapy.
PMCID: PMC4464398  PMID: 25873351
microarray; radioresistance; mitogen-activated protein kinase; neurotrophin
25.  Mesenchymal Chondrosarcoma of Bone and Soft Tissue: A Systematic Review of 107 Patients in the Past 20 Years 
PLoS ONE  2015;10(4):e0122216.
Mesenchymal chondrosarcoma(MCS) is a rare high-grade variant of chondrosarcoma. Consensus has not been reached on its optimal management. Resection with wide margins is usually recommended, but the effect of margins has been demonstrated by little positive evidence. Moreover, the effectiveness of adjuvant chemo- and/or radiotherapy remains controversial.
To describe the clinical characteristics and outcomes of MCS of bone and soft tissue, to assess the efficacies of surgery, chemotherapy and radiation, and finally to deliver a more appropriate therapy.
Materials and Methods
We reviewed EMBASE-, MEDLINE-, Cochrane-, Ovid- and PubMed-based to find out all cases of MCS of bone and soft tissue described between April 1994 and April 2014. Description of treatment and regular follow-up was required for each study. Language was restricted to English and Chinese. Issues of age, gender, location, metastasis, and treatment were all evaluated for each case. Kaplan-Meier Method and Cox Proportional Hazard Regression Model were used in the survival analysis.
From the 630 identified publications, 18 meeting the inclusion criteria were selected, involving a total of 107 patients. Based on these data, the 5-, 10-and 20-year overall survival are 55.0%, 43.5% and 15.7% respectively. The 5-, 10-, 20- year event-free survival rates are 45.0%, 27.2% and 8.1%, respectively. Treatment without surgery is associated with poorer overall survival and event-free survival. Negative surgical margins could significantly bring down the local-recurrence rate and are associated with a higher event-free survival rate. Chemotherapy regime based on anthracyclines does not benefit the overall survival. The addition of radiation therapy is not significantly associated with the overall or event-free survival. However, we recommend radiation as the salvage therapy for patients with positive margin so as to achieve better local control.
This review shows that surgery is essential in the management of MCS of bone and soft tissue. Appropriate adjuvant therapy may reduce local recurrence, but cannot benefit the overall survival.
PMCID: PMC4388572  PMID: 25849226

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