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1.  Periconceptional folic acid supplementation and the risk of preterm births in China: a large prospective cohort study 
Background: Folic acid-containing multivitamins have been associated with a reduced risk of preterm birth. We examined whether periconceptional use of folic acid alone reduced this risk.
Methods: Data were derived from a large population-based cohort study conducted in China to evaluate the prevention of neural tube defects with folic acid supplementation. The sample comprised 207 936 singleton live births delivered at gestational ages of 20–42 weeks to women from two provinces in southern China. Healthcare workers recorded folic acid intake prospectively each month. Gestational age calculation was based on the first day of the last menstrual period. Preterm births were categorized into three clinical subtypes: iatrogenic preterm birth, preterm premature rupture of membranes (PPROM) and spontaneous preterm birth. Logistic regression was used to evaluate the association between folic acid use and the risk of preterm birth, adjusting for potential confounders.
Results: The incidence of preterm birth was significantly lower among folic acid users (5.28%) than among non-users (6.10%). Folic acid use showed a 14% risk reduction for preterm birth overall [adjusted risk ratio (RR) = 0.86, 95% confidence interval (CI) 0.82–0.90]. This association was strongest for spontaneous preterm birth (adjusted RR = 0.81, 95% CI 0.78–0.86) and was not significant for iatrogenic preterm birth (adjusted RR = 0.97, 95% CI 0.88–1.07) or PPROM (adjusted RR = 1.07, 95% CI 0.93–1.23).
Conclusions: Daily intake of 400 μg folic acid alone during the periconceptional period was associated with a reduced risk of spontaneous preterm birth.
PMCID: PMC4258769  PMID: 24603317
Folic acid; periconceptional supplementation; spontaneous preterm birth; preterm premature rupture of membranes; iatrogenic preterm birth; cohort study
2.  Clinicopathological significance of matrix metalloproteinase-7 protein expression in esophageal cancer: a meta-analysis 
The MMP-7 basement membrane and extracellular matrix may be essential for tumor invasion and metastasis, and the results presented herein showed a relationship between MMP-7 expression and esophageal cancer (EC). However, its clinicopathological value for EC patients remains inconsistent. To clarify their associations, a meta-analysis of the relevant published literature was conducted.
Materials and methods
Databases including PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, and Google Scholar were electronically searched. Only those studies analyzing MMP-7 expression in EC patients with regard to series of different demographic variables and clinicopathological stages (TNM stage, differentiation and invasion grade, and lymph-node [LN] metastasis) were eligible for inclusion. Summary odds ratios (ORs) were pooled in accordance with the random-effect model.
Fourteen clinical cohort studies (tumor samples =935) were incorporated into the current meta-analysis. Results revealed that increased MMP-7 expression in EC patients was positively correlated to TNM stage III–IV (OR 3.04, 95% confidence interval [CI] 1.43–6.46; P=0.004). Similar connections were also detected in the differentiation grade, invasion grade, and LN metastasis (all P<0.05). Country-stratified analysis yielded significant association of elevated MMP-7 expression with EC in the People’s Republic of China (PRC) under both TNM III–IV versus I–II and differentiation low versus high comparisons (TNM stage, OR 2.01, 95% CI 1.55–2.59, P<0.001; differentiation grade, OR 1.32, 95% CI 1.11–1.57, P=0.002). With regard to invasion grade and LN metastasis, significant association was observed in all the experimental subgroups (all P-values [PRC and Japan] were lower than 0.05).
These data showed an obvious connection between MMP-7 and TNM stages, differentiation grade, invasive grade, and LN metastasis of EC, indicating that overexpression of MMP-7 may be a suitable diagnostic biomarker for variation in EC clinicopathological features.
PMCID: PMC4516179
MMP-7; esophagus carcinoma; statistical analysis
3.  Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach 
Bioinformatics  2014;30(13):1899-1907.
Motivation: p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.
Method: To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography–mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph.
Results: New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection.
Availability and implementation: RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at
Contact: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4071201  PMID: 24618474
4.  Mutation breeding of high 4-androstene-3,17-dione-producing Mycobacterium neoaurum ZADF-4 by atmospheric and room temperature plasma treatment*  
Steroid medication is used extensively in clinical applications and comprises a large and vital part of the pharmaceutical industry. However, the difficulty of separating 4-androstene-3,17-dione (AD) from 1,4-androstadiene-3,17-dione (ADD) restricts the application of the microbial transformation of phytosterols in the industry. A novel atmospheric and room temperature plasma (ARTP) treatment, which employs helium as the working gas, was used to generate Mycobacterium neoaurum mutants producing large amounts of AD. After treatment of cultures with ARTP, four mutants were selected using a novel screening method with a color assay. Among the mutants, M. neoaurum ZADF-4 was considered the best candidate for industrial application. When the fermentation medium contained 15 g/L phytosterols and was cultivated on a rotary shaker at 160 r/min at 30 °C for 7 d, (6.28±0.11) g/L of AD and (0.82±0.05) g/L of ADD were produced by the ZADF-4 mutant, compared with (4.83±0.13) g/L of AD and (2.34±0.06) g/L of ADD by the original strain, M. neoaurum ZAD. Compared with ZAD, the molar yield of AD increased from 48.3% to 60.3% in the ZADF-4 mutant. This result indicates that ZADF-4 may have potential for industrial production of AD.
PMCID: PMC4399429  PMID: 25845362
Mycobacterium neoaurum; Atmospheric and room temperature plasma (ARTP); Mutation breeding; 4-Androstene-3,17-dione (AD); 1,4-Androstadiene-3,17-dione (ADD)
5.  ZNF32 inhibits autophagy through the mTOR pathway and protects MCF-7 cells from stimulus-induced cell death 
Scientific Reports  2015;5:9288.
ZNF32 is a recently identified zinc finger protein and its functions remain largely unknown. Autophagy has been shown to affect cell proliferation and survival. Here, we innovatively show the effect of ZNF32 on cell autophagy and autophagy-associated cell death in breast carcinoma cells and also elucidate its underlying mechanisms. We examined the autophagic activity and LC3 II expression in human carcinoma cell lines with increased or decreased ZNF32 expression. Pharmacological inhibition (rapamycin) or activation (EGF) assays were used to investigate the function of the AKT/mTOR pathway during this process. H2O2- and diamide-induced MCF-7 cell death models were used to elucidate the role of ZNF32-associated autophagy in breast carcinoma cell death. Our results show that increasing ZNF32 expression in MCF-7 cells inhibits autophagy initiation by activating the AKT/mTOR pathway, and further reduced autophagy-associated cell death and maintained MCF-7 cell survival. Conversely, impairing ZNF32 expression by transfecting ZNF32 siRNA strongly promoted autophagy, further augmenting autophagy-associated cell death. Furthermore, correlations between ZNF32 and autophagy were observed in both MCF-7 xenograft tumors and in breast cancer patients. In conclusion, ZNF32 acts as an effective autophagy inhibitor to protect breast cancer cells from excessive stimulus-autophagy-induced cell death.
PMCID: PMC4365391  PMID: 25786368
6.  Overexpression of DNA methyltransferase 1 as a negative independent prognostic factor in primary gastrointestinal diffuse large B-cell lymphoma treated with CHOP-like regimen and rituximab 
Oncology Letters  2015;9(5):2307-2312.
The aims of the present study were to elucidate the transcript levels of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b by quantitative polymerase chain reaction in patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL), and determine the association of their expression with the clinical parameters and prognostic values of the disease. The results revealed that the expression of DNMT1 in patients with PGI-DLBCL was significantly higher than that in healthy controls (P=0.04), while the expression of DNMT3a and DNMT3b were significantly lower (P<0.001 and P=0.001, respectively). The increased expression of DNMT1 was significantly correlated with shorter overall survival and progression-free survival rates (P=0.018 and P=0.008, respectively). The multivariate analysis demonstrated that the level of DNMT1 was an independent prognostic factor. In conclusion, DNMT1 was identified to be an independent prognostic factor for predicting the survival of patients with PGI-DLBCL; this suggests that it could be used as a marker to indicate the prognosis of PGI-DLBCL.
PMCID: PMC4467357  PMID: 26137062
gastrointestinal lymphoma; DNA methyltransferase 1; diffuse large B-cell lymphoma; prognosis
7.  Effects of anesthesia on conventional and speckle tracking echocardiographic parameters in a mouse model of pressure overload 
Genetically-modified mice are widely applied in cardiovascular studies as model organisms. Echocardiography is a key tool for evaluating cardiac and hemodynamic functions in mice. The present study aimed to examine the effects of isoflurane (ISF) on conventional and speckle tracking echocardiography (STE) parameters under healthy and pathological conditions using a murine model of pressure overload. In addition, the optimal dose of ISF in the process of echocardiographic measurement, with minimum cardiac contraction depression, was investigated. Conventional echocardiographic and STE examinations were performed on 38 adult C57BL/6 male mice. The mice were divided into the following three groups: The sham (n=15); mild thoracic aortic banding (TAB; n=15); and severe TAB (n=8) groups. ISF was administered under deep anesthesia (DA; 1–2% ISF), light anesthesia (LA; 0.5–1% ISF) and immediately prior to the mice waking up (awake; 0–0.5% ISF). Conventional echocardiographic parameters were preserved within the sham and mild TAB groups (P>0.05 for each parameter) under LA and awake conditions. However, under DA conditions, the majority of these parameters were reduced compared with the LA and awake conditions (P<0.05). In the severe TAB group, conventional echocardiographic parameters remained constant under LA, DA and awake conditions. STE parameters in the groups remained similar between the LA and awake conditions, but were significantly reduced under DA conditions. Therefore, conventional echocardiography and STE may be performed using LA induced with low doses of ISF, under various pathological conditions without affecting cardiac function.
PMCID: PMC4471799  PMID: 26136877
mouse; heart failure; hypertrophy; echocardiography; left ventricular function
8.  Coexpression of MYC and BCL-2 predicts prognosis in primary gastrointestinal diffuse large B-cell lymphoma 
AIM: To investigate whether MYC and BCL-2 coexpression has prognostic significance in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients, and explore its associations with patients’ clinical parameters.
METHODS: Fresh and paraffin-embedded tumor tissue samples from 60 PGI-DLBCL patients who had undergone surgery at the Tianjin Medical University Cancer Institute and Hospital from January 2005 to May 2010 were obtained, and 30 lymphoid tissue samples from reactive lymph nodes of age- and sex-matched patients represented control samples. Staging and diagnostic procedures were conducted according to the Lugano staging system. All patients had been treated with three therapeutic modalities: surgery, chemotherapy, or radiotherapy. Expression of MYC and BCL-2 were detected at both protein and mRNA levels by immunohistochemistry and real-time RT-PCR.
RESULTS: Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein levels were correlated with high MYC and BCL-2 mRNA expression, respectively (both P < 0.05). We found that advanced-stage disease (at IIE-IV) was associated with MYC and BCL-2 coexpression levels (P < 0.05). In addition, MYC+/BCL-2+ patients had more difficulty in achieving complete remission than others (P < 0.05). Presence of MYC protein expression only affected overall survival and progression-free survival (PFS) when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (P < 0.05) even after adjusting for age, Lugano stage, international prognostic index, and BCL-2 protein expression in a multivariable model.
CONCLUSION: MYC+/BCL-2+ patients have worse chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting clinical outcomes of PGI-DLBCL patients.
PMCID: PMC4342921  PMID: 25741152
MYC; BCL-2; Survival; Primary gastrointestinal diffuse large B-cell lymphoma; Prognosis
9.  Role of tissue transglutaminase in the pathogenesis of diabetic cardiomyopathy and the intervention effect of rutin 
The aim of this study was to investigate the role of tissue transglutaminase (tTG) in the pathogenesis of diabetic cardiomyopathy (DCM) and the intervention effect of rutin. DCM was induced in rats by the injection of streptozotocin (STZ; 25 mg/kg). After a preliminary examination, the rats were randomly divided into four groups: Control (n=8), STZ-induced DCM (n=8), STZ + positive drug (captopril; n=6) and STZ + rutin (n=8) groups. The DCM model was evaluated using blood sugar values, serum enzyme levels, hematoxylin and eosin staining and Masson’s staining, ex vivo. The protein and mRNA expression of tTG was assessed with immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The rat model of DCM was successfully established by STZ administration, and the expression levels of tTG were significantly increased in the DCM model. Following the injection of captopril or rutin, the blood sugar values, collagen content and expression levels of tTG were gradually reduced and serum enzyme levels were increased, as compared with those in the STZ-induced DCM group. In conclusion, tTG plays an important role in STZ-induced DCM. In addition, rutin may inhibit the expression of tTG and regulate myocardial injury in STZ-induced DCM.
PMCID: PMC4353750  PMID: 25780394
diabetic; diabetic cardiomyopathy; tissue transglutaminase; rutin
10.  Correlation of CCNA1 Promoter Methylation with Malignant Tumors: A Meta-Analysis Introduction 
BioMed Research International  2015;2015:134027.
Epigenetic silencing of tumor suppressor genes by promoter methylation plays vital roles in the process of carcinogenesis. The purpose of this meta-analysis was to determine whether the aberrant methylation of cyclin A1 (CCNA1) may be of great significance to human malignant tumors. By searching both English and Chinese language-based electronic databases carefully, we tabulated and analyzed parameters from each study. All human-associated case-control studies were included providing available data for CCNA1 methylation and reporting the adjusted odds ratios (ORs) and 95% confidence intervals (CI) conducted with the use of Version 12.0 STATA software. A total of 10 case-control studies (619 patients with cancers and 292 healthy controls) were included for the following statistical analysis. Pooled OR values from all articles revealed that the frequency of CCNA1 methylation in cancer tissues was significantly higher than those of normal tissues (P < 0.001). Further ethnicity indicated that the frequency of CCNA1 methylation was correlated with the development of malignant tumors among all those included experimental subgroups (all P < 0.05). These data from results indicated a significant connection of CCNA1 methylation with poor progression in human malignant tumors among both Caucasian and Asian populations.
PMCID: PMC4310450  PMID: 25654082
11.  Gemcitabine sensitivity factors, hENT1 and RRM1 as potential prognostic biomarker for advanced biliary tract cancer 
Background and aims: Biliary tract caner (BTC) is one of rare malignant disease with poor prognosis. Gemcitabine has been widely used as chemotherapeutic agent for advanced BTC treatment. Several molecules involved in gemcitabine metabolism, including human equilibrative nucleoside transporter (hENT1) and ribonucleotide reductase subunit M1 (RRM1), have been investigated as predictive biomarkers of chemotherapy efficacy. The aim of present study is to determine whether hENT1 and RRM1 could be used as the biomarkers to assess the efficacy of chemotherapy and predict survival in patients with advanced BTC. Methods: The analysis was performed on samples from 44 patients with unresectable or recurrent BTC who were treated with gemcitabine as first-line therapy. We determined levels of hENT1 and RRM1 with immunohistochemistry (IHC). Also, its prognostic and predictive role on tumor response and several clinical factors for survival were evaluated with Kaplan-Meier or Cox analysis. Results: The patients who were clinical benefit (partial response [PR] or stable disease [SD]) had high level of hENT1 (P = 0.046) and low level of RRM1 (P = 0.033). Moreover, hENT1 expression was a significant factor for progression free survival (PFS) (P = 0.005) and overall survival (OS) (P = 0.048) in Cox univariate analysis. Also, hENT1 was an independent prognostic factor of OS based on Cox multivariate analysis (P = 0.005). Conclusions: The expression of hENT1 and RRM1 was associated with gemcitabine efficacy. hENT1 was one of reliable predictive marker of survival in patients with advanced BTC patients.
PMCID: PMC4307450  PMID: 25664003
Biliary tract cancer; gemcitabine; human equilibrative nucleoside transporter 1; ribonucleotide reductase subunit M1
12.  Modeling the Dynamics and Migratory Pathways of Virus-Specific Antibody-Secreting Cell Populations in Primary Influenza Infection 
PLoS ONE  2014;9(8):e104781.
The B cell response to influenza infection of the respiratory tract contributes to viral clearance and establishes profound resistance to reinfection by related viruses. Numerous studies have measured virus-specific antibody-secreting cell (ASC) frequencies in different anatomical compartments after influenza infection and provided a general picture of the kinetics of ASC formation and dispersion. However, the dynamics of ASC populations are difficult to determine experimentally and have received little attention. Here, we applied mathematical modeling to investigate the dynamics of ASC growth, death, and migration over the 2-week period following primary influenza infection in mice. Experimental data for model fitting came from high frequency measurements of virus-specific IgM, IgG, and IgA ASCs in the mediastinal lymph node (MLN), spleen, and lung. Model construction was based on a set of assumptions about ASC gain and loss from the sampled sites, and also on the directionality of ASC trafficking pathways. Most notably, modeling results suggest that differences in ASC fate and trafficking patterns reflect the site of formation and the expressed antibody class. Essentially all early IgA ASCs in the MLN migrated to spleen or lung, whereas cell death was likely the major reason for IgM and IgG ASC loss from the MLN. In contrast, the spleen contributed most of the IgM and IgG ASCs that migrated to the lung, but essentially none of the IgA ASCs. This finding points to a critical role for regional lymph nodes such as the MLN in the rapid generation of IgA ASCs that seed the lung. Results for the MLN also suggest that ASC death is a significant early feature of the B cell response. Overall, our analysis is consistent with accepted concepts in many regards, but it also indicates novel features of the B cell response to influenza that warrant further investigation.
PMCID: PMC4149352  PMID: 25171166
13.  Down-regulation of miR-34a alleviates mesangial proliferation in vitro and glomerular hypertrophy in early diabetic nephropathy mice by targeting GAS1 
Diabetic nephropathy (DN) is a major diabetic complication characterized by mesangial proliferation and glomerular hypertrophy. MicroRNAs might play an important role in these pathological processes. The aim of this study is to examine the possible association of miR-34a as one of the microRNAs with DN and underlying mechanisms in vitro and in vivo.
According to previous results of microarray which compared the different microRNAs between diabetic and normal control mice, miR-34a was chosen and its expression was detected by qRT-PCR. Cell viability was then assessed using Cell Counting Kit-8 (CCK8) and 5-ethynyl-20-deoxyuridine (EDU) incorporation. Antagomir was injected in db/db mice to down regulate miR-34a. Average diameter of glomeruli was analyzed by periodic acid-Schiff (PAS) stain of kidney. Luciferase gene report assay was then performed to identify the target gene of miR-34a. Additional immunoblotting and immunohistochemical analyses were implemented to verify the expression level of growth arrest-specific 1 (GAS1).
MiR-34a expression level was increased under high glucose condition in vitro and in vivo. Down-regulation of miR-34a inhibits mice mesangial cells (MMCs) proliferation in vitro and alleviates glomerular hypertrophy in vivo. GAS1 was proved to be the target of miR-34a through luciferase report. Moreover, up-regulation of GAS1 expression was observed in the presence of miR-34a antagomir as compared withmiR-34a antagomir-NC in high-glucose-treated MMCs and db/db mice, respectively.
MiR-34a regulated mesangial proliferation and glomerular hypertrophy by directly inhibiting GAS1 in early DN.
PMCID: PMC4087162  PMID: 24560136
Diabetic nephropathy; Glomerular hypertrophy; miR-34a; GAS1
14.  Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury 
Molecular Pain  2014;10:33.
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.
PMCID: PMC4060852  PMID: 24890933
15.  Levels of PAH-DNA Adducts in Placental Tissue and the Risk of Fetal Neural Tube Defects in a Chinese Population 
We examined the relationship between PAH-DNA adduct levels in the placental tissue, measured by a highly sensitive 32P-postlabeling assay, and the risk of fetal neural tube defects (NTDs). We further explored the interaction between PAH-DNA adducts and placental PAHs with respect to NTD risk. Placental tissues from 80 NTD-affected pregnancies and 50 uncomplicated normal pregnancies were included in this case-control study. Levels of PAH-DNA adducts were lower in the NTD group (8.12 per 108 nucleotides) compared to controls (9.92 per 108 nucleotides). PAH-DNA adduct concentrations below the median was associated with a 3-fold increased NTD risk. Women with a low PAH-DNA adduct level in concert with a high placental PAH level resulted in a 10-fold elevated risk of having an NTD-complicated pregnancy. A low level of placental PAH-DNA adducts was associated with an increased risk of NTDs; this risk increased dramatically when a low adduct level was coupled with a high placental PAH concentration.
PMCID: PMC4040017  PMID: 23416326
Polycyclic aromatic hydrocarbons (PAHs); DNA adducts; Neural tube defects (NTDs); Placenta; Fetus
16.  Obesity Increases Cerebrocortical Reactive Oxygen Species And Impairs Brain Function 
Nearly two-thirds of the population in the United States is overweight or obese, and this unprecedented level of obesity will undoubtedly have a profound impact on overall health, although little is currently known about the effects of obesity on the brain. The objective of the current study was to investigate cerebral oxidative stress and cognitive decline in the context of diet-induced obesity (DIO). We demonstrate for the first time that DIO induces higher levels of reactive oxygen species (ROS) in the brain, and promotes cognitive impairment. Importantly, we also demonstrate for the first time in these studies that both body weight and adiposity are tightly correlated with the level of ROS. Interestingly, ROS were not correlated with cognitive decline in this model. Alterations in the antioxidant/detoxification Nrf2 pathway, superoxide dismutase, and catalase were not significantly altered in response to DIO. A significant impairment in glutathione peroxidase was observed in response to DIO. Taken together, these data demonstrate for the first time that DIO increases the level of total and individual ROS in the brain, and highlight a direct relationship between the amount of adiposity and the level of oxidative stress within the brain. These data have important implications for understanding the negative effects of obesity on the brain, and are vital to understanding the role of oxidative stress in mediating the effects of obesity on the brain.
PMCID: PMC4038352  PMID: 23116605
adipose; brain; cognitive impairment; free radicals; neurodegeneration; oxidative stress
17.  Role of Physiological Levels of 4-Hydroxynonenal on Adipocyte Biology: Implications for Obesity and Metabolic Syndrome 
Free radical research  2012;47(1):8-19.
Lipid peroxidation products such as 4-hydroxynonenal (HNE) are known to be increased in response to oxidative stress, and are known to cause dysfunction and pathology in a variety of tissues during periods of oxidative stress. The aim of the current study was to determine the chronic (repeated HNE exposure) and acute effects of physiological concentrations of HNE towards multiple aspects of adipocyte biology using differentiated 3T3-L1 adipocytes. Our studies demonstrate that acute and repeated exposure of adipocytes with physiological low concentrations of HNE is sufficient to promote subsequent oxidative stress, impaired adipogenesis, alter the expression of adipokines, and increase lipolytic gene expression and increase FFA release. These results provide an insight in to the role of HNE induced oxidative stress in regulation of adipocyte differentiation and adipose dysfunction. Taken together, these data indicate a potential role for HNE promoting diverse effects towards adipocyte homeostasis and adipocyte differentiation, which may be important to the pathogenesis observed in obesity and metabolic syndrome.
PMCID: PMC4038367  PMID: 23025469
adipose; adipogenesis; Insulin resistance; diabetes; metabolic syndrome; obesity; oxidative stress
18.  AIM2 Mediates Inflammation-Associated Renal Damage in Hepatitis B Virus-Associated Glomerulonephritis by Regulating Caspase-1, IL-1β, and IL-18 
Mediators of Inflammation  2014;2014:190860.
Background & Aims. AIM2 plays an important role in innate immunity, but its role in regulating the immune response to hepatitis B virus (HBV) is unknown. We hypothesized that AIM2 expression is positively correlated with HBV-mediated inflammation in patients with HBV-associated glomerulonephritis (HBV-GN), potentiating inflammation and leading to renal damage. We therefore analyzed the expression of AIM2 and inflammatory factors in HBV-GN tissues and cell lines relative to the inflammatory response to HBV infection and HBV status. Methods. Seventy-nine patients with chronic nephritis (CN) were included: 54 with HBV-GN and 24 with chronic glomerulonephritis (CGN). Expression of AIM2, caspase-1, and IL-1β was detected by immunohistochemistry in renal biopsies from each patient. Following siRNA-mediated knockdown of AIM2 in HBV-infected and HBV-uninfected human glomerular mesangial (HGM) cells, expression of caspase-1, IL-1β, and IL-18 was detected by qRT-PCR and Western blot. Results. AIM2 expression in HBV-GN biopsies (81.4%) was significantly higher than in CGN (4.0%) and positively correlated with caspase-1 and IL-1β expression in HBV-GN. In vitro, AIM2 knockdown reduced caspase-1, IL-1β, and IL-18 expression in HBV-infected and HBV-uninfected HGM cells. Conclusion. AIM2 elevation during HBV infection or replication may contribute to inflammatory damage, thus providing a putative therapeutic target for HBV-GN.
PMCID: PMC3950499  PMID: 24701032
19.  A PSO-Based Hybrid Metaheuristic for Permutation Flowshop Scheduling Problems 
The Scientific World Journal  2014;2014:902950.
This paper investigates the permutation flowshop scheduling problem (PFSP) with the objectives of minimizing the makespan and the total flowtime and proposes a hybrid metaheuristic based on the particle swarm optimization (PSO). To enhance the exploration ability of the hybrid metaheuristic, a simulated annealing hybrid with a stochastic variable neighborhood search is incorporated. To improve the search diversification of the hybrid metaheuristic, a solution replacement strategy based on the pathrelinking is presented to replace the particles that have been trapped in local optimum. Computational results on benchmark instances show that the proposed PSO-based hybrid metaheuristic is competitive with other powerful metaheuristics in the literature.
PMCID: PMC3928865  PMID: 24672389
20.  Targeting the Biophysical Properties of the Myeloma Initiating Cell Niches: A Pharmaceutical Synergism Analysis Using Multi-Scale Agent-Based Modeling 
PLoS ONE  2014;9(1):e85059.
Multiple myeloma, the second most common hematological cancer, is currently incurable due to refractory disease relapse and development of multiple drug resistance. We and others recently established the biophysical model that myeloma initiating (stem) cells (MICs) trigger the stiffening of their niches via SDF-1/CXCR4 paracrine; The stiffened niches then promote the colonogenesis of MICs and protect them from drug treatment. In this work we examined in silico the pharmaceutical potential of targeting MIC niche stiffness to facilitate cytotoxic chemotherapies. We first established a multi-scale agent-based model using the Markov Chain Monte Carlo approach to recapitulate the niche stiffness centric, pro-oncogenetic positive feedback loop between MICs and myeloma-associated bone marrow stromal cells (MBMSCs), and investigated the effects of such intercellular chemo-physical communications on myeloma development. Then we used AMD3100 (to interrupt the interactions between MICs and their stroma) and Bortezomib (a recently developed novel therapeutic agent) as representative drugs to examine if the biophysical properties of myeloma niches are drugable. Results showed that our model recaptured the key experimental observation that the MBMSCs were more sensitive to SDF-1 secreted by MICs, and provided stiffer niches for these initiating cells and promoted their proliferation and drug resistance. Drug synergism analysis suggested that AMD3100 treatment undermined the capability of MICs to modulate the bone marrow microenvironment, and thus re-sensitized myeloma to Bortezomib treatments. This work is also the first attempt to virtually visualize in 3D the dynamics of the bone marrow stiffness during myeloma development. In summary, we established a multi-scale model to facilitate the translation of the niche-stiffness centric myeloma model as well as experimental observations to possible clinical applications. We concluded that targeting the biophysical properties of stem cell niches is of high clinical potential since it may re-sensitize tumor initiating cells to chemotherapies and reduce risks of cancer relapse.
PMCID: PMC3903473  PMID: 24475036
21.  Prognostic factors associated with solitary plasmacytoma 
OncoTargets and therapy  2013;6:1659-1666.
Solitary plasmacytoma (SP) is a rare tumor with low incidence. The aim of this study was to investigate the clinical features, treatment strategies, and relative prognostic factors of 66 patients with SP. These patients made up 10.25% of the 644 patients with plasma cell dyscrasias treated at the Tianjin Medical University Cancer Institute and Hospital over the past 12 years. SP always presented with either solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (EMP), as determined by the location of the lesions. SBP occurred most frequently in the vertebral column and EMP in the upper respiratory tract. In addition to other factors, tumor size, serum M protein level, urinary Bence Jones protein level, and disease progression toward multiple myeloma were significantly different between the two groups (P<0.05). Larger tumor size (≥5 cm) was associated with poor prognosis of local control, multiple myeloma–free survival, overall survival and progression-free survival for SBP patients. Radiotherapy and serum β2 microglobulin <3.5 mg/L were favorable prognostic factors for local control, multiple myeloma-free survival, and progression-free survival in patients with EMP.
PMCID: PMC3833869  PMID: 24259986
solitary bone plasmacytoma; extramedullary plasmacytoma; clinical characteristics; prognosis; radiotherapy
22.  Cytokine Combination Therapy Prediction for Bone Remodeling in Tissue Engineering Based on the Intracellular Signaling Pathway 
Biomaterials  2012;33(33):8265-8276.
The long-term performance of tissue-engineered bone grafts is determined by a dynamic balance between bone regeneration and resorption. We proposed using embedded cytokine slow-releasing hydrogels to tune this balance toward a desirable final bone density. In this study we established a systems biology model, and quantitatively explored the combinatorial effects of delivered cytokines from hydrogels on final bone density. We hypothesized that: 1) bone regeneration was driven by transcription factors Runx2 and Osterix, which responded to released cytokines, such as Wnt, BMP2, and TGFβ, drove the development of osteoblast lineage, and contributed to bone mass generation; and 2) the osteoclast lineage, on the other hand, governed the bone resorption, and communications between these two lineages determined the dynamics of bone remodeling. In our model, Intracellular signaling pathways were represented by ordinary differential equations, while the intercellular communications and cellular population dynamics were modeled by stochastic differential equations. Effects of synergistic cytokine combinations were evaluated by Loewe index and Bliss index. Simulation results revealed that the Wnt/BMP2 combinations released from hydrogels showed best control of bone regeneration and synergistic effects, and suggested optimal dose ratios of given cytokine combinations released from hydrogels to most efficiently control the long-term bone remodeling. We revealed the characteristics of cytokine combinations of Wnt/BMP2 which could be used to guide the design of in vivo bone scaffolds and the clinical treatment of some diseases such as osteoporosis.
PMCID: PMC3444627  PMID: 22910219
Bone tissue engineering; Bone remodeling; Cytokine combination therapy; Systems biology; Osteogenic differentiation; Signaling pathway
23.  Hypoxia Promotes Epithelial - Mesenchymal Transition of Hepatocellular Carcinoma Cells via Inducing GLIPR-2 Expression 
PLoS ONE  2013;8(10):e77497.
Glioma pathogenesis related-2 (GLIPR-2) belongs to pathogenesis related-1 (PR-1) family whose function remains unknown. In our previous studies, GLIPR-2 was found to be a novel potent stimulator of epithelial-to-mesenchymal transition (EMT) in renal fibrosis which has been classified as type 2 EMT. However, whether GLIPR-2 could induce type 3 EMT in carcinogenesis needs further investigation. In this study, we showed that GLIPR-2 was expressed in hepatocellular carcinoma (HCC) tissues, hypoxia could upregulate the expression of GLIPR-2 in HepG2 and PLC/PRF/5 cells in vitro, overexpression of this protein promoted migration and invasion via EMT, knockdown of GLIPR-2 attenuated migration and invasion of HepG2 and PLC/PRF/5 cells in hypoxia. Moreover, extracellular signal-regulated kinases 1 and 2 (ERK1/2) are positively regulated by GLIPR-2. Taken together, we provide evidence for a hypoxia/GLIPR-2/EMT/migration and invasion axis in HCC cells and it provides novel insights into the mechanism of migration and invasion of hepatocellular carcinoma cells in hypoxia condition.
PMCID: PMC3812270  PMID: 24204846
24.  Programmable folding of fusion RNA in vivo and in vitro driven by pRNA 3WJ motif of phi29 DNA packaging motor 
Nucleic Acids Research  2013;42(2):e10.
Misfolding and associated loss of function are common problems in constructing fusion RNA complexes due to changes in energy landscape and the nearest-neighbor principle. Here we report the incorporation and application of the pRNA-3WJ motif of the phi29 DNA packaging motor into fusion RNA with controllable and predictable folding. The motif included three discontinuous ∼18 nucleotide (nt) fragments, displayed a distinct low folding energy (Shu D et al., Nature Nanotechnology, 2011, 6:658–667), and folded spontaneously into a leading core that enabled the correct folding of other functionalities fused to the RNA complex. Three individual fragments dispersed at any location within the sequence allowed the other RNA functional modules to fold into their original structures with authentic functions, as tested by Hepatitis B virus ribozyme, siRNA, and aptamers for malachite green (MG), spinach, and streptavidin (STV). Only nine complementary nucleotides were present for any two of the three ∼18-nt fragments, but the three 9 bp branches were so powerful that they disrupted other double strands with more than 15 bp within the fusion RNA. This system enabled the production of fusion complexes harboring multiple RNA functionalities with correct folding for potential applications in biotechnology, nanomedicine and nanotechnology. We also applied this system to investigate the principles governing the folding of RNA in vivo and in vitro. Temporal production of RNA sequences during in vivo transcription caused RNA to fold into different conformations that could not be predicted with routine principles derived from in vitro studies.
PMCID: PMC3902900  PMID: 24084081
25.  In Vivo Noninvasive Detection of Brown Adipose Tissue through Intermolecular Zero-Quantum MRI 
PLoS ONE  2013;8(9):e74206.
The recent discovery of active Brown Adipose Tissue (BAT) in adult humans has opened new avenues for obesity research and treatment, as reduced BAT activity seem to be implicated in human energy imbalance, diabetes, and hypertension. However, clinical applications are currently limited by the lack of non-invasive tools for measuring mass and function of this tissue in humans. Here we present a new magnetic resonance imaging method based on the normally invisible intermolecular multiple-quantum coherence 1H MR signal. This method, which doesn’t require special hardware modifications, can be used to overcome partial volume effect, the major limitation of MR-based approaches that are currently being investigated for the detection of BAT in humans. With this method we can exploit the characteristic cellular structure of BAT to selectively image it, even when (as in humans) it is intimately mixed with other tissues. We demonstrate and validate this method in mice using PET scans and histology. We compare this methodology with conventional 1H MR fat fraction methods. Finally, we investigate its feasibility for the detection of BAT in humans.
PMCID: PMC3769256  PMID: 24040203

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