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1.  An Antifungal Role of Hydrogen Sulfide on the Postharvest Pathogens Aspergillus niger and Penicillium italicum 
PLoS ONE  2014;9(8):e104206.
In this research, the antifungal role of hydrogen sulfide (H2S) on the postharvest pathogens Aspergillus niger and Penicillium italicum growing on fruits and under culture conditions on defined media was investigated. Our results show that H2S, released by sodium hydrosulfide (NaHS) effectively reduced the postharvest decay of fruits induced by A. niger and P. italicum. Furthermore, H2S inhibited spore germination, germ tube elongation, mycelial growth, and produced abnormal mycelial contractions when the fungi were grown on defined media in Petri plates. Further studies showed that H2S could cause an increase in intracellular reactive oxygen species (ROS) in A. niger. In accordance with this observation we show that enzyme activities and the expression of superoxide dismutase (SOD) and catalase (CAT) genes in A. niger treated with H2S were lower than those in control. Moreover, H2S also significantly inhibited the growth of Saccharomyces cerevisiae, Rhizopus oryzae, the human pathogen Candida albicans, and several food-borne bacteria. We also found that short time exposure of H2S showed a microbicidal role rather than just inhibiting the growth of microbes. Taken together, this study suggests the potential value of H2S in reducing postharvest loss and food spoilage caused by microbe propagation.
PMCID: PMC4125178  PMID: 25101960
2.  Differential Effect of Traumatic Brain Injury on the Nuclear Factor of Activated T Cells C3 and C4 Isoforms in the Rat Hippocampus 
Brain research  2013;1548:63-72.
The interaction between the phosphatase calcineurin and transcription factor nuclear factor of activated T cells (NFAT) plays an important role numerous signaling and the regulatory events. Although NFAT is mostly known for its transcription function in the immune system, NFAT also has essential functions even in the central nervous system (CNS). The effects of traumatic brain injury (TBI) on NFAT are currently unknown. To determine if there is an alteration in NFAT after TBI, we examined NFATc3 and c4 levels at 6 hours, 1 day, 1 week, 2 weeks and 4 weeks post injury. Rats were anesthetized and surgically prepared for controlled cortical impact (CCI) injury or sham surgery. Semi-quantitative measurements of NFATc3 and c4 in the hippocampal homogenates from injured and sham rats sacrificed at the appropriate time after injury were assessed using Western blot analysis. After TBI insult, in the hippocampus ipsilateral to the injury, NFATc3 expression levels were decreased both in the cytoplasmic and nuclear fractions. However, NFATc4 expression levels were increased in the cytoplasmic fraction but decreased in the nuclear fraction. Double labeling (with NeuN and GFAP) immunohistochemistry revealed that NFATc3 was expressed in subset of astrocytes and NFATc4 was expressed primarily in neurons. These differential responses in NFATc3 and c4 expression after TBI insult may indicate long-term changes in hippocampal excitability and may contribute to behavioral deficits. Further study is warranted to illustrate the role of NFATc3 and c4 in the setting of TBI.
PMCID: PMC4017626  PMID: 24389074
Nuclear factor of activated T cells (NFAT); Immunohistochemistry; Rat; Traumatic brain injury (TBI); Calcineurin
3.  Predictors of Percutaneous Catheter Drainage (PCD) after Abdominal Paracentesis Drainage (APD) in Patients with Moderately Severe or Severe Acute Pancreatitis along with Fluid Collections 
PLoS ONE  2015;10(2):e0115348.
Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
PMCID: PMC4319763  PMID: 25659143
4.  The expression dynamics of transforming growth factor-β/Smad signaling in the liver fibrosis experimentally caused by Clonorchis sinensis 
Parasites & Vectors  2015;8:70.
Liver fibrosis is a hallmark of clonorchiasis suffered by millions people in Eastern Asian countries. Recent studies showed that the activation of TGF-β/Smad signaling pathway can potently regulate the hepatic fibrogenesis including Schistosoma spp. and Echinococcus multilocularis-caused liver fibrosis. However, little is known to date about the expression of transforming growth factor-β (TGF-β) and other molecules in TGF-β/Smad signaling pathway which may play an important role in hepatic fibrosis caused by C. sinensis.
A total of 24 mice were individually infected orally with 45 metacercariae, both experimental mice and mocked-infected control mice were anesthetized at 4 week post-infection (wk p.i.), 8 wk p.i. and 16 wk p.i., respectively. For each time-point, the liver and serum from each animal were collected to analyze histological findings and various fibrotic parameters including TGF-β1, TGF-β receptors and down-stream Smads activation, as well as fibrosis markers expression.
The results showed that collagen deposition indicated by hydroxyproline content and Masson’s trichrome staining was increased gradually with the development of infection. The expression of collagen type α1 (Col1a) mRNA transcripts was steadily increased during the whole infection. The mRNA levels of Smad2, Smad3 as well as the protein of Smad3 in the liver of C. sinensis-infected mice were increased after 4 wk p.i. (P < 0.05, compared with normal control) whereas the TGF-β1, TGF-β type I receptor (TGFβRI) and TGF-β type II receptor (TGFβRII) mRNA expression in C. sinensis-infected mice were higher than those of normal control mice after 8 wk p.i. (P < 0.05). However, the gene expression of Smad4 and Smad7 were peaked at 4 wk p.i. (P < 0.05), and thereafter dropped to the basal level at 8 wk p.i., and 16 wk p.i., respectively. The concentrations of TGF-β1 in serum in the C. sinensis-infected mice at 8 wk p.i. and 16 wk p.i (P < 0.05) were significantly higher than those in the control mice.
The results of the present study indicated for the first time that the activation of TGF-β/Smad signaling pathway might contribute to the synthesis of collagen type I which leads to liver fibrosis caused by C. sinensis.
PMCID: PMC4329204  PMID: 25649869
Clonorchis sinensis; Liver fibrosis; Transforming growth factor-β; Smads
5.  Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia 
Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear.
Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis.
EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells.
In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details.
Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.
PMCID: PMC4311429  PMID: 25609158
Early B-cell factor 3; Pediatric acute myeloid leukemia; Methylation; Tumor suppressor; Real-time PCR array
6.  Elevation of Tim-3 and PD-1 Expression on T Cells Appears Early in HIV Infection, and Differential Tim-3 and PD-1 Expression Patterns Can Be Induced by Common γ-Chain Cytokines 
BioMed Research International  2015;2015:916936.
Purpose. To explore the association between differential Tim-3 and PD-1 expression patterns and HIV disease progression, and to investigate the impact of common γ-chain cytokines on Tim-3 and PD-1 expression patterns on T cells. Methods. Tim-3/PD-1 expression on the T cells of patients with early and chronic HIV infections was detected. The expression levels and functional profiles of T cells with differential Tim-3 and PD-1 expression patterns induced by γ-chain cytokines were studied. Results. The elevation of differential Tim-3 and PD-1 expression patterns on T cells appeared early in HIV infection. Co-expression of Tim-3 and PD-1 (Tim-3+PD-1+) correlates with more severe exhaustion of T cells during HIV infection. In vitro stimulation of common γ-chain cytokines can induce differential expression patterns of Tim-3 and PD-1 on T cells. The enhancement of Tim-3 and PD-1 expression by common γ-chain IL-2 can inhibit the function of T cells re-stimulated by HIV gag and TCR, not by the re-stimulation of IL-2. Conclusions. The elevation of differential Tim-3 and PD-1 expression patterns on T cells represents a state of T cell exhaustion and can be induced by common γ-chain cytokines. These findings provide insights into HIV pathogenesis and help inform immune intervention strategies.
PMCID: PMC4317591
7.  Quantitative analysis of Plasmodium ookinete motion in three dimensions suggests a critical role for cell shape in the biomechanics of malaria parasite gliding motility 
Cellular Microbiology  2014;16(5):734-750.
Motility is a fundamental part of cellular life and survival, including for Plasmodium parasites – single‐celled protozoan pathogens responsible for human malaria. The motile life cycle forms achieve motility, called gliding, via the activity of an internal actomyosin motor. Although gliding is based on the well‐studied system of actin and myosin, its core biomechanics are not completely understood. Currently accepted models suggest it results from a specifically organized cellular motor that produces a rearward directional force. When linked to surface‐bound adhesins, this force is passaged to the cell posterior, propelling the parasite forwards. Gliding motility is observed in all three life cycle stages of Plasmodium: sporozoites, merozoites and ookinetes. However, it is only the ookinetes – formed inside the midgut of infected mosquitoes – that display continuous gliding without the necessity of host cell entry. This makes them ideal candidates for invasion‐free biomechanical analysis. Here we apply a plate‐based imaging approach to study ookinete motion in three‐dimensional (3D) space to understand Plasmodium cell motility and how movement facilitates midgut colonization. Using single‐cell tracking and numerical analysis of parasite motion in 3D, our analysis demonstrates that ookinetes move with a conserved left‐handed helical trajectory. Investigation of cell morphology suggests this trajectory may be based on the ookinete subpellicular cytoskeleton, with complementary whole and subcellular electron microscopy showing that, like their motion paths, ookinetes share a conserved left‐handed corkscrew shape and underlying twisted microtubular architecture. Through comparisons of 3D movement between wild‐type ookinetes and a cytoskeleton‐knockout mutant we demonstrate that perturbation of cell shape changes motion from helical to broadly linear. Therefore, while the precise linkages between cellular architecture and actomyosin motor organization remain unknown, our analysis suggests that the molecular basis of cell shape may, in addition to motor force, be a key adaptive strategy for malaria parasite dissemination and, as such, transmission.
PMCID: PMC4286792  PMID: 24612056
8.  Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells 
Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.
PMCID: PMC4307303  PMID: 25574601
RO3280; pediatric acute myeloid leukemia (AML); polo-like kinase 1 (PLK1); apoptosis; oncogene target
9.  Analysis of synonymous codon usage in enterovirus 71 
Virusdisease  2014;25(2):243-248.
Enterovirus 71 (EV71) is the major cause of hand-foot-and-mouth disease in children. In our study, using the complete genome sequences of 42 EV71 representing all three genotypes, we analyzed synonymous codon usage and the relative dinucleotide abundance in EV71 genome. The general correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in EV71 genome. Furthermore, we observed that the relative abundance of dinucleotides in EV71 is independent of the overall base composition but is still the result of differential mutational pressure, which also shapes codon usage. In addition, other factors, such as hydrophobicity and aromaticity, also influence the codon usage variation among the genomes of EV71. This study represents the most comprehensive analysis of EV71 codon usage patterns and provides a basic understanding of the mechanisms for codon usage bias.
PMCID: PMC4188181
EV71; Synonymous codon usage; Mutational bias; Dinucleotide bias; Subgenotype
10.  Activation of KRAS promotes the mesenchymal features of basal-type breast cancer 
Basal-type breast cancers are among the most aggressive and deadly breast cancer subtypes, displaying a high metastatic ability associated with mesenchymal features. However, the molecular mechanisms underlying the maintenance of mesenchymal phenotypes of basal-type breast cancer cells remain obscure. Here, we report that KRAS is a critical regulator for the maintenance of mesenchymal features in basal-type breast cancer cells. KRAS is preferentially activated in basal-type breast cancer cells as compared with luminal type. By loss and gain of KRAS, we found that KRAS is necessary and sufficient for the maintenance of mesenchymal phenotypes and metastatic ability through SLUG expression. Taken together, this study demonstrates that KRAS is a critical regulator for the metastatic behavior associated with mesenchymal features of breast cancer cells, implicating a novel therapeutic target for basal-type breast cancer.
PMCID: PMC4314588  PMID: 25633745
11.  Gadd45b is a Novel Mediator of Neuronal Apoptosis in Ischemic Stroke 
Apoptosis plays an essential role in ischemic stroke pathogenesis. Research on the process of neuronal apoptosis in models of ischemic brain injury seems promising. The role of growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) in brain ischemia has not been fully examined to date. This study aims to investigate the function of Gadd45b in ischemia-induced apoptosis. Adult male Sprague-Dawley rats were subjected to brain ischemia by middle cerebral artery occlusion (MCAO). RNA interference (RNAi) system, which is mediated by a lentiviral vector (LV), was stereotaxically injected into the ipsilateral lateral ventricle to knockdown Gadd45b expression. Neurologic scores and infarct volumes were assessed 24 h after reperfusion. Apoptosis-related molecules were studied using immunohistochemistry and Western blot analysis. We found that Gadd45b-RNAi significantly increased infarct volumes and worsened the outcome of transient focal cerebral ischemia. Gadd45b-RNAi also significantly increased neuronal apoptosis as indicated by increased levels of Bax and active caspase-3, and decreased levels of Bcl-2. These results indicate that Gadd45b is a beneficial mediator of neuronal apoptosis.
PMCID: PMC4323375
MCAO; Gadd45b; BDNF; Apoptosis
12.  Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway 
Histone acetyltransferase (HAT) inhibitors can inhibit proliferation and induce apoptosis in cancer cell lines. The novel cell-permeable p300/CREB-binding protein (CBP)-selective HAT inhibitor HATi II can reduce histone H3 acetylation and induce chromatin condensation in HeLa cells. Here, we examined the effects and mechanism of action of HATi II in glioma cell lines.
Cell viability was assessed using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry. Apoptosis was evaluated using Annexin V staining and flow cytometry, Hoechst 33342 staining and the TUNEL assay. Expression and cleavage of caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) were assessed by Western blotting. Statistical analysis was performed using two-tailed Student’s t-tests. The gene expression profiles of U251 glioma cells treated with HATi II or DMSO were analyzed using the Arraystar Human 8 x 60 K LncRNA/mRNA expression array; data was analyzed using MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profiles (≥2-fold) derived from the cluster analyses were subjected to gene ontology and pathway analysis.
HATi II inhibited the proliferation of U251, U87, HS683 and SHG44 cells in a dose-dependent manner. HATi II induced cell cycle arrest at the G2/M phase, and induced significant levels of apoptosis, apoptotic body formation and DNA fragmentation in HATi II-treated U251 and SHG44 cells. HATi II induced cleavage of caspase-3, caspase-9 and PARP in U251 and SHG44 cells. In HATi II-treated U251 cells, 965 genes were upregulated, 984 genes were downregulated and 3492/33327 lncRNAs were differentially expressed. GO analysis showed the differentially expressed genes with known functions are involved in a variety of processes; alcoholism, p53 signaling pathway, cytokine-cytokine receptor interaction and transcriptional mis-regulation in cancer were the four most significant pathways. Upregulation of p53 signaling pathway-related genes in HATi II-treated cells was confirmed by quantitative RT-PCR and Western blotting.
HATi II inhibits proliferation and induces apoptosis via the caspase-dependent pathway in human glioma cell lines, possibly by activating the p53 signaling pathway. HATi II deserves further investigation as a novel treatment for glioma.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0108-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4321714  PMID: 25523932
HATi II; Glioma; Apoptosis; LncRNA/mRNA; p53 signaling pathway
13.  Enantioselective metabolism of primaquine by human CYP2D6 
Malaria Journal  2014;13(1):507.
Primaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers.
Stable isotope 13C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites.
The rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 μM in 120 min) compared to (−)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated Vmax (μmol/min/mg) were 0.75, 0.98 and 0.42, with Km (μM) of 24.2, 33.1 and 21.6 for (±)-primaquine, (+)-primaquine and (−)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH-PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+)-primaquine in a ratio of 4:1 compared to (−)-primaquine. The racemic (±)-primaquine showed a pattern similar to the (−)-primaquine; 2-OH-PQ accounted for about 15–17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (−)-primaquine (5:1), accounting for 22% of the total (−)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (−)-primaquine) was identified and accounted for 18–20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers.
The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers.
PMCID: PMC4301821  PMID: 25518709
Primaquine enantiomers; CYP2D6; Metabolism; Ring-hydroxylation; Quinone-imines; Orthoquinone
14.  Meta-analysis of plasma homocysteine content and cognitive function in elderly patients with Alzheimer’s disease and vascular dementia 
Objective: To evaluate the relationship between homocysteine and cognitive function of Alzheimer’s disease (AD) patients and vascular dementia (VD) patients. Methods: By Cochrane system evaluation we retrieved relevant publications from MEDLINE, Embase, OVID, controlled clinical trial database of the Cochrane library and others. Two evaluators jointly assessed the research quality of the retrieved publications and carried out meta-analysis on the homogeneous study. Results: MMSE score in the AD group was lower than that in normal control group (MD = -11.98, 95% CI (-13.30, -10.65)), and the homocysteine content was higher than that in the normal control group (MD = 2.72, 95% CI (1.79, 3.64)), with a statistical difference between the two groups (P < 0.05). The homocysteine content in the AD group was higher than that in the VD group (MD = -4.76, 95% CI (-7.59, -1.93), P < 0.05). Conclusions: MSE score and homocysteine content can be used as useful indicators to distinguish AD and normal subjects; homocysteine content can be used as an indicator to differentiate AD from VD. Clinically, more randomized controlled trials are needed to test and verify the relationship in cognitive function between homocysteine and AD and VD.
PMCID: PMC4307460  PMID: 25664013
Alzheimer’s disease; homocysteine; cognitive function; elderly people; meta analysis
15.  Recreational drug use and risks of HIV and sexually transmitted infections among Chinese men who have sex with men: Mediation through multiple sexual partnerships 
BMC Infectious Diseases  2014;14(1):642.
Recreational drug use (RDU) may result in sexual disinhibition and higher risk for HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) in China. We assessed whether RDU was associated with HIV, syphilis, and herpes simplex virus type 2 (HSV-2) within the context of multiple sexual partnerships and unprotected sex.
We conducted a cross-sectional study among sexually-active MSM in six Chinese cities (Kunming, Jinan, Changsha, Zhengzhou, Nanjing, and Shanghai) in 2012–2013. We interviewed participants regarding RDU and sexual activity and drew blood for HIV, syphilis, and HSV-2. We fit multiple logistic regression models to assess associations of drug use and HIV, syphilis and HSV-2 infections, controlling for number of sexual partners and unprotected sex.
Of 3830 participants, 28% reported ever using ≥1 of these drugs in the past 6 months: popper (alkyl nitrites), ecstasy, ice (methamphetamine), amphetamine, tramadol, and ketamine. In the past six months, 62% of MSM reported ≥2 sexual partners and 76% did not use condoms at last sexual encounter. HIV, syphilis and HSV-2 prevalences were 9.2%, 12.2%, and 10.3%, respectively.RDU was associated with HIV infection (aOR = 1.67; 95% CI, 1.31-2.13). Men with RDU were more likely to report multiple sexual partners (OR = 1.69; 95% CI, 1.44-1.98) and unprotected sex (aOR = 1.25; 95% CI, 1.05-1.49). The RDU-HIV association persisted (aOR = 1.58; 95% CI = 1.23-2.02) after adjusting for numbers of partners.
RDU was associated with multiple sexual partnerships, unprotected sex, and HIV among Chinese MSM. It is plausible that RDU is a driver of increased sexual/HIV risk and/or may be an associated behavior with sexually risky lifestyles. Community engagement is needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0642-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4272794  PMID: 25443542
Men who have sex with men; Multiple sexual partners; Unprotected sex; HIV; Syphilis; HSV-2; Recreational drug use; Substance use; China
16.  Intestinal Epithelial Barrier Disruption through Altered Mucosal MicroRNA Expression in Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections 
Journal of Virology  2014;88(11):6268-6280.
Epithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4+ T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5′-3′-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy.
IMPORTANCE MicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.
PMCID: PMC4093871  PMID: 24672033
17.  Comparison of three mathematical prediction models in patients with a solitary pulmonary nodule 
Effective methods for managing patients with solitary pulmonary nodules (SPNs) depend critically on the predictive probability of malignancy.
Between July 2009 and June 2011, data on gender, age, cancer history, tumor familial history, smoking status, tumor location, nodule size, spiculation, calcification, the tumor border, and the final pathological diagnosis were collected retrospectively from 154 surgical patients with an SPN measuring 3-30 mm. Each final diagnosis was compared with the probability calculated by three predicted models—the Mayo, VA, and Peking University (PU) models. The accuracy of each model was assessed using area under the receiver operating characteristics (ROC) and calibration curves.
The area under the ROC curve of the PU model [0.800; 95% confidence interval (CI): 0.708-0.891] was higher than that of the Mayo model (0.753; 95% CI: 0.650-0.857) or VA model (0.728; 95% CI: 0.623-0.833); however, this finding was not statistically significant. To varying degrees, calibration curves showed that all three models overestimated malignancy.
The three predicted models have similar accuracy for prediction of SPN malignancy, although the accuracy is not sufficient. For Chinese patients, the PU model may has greater predictive power.
PMCID: PMC4279199  PMID: 25561761
Solitary pulmonary nodule (SPN); benign and malignant; model; comparison
18.  Transcatheter arterial chemoembolization combined with radiofrequency ablation delays tumor progression and prolongs overall survival in patients with intermediate (BCLC B) hepatocellular carcinoma 
BMC Cancer  2014;14(1):849.
This study was designed to evaluate the effectiveness of radiofrequency ablation in patients with intermediate (BCLC B) stage hepatocellular carcinoma who underwent transcatheter arterial chemoembolization.
Included in this study were 211 patients with intermediate stage HCC who underwent initial transcatheter arterial chemoembolization and were potentially amendable for radiofrequency ablation (single tumor with diameter 5-8 cm, median 6.0 cm; 2–5 multiple nodules with diameter less than 5 cm) between January 2005 and December 2011. According to the inclusion and exclusion criteria, 55 patients were treated with following radiofrequency ablation, and the remaining 156 patients were treated with transcatheter arterial chemoembolization alone. The treatment effectiveness, local tumor control and survival outcome between the two groups were compared.
The complete tumor necrosis rate after treatment was 76.9% in combination group vs. 46.5% in transcatheter arterial chemoembolization alone group (P = 0.02). The major complication rate was 1.8% in combination group vs. 2.6% in transcatheter arterial chemoembolization alone group. Follow-up observation showed that the total tumor control rate was 74.5% in combination group versus 54.5% in transcatheter arterial chemoembolization alone group (P < 0.001). The 1-, 3- and 5-year survival rates in combination group were significantly higher than those in TACE alone group (P = 0.01).
Radiofrequency ablation following initial transcatheter arterial chemoembolization delays tumor progression and prolongs overall survival of patients with intermediate stage HCC tumors.
PMCID: PMC4256894  PMID: 25409554
Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Radiofrequency ablation; Combination therapy; Survival
19.  The Status of Vitamin B12 and Folate among Chinese Women: A Population-Based Cross-Sectional Study in Northwest China 
PLoS ONE  2014;9(11):e112586.
To assess the status of the vitamin B12 and folate of Chinese women living in northwest China.
A population-based cross-sectional study was conducted in 2008 among Chinese women aged 10–49 years living in Shaanxi province of northwest China. A stratified multistage random sampling method was adopted to obtain a sample of 1170 women. The women were interviewed for collection of their background information and their plasma vitamin B12 and folate were measured with the immunoassay method. The status of both vitamins was evaluated and the prevalence of deficiency was estimated.
The median value of the women was 214.5 pg/mL for vitamin B12 and 4.6 ng/mL for folate. The urban women had a significantly higher vitamin B12 (254.1 vs. 195.9 pg/mL) but lower folate (4.4 vs. 4.7 ng/mL) than rural women. Total prevalence of deficiency was 45.5% (95% CI: 42.6%∼48.4%) for vitamin B12 and 14.7% (95% CI: 12.6%∼16.8%) for folate. About 36% of women presented vitamin B12 deficiency alone, 5.2% belonged to folate deficiency alone and 9.5% was combined deficiency in both vitamins. More than 25% of the women were in marginal vitamin B12 status (200–299 pg/mL) and 60% in marginal status of folate (3–6 ng/mL). About 75.2% of rural women with folate deficiency were deficient in vitamin B12 and 46% for urban women. Quantile regression model found decreasing coefficient of folate status across 73 different quantiles of vitamin B12, which indicated that the women with folate deficiency had lower vitamin B12 significantly compared with those with no deficiency.
The deficiency of vitamin B12 and folate is still prevalent among the Chinese women in northwest China. Vitamin B12 deficiency could be more serious and the improvement of poor vitamin B12 status should be invoked when practicing the supplementation of folate against the neural tube defects in northwest China.
PMCID: PMC4229226  PMID: 25390898
20.  Correlation between red blood cell transfusion volume and mortality in patients with massive blood transfusion: A large multicenter retrospective study 
This study aimed to explore the correlation between red blood cell (RBC) transfusion volume and patient mortality in massive blood transfusion. A multicenter retrospective study was carried out on 1,601 surgical inpatients who received massive blood transfusion in 20 large comprehensive hospitals in China. According to RBC transfusion volume and duration, the patients were divided into groups as follows: 0–4, 5–9, 10–14, 15–19, 20–24, 25–29, 30–39 and ≥40 units within 24 or 72 h. Mortality in patients with different RBC transfusion volumes was analyzed. It was found that patient mortality increased with the increase in the volume of RBC transfusion when the total RBC transfusion volume was ≥10 units within 24 or 72 h. Survival analysis revealed significant differences in mortality according to the RBC transfusion volume (χ2=72.857, P<0.001). Logistic regression analysis revealed that RBC transfusion volume is an independent risk factor [odds ratio (OR) = 0.52; confidence interval (CI): 0.43–0.64; P<0.01] for the mortality of patients undergoing a massive blood transfusion. When RBCs were transfused at a volume of 5–9 units within 24 and 72 h, the mortality rate was the lowest, at 3.7 and 2.3% respectively. It is concluded that during massive blood transfusion in surgical inpatients, there is a correlation between RBC transfusion volume within 24 or 72 h and the mortality of the patients. Patient mortality increases with the increase in the volume of RBC transfusion. RBC transfusion volume, the length of stay at hospital and intensive care unit stay constitute the independent risk factors for patient mortality.
PMCID: PMC4247322  PMID: 25452789
massive blood transfusion; red blood cell; mortality; retrospective analysis; multicenter
21.  SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling 
The prevalence of obesity is increasing worldwide and significantly affects fertility and reproduction in both men and women. Our recent study has shown that excess body fat accelerates ovarian follicle development and follicle loss in rats. The aim of the present study is to explore the effect of SIRT1 activator SRT1720 on the reserve of ovarian follicle pool and ovarian lifespan of obese mice and the underlying mechanism associated with SIRT1 and mTOR signaling.
Adult female Kunming mice (n = 36) were randomly divided into three groups: the normal control (NC) group (n = 8), the caloric restriction (CR) group (fed 70% food of the NC group, n = 8) and the high-fat diet (HF) group (fed a rodent chow containing 20% fat, n = 20). After 4 months, the HF mice were further randomly divided into three groups: the control high-fat diet (CHF, n = 8) group (treated every day with an intraperitoneal injection of vehicle), the SRT1720 (SRT, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg)), the SRT1720 and nicotinamide (NAM, n = 6) group (treated every other day with an intraperitoneal injection of SRT1720 (50 mg/kg) and every day with an intraperitoneal injection of nicotinamide (100 mg/kg)). After 6 weeks of treatment, ovaries were harvested for histological and Western blotting analyses.
The body weight, ovary weight and visceral fat in the SRT group were significantly lower than those in the CHF group at the end of treatment. Histological analysis showed that the SRT mice had significantly greater number and percentage of primordial follicles, but lower number and percentage of corpora lutea and atretic follicles than the CHF mice and NAM mice. Western blot analysis demonstrated that the levels of SIRT1, SIRT6, FOXO3a and NRF-1 protein expression significantly increased in the ovaries of SRT mice, whereas those of mTORC1, p-mTOR, p-p70S6K, NFκB and p53 decreased compared to the CHF and NAM mice.
Our study suggests that SRT1720 may improve the follicle pool reserve in HF diet-induced obese female mice via activating SIRT1 signaling and suppressing mTOR signaling, thus extending the ovarian lifespan.
PMCID: PMC4232623  PMID: 25330910
SRT1720; Nicotinamide; Ovarian development; Obesity; Mice
22.  Protection Motivation Theory in Predicting Intention to Engage in Protective Behaviors against Schistosomiasis among Middle School Students in Rural China 
Among millions of people who suffer from schistosomiasis in China, adolescents are at increased risk to be infected. However, there is a lack of theory-guided behavioral prevention intervention programs to protect these adolescents. This study attempted to apply the Protection Motivation Theory (PMT) in predicting intentions to engage in protective behaviors against schistosomiasis infection.
The participants were selected using the stratified cluster sampling method. Survey data were collected using anonymous self-reported questionnaire. The advanced structural equation modeling (SEM) method was utilized to assess the complex relationship among schistosomiasis knowledge, previous risk exposure and protective measures in predicting intentions to engage in protective behavior through the PMT constructs.
Principal Findings
Approximately 70% of participants reported they were always aware of schistosomiasis before exposure to water with endemic schistosomiasis, 6% of the participants reported frequency of weekly or monthly prior exposure to snail-conditioned water. 74% of participants reported having always engaged in protective behaviors in the past three months. Approximately 7% were unlikely or very unlikely to avoid contact with snail-conditioned water, and to use protective behaviors before exposure. Results from SEM analysis indicated that both schistosomiasis knowledge and prior exposure to schistosomiasis were indirectly related to behavior intentions through intrinsic rewards and self-efficacy; prior protective behaviors were indirectly related to behavior intentions through severity, intrinsic rewards and self-efficacy, while awareness had an indirect relationship with behavior intentions through self-efficacy. Among the seven PMT constructs, severity, intrinsic rewards and self-efficacy were significantly associated with behavior intentions.
The PMT can be used to predict the intention to engage in protective behaviors against schistosomiasis. Schistosomiasis intervention programs should focus on the severity, intrinsic rewards and self-efficacy of protection motivation, and also increase the awareness of infection, and enrich the contents of schistosomiasis education.
Author Summary
In China, millions of population suffer from schistosomiasis infection and adolescents tend to have higher infection rates than adults. The Knowledge-Attitude-Practice (KAP) Theory has traditionally been used as guidance to schistosomiasis prevention in China. However, despite increases in knowledge among residents in the epidemic areas due to KAP theory-based schistosomiasis health education, no significant reduction in water-contact behavior was evident. Therefore, it is of crucial importance to seek alternative health behavior change theories/models that are more effective than the KAP theory to promote purposeful behavioral change. The Protection Motivation Theory (PMT) as a social cognitive model may be an alternative to the KAP theory. In this study, we found that the PMT can be used to predict intention to engage in protective behaviors against schistosomiasis infection among middle school students in rural China. Based on the PMT, in addition to enhancing awareness of schistosomiasis infection, intervention programs should focus on the severity, intrinsic rewards and self-efficacy of protection motivation.
PMCID: PMC4199519  PMID: 25329829
23.  Intraoperative systemic lidocaine inhibits the expression of HMGB1 in patients undergoing radical hysterectomy 
Surgery stressors trigger inflammatory response and excessive inflammatory response leads to organ failure or even septic shock. HMGB1 as a later inflammatory cytokines and a critical mediator of severe sepsis is always associated with the aggravation of organ failure. Previous study shows that lidocaine can inhibit the expression of HMGB1 in macrophage of septic rats and protect animals from organ failure. The present study sought to determine whether intraoperative systemic lidocaine could attenuate the level of HMGB1 by inhibiting it expression in PBMC from patients underwent radical hysterectomy. Thirty patients were recruited and divided randomly into two groups according to the difference of study medicine. Patients in lidocaine group received an intravenous bolus infusion of 1.5 mg/kg of lidocaine followed by a continuous infusion of 1.5 mg/kg/h till discharged from operating room, and those in the control group received normal saline. Peripheral blood sample was drawn at pre-surgery, discharge from operating room and 48 h post-surgery. Monocytes were isolated and cultured with medium alone or with LPS. HMGB1 protein in serum or in supernatant of PBMC was detected with ELISA, while the HMGB1 mRNA in PBMC was determined by real-time quantitative PCR. The result showed that lidocaine not only attenuated the level of HMGB1 protein in serum and supernatant, but inhibited the transcription of HMGB1 mRAN in PBMC. The present study of us demonstrated that intraoperative systemic lidocaine can attenuate the level of HMGB1 and inhibit its expression in PBMC from patients underwent radical hysterectomy. Therefore, lidocaine may play an important role in many other clinical diseases by inhibiting HMGB1.
PMCID: PMC4238473  PMID: 25419374
High mobility group box1; lidocaine; monocytes; gynecologic oncology
24.  Zinc finger protein 382 is downregulated by promoter hypermethylation in pediatric acute myeloid leukemia patients 
Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation-specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5-aza-2′-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required.
PMCID: PMC4214337  PMID: 25319049
zinc finger protein 382; pediatric acute myeloid leukemia; methylation; tumor suppressor
25.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
Background Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods Using extant longitudinal birth cohorts (n = 19) with data on birthweight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood

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