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1.  Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage 
Background
Intracerebral hemorrhage (ICH) induces a series of inflammatory processes that contribute to neuronal damage and neurological deterioration. Liver X receptors (LXRs) are nuclear receptors that negatively regulate transcriptional processes involved in inflammatory responses, but their role in the pathology following ICH remains unclear. The present study investigated the neuroprotective effects and anti-inflammatory actions of TO901317, a synthetic LXR agonist, in a model of collagenase-induced ICH and in microglial cultures.
Methods
Mice subjected to collagenase-induced ICH injury were injected with either TO901317 (30 mg/kg) or vehicle 10 min after ICH and subsequently daily for 2 days. Behavioral studies, histology analysis, and assessments of hematoma volumes, brain water content, and blood-brain barrier (BBB) permeability were performed. The protein expression of LXR-α, LXR-β, ATP binding cassette transporter-1 (ABCA-1), and inflammatory molecules was analyzed. The anti-inflammatory mechanism of TO901317 was investigated in cultured microglia that were stimulated with either lipopolysaccharide (LPS) or thrombin.
Results
ICH induced an increase in LXR-α protein levels in the hemorrhagic hemisphere at 6 h whereas LXR-β expression remained unaffected. Both LXR-α and LXR-β were expressed in neurons and microglia in the peri-ICH region and but rarely in astrocytes. TO901317 significantly attenuated functional deficits and brain damage up to 28 days post-ICH. TO901317 also reduced neuronal death, BBB disruption, and brain edema at day 4 post-ICH. These changes were associated with marked reductions in microglial activation, neutrophil infiltration, and expression levels of inflammatory mediators at 4 and 7 days. However, TO901317 had no effect on matrix metalloproteinase-9 activity. In BV2 microglial cultures, TO901317 attenuated LPS- and thrombin-stimulated nitric oxide production and reduced LPS-induced p38, JNK, MAPK, and nuclear factor-kappa B (NF-κB) signaling. Moreover, delaying administration of TO901317 to 3 h post-ICH reduced brain tissue damage and neuronal death.
Conclusions
Our results suggest that enhancing LXR activation may provide a potential therapy for ICH by modulating the cytotoxic functions of microglia.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0524-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0524-8
PMCID: PMC4788882  PMID: 26968836
Liver X receptors; Microglia; Inflammation; Intracerebral hemorrhage; Neuronal damage; TO901317
2.  Immunization with Recombinant SFTSV/NSs Protein Does Not Promote Virus Clearance in SFTSV-Infected C57BL/6J Mice 
Viral Immunology  2015;28(2):113-122.
Abstract
The severe fever with thrombocytopenia syndrome (SFTS), caused by a novel Phlebovirus in the Bunyaviridae family named SFTS virus (SFTSV), is an emerging hemorrhagic fever with a wide distribution and high case-fatality rate. Neither effective treatment nor vaccines are available to treat and prevent this disease to date. It was recently reported that SFTSV nonstructural protein in S segment (SFTSV/NSs) functioned as the interferon (IFN) antagonist targeting for suppressing host's innate immunity. This study was designed to investigate the potential of recombinant SFTSV (rSFTSV)/NSs protein for inducing anti-NSs antibodies by pre-exposure vaccination to block SFTSV/NSs in the SFTSV-infected C57BL/6J mice. All mice in the rSFTSV/NSs-vaccinated group, negative control group, and blank control group survived with no visible clinical abnormities throughout the experiment, except for their sacrifice for sampling at each observation point. However, unexpectedly, a negative effect on the bodyweight of rSFTSV/NSs-vaccinated mice was observed after 21 days postinoculation. Pre-exposure vaccination with rSFTSV/NSs did not accelerate virus removal in mice though high titer of anti-NSs antibodies and elevated IFN-γ were detected in sera. Before virus challenge, the rSFTSV/NSs-vaccinated mice and negative control mice had a larger amount of platelets (PLT) than the blank control mice, which indicated that Freund's adjuvants could stimulate PLT production. In the aspect of cytokines, the rSFTSV/NSs-vaccinated mice had a 5- to 10-fold increase in interleukin (IL)-2, IL-5, IL-6, IFN-γ, and tumor necrosis factor-α, which probably just had a negative effect on the bodyweight of mice. In general, therefore, previous vaccination with rSFTSV/NSs did not accelerate virus clearance in the SFTSV-infected mice.
doi:10.1089/vim.2014.0100
PMCID: PMC4334103  PMID: 25594805
3.  Gastric microbiota and predicted gene functions are altered after subtotal gastrectomy in patients with gastric cancer 
Scientific Reports  2016;6:20701.
Subtotal gastrectomy (i.e., partial removal of the stomach), a surgical treatment for early-stage distal gastric cancer, is usually accompanied by highly selective vagotomy and Billroth II reconstruction, leading to dramatic changes in the gastric environment. Based on accumulating evidence of a strong link between human gut microbiota and host health, a 2-year follow-up study was conducted to characterize the effects of subtotal gastrectomy. Gastric microbiota and predicted gene functions inferred from 16S rRNA gene sequencing were analyzed before and after surgery. The results demonstrated that gastric microbiota is significantly more diverse after surgery. Ralstonia and Helicobacter were the top two genera of discriminant abundance in the cancerous stomach before surgery, while Streptococcus and Prevotella were the two most abundant genera after tumor excision. Furthermore, N-nitrosation genes were prevalent before surgery, whereas bile salt hydrolase, NO and N2O reductase were prevalent afterward. To our knowledge, this is the first report to document changes in gastric microbiota before and after surgical treatment of stomach cancer.
doi:10.1038/srep20701
PMCID: PMC4748256  PMID: 26860194
4.  Synthesis, Crystal Structure, Spectroscopic Properties, and Interaction with Ct-DNA of Zn(II) with 2-Aminoethanethiol Hydrochloride Ligand 
The zinc(II) complex (C2H6NS)2Zn·ZnCl2 was synthesized with 2-aminoethanethiol hydrochloride and zinc sulfate heptahydrate as the raw materials in aqueous solution. The composition and structure of the complex were characterized by elemental analysis, infrared spectra, single crystal X-ray diffraction, and thermogravimetry. The crystal structure of the zinc(II) complex belongs to monoclinic system, space group P  21/n, with cell parameters of a = 0.84294(4), b = 0.83920(4), c = 1.65787(8) nm, Z = 2, and D = 2.041 g/cm3. In this paper, the interaction of complex with Ct-DNA was investigated by UV-visible and viscosimetric techniques. Upon addition of the complex, important changes were observed in the characteristic UV-Vis bands (hyperchromism) of calf thymus DNA and some changes in specific viscosity. The experimental results showed that the complex is bound to DNA intercalative (intercalation binding).
doi:10.1155/2016/2691253
PMCID: PMC4764736  PMID: 26977140
5.  Interaction of XRCC1 Arg399Gln Polymorphism and Alcohol Consumption Influences Susceptibility of Esophageal Cancer 
Background. To explore the correlation between the Arg399Gln polymorphism and susceptibility to esophageal cancer in Korean and Han Chinese individuals in Harbin, China, and its potential interaction with alcohol consumption. Methods. This prospective study included 203 patients with esophageal squamous cell carcinoma; 88 were of Korean descent and 115 were of Han Chinese descent. A group of healthy controls included 105 participants of Korean descent and 105 of Han Chinese descent. Genotyping of the Arg399Gln locus of XRCC1 was performed by PCR-RFLP. Results. The allelic and genotypic frequencies were not significantly different between individuals with esophageal cancer and controls or between individuals of Korean and Han Chinese descent (P > 0.05). However, when individuals with the wild-type Arg/Arg genotype also consumed alcohol, the risk of esophageal cancer was lower (OR = 3.539; 95% CI = 2.039–6.142; P < 0.05). Conclusions. The XRCC1 Arg399Gln polymorphism does not appear to be associated with esophageal cancer in individuals of Korean or Han Chinese descent in Harbin, China. However, alcohol consumption may decrease the risk of esophageal cancer in persons with the wild-type genotype.
doi:10.1155/2016/9495417
PMCID: PMC4753333  PMID: 26949387
6.  The role of PD-L1 in the radiation response and clinical outcome for bladder cancer 
Scientific Reports  2016;6:19740.
Identification of potential factors that can stratify a tumor’s response to specific therapies will aid in the selection of cancer therapy. The aim was to highlight the role of programmed cell death 1 ligand 1 (PD-L1) in bladder cancer. In this study, 92 of muscle-invasive bladder cancers and 28 of non- muscle invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human and murine bladder cancer cell lines were used to examine the correlation between PD-L1 and radiation response. Our data revealed that PD-L1 was overexpressed in the bladder tumor specimens compared with adjacent non-malignant specimens. Furthermore, the staining of PD-L1 was significantly linked to higher clinical stage, lower complete response rates and reduced disease-free survival rates. By in vitro and in vivo experiments, irradiation up-regulated the expression of PD-L1 in tumor cells, and its increase correlated with the irradiation dose. In immunocompetent mouse models, blocking PD-L1 induced a longer tumour growth delay following irradiation. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells was responsible to the effects of PD-L1 on radiation response. In conclusion, PD-L1 could be a significant clinical predictor for clinical stage and treatment response of bladder cancer.
doi:10.1038/srep19740
PMCID: PMC4726250  PMID: 26804478
7.  Genetic variation of hepatitis B virus and its significance for pathogenesis 
World Journal of Gastroenterology  2016;22(1):126-144.
Hepatitis B virus (HBV) has a worldwide distribution and is endemic in many populations. Due to its unique life cycle which requires an error-prone reverse transcriptase for replication, it constantly evolves, resulting in tremendous genetic variation in the form of genotypes, sub-genotypes, and mutations. In recent years, there has been considerable research on the relationship between HBV genetic variation and HBV-related pathogenesis, which has profound implications in the natural history of HBV infection, viral detection, immune prevention, drug treatment and prognosis. In this review, we attempted to provide a brief account of the influence of HBV genotype on the pathogenesis of HBV infection and summarize our current knowledge on the effects of HBV mutations in different regions on HBV-associated pathogenesis, with an emphasis on mutations in the preS/S proteins in immune evasion, occult HBV infection and hepatocellular carcinoma (HCC), mutations in polymerase in relation to drug resistance, mutations in HBV core and e antigen in immune evasion, chronicalization of infection and hepatitis B-related acute-on-chronic liver failure, and finally mutations in HBV x proteins in HCC.
doi:10.3748/wjg.v22.i1.126
PMCID: PMC4698480  PMID: 26755865
Hepatitis B virus; Genotype; Variation; Pathogenesis
8.  Risk Distribution of Human Infections with Avian Influenza H7N9 and H5N1 virus in China 
Scientific Reports  2015;5:18610.
It has been documented that the epidemiological characteristics of human infections with H7N9 differ significantly between H5N1. However, potential factors that may explain the different spatial distributions remain unexplored. We use boosted regression tree (BRT) models to explore the association of agro-ecological, environmental and meteorological variables with the occurrence of human cases of H7N9 and H5N1, and map the probabilities of occurrence of human cases. Live poultry markets, density of human, coverage of built-up land, relative humidity and precipitation were significant predictors for both. In addition, density of poultry, coverage of shrub and temperature played important roles for human H7N9 infection, whereas human H5N1 infection was associated with coverage of forest and water body. Based on the risks and distribution of ecological characteristics which may facilitate the circulation of the two viruses, we found Yangtze River Delta and Pearl River Delta, along with a few spots on the southeast coastline, to be the high risk areas for H7N9 and H5N1. Additional, H5N1 risk spots were identified in eastern Sichuan and southern Yunnan Provinces. Surveillance of the two viruses needs to be enhanced in these high risk areas to reduce the risk of future epidemics of avian influenza in China.
doi:10.1038/srep18610
PMCID: PMC4686887  PMID: 26691585
9.  Structural and Biochemical Characterization of AidC, a Quorum-Quenching Lactonase With Atypical Selectivity 
Biochemistry  2015;54(28):4342-4353.
Quorum-quenching catalysts are of interest for potential application as biochemical tools to interrogate interbacterial communication pathways, as anti-biofouling agents, and as anti-infective agents in plants and animals. Herein, the structure and function of AidC, an N-acyl-L-homoserine (AHL) lactonase from Chryseobacterium, is characterized. Steady-state kinetics show that zinc-supplemented AidC is one of the most efficient wild-type quorum-quenching enzymes characterized to date, with a kcat/KM value of approximately 2 × 106 M−1s−1 for N-heptanoyl-L-homoserine lactone. The enzyme has stricter substrate selectivity and significantly lower KM values (ca. 50 μM for preferred substrates) than typical AHL lactonases (ca. > 1 mM). X-ray crystal structures of AidC alone, and with the product N-hexanoyl-L-homoserine were determined at resolutions of 1.09 and 1.67 Å, respectively. Each structure displays as a dimer, and dimeric oligiomerization was also observed in solution by size-exclusion chromatography coupled with multi-angle light scattering. The structures reveal two atypical features as compared to previously characterized AHL lactonases: a ‘kinked’ α-helix that forms part of a closed binding pocket which provides affinity and enforces selectivity for AHL substrates, and an active-site His substitution that is usually found in a homologous family of phosphodiesterases. Implications for the catalytic mechanism of AHL lactonases are discussed.
doi:10.1021/acs.biochem.5b00499
PMCID: PMC4681436  PMID: 26115006
Quorum-quenching; N-acyl-L-homoserine lactone; lactonase; dizinc
10.  Diterpenoids from the Roots of Salvia yunnanensis 
Abstract
Two new diterpenoids, salyunnanins I and J (1 and 2), together with ten analogues, were isolated from the roots of Salvia yunnanensis. The structures of the new isolates, possessing different neo-clerodane and seco-abietane diterpenoid skeletons respectively, were elucidated on the basis of comprehensive spectroscopic data. All of the compounds were tested for the inhibitory activities against six human tumor lines in vitro, and several ones showed moderate cytotoxic activities.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0080-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-015-0080-4
PMCID: PMC4681706  PMID: 26667937
Salvia yunnanensis; Diterpenoid; Cytotoxicity
11.  Trends in All-Cause Mortality across Gestational Age in Days for Children Born at Term 
PLoS ONE  2015;10(12):e0144754.
Background
Term birth is a gestational age from 259 days to 293 days. However trends in mortality according to gestational ages in days have not yet been described in this time period.
Methods and Findings
Based on nation-wide registries, we conducted a population-based cohort study among all children born at term in Denmark from 1997 to 2004 to estimate differences in mortality across gestational ages in days among singletons born at term. We studied early-neonatal mortality, neonatal mortality, infant mortality, and five-year mortality. Children were followed from birth up to the last day of the defined mortality period or December 31, 2009. A total of 360,375 singletons born between 259 and 293 days of gestation were included in the study. Mortality decreased with increasing gestational age in days and the highest mortality was observed among children born at 37 week of gestation. A similar pattern was observed when analyses were restricted to children born to by mothers without pregnancy complications.
Conclusions
This study demonstrates heterogeneity in mortality rates even among singletons born at term. The highest mortality was observed among children born 37 weeks of gestation, which call for cautions when inducing labor in term pregnancies just reaching 37 weeks of gestation. The findings support that 37 weeks of gestation should be defined as early term.
doi:10.1371/journal.pone.0144754
PMCID: PMC4684378  PMID: 26656842
12.  Effects of different types of fluid resuscitation for hemorrhagic shock on splanchnic organ microcirculation and renal reactive oxygen species formation 
Critical Care  2015;19:434.
Introduction
Fluid resuscitation is an indispensable procedure in the acute management of hemorrhagic shock for restoring tissue perfusion, particularly microcirculation in splanchnic organs. Resuscitation fluids include crystalloids, hypertonic saline (HTS), and synthetic colloids, and their selection affects the recovery of microcirculatory blood flow and reactive oxygen species (ROS) formation, which is often evident in the kidney, following reperfusion. In this study, the effects of acute resuscitation with 0.9 % saline (NS), 3 % HTS, 4 % succinylated gelatin (GEL), and 6 % hydroxyethyl starch (HES) 130/0.4 were compared in a hemorrhagic shock rat model to analyze restoration of microcirculation among various splanchnic organs and the gracilis muscle and reperfusion-induced renal ROS formation.
Methods
A total of 96 male Wistar rats were subjected to sham operation (sham group), hemorrhagic shock (control group), and resuscitation with NS, HTS, GEL and HES. Two hours after resuscitation, changes in the mean arterial pressure (MAP), serum lactate level and the microcirculatory blood flow among various splanchnic organs, namely the liver, kidney, and intestine (mucosa, serosal muscular layer, and Peyer’s patch), and the gracilis muscle, were compared using laser speckle contrast imaging. Renal ROS formation after reperfusion was investigated using an enhanced in vivo chemiluminescence (CL) method.
Results
Microcirculatory blood flow was less severely affected by hemorrhaging in the liver and gracilis muscle. Impairment of microcirculation in the kidney was restored in all resuscitation groups. Resuscitation in the NS group failed to restore intestinal microcirculation. Resuscitation in the HTS, GEL, and HES groups restored intestinal microcirculatory blood flow. By comparison, fluid resuscitation restored hemorrhagic shock-induced hypotension and decreased lactatemia in all resuscitation groups. Reperfusion-induced in vivo renal ROS formation was significantly higher in the GEL and HES groups than in the other groups.
Conclusion
Although fluid resuscitation with NS restored the MAP and decreased lactatemia following hemorrhagic shock, intestinal microcirculation was restored only by other volume expanders, namely 3 % HTS, GEL, and HES. However, reperfusion-induced renal ROS formation was significantly higher when synthetic colloids were used.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-1135-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-015-1135-y
PMCID: PMC4699328  PMID: 26651994
13.  Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis. A nationwide cohort study 
Objective
To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA).
Methods
Through linkage of Danish national registries we identified all children born in Denmark between 1977 and 2008. We used general linear regression models to estimate mean differences in indicators of fetal growth among children having a parent with RA compared to unexposed children. Odds ratios of preterm birth were calculated by a logistic regression model.
Results
Of the 1,917,723 children included, a total of 13,556 children were exposed to maternal RA or maternal preclinical RA. Children exposed to maternal RA (2,101) had approximately similar length, head and abdominal circumference at birth, compared with children of mothers without RA. Birth weight was 87 gram lower (−87.04 g; 95% CI, −111.23; −62.84) and placenta weight was 14 gram lower (−13.45 g; 95% CI, −21.46; −5.43). Rather similar results were found in children exposed to maternal preclinical RA (11,455). Compared with unexposed children a higher risk of preterm birth was found in children exposed to maternal RA and maternal preclinical RA respectively (OR, 1.48; 95% CI,1.20;1.84 and OR, 1.32; 95% CI,1.07;1.64). No associations were found with paternal RA.
Conclusion
Children exposed to either maternal RA or maternal preclinical RA are more often born preterm. However, indicators of fetal growth measured at birth were only slightly lower than in unexposed children.
doi:10.1002/art.38874
PMCID: PMC4245456  PMID: 25393524
Rheumatoid arthritis; birth weight; birth length; indicators of fetal growth; preterm birth; pregnancy outcome
14.  Screening and Molecular Analysis of Single Circulating Tumor Cells Using Micromagnet Array 
Scientific Reports  2015;5:16047.
Immunomagnetic assay has been developed to detect rare circulating tumor cells (CTCs), which shows clinical significance in cancer diagnosis and prognosis. The generation and fine-tuning of the magnetic field play essential roles in such assay toward effective single-cell-based analyses of target cells. However, the current assay has a limited range of field gradient, potentially leading to aggregation of cells and nanoparticles. Consequently, quenching of the fluorescence signal and mechanical damage to the cells may occur, which lower the system sensitivity and specificity. We develop a micromagnet-integrated microfluidic system for enhanced CTC detection. The ferromagnetic micromagnets, after being magnetized, generate localized magnetic field up to 8-fold stronger than that without the micromagnets, and strengthen the interactions between CTCs and the magnetic field. The system is demonstrated with four cancer cell lines with over 97% capture rate, as well as with clinical samples from breast, prostate, lung, and colorectal cancer patients. The system captures target CTCs from patient blood samples on a standard glass slide that can be examined using the fluorescence in-situ hybridization method for the single-cell profiling. All cells showed clear hybridization signals, indicating the efficacy of the compact system in providing retrievable cells for molecular studies.
doi:10.1038/srep16047
PMCID: PMC4633592  PMID: 26538094
15.  miR-132 can inhibit glioma cells invasion and migration by target MMP16 in vitro 
OncoTargets and therapy  2015;8:3211-3218.
Gliomas are the most common malignant primary brain tumors, and new clinical biomarkers and therapeutic targets are imminently required. MicroRNAs (miRNAs) are a novel class of small non-coding RNAs (∼22nt) involved in the regulation of various biological processes. Here, by using real-time polymerase chain reaction, miRNA-132 was found to be significantly deregulated in glioma tissues. Based on the prediction of the target genes of miR-132, we hypothesized that there is a significant association between miR-132 and matrix metalloproteinase (MMP) 16 (MT3-MMP), a protein of the MMP family. We showed that the up-expression of miR-132 inhibited cell migration and invasion in the human glioma cell lines A172, SHG44, and U87. Furthermore, the overexpression of miR-132 reduced the expression of MMP16 in A172, SHG44, and U87 cells. Taken together, our study suggested that miR-132 affects glioma cell migration and invasion by MMP16 and implicates miR-132 as a metastasis-inhibiting miRNA in gliomas.
doi:10.2147/OTT.S79282
PMCID: PMC4640442  PMID: 26604788
gliocytoma; microRNA; MT3-MMP; invasions
16.  Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity 
Acute lung injury (ALI) is characterized by excessive inflammatory responses and oxidative injury in the lung tissue. It has been suggested that anti-inflammatory or antioxidative agents could have therapeutic effects in ALI, and eriodictyol has been reported to exhibit antioxidative and anti-inflammatory activity in vitro. The aim of the present study was to investigate the effect of eriodictyol on lipopolysaccharide (LPS)-induced ALI in a mouse model. The mice were divided into four groups: Phosphate-buffered saline-treated healthy control, LPS-induced ALI, vehicle-treated ALI (LPS + vehicle) and eriodictyol-treated ALI (LPS + eriodictyol). Eriodictyol (30 mg/kg) was administered orally once, 2 days before the induction of ALI. The data showed that eriodictyol pretreatment attenuated LPS-induced ALI through its antioxidative and anti-inflammatory activity. Furthermore, the eriodictyol pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in the ALI mouse model, which attenuated the oxidative injury and inhibited the inflammatory cytokine expression in macrophages. In combination, the results of the present study demonstrated that eriodictyol could alleviate the LPS-induced lung injury in mice by regulating the Nrf2 pathway and inhibiting the expression of inflammatory cytokines in macrophages, suggesting that eriodictyol could be used as a potential drug for the treatment of LPS-induced lung injury.
doi:10.3892/etm.2015.2827
PMCID: PMC4665393  PMID: 26668626
eriodictyol; lipopolysaccharide-induced acute lung injury; acute lung injury; nuclear factor erythroid-2-related factor 2 pathway
17.  Disruption of Type I Interferon Signaling by the Nonstructural Protein of Severe Fever with Thrombocytopenia Syndrome Virus via the Hijacking of STAT2 and STAT1 into Inclusion Bodies 
Journal of Virology  2015;89(8):4227-4236.
ABSTRACT
The type I interferon (IFN) system, including IFN induction and signaling, is the critical component of the host defense line against viral infection, which, in turn, is also a vulnerable target for viral immune evasion. Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus. Previous data have shown that SFTSV can interfere with the early induction of type I IFNs through targeting host kinases TBK1/IKKε. In this study, we demonstrated that SFTSV also can suppress type I IFN-triggered signaling and interferon-stimulated gene (ISG) expression. Interestingly, we observed the significant inhibition of IFN signaling in cells transfected with the plasmids encoding the nonstructural protein (NSs) but not the nucleocapsid protein (NP), indicating the role of NSs as an antagonist of IFN signaling. Furthermore, coimmunoprecipitation (Co-IP) and pulldown assays indicated that NSs interacts with the cellular signal transducer and activator of transcription 2 (STAT2), and the DNA-binding domain of STAT2 may contribute to the NSs-STAT2 interaction. Combined with confocal microscopy analyses, we demonstrated that NSs sequesters STAT2 and STAT1 into viral inclusion bodies (IBs) and impairs IFN-induced STAT2 phosphorylation and nuclear translocation of both STATs, resulting in the inhibition of IFN signaling and ISG expression. SFTSV NSs-mediated hijacking of STATs in IBs represents a novel mechanism of viral suppression of IFN signaling, highlighting the role of viral IBs as the virus-built “jail” sequestering some crucial host factors and interfering with the corresponding cellular processes.
IMPORTANCE SFTSV is an emerging bunyavirus which can cause a severe hemorrhagic fever-like disease with high case fatality rates in humans, posing a serious health threat. However, there are no specific antivirals available, and the pathogenesis and virus-host interactions are largely unclear. Here, we demonstrated that SFTSV can inhibit type I IFN antiviral signaling by the NSs-mediated hijacking of STAT2 and STAT1 into viral IBs, highlighting the interesting role of viral IBs in virus-host interactions as the virus-built jail. Sequestering signaling molecules into IBs represents a novel and, perhaps, also a general mechanism of viral suppression of IFN signaling, the understanding of which may benefit the study of viral pathogenesis and the development of antiviral therapies.
doi:10.1128/JVI.00154-15
PMCID: PMC4442386  PMID: 25631085
18.  Severity of Birth Defects After Propylthiouracil Exposure in Early Pregnancy 
Thyroid  2014;24(10):1533-1540.
Background: Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated.
Methods: Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730).
Results: Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04–11.86) and in the urinary system 2.73 (1.22–6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs).
Conclusions: We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.
doi:10.1089/thy.2014.0150
PMCID: PMC4195247  PMID: 24963758
19.  Surface Engineering of ZnO Thin Film for High Efficiency Planar Perovskite Solar Cells 
Scientific Reports  2015;5:13211.
Sputtering made ZnO thin film was used as an electron-transport layer in a regular planar perovskite solar cell based on high quality CH3NH3PbI3 absorber prepared with a two-step spin-coating. An efficiency up to 15.9% under AM 1.5G irradiation is achieved for the cell based on ZnO film fabricated under Ar working gas. The atmosphere of the sputtering chamber can tune the surface electronic properties (band structure) of the resulting ZnO thin film and therefore the photovoltaic performance of the corresponding perovskite solar cell. Precise surface engineering of ZnO thin film was found to be one of the key steps to fabricate ZnO based regular planar perovskite solar cell with high power conversion efficiency. Sputtering method is proved to be one of the excellent techniques to prepare ZnO thin film with controllable properties.
doi:10.1038/srep13211
PMCID: PMC4585934  PMID: 26411577
20.  Bioinformatics and Molecular Biological Characterization of a Hypothetical Protein SAV1226 as a Potential Drug Target for Methicillin/Vancomycin-Staphylococcus aureus Infections 
Methicillin/multiple-resistant Staphylococcus aureus (MRSA) are infectious bacteria that are resistant to common antibiotics. A previous in silico study in our group has identified a hypothetical protein SAV1226 as one of the potential drug targets. In this study, we reported the bioinformatics characterization, as well as cloning, expression, purification and kinetic assays of hypothetical protein SAV1226 from methicillin/vancomycin-resistant Staphylococcus aureus Mu50 strain. MALDI-TOF/MS analysis revealed a low degree of structural similarity with known proteins. Kinetic assays demonstrated that hypothetical protein SAV1226 is neither a domain of an ATP dependent dihydroxyacetone kinase nor of a phosphotransferase system (PTS) dihydroxyacetone kinase, suggesting that the function of hypothetical protein SAV1226 might be misannotated on public databases such as UniProt and InterProScan 5.
PMCID: PMC4572700  PMID: 26388980
Dihydroxyacetone kinase; essential genes; Methicillin-resistant Staphylococcus aureus; drug target
21.  DNMT1-dependent suppression of microRNA424 regulates tumor progression in human bladder cancer 
Oncotarget  2015;6(27):24119-24131.
The aim of this study was to examine the role of miRNAs regulation by DNMT1 and its underlying mechanisms in bladder cancer. The choice of target miRNAs was based on the analysis of a TaqMan MicroRNA Panel assay. The role of target miRNA in tumor behavior and the related signaling pathways were assessed using the human bladder cancer cell lines. We also evaluated the predictive power of the target miRNA and its link to DNMT1 from 124 clinical bladder cancer specimens. Our results revealed that the miR-424 level is significantly increased when blocking DNMT1 in bladder cancer cells. From the clinical specimen analysis, the staining of miR-424 was inversely correlated with DNMT1 immunoreactivity. The lack of miR-424 expression was significantly linked to aggressive tumor growth, advanced clinical stage and poor prognosis in bladder cancer. Increased miR-424 suppressed the tumor growth rate and invasion ability determined in vitro and in vivo. Furthermore, the EGFR pathway plays a role in the transmission of the miR-424 signal that regulates cell growth and the epithelial-to-mesenchymal transition. These results highlight a potential role for miR-424 as a molecular predictor and therapeutic target in bladder cancer.
PMCID: PMC4695174  PMID: 26090723
bladder cancer; miR424; DNMT1; EGFR
22.  A Novel Method for the Discrimination of Semen Arecae and Its Processed Products by Using Computer Vision, Electronic Nose, and Electronic Tongue 
Areca nut, commonly known locally as Semen Arecae (SA) in China, has been used as an important Chinese herbal medicine for thousands of years. The raw SA (RAW) is commonly processed by stir-baking to yellow (SBY), stir-baking to dark brown (SBD), and stir-baking to carbon dark (SBC) for different clinical uses. In our present investigation, intelligent sensory technologies consisting of computer vision (CV), electronic nose (E-nose), and electronic tongue (E-tongue) were employed in order to develop a novel and accurate method for discrimination of SA and its processed products. Firstly, the color parameters and electronic sensory responses of E-nose and E-tongue of the samples were determined, respectively. Then, indicative components including 5-hydroxymethyl furfural (5-HMF) and arecoline (ARE) were determined by HPLC. Finally, principal component analysis (PCA) and discriminant factor analysis (DFA) were performed. The results demonstrated that these three instruments can effectively discriminate SA and its processed products. 5-HMF and ARE can reflect the stir-baking degree of SA. Interestingly, the two components showed close correlations to the color parameters and sensory responses of E-nose and E-tongue. In conclusion, this novel method based on CV, E-nose, and E-tongue can be successfully used to discriminate SA and its processed products.
doi:10.1155/2015/753942
PMCID: PMC4558443  PMID: 26366185
23.  Defining the Molecular Basis of Amyloid Inhibitors: Human Islet Amyloid Polypeptide–Insulin Interactions 
Journal of the American Chemical Society  2014;136(37):12912-12919.
Human islet amyloid polypeptide (hIAPP or Amylin) is a 37 residue hormone that is cosecreted with insulin from the pancreatic islets. The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts. Despite considerable effort, little is known about the mode of action of IAPP amyloid inhibitors, and this has limited rational drug design. Insulin is one of the most potent inhibitors of hIAPP fibril formation, but its inhibition mechanism is not understood. In this study, the aggregation of mixtures of hIAPP with insulin, as well as with the separate A and B chains of insulin, were characterized using ion mobility spectrometry-based mass spectrometry and atomic force microscopy. Insulin and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform, an aggregation-prone conformation, and thus inhibit hIAPP from forming β-sheets and subsequently amyloid fibrils. All-atom molecular modeling supports these conclusions.
doi:10.1021/ja504031d
PMCID: PMC4183647  PMID: 25144879
24.  Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors 
BMC Infectious Diseases  2015;15:352.
Background
Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.
Methods
In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7−/− mice) blockages of α7 nAChR.
Results
As shown in our in vivo studies, BBB injury was significantly reduced in α7−/− mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7−/− animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).
Conclusions
Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.
doi:10.1186/s12879-015-1075-9
PMCID: PMC4543465  PMID: 26285576
25.  Identification of Bufavirus-1 and Bufavirus-3 in Feces of Patients with Acute Diarrhea, China 
Scientific Reports  2015;5:13272.
Bufavirus (BuV) is a newly discovered human parvovirus that has been detected in some countries. The current study was designed to understand the epidemic of BuV in China. Totally 1877 fecal specimens were collected from pediatric and adult patients with acute diarrhea in two large hospitals from 2010 to 2014. BuV was detected in 0.5% (9/1877) of the fecal samples by PCR and subsequent sequencing. The positive patients had a wide age range from 1 month through 60 years (median 24 years old) and 6 were male. A geographic specific pattern was obvious, with significantly higher frequency of BuV presented in Northern than in Southern China. Four BuV-1 and five BuV-3 were determined. Mixed-infections of BuV with sapovirus and novavirus were found in 2 cases, respectively. A temporal clustering was identified, with most positive detection focused in the cold weather. These findings have expanded the current knowledge on the geographic boundaries of BuV circulation.
doi:10.1038/srep13272
PMCID: PMC4541159  PMID: 26286376

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