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1.  A Cationic-Independent Mannose 6-Phosphate Receptor Inhibitor (PXS64) Ameliorates Kidney Fibrosis by Inhibiting Activation of Transforming Growth Factor-β1 
PLoS ONE  2015;10(2):e0116888.
The activity of transforming growth factor-β1 (TGF-β1) is regulated by its conversion from the latent to the active form. We have previously shown that the conversion is at least in part mediated by the cationic-independent mannose 6-phosphate receptor (CI-M6PR), as the CI-M6PR inhibitor, PXS-25 has anti-fibrotic properties in human kidney tubular (HK-2) cells under high glucose conditions. However, its clinical use is limited by low bioavailability. Our aim was to determine the effects of PXS64, a pro-drug of PXS25, in in vitro and in vivo models of renal fibrosis. HK-2 cells were exposed to latent TGFβ1+/- PXS64 for 48 hours. The mRNA and protein levels of pro-fibrotic and pro-inflammatory markers were determined. A 7 day unilateral ureteric obstruction (UUO) model was used and the following experimental groups were studied: (i) Sham operated, (ii) UUO, (iii) UUO + telmisartan (iv) UUO + PSX64. HK-2 cells exposed to PXS64 reduced TGFβ mediated effects on collagen IV, fibronectin, macrophage chemotactic protein-1 (MCP-1) and phospho-smad2 protein expression, consistent with inhibition of the conversion of latent to active TGF-β1. PXS 64 treated UUO mice had a lower tubulointerstitial fibrosis index, collagen IV and fibronectin protein and mRNA expression when compared to untreated UUO mice. In addition, these animals had lower MCP-1 mRNA expression, reduced inflammarory cell infiltrate, as indicated by fewer CD45, F4/80 positive cells, and reduced phospho-Smad2 protein expression when compared to untreated UUO animals. Our data demonstrates that PSX64 is an effective anti-fibrotic agent by inhibiting the activation of latent TGF-β1.
doi:10.1371/journal.pone.0116888
PMCID: PMC4319899  PMID: 25658916
2.  Transcription of the Lysine-2,3-Aminomutase Gene in the kam Locus of Bacillus thuringiensis subsp. kurstaki HD73 Is Controlled by Both σ54 and σK Factors 
Journal of Bacteriology  2014;196(16):2934-2943.
Lysine 2,3-aminomutase (KAM; EC 5.4.3.2) catalyzes the interconversion of l-lysine and l-β-lysine. The transcription and regulation of the kam locus, including lysine-2,3-aminomutase-encoding genes, in Bacillus thuringiensis were analyzed in this study. Reverse transcription-PCR (RT-PCR) analysis revealed that this locus forms two operons: yodT (yodT-yodS-yodR-yodQ-yodP-kamR) and kamA (kamA-yokU-yozE). The transcriptional start sites (TSSs) of the kamA gene were determined using 5′ rapid amplification of cDNA ends (RACE). A typical −12/−24 σ54 binding site was identified in the promoter PkamA, which is located upstream of the kamA gene TSS. A β-galactosidase assay showed that PkamA, which directs the transcription of the kamA operon, is controlled by the σ54 factor and is activated through the σ54-dependent transcriptional regulator KamR. The kamA operon is also controlled by σK and regulated by the GerE protein in the late stage of sporulation. kamR and kamA mutants were prepared by homologous recombination to examine the role of the kam locus. The results showed that the sporulation rate in B. thuringiensis HD(ΔkamR) was slightly decreased compared to that in HD73, whereas that in HD(ΔkamA) was similar to that in HD73. This means that other genes regulated by KamR are important for sporulation.
doi:10.1128/JB.01675-14
PMCID: PMC4135644  PMID: 24914178
3.  Use of Health Plan Combined with Registry Data to Predict Clinical Trial Recruitment 
Background
Large pragmatic clinical trials (PCTs) are increasingly used to conduct comparative effectiveness research. In the context of planning a safety PCT of the live herpes zoster vaccine in rheumatoid arthritis (RA) patients age ≥ 50 receiving anti- tumor necrosis factor (TNF) therapy, we evaluated the use of health plan combined with registry data to assess the feasibility of recruiting the 4,000 patients needed for the trial and to facilitate site selection.
Methods
Using national United States data from Medicare, we identified older RA patients who received anti-TNF therapy in the last quarter of 2009. Extrapolations were made from the Medicare patient population to younger patients and those with other types of insurance using the Consortium of Rheumatology Researchers of North America (CORRONA) disease registry. Patients’ treating rheumatologists were grouped into practices and sorted by size from the greatest to the least number of eligible patients.
Results
Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1,980 physician practices. After augmenting Medicare data with information from CORRONA and extrapolating to younger patients and those with other types of insurance, more than 12,000 potentially eligible study subjects were identified from the 40-45 largest rheumatology practices.
Conclusion
Health plan and registry databases appear useful to assess feasibility of large pragmatic trials and to assist in selection of recruitment sites with the greatest number of potentially eligible patients. This novel approach is applicable to trials with simple inclusion/exclusion criteria that can be readily assessed in these data sources.
doi:10.1177/1740774513512185
PMCID: PMC4199104  PMID: 24346611
pragmatic trial; clinical trial; registry; administrative data; recruitment; rheumatoid arthritis; anti-TNF therapy; herpes zoster; shingles
4.  Functional Study of -724I/D Polymorphism in Apolipoprotein M (apoM) Gene Promoter Region and its Association with Myocardial Infarction 
Background
The aim of this study was to detect the function of -724I/D polymorphism in the apolipoprotein M (apoM) gene promoter region and to determine its relationship with myocardial infarction (MI).
Material/Methods
We selected 309 patients with MI and 309 healthy controls for this case-control study. The PCR products of the apoM gene promoter region were directly sequenced to analyze the -724I/D polymorphism. Differences in frequency distributions of genotype and allele were compared between the MI group and the control group. We used gene recombination and site-directed mutagenesis technique to observe the impact of -724 I/D on transcription activity of apoM gene promoter in vitro.
Results
The allele frequency of the -724Del in the MI group was higher than that in the control group (9.5% vs. 3.2%, OR=3.156, 95% CI (1.876~5.309), P<0.001). Compared to the I/I genotype carriers, the apoM levels decreased but the total cholesterol (TC) levels increased significantly in the -724Del allele carriers in plasma. The activity of apoM I/I genotype promoter decreased significantly after the deletion mutation at -724 position in apoM gene.
Conclusions
-724 I/D polymorphism decreases the apoM promoter activity, down-regulates the apoM protein expression level, and increases the risk of MI.
doi:10.12659/MSM.893077
PMCID: PMC4321410  PMID: 25637426
Amplified Fragment Length Polymorphism Analysis; Apoprotein(a); Coronary Artery Disease
5.  Spatiotemporal chaotic unjamming and jamming in granular avalanches 
Scientific Reports  2015;5:8128.
We have investigated the spatiotemporal chaotic dynamics of unjamming and jamming of particles in a model experiment – a rotating drum partially filled with bidisperse disks to create avalanches. The magnitudes of the first Lyapunov vector δu(t) and velocity v(t) of particles are directly measured for the first time to yield insights into their spatial correlation Cδu,v, which is on statistical average slightly larger near the unjamming than the value near the jamming transition. These results are consistent with the recent work of Banigan et al (Nature Phys. 2013), and it is for the first time to validate their theoretical models in a real scenario. v(t) shows rich dynamics: it grows exponentially for unstable particles and keeps increasing despite stochastic interactions; after the maximum, it decays with large fluctuations. Hence the spatiotemporal chaotic dynamics of avalanche particles are entangled, causing temporal correlations of macroscopic quantities of the system. We propose a simple model for these observations.
doi:10.1038/srep08128
PMCID: PMC4311237  PMID: 25634753
6.  Oxygen Transport in a Three-Dimensional Microvascular Network Incorporated with Early Tumour Growth and Preexisting Vessel Cooption: Numerical Simulation Study 
BioMed Research International  2015;2015:476964.
We propose a dynamic mathematical model of tissue oxygen transport by a preexisting three-dimensional microvascular network which provides nutrients for an in situ cancer at the very early stage of primary microtumour growth. The expanding tumour consumes oxygen during its invasion to the surrounding tissues and cooption of host vessels. The preexisting vessel cooption, remodelling and collapse are modelled by the changes of haemodynamic conditions due to the growing tumour. A detailed computational model of oxygen transport in tumour tissue is developed by considering (a) the time-varying oxygen advection diffusion equation within the microvessel segments, (b) the oxygen flux across the vessel walls, and (c) the oxygen diffusion and consumption within the tumour and surrounding healthy tissue. The results show the oxygen concentration distribution at different time points of early tumour growth. In addition, the influence of preexisting vessel density on the oxygen transport has been discussed. The proposed model not only provides a quantitative approach for investigating the interactions between tumour growth and oxygen delivery, but also is extendable to model other molecules or chemotherapeutic drug transport in the future study.
doi:10.1155/2015/476964
PMCID: PMC4324812
7.  Anti-inflammatory deficiencies in neutrophilic asthma: reduced galectin-3 and IL-1RA/IL-1β 
Respiratory Research  2015;16(1):5.
Background
Galectin-3 (gal-3), a member of the β-galactoside-binding animal lectins, is involved in the recruitment, activation and removal of neutrophils. Neutrophilic asthma is characterized by a persistent elevation of airway neutrophils and impaired efferocytosis. We hypothesized that sputum gal-3 would be reduced in neutrophilic asthma and the expression of gal-3 would be associated with other markers of neutrophilic inflammation.
Methods
Adults with asthma (n = 80) underwent a sputum induction following clinical assessment and blood collection. Sputum was dispersed for a differential cell count and ELISA assessment of gal-3, gal-3 binding protein (BP), interleukin (IL)-1β, IL-1 receptor antagonist (RA), IL-8 and IL-6. Gal-3 and gal-3BP immunoreactivity were assessed in mixed sputum cells.
Results
Sputum gal-3 (median, (q1,q3)) was significantly reduced in neutrophilic asthma (183 ng/mL (91,287)) compared with eosinophilic (293 ng/mL (188,471), p = 0.021) and paucigranulocytic asthma (399 ng/mL (213,514), p = 0.004). The gal-3/gal-3BP ratio and IL-1RA/IL-1β ratio were significantly reduced, while gal-3BP and IL-1β were significantly elevated in neutrophilic asthma compared with eosinophilic and paucigranulocytic asthma.
Conclusion
Patients with neutrophilic asthma have impairment in anti-inflammatory ratio of gal-3/gal-3BP and IL-1RA/IL-1β which provides a further framework for exploration into pathologic mechanisms of asthma phenotypes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0163-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-014-0163-5
PMCID: PMC4314745  PMID: 25616863
Asthma; Galectin-3; Induced sputum; Neutrophil; Macrophage; IL-1β; lectin
8.  Self-assembling surfactant-like peptide A6K as potential delivery system for hydrophobic drugs 
Background
Finding a suitable delivery system to improve the water solubility of hydrophobic drugs is a critical challenge in the development of effective formulations. In this study, we used A6K, a self-assembling surfactant-like peptide, as a carrier to encapsulate and deliver hydrophobic pyrene.
Methods
Pyrene was mixed with A6K by magnetic stirring to form a suspension. Confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, atomic force microscopy, fluorescence, and cell uptake measurements were carried out to study the features and stability of the nanostructures, the state and content of pyrene, as well as the pyrene release profile.
Results
The suspension formed contained pyrene monomers trapped in the hydrophobic cores of the micellar nanofibers formed by A6K, as well as nanosized pyrene crystals wrapped up and stabilized by the nanofibers. The two different encapsulation methods greatly increased the concentration of pyrene in the suspension, and formation of pyrene crystals wrapped up by A6K nanofibers might be the major contributor to this effect. Furthermore, the suspension system could readily release and transfer pyrene into living cells.
Conclusion
A6K could be further exploited as a promising delivery system for hydrophobic drugs.
doi:10.2147/IJN.S71696
PMCID: PMC4315539
pyrene; self-assembling peptide; micelles; nanofibers; drug delivery
9.  Efficacy of fine-needle aspiration cytology for a thyroid abscess in children: Two case reports 
A thyroid abscess caused by acute suppurative thyroiditis (AST) is a rare form of thyroid nodule, and is most common in children, particularly in the first decade of life. The echotexture of an abscess may vary depending on the extent of internal debris or hemorrhage and on the peripheral and interval vascular flow; thus, a definitive diagnosis of AST is difficult to establish. The present study reports two cases of a thyroid abscess in children caused by viridans streptococci, diagnosed using ultrasound-guided fine-needle aspiration cytology (FNAC) and bacterial culturing. FNAC of the thyroid gland may be used extensively in children for the diagnosis of AST and thyroid abscesses. In addition, FNAC is an efficient method for differentiating between benign and malignant nodules of the thyroid gland, in order to ensure that the appropriate treatment is administered.
doi:10.3892/etm.2015.2189
PMCID: PMC4316975  PMID: 25667642
acute suppurative thyroiditis; thyroid abscess; ultrasound-guided fine-needle aspiration cytology; children
10.  Developing the Psychological Strain Scales (PSS): Reliability, Validity, and Preliminary Hypothesis Tests1 
Social indicators research  2012;115(1):337-361.
Since its inception, the Strain Theory of Suicide has been tested and supported in a number of empirical studies. This social psychological theory can be employed as a complementary conceptualization to account for suicidal behaviors as well as mental disorders. However, the lack of consistent measurements of the strains limits the application of the theory in scientific research. Our research team has developed such scales for future testing of the Strain Theory of Suicide in a more systematic approach. For the initial items to measure the four strains (value, aspiration, deprivation, and coping), we solicited approximately 40 items for each strain with high face validity by about 30 fellow researchers. A preliminary examination of about 160 items for consistency and validity, with a sample of about 300 college students, yielded 20 consistent items for each of the four strain scales. Then, a second study was conducted at a different university with approximately 500 students to further streamline each of the four strain scales and test the validity of each with corresponding established scales and variables. As a result, 15 items were selected for each of the four Psychological Strain Scales (PSS). In correlation and multiple regression analyses, we found support for the hypotheses regarding the positive associations between psychological strains measured by the PSS and psychopathology including suicidal ideation. Follow up research with the new scales needs to be carried out in order to test the effects of psychological strains on suicide and mental disorders for various populations.
doi:10.1007/s11205-012-0222-6
PMCID: PMC3891678  PMID: 24443628
Psychological Strain; Reliability; Validity; Mental Disorder; Suicide
11.  Suicide Risks among Adolescents and Young Adults in Rural China 
Background: In China, suicide is one of the major causes of death among adolescents and young adults aged 15 to 34 years. Aim: The current study examines how risk factors vary by age groups in rural China, referring to those aged 15 to 24 years and those aged 25 to 34 years. Method: A case-control psychological autopsy (PA) study is conducted in sixteen counties from three Chinese provinces, including 392 suicide cases and 416 community living controls in the sample. Results: In China, young adults aged 25 to 34 years have a higher risk for suicide than adolescents aged 15 to 24 years, and it holds true even controlling for relevant social factors. In addition, age-related factors such as education, marital status, whether having children, status in the family, physical health, and personal income all have varying degrees of impact on suicide risks for rural youth. Conclusions: This study shows that there are some age-related risk factors for suicide at certain life stages and emphasizes that young adults in rural China aged 25 to 34 years have an increased risk of suicide as a result of experiencing more psychological strains with age.
doi:10.3390/ijerph120100131
PMCID: PMC4306853  PMID: 25546276
suicide; risk factors; adolescent; young adult
12.  MicroRNA-503 Acts as a Tumor Suppressor in Osteosarcoma by Targeting L1CAM 
PLoS ONE  2014;9(12):e114585.
Deregulated microRNAs and their roles in tumorigenesis have attracted much attention in recent years. Although miR-503 was shown to be important in tumorigenesis, its role in osteosarcoma remains unknown. In this study, we focused on the expression and mechanisms of miR-503 in osteosarcoma development. We found that miR-503 was down-regulated in osteosarcoma cell lines and primary tumor samples, and the restoration of miR-503 reduced cell proliferation, migration and invasion. Low level of miR-503 in patients with osteosarcoma was associated with considerably shortened disease-free survival. Furthermore, bioinformatic prediction and experimental validation revealed that the anti-tumor effect of miR-503 was probably exerted through targeting and repressing of L1CAM expression. L1CAM was up-regulated in osteosarcoma cell lines and primary tumor samples and the expression level of L1CAM were negatively correlated with miR-503 levels in osteosarcoma tissues. Collectively, our data identify the important roles of miR-503 in osteosarcoma pathogenesis, indicating its potential application in cancer therapy.
doi:10.1371/journal.pone.0114585
PMCID: PMC4275157  PMID: 25536034
13.  Activation of gab cluster transcription in Bacillus thuringiensis by γ-aminobutyric acid or succinic semialdehyde is mediated by the Sigma 54-dependent transcriptional activator GabR 
BMC Microbiology  2014;14(1):2317.
Background
Bacillus thuringiensis GabR is a Sigma 54-dependent transcriptional activator containing three typical domains, an N-terminal regulatory domain Per-ARNT-Sim (PAS), a central AAA+ (ATPases associated with different cellular activities) domain and a C-terminal helix-turn-helix (HTH) DNA binding domain. GabR positively regulates the expression of the gabT gene of the gab gene cluster, which is responsible for the γ-aminobutyric acid (GABA) shunt.
Results
Purified GabR was shown to specifically bind to a repeat region that mapped 58 bp upstream of the gabT start codon. The specific signal factors GABA and succinic semialdehyde (SSA) activated gabT expression, whereas GABA- and SSA-inducible gabT transcription was abolished in sigL and gabR mutants. GABA and SSA did not induce the expression of either SigL or GabR. Deletion of the PAS domain of GabR resulted in increased gabT transcriptional activity, both in the presence and absence of GABA.
Conclusions
This study identified the GabR-binding site on the gabT promoter; however, GabR does not bind to its own promoter. gabT transcription is induced by GABA and SSA, and inducible expression is dependent on SigL and activated by GabR. The PAS domain in GabR is repressing its enhancer transcriptional activity on the gabT promoter. Repression is released upon GABA addition, whereupon transcription is induced.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0306-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0306-3
PMCID: PMC4279683  PMID: 25527261
GabR; Sigma 54; GABA; SSA; PAS domain
14.  Brd4 and JMJD6-associated Anti-pause Enhancers in Regulation of Transcriptional Pause Release 
Cell  2013;155(7):1581-1595.
SUMMARY
Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease.
doi:10.1016/j.cell.2013.10.056
PMCID: PMC3886918  PMID: 24360279
15.  Real-time earthquake monitoring using a search engine method 
Nature Communications  2014;5:5664.
When an earthquake occurs, seismologists want to use recorded seismograms to infer its location, magnitude and source-focal mechanism as quickly as possible. If such information could be determined immediately, timely evacuations and emergency actions could be undertaken to mitigate earthquake damage. Current advanced methods can report the initial location and magnitude of an earthquake within a few seconds, but estimating the source-focal mechanism may require minutes to hours. Here we present an earthquake search engine, similar to a web search engine, that we developed by applying a computer fast search method to a large seismogram database to find waveforms that best fit the input data. Our method is several thousand times faster than an exact search. For an Mw 5.9 earthquake on 8 March 2012 in Xinjiang, China, the search engine can infer the earthquake’s parameters in <1 s after receiving the long-period surface wave data.
Reporting earthquakes, including location and focal mechanism, in real time is a challenge. Here, the authors present an approach similar to a web search engine, estimating earthquake parameters by searching a large database within a second, which will potentially enable early warning systems.
doi:10.1038/ncomms6664
PMCID: PMC4268708  PMID: 25472861
16.  Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study 
BMC Bioinformatics  2014;15(Suppl 17):S6.
Background
Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health.
Methods
In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options.
Results
After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases.
Conclusion
In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety.
doi:10.1186/1471-2105-15-S17-S6
PMCID: PMC4304199  PMID: 25559675
17.  POLY(ADP-RIBOSE) POLYMERASE (PARP) INHIBITION COUNTERACTS MULTIPLE MANIFESTATIONS OF KIDNEY DISEASE IN LONG-TERM STREPTOZOTOCIN-DIABETIC RAT MODEL 
Biochemical pharmacology  2009;79(7):1007-1014.
Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30 mg kg−1d−1, for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2′-deoxyguanosine excretion, and renal concentrations of transforming growth factor-β1, vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays. PARP inhibition counteracted diabetes-associated increase in renal cortex poly(ADP-ribosyl)ated protein level. Urinary albumin, isoprostane, and 8-hydroxy-2′-deoxyguanosine excretions and urinary albumin/creatinine ratio were increased in diabetic rats, and all these changes were at least partially prevented by GPI-15,427 treatment. PARP inhibition counteracted diabetes-induced renal transforming growth factor-β1, vascular endothelial growth factor, and fibronectin, but not soluble intercellular adhesion molecule-1 and nitrotyrosine, accumulations. Lipid peroxidation product concentrations were indistinguishable among control and diabetic rats maintained with or without GPI-15,427 treatment. In conclusion, PARP activation plays an important role in kidney disease in long-term diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies, for prevention and treatment of diabetic nephropathy.
doi:10.1016/j.bcp.2009.11.018
PMCID: PMC4259265  PMID: 19945439
Poly(ADP-ribose) polymerase; diabetic nephropathy; streptozotocin-diabetic rat; oxidative-nitrosative stress; vascular endothelial growth factor; transforming growth factor-β
18.  Induction of mucosal immune responses and protection of cattle against direct-contact challenge by intranasal delivery with foot-and-mouth disease virus antigen mediated by nanoparticles 
The aim of this study was to enhance specific mucosal, systemic, and cell-mediated immunity and to induce earlier onset of protection against direct-contact challenge in cattle by intranasal delivery of a nanoparticle-based nasal vaccine against type A foot-and-mouth disease (FMD). In this study, two kinds of nanoparticle-based nasal vaccines against type A FMD were designed: (1) chitosan-coated poly(lactic-co-glycolic acid) (PLGA) loaded with plasmid DNA (Chi-PLGA-DNA) and (2) chitosan-trehalose and inactivated foot-and-mouth disease virus (FMDV) (Chi-Tre-Inactivated). Cattle were immunized by an intranasal route with nanoparticles and then challenged for 48 hours by direct contact with two infected donor cattle per pen. Donors were inoculated intradermally in the tongue 48 hours before challenge, with 0.2 mL cattle-passaged FMDV. Serological and mucosal antibody responses were evaluated, and virus excretion and the number of contact infections were quantified. FMDV-specific secretory immunoglobulin (Ig)A (sIgA) antibodies in nasal washes were initially detected at 4 days postvaccination (dpv) with two kinds of nanoparticles. The highest levels of sIgA expression were observed in nasal washes, at 10 dpv, from animals with Chi-PLGA-DNA nanoparticles, followed by animals immunized once by intranasal route with a double dose of Chi-Tre-Inactivated nanoparticles and animals immunized by intranasal route three times with Chi-Tre-Inactivated nanoparticles (P<0.05). FMDV-specific IgA antibodies in serum showed a similar pattern. All animals immunized by intranasal route developed low levels of detectable IgG in serum at 10 dpv. Following stimulation with FMDV, the highest levels of proliferation were observed in splenocytes harvested from Chi-PLGA-DNA-immunized animals, followed by proliferation of cells harvested from Chi-Tre-Inactivated nanoparticle-immunized animals (P<0.05). Higher protection rates were associated with the highest sIgA antibody responses induced in the Chi-PLGA-DNA nanoparticle-immunized group. Only one animal was clinically affected with mild signs after 7 days of contact challenge, after a delay of 2–3 days compared with the clinically affected negative-control group. Of the five animals directly challenged that were vaccinated by intranasal route with a double dose of Chi-Tre-Inactivated, four were clinically infected; however, the degree of severity of disease in this group was lower than in control cattle. The number of viral RNA copies in nasal swabs from the vaccinated, severely infected group was significantly higher than in swabs from the vaccinated, clinically protected group. These data suggested that intranasal delivery of Chi-PLGA-DNA nanoparticles resulted in higher levels of mucosal, systemic, and cell-mediated immunity than did of Chi-Tre-Inactivated nanoparticles. In conclusion, although intranasal delivery with FMDV antigen mediated by nanoparticles did not provide complete clinical protection, it reduced disease severity and virus excretion and delayed clinical symptoms. Chi-PLGA-DNA nanoparticle vaccines have potential as a nasal delivery system for vaccines.
doi:10.2147/IJN.S72318
PMCID: PMC4260661  PMID: 25506214
FMDV; nanoparticles; chitosan; trehalose; poly(lactic-co-glycolic acid); PLGA
19.  Lentiviral vector-mediated RBM5 overexpression downregulates EGFR expression in human non-small cell lung cancer cells 
Background
RNA binding motif 5 (RBM5) is a tumor suppressor gene that modulates apoptosis through the regulation of alternative splicing of apoptosis-related genes. Our previous studies suggested that RBM5 expression was negatively correlated with the expression of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) tissues. This study was aimed at determining whether RBM5 is able to regulate EGFR expression.
Methods
Both in vitro and in vivo studies were carried out to determine the effect of RBM5 on the expression of EGFR. Lentiviral vector-mediated RBM5 overexpression was employed in lung adenocarcinoma cell line A549. A549 xenograft mice were treated with recombinant RBM5 plasmid carried by attenuated Salmonella typhi Ty21a. Real-time quantitative polymerase chain reaction and Western blot were carried out to detect RBM5 and EGFR expression.
Results
Both in vivo and in vitro studies indicated that the expression of EGFR mRNA and protein was decreased significantly in the RBM5 overexpression group compared to control groups as shown by real-time PCR and Western blot analysis. We identified that RBM5 overexpression inhibited EGFR expression both in A549 cells and in A549 xenograft mice model.
Conclusions
Our study demonstrated that EGFR expression is regulated by RBM5 in lung adenocarcinomas cells either in a direct or indirect way, which might be meaningful with regards to target therapy in lung cancer.
doi:10.1186/1477-7819-12-367
PMCID: PMC4289049  PMID: 25441176
RNA binding motif 5; Epidermal growth factor receptor; Non-small cell lung cancer; Lentiviral vector; A549; Xenograft mice model
20.  Effects of Value Strains on Psychopathology of Chinese Rural Youths 
Asian journal of psychiatry  2013;6(6):10.1016/j.ajp.2013.06.007.
The Strain Theory of Suicide postulates that psychological strains usually precede mental disorders including suicidal behavior. This paper focuses on the effect of conflicting social value strains on the individual’s psychopathology. We analyzed the data of 2,031 respondents who were proxy informants for suicides and community living controls in a large scale psychological autopsy study in rural China, with the CES-D depression measure for the psychopathology. Individuals having experienced value conflicts between Confucian gender role and gender equalitarianism in modern society scored on depression significantly higher than the individuals who do not experience the value conflict, and it is also true when several other relevant variables were held constant in the multiple regression model. This study supports the hypotheses that people who confront value conflicts is likely to lead to psychopathological strain, and the higher the level of strain, the stronger the depression.
doi:10.1016/j.ajp.2013.06.007
PMCID: PMC3855650  PMID: 24309863
Value Strain; Depression; Suicide; Psychopathology; China
21.  Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders 
Molecular psychiatry  2014;19(6):641-651.
Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that elucidates how this early, developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders.
doi:10.1038/mp.2014.35
PMCID: PMC4031286  PMID: 24751963
22.  Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma 
Objective
The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.
Patients and methods
One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.
Results
The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).
Conclusions
Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.
doi:10.3978/j.issn.1000-9604.2014.12.19
PMCID: PMC4279200  PMID: 25561769
Epidermal growth factor receptor (EGFR) mutation; lung adenocarcinoma; pemetrexed; bevacizumab
23.  C3a Receptor Antagonist Ameliorates Inflammatory and Fibrotic Signals in Type 2 Diabetic Nephropathy by Suppressing the Activation of TGF-β/smad3 and IKBα Pathway 
PLoS ONE  2014;9(11):e113639.
Objective
Diabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM).
Methods
T2DM was induced in SD rats by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections. T2DM rats were treated with vehicle or C3aRA for 8 weeks. Biochemical analysis, HE and PAS stains were performed to evaluate the renal function and pathological changes. Human renal glomerular endothelial cells (HRGECs) were cultured and treated with normal glucose (NG), high glucose (HG), HG+C3a, HG+C3a+C3aRA and HG+C3a+BAY-11-7082 (p-IKBα Inhibitor) or SIS3 (Smad3 Inhibitor), respectively. Real-time PCR, immunofluorescent staining and western blot were performed to detect the mRNA and protein levels, respectively.
Results
T2DM rats showed worse renal morphology and impaired renal function compared with control rats, including elevated levels of serum creatinine (CREA), blood urea nitrogen (BUN) and urine albumin excretion (UACR), as well as increased levels of C3a, C3aR, IL-6, p-IKBα, collagen I, TGF-β and p-Smad3 in the kidney of T2DM rats and C3a-treated HRGECs. In contrast, C3aRA treatment improved renal function and morphology, reduced CREA, UACR and the intensity of PAS and collagen I staining in the kidney of T2DM rats, and decreased C3a, p-IKBα, IL-6, TGF-β, p-Smad3 and collagen I expressions in HRGECs and T2DM rats.
Conclusion
C3a mediated pro-inflammatory and pro-fibrotic responses and aggravated renal injury in T2DM rats. C3aRA ameliorated T2DN by inhibiting IKBα phosphorylation and cytokine release, and also TGF-β/Smad3 signaling and ECM deposition. Therefore, complement C3a receptor is a potential therapeutic target for DN.
doi:10.1371/journal.pone.0113639
PMCID: PMC4244104  PMID: 25422985
24.  Induction, Purification and Characterization of a Novel Manganese Peroxidase from Irpex lacteus CD2 and Its Application in the Decolorization of Different Types of Dye 
PLoS ONE  2014;9(11):e113282.
Manganese peroxidase (MnP) is the one of the important ligninolytic enzymes produced by lignin-degrading fungi which has the great application value in the field of environmental biotechnology. Searching for new MnP with stronger tolerance to metal ions and organic solvents is important for the maximization of potential of MnP in the biodegradation of recalcitrant xenobiotics. In this study, it was found that oxalic acid, veratryl alcohol and 2,6-Dimehoxyphenol could stimulate the synthesis of MnP in the white-rot fungus Irpex lacteus CD2. A novel manganese peroxidase named as CD2-MnP was purified and characterized from this fungus. CD2-MnP had a strong capability for tolerating different metal ions such as Ca2+, Cd2+, Co2+, Mg2+, Ni2+ and Zn2+ as well as organic solvents such as methanol, ethanol, DMSO, ethylene glycol, isopropyl alcohol, butanediol and glycerin. The different types of dyes including the azo dye (Remazol Brilliant Violet 5R, Direct Red 5B), anthraquinone dye (Remazol Brilliant Blue R), indigo dye (Indigo Carmine) and triphenylmethane dye (Methyl Green) as well as simulated textile wastewater could be efficiently decolorized by CD2-MnP. CD2-MnP also had a strong ability of decolorizing different dyes with the coexistence of metal ions and organic solvents. In summary, CD2-MnP from Irpex lacteus CD2 could effectively degrade a broad range of synthetic dyes and exhibit a great potential for environmental biotechnology.
doi:10.1371/journal.pone.0113282
PMCID: PMC4239052  PMID: 25412169
25.  Synthetically chemical-electrical mechanism for controlling large scale reversible deformation of liquid metal objects 
Scientific Reports  2014;4:7116.
Reversible deformation of a machine holds enormous promise across many scientific areas ranging from mechanical engineering to applied physics. So far, such capabilities are still hard to achieve through conventional rigid materials or depending mainly on elastomeric materials, which however own rather limited performances and require complicated manipulations. Here, we show a basic strategy which is fundamentally different from the existing ones to realize large scale reversible deformation through controlling the working materials via the synthetically chemical-electrical mechanism (SCHEME). Such activity incorporates an object of liquid metal gallium whose surface area could spread up to five times of its original size and vice versa under low energy consumption. Particularly, the alterable surface tension based on combination of chemical dissolution and electrochemical oxidation is ascribed to the reversible shape transformation, which works much more flexible than many former deformation principles through converting electrical energy into mechanical movement. A series of very unusual phenomena regarding the reversible configurational shifts are disclosed with dominant factors clarified. This study opens a generalized way to combine the liquid metal serving as shape-variable element with the SCHEME to compose functional soft machines, which implies huge potential for developing future smart robots to fulfill various complicated tasks.
doi:10.1038/srep07116
PMCID: PMC4236740  PMID: 25408295

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