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1.  All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis 
PLoS ONE  2015;10(7):e0133414.
Myocardial ischemia/reperfusion (I/R) injury interferes with the restoration of blood flow to ischemic myocardium. Oxidative stress-elicited apoptosis has been reported to contribute to I/R injury. All-trans retinoic acid (ATRA) has anti-apoptotic activity as previously reported. Here, we investigated the effects and the mechanism of action of ATRA on myocardial I/R injury both in vivo and in vitro. In vivo, ATRA reduced the size of the infarcted area (17.81±1.05% vs. 24.41±1.03%, P<0.05) and rescued cardiac function loss (ejection fraction 46.42±6.76% vs. 37.18±4.63%, P<0.05) after I/R injury. Flow-cytometric analysis and TUNEL assay demonstrated that the protective role of ATRA on myocardial I/R injury was related to its anti-apoptotic effects. The anti-apoptotic effects of ATRA were associated with partial inhibition of reactive oxygen species (ROS) production and significantly less phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, JNK, and ERK. Western blot analysis also revealed that ATRA pre-treatment increased a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression (0.65 ± 0.20 vs. 0.41±0.02 in vivo) and reduced the level of receptor for advanced glycation end-products (RAGE) (0.38 ± 0.17 vs. 0.52 ± 0.11 in vivo). Concomitantly, the protective role of ATRA on I/R injury was not observed in RAGE-KO mice. The current results indicated that ATRA could prevent myocardial injury and reduced cardiomyocyte apoptosis after I/R effectively. One possible mechanism underlying these effects is that ATRA could increase ADAM10 expression and thus cleave RAGE, which is the main receptor up-stream of MAPKs in myocardial I/R injury, resulting in the down-regulation of MAPK signaling and protective role on myocardial I/R injury.
doi:10.1371/journal.pone.0133414
PMCID: PMC4506146  PMID: 26186635
2.  Increased Thymic Cell Turnover under Boron Stress May Bypass TLR3/4 Pathway in African Ostrich 
PLoS ONE  2015;10(6):e0129596.
Previous studies revealed that thymus is a targeted immune organ in malnutrition, and high-boron stress is harmful for immune organs. African ostrich is the living fossil of ancient birds and the food animals in modern life. There is no report about the effect of boron intake on thymus of ostrich. The purpose of present study was to evaluate the effect of excessive boron stress on ostrich thymus and the potential role of TLR3/4 signals in this process. Histological analysis demonstrated that long-term boron stress (640 mg/L for 90 days) did not disrupt ostrich thymic structure during postnatal development. However, the numbers of apoptotic cells showed an increased tendency, and the expression of autophagy and proliferation markers increased significantly in ostrich thymus after boron treatment. Next, we examined the expression of TLR3 and TLR4 with their downstream molecular in thymus under boron stress. Since ostrich genome was not available when we started the research, we first cloned ostrich TLR3 TLR4 cDNA from thymus. Ostrich TLR4 was close to white-throated Tinamou. Whole avian TLR4 codons were under purify selection during evolution, whereas 80 codons were under positive selection. TLR3 and TLR4 were expressed in ostrich thymus and bursa of fabricius as was revealed by quantitative real-time PCR (qRT-PCR). TLR4 expression increased with age but significantly decreased after boron treatment, whereas TLR3 expression showed the similar tendency. Their downstream molecular factors (IRF1, JNK, ERK, p38, IL-6 and IFN) did not change significantly in thymus, except that p100 was significantly increased under boron stress when analyzed by qRT-PCR or western blot. Taken together, these results suggest that ostrich thymus developed resistance against long-term excessive boron stress, possibly by accelerating intrathymic cell death and proliferation, which may bypass the TLR3/4 pathway. In addition, attenuated TLRs activity may explain the reduced inflammatory response to pathogens under boron stress.
doi:10.1371/journal.pone.0129596
PMCID: PMC4460079  PMID: 26053067
3.  A Novel Injectable Magnesium/Calcium Sulfate Hemihydrate Composite Cement for Bone Regeneration 
BioMed Research International  2015;2015:297437.
Objective. A novel injectable magnesium/calcium sulfate hemihydrate (Mg/CSH) composite with improved properties was reported here. Methods. Composition, setting time, injectability, compressive strength, and bioactivity in simulated body fluid (SBF) of the Mg/CSH composite were evaluated. Furthermore, the cellular responses of canine bone marrow stromal cells (cBMSCs) and bone formation capacity after the implantation of Mg/CSH in tibia defects of canine were investigated. Results. Mg/CSH possessed a prolonged setting time and markedly improved injectability and mechanical property (p < 0.05). Mg/CSH samples showed better degradability than CSH in SBF after 21 days of soaking (p < 0.05). Moreover, the degrees of cell attachment, proliferation, and capability of osteogenic differentiation on the Mg/CSH specimens were higher than those on CSH, without significant cytotoxicity and with the increased proliferation index, ALP activity, and expression levels of integrin β1 and Coll I in cBMSCs (p < 0.05). Mg/CSH enhanced the efficiency of new bone formation at the tibia defect area, including the significantly elevated bone mineral density, bone area fraction, and Coll I expression level (p < 0.05). Conclusions. The results implied that this new injectable bone scaffold exhibited promising prospects for bone repair and had a great potential in bone tissue engineering.
doi:10.1155/2015/297437
PMCID: PMC4465663  PMID: 26114102
4.  Antibacterial Properties of Magnesium In Vitro and in an In Vivo Model of Implant-Associated Methicillin-Resistant Staphylococcus aureus Infection 
Antimicrobial Agents and Chemotherapy  2014;58(12):7586-7591.
Periprosthetic infection remains a challenging clinical complication. We investigated the antibacterial properties of pure (99.9%) magnesium (Mg) in vitro and in an in vivo rat model of implant-related infection. Mg was highly effective against methicillin-resistant Staphylococcus aureus-induced osteomyelitis and improved new peri-implant bone formation. Bacterial icaA and agr RNAIII transcription levels were also assessed to characterize the mechanism underlying the antibacterial properties of the Mg implant.
doi:10.1128/AAC.03936-14
PMCID: PMC4249557  PMID: 25288077
5.  Physiological and proteomic analyses of salt stress response in the halophyte Halogeton glomeratus 
Plant, Cell & Environment  2014;38(4):655-669.
Very little is known about the adaptation mechanism of Chenopodiaceae Halogeton glomeratus, a succulent annual halophyte, under saline conditions. In this study, we investigated the morphological and physiological adaptation mechanisms of seedlings exposed to different concentrations of NaCl treatment for 21 d. Our results revealed that H. glomeratus has a robust ability to tolerate salt; its optimal growth occurs under approximately 100 mm NaCl conditions. Salt crystals were deposited in water-storage tissue under saline conditions. We speculate that osmotic adjustment may be the primary mechanism of salt tolerance in H. glomeratus, which transports toxic ions such as sodium into specific salt-storage cells and compartmentalizes them in large vacuoles to maintain the water content of tissues and the succulence of the leaves. To investigate the molecular response mechanisms to salt stress in H. glomeratus, we conducted a comparative proteomic analysis of seedling leaves that had been exposed to 200 mm NaCl for 24 h, 72 h and 7 d. Forty-nine protein spots, exhibiting significant changes in abundance after stress, were identified using matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS/MS) and similarity searches across EST database of H. glomeratus. These stress-responsive proteins were categorized into nine functional groups, such as photosynthesis, carbohydrate and energy metabolism, and stress and defence response.
doi:10.1111/pce.12428
PMCID: PMC4407928  PMID: 25124288
EST database; physiology; proteomic; salinity; tolerance
6.  Informational Analysis for Compressive Sampling in Radar Imaging 
Sensors (Basel, Switzerland)  2015;15(4):7136-7155.
Compressive sampling or compressed sensing (CS) works on the assumption of the sparsity or compressibility of the underlying signal, relies on the trans-informational capability of the measurement matrix employed and the resultant measurements, operates with optimization-based algorithms for signal reconstruction and is thus able to complete data compression, while acquiring data, leading to sub-Nyquist sampling strategies that promote efficiency in data acquisition, while ensuring certain accuracy criteria. Information theory provides a framework complementary to classic CS theory for analyzing information mechanisms and for determining the necessary number of measurements in a CS environment, such as CS-radar, a radar sensor conceptualized or designed with CS principles and techniques. Despite increasing awareness of information-theoretic perspectives on CS-radar, reported research has been rare. This paper seeks to bridge the gap in the interdisciplinary area of CS, radar and information theory by analyzing information flows in CS-radar from sparse scenes to measurements and determining sub-Nyquist sampling rates necessary for scene reconstruction within certain distortion thresholds, given differing scene sparsity and average per-sample signal-to-noise ratios (SNRs). Simulated studies were performed to complement and validate the information-theoretic analysis. The combined strategy proposed in this paper is valuable for information-theoretic orientated CS-radar system analysis and performance evaluation.
doi:10.3390/s150407136
PMCID: PMC4431244  PMID: 25811226
compressive sampling; rate distortion; mutual information; complex-valued scenes; radar imaging; under-sampling ratios; Gaussian mixtures
7.  Cobalt-catalysed site-selective intra- and intermolecular dehydrogenative amination of unactivated sp3 carbons 
Nature Communications  2015;6:6462.
Cobalt-catalysed sp2 C–H bond functionalization has attracted considerable attention in recent years because of the low cost of cobalt complexes and interesting modes of action in the process. In comparison, much less efforts have been devoted to the sp3 carbons. Here we report the cobalt-catalysed site-selective dehydrogenative cyclization of aliphatic amides via a C–H bond functionalization process on unactivated sp3 carbons with the assistance of a bidentate directing group. This method provides a straightforward synthesis of monocyclic and spiro β- or γ-lactams with good to excellent stereoselectivity and functional group tolerance. In addition, a new procedure has been developed to selectively remove the directing group, which enables the synthesis of free β- or γ-lactam compounds. Furthermore, the first cobalt-catalysed intermolecular dehydrogenative amination of unactivated sp3 carbons is also realized.
Functionalizing unactivated carbon–hydrogen bonds is challenging, especially when using non-precious metals and dealing with sp3 hybridized carbons. Here, the authors report an intramolecular cobalt catalysed amination of C–H bonds of sp3 carbons, giving access to β- and γ-lactams.
doi:10.1038/ncomms7462
PMCID: PMC4366490  PMID: 25753366
8.  Transcriptomic profiling of the salt-stress response in the halophyte Halogeton glomeratus 
BMC Genomics  2015;16(1):169.
Background
Halogeton glomeratus (H. glomeratus) is an extreme halophyte that is widely distributed in arid regions, including foothills, the Gobi desert of northwest China, and the marginal loess of Central Asia. However, research on the salt-tolerant mechanisms and genes of this species are limited because of a lack of genomic sequences. In the present study, the transcriptome of H. glomeratus was analyzed using next-generation sequencing technology to identify genes involved in salt tolerance and better understand mechanisms of salt response in the halophyte H. glomeratus.
Results
Illumina RNA-sequencing was performed in five sequencing libraries that were prepared from samples treated with 200 mM NaCl for 6, 12, 24, and 72 h and a control sample to investigate changes in the H. glomeratus transcriptome in response to salt stress. The de novo assembly of five transcriptomes identified 50,267 transcripts. Among these transcripts, 31,496 (62.66%) were annotated, including 44 Gene Ontology (GO) terms and 128 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Compared with transcriptomes from the control and NaCl-treated samples, there were 2,223, 5,643, 7,510 and 10,908 genes that were differentially expressed after exposure to NaCl for 6, 12, 24, and 72 h, respectively. One hundred and eighteen salt-induced genes were common to at least two stages of salt stress, and 291 up-regulated genes were common to various stages of salt stress. Numerous genes that are related to ion transport, reactive oxygen species scavenging, energy metabolism, hormone-response pathways, and responses to biotic and abiotic stress appear to play a significant role in adaptation to salinity conditions in this species. The detection of expression patterns of 18 salt-induced genes by quantitative real-time polymerase chain reaction were basically consistent with their changes in transcript abundance determined by RNA sequencing.
Conclusions
Our findings provide a genomic sequence resource for functional genetic assignments of an extreme halophyte, H. glomeratus. We believe that the transcriptome datasets will help elucidate the genetic basis of this species’ response to a salt environment and develop stress-tolerant crops based on favorable wild genetic resources.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1373-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1373-z
PMCID: PMC4363069  PMID: 25880042
Halophyte; Halogeton glomeratus; Transcriptome; Illumina sequencing; Salt-stress
9.  TRAF4 promotes the growth and invasion of colon cancer through the Wnt/β-catenin pathway 
The tumor necrosis factor receptor-associated factor 4 (TRAF4) has been linked to carcinogenesis. However, the role of TRAF4 in colon cancer is still unclear. Therefore, we investigated the role of TRAF4 in colon cancer and the underlying mechanism. In the present study, we found that TRAF4 was overexpressed in colon cancer tissues and cells, and small interfering RNA (siRNA)-mediated gene knockdown of TRAF4 significantly inhibited cell proliferation, invasion and tumorigenesis, both in vitro and in vivo, but induced apoptosis in colon cancer cells. Furthermore, siRNA-TRAF4 significantly inhibited the expression levels of β-catenin, cyclinD1, and c-myc proteins in colon cancer cells. Taken together, these results suggest that TRAF4 promoted colon cancer cell growth and invasion by potentiating the Wnt/β-catenin pathway, suggesting that TRAF4 may be a potential molecular target for colon cancer prevention and therapy.
PMCID: PMC4396239  PMID: 25973026
Tumor necrosis factor receptor-associated factor 4 (TRAF4); colon cancer; cell growth; Wnt/β-catenin pathway
10.  Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo 
Oncotarget  2014;5(23):11971-11985.
Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2-overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.
PMCID: PMC4322967  PMID: 25436978
Multidrug resistance; ABCG2; tyrosine kinase inhibitor; afatinib; combined chemotherapy
11.  Conventional empirical law reverses in the phase transitions of 122-type iron-based superconductors 
Scientific Reports  2014;4:7172.
Phase transition of solid-state materials is a fundamental research topic in condensed matter physics, materials science and geophysics. It has been well accepted and widely proven that isostructural compounds containing different cations undergo same pressure-induced phase transitions but at progressively lower pressures as the cation radii increases. However, we discovered that this conventional law reverses in the structural transitions in 122-type iron-based superconductors. In this report, a combined low temperature and high pressure X-ray diffraction (XRD) measurement has identified the phase transition curves among the tetragonal (T), orthorhombic (O) and the collapsed-tetragonal (cT) phases in the structural phase diagram of the iron-based superconductor AFe2As2 (A = Ca, Sr, Eu, and Ba). The cation radii dependence of the phase transition pressure (T → cT) shows an opposite trend in which the compounds with larger ambient radii cations have a higher transition pressure.
doi:10.1038/srep07172
PMCID: PMC4241531  PMID: 25417655
12.  Methylation-associated silencing of MicroRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer 
MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of target genes, previous studies have shown that miR-335 play an important role in suppressing metastasis and migration in human cancer including gastric cancer (GC). However, the mechanisms which result in aberrant expression of miR-335 in GC are still unknown. Recent studies have shown that the silencing of some miRNAs is associated with DNA hypermethylation. In this study, we find the promoter of miR-335 we embedded in CpG island by accessing to bioinformatics data and the low expression of miR-335 in 5 gastric cell lines can be restored by 5-aza-2’-deoxycytidine (5-Aza-dC) treatment. So we postulated that the miR-335 genes undergo epigenetic inactivation in GC. Subsequently, in GC cells and tissues, we performed quantitative real-time PCR (RTQ-PCR) to assess the expression of miR-335, and methylation-specific PCR (MSP) and bisulfite sequence-PCR (BSP) to evaluate the DNA methylation status in the CpG islands upstream of MiR-335. The result showed that the expression of miR-335 was significantly reduce in gastric cancer cell lines and tumor tissues compared to matched normal gastric tissues, and cell lines, and which is inverse correlation with DNA hypermethylation of miR-335 both in GC cells lines and tissues, but not in normal tissues. In addition, we found that the lower miR-335 expression induced by abnormal methylation may be mainly involved in gastric cell invasion and metastasis in GC tissues. No statistical significance was found about miR-335 expression and methylation level between healthy individuals with and without H. pylori (HP) infection. Finally, we carry out miRNA transfection, RTQ-PCR and western blot assay to find the RAS p21 protein activator (GTPase activating protein) 1 (RASA1) may be the possible target genes which lead to the gastric cell invasion and metastasis, furthermore, the re-expression of endogenous miR-335 by 5-Aza-dC treatment can exert effects similar to exogenous miRNAs transfection. Taken together, our results suggest that miR-335 may be silenced by promoter hypermethylation and play important roles in gastric cell invasion and metastasis through its target genes, such as RASA1. Its methylation level might be a predictive epigenetic marker of GC and remodeling on the expression by demethylation can provided a potential therapeutic strategy.
PMCID: PMC4266701  PMID: 25520857
MiR-335; methylation; gastric carcinoma; Cancer metastasis; cancer invasion; RASA1
13.  Reporting Quality of Systematic Reviews/Meta-Analyses of Acupuncture 
PLoS ONE  2014;9(11):e113172.
Background
The QUOROM and PRISMA statements were published in 1999 and 2009, respectively, to improve the consistency of reporting systematic reviews (SRs)/meta-analyses (MAs) of clinical trials. However, not all SRs/MAs adhere completely to these important standards. In particular, it is not clear how well SRs/MAs of acupuncture studies adhere to reporting standards and which reporting criteria are generally ignored in these analyses.
Objectives
To evaluate reporting quality in SRs/MAs of acupuncture studies.
Methods
We performed a literature search for studies published prior to 2014 using the following public archives: PubMed, EMBASE, Web of Science, the Cochrane Database of Systematic Reviews (CDSR), the Chinese Biomedical Literature Database (CBM), the Traditional Chinese Medicine (TCM) database, the Chinese Journal Full-text Database (CJFD), the Chinese Scientific Journal Full-text Database (CSJD), and the Wanfang database. Data were extracted into pre-prepared Excel data-extraction forms. Reporting quality was assessed based on the PRISMA checklist (27 items).
Results
Of 476 appropriate SRs/MAs identified in our search, 203, 227, and 46 were published in Chinese journals, international journals, and the Cochrane Database, respectively. In 476 SRs/MAs, only 3 reported the information completely. By contrast, approximately 4.93% (1/203), 8.81% (2/227) and 0.00% (0/46) SRs/Mas reported less than 10 items in Chinese journals, international journals and CDSR, respectively. In general, the least frequently reported items (reported≤50%) in SRs/MAs were “protocol and registration”, “risk of bias across studies”, and “additional analyses” in both methods and results sections.
Conclusions
SRs/MAs of acupuncture studies have not comprehensively reported information recommended in the PRISMA statement. Our study underscores that, in addition to focusing on careful study design and performance, attention should be paid to comprehensive reporting standards in SRs/MAs on acupuncture studies.
doi:10.1371/journal.pone.0113172
PMCID: PMC4232579  PMID: 25397774
14.  New β-phospholactam as a carbapenem transition state analog: synthesis of a broad-spectrum inhibitor of metallo-β-lactamases 
Bioorganic & medicinal chemistry letters  2013;23(21):10.1016/j.bmcl.2013.08.098.
In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100 µM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.
doi:10.1016/j.bmcl.2013.08.098
PMCID: PMC3833270  PMID: 24064498
15.  Pharmacokinetic and Pharmacodynamic Evaluation of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients with Morquio A Syndrome 
Clinical Pharmacokinetics  2014;53(12):1137-1147.
Background and Objectives
Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, an enzyme required for degradation of the glycosaminoglycan keratan sulfate. Enzyme replacement therapy with elosulfase alfa provides a potential therapy for Morquio A syndrome. We analyzed the pharmacokinetics and pharmacodynamics of elosulfase alfa in Morquio A patients from a phase III clinical trial.
Methods
In a randomized double-blind study, elosulfase alfa at 2.0 mg/kg was administrated weekly or every other week for 24 weeks. Pharmacokinetic parameters of elosulfase alfa were determined at weeks 0 and 22 by non-compartmental analysis. Safety was assessed throughout the study. The relationship of pharmacokinetic parameters to patient demographics, pharmacodynamic assessments, immunogenicity, and efficacy and safety outcomes were assessed graphically by treatment group.
Results
Elosulfase alfa exposure and half-life (t½) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patient’s sex, race, body weight, or age. All patients developed anti-drug antibodies, but no association was noted between total antibody titer and CL. In contrast, positive neutralizing antibody (NAb) status appeared to associate with decreased CL and prolonged t½ for patients in the cohort dosed weekly. NAb may interfere with receptor-mediated cellular uptake and lead to increased circulation time of elosulfase alfa.
Conclusion
Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events.
Electronic supplementary material
The online version of this article (doi:10.1007/s40262-014-0173-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s40262-014-0173-y
PMCID: PMC4243006  PMID: 25234648
16.  Regulation of pre-natal circle of Willis assembly by vascular smooth muscle Notch signaling 
Developmental biology  2013;381(1):107-120.
The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies in adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfrβ and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW.
doi:10.1016/j.ydbio.2013.06.007
PMCID: PMC3805056  PMID: 23769842
Notch signaling; angiogenesis; vascular smooth muscle cell; circle of Willis
17.  Phenotypic Modulation of Corpus Cavernosum Smooth Muscle Cells in a Rat Model of Cavernous Neurectomy 
PLoS ONE  2014;9(8):e105186.
Background
Patients undergoing radical prostatectomy (RP) are at high risk for erectile dysfunction (ED) due to potential cavernous nerve (CN) damage during surgery. Penile hypoxia after RP is thought to significantly contribute to ED pathogenesis.
Aim
We previously showed that corpora cavernosum smooth muscle cells (CCSMCs) undergo phenotypic modulation under hypoxic conditions in vitro. Here, we studied such changes in an in vivo post-RP ED model by investigating CCSMCs in bilateral cavernous neurectomy (BCN) rats.
Methods
Sprague-Dawley rats underwent sham (n = 12) or BCN (n = 12) surgery. After 12 weeks, they were injected with apomorphine to determine erectile function. The penile tissues were harvested and assessed for fibrosis using Masson trichrome staining and for molecular markers of phenotypic modulation using immunohistochemistry and western blotting. CCSMC morphological structure was evaluated by hematoxylin-eosin (H&E) staining and transmission electron microscopy (TEM).
Results
Erectile function was significantly lower in BCN rats than in sham rats. BCN increased hypoxia-inducible factor-1α and collagen protein expression in corpora cavernous tissue. H&E staining and TEM showed that CCSMCs in BCN rats underwent hypertrophy and showed rough endoplasmic reticulum formation. The expression of CCSMC phenotypic markers, such as smooth muscle α-actin, smooth muscle myosin heavy chain, and desmin, was markedly lower, whereas vimentin protein expression was significantly higher in BCN rats than in control rats.
Conclusions
CCSMCs undergo phenotype modulation in rats with cavernous neurectomy. The results have unveiled physiological transformations that occur at the cellular and molecular levels and have helped characterize CN injury–induced ED.
doi:10.1371/journal.pone.0105186
PMCID: PMC4134279  PMID: 25127037
19.  Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects 
Biomedical Reports  2014;2(5):699-708.
The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta-analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% confidence interval were calculated using the random-effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20–1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25–1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18–1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32–1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20–1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta-regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital-based studies have a stronger association than population-based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger’s test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH.
doi:10.3892/br.2014.302
PMCID: PMC4106611  PMID: 25054014
methylenetetrahydrofolate reductase; meta-analysis; essential hypertension; gene polymorphism
20.  Toll-Like Receptor 4 Mediates Inflammatory Cytokine Secretion in Smooth Muscle Cells Induced by Oxidized Low-Density Lipoprotein 
PLoS ONE  2014;9(4):e95935.
Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation.
doi:10.1371/journal.pone.0095935
PMCID: PMC3995878  PMID: 24755612
21.  Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium 
Developmental biology  2013;376(2):136-149.
During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1α (HIF-1α) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduced adenovirus mediated expression of constitutively active HIF-1α (AdcaHIF1α) into the embryonic avian epicardium where the vascular precursors reside. We found that introducing caHIF1α into the epicardial mesothelium prevented EPDCs from proper migration into the myocardium. In vitro collagen gel assays and ex vivo organ culture data further confirmed that infection with AdcaHIF1α impaired the ability of EPDCs to invade. However, the proficiency of epicardial cells to undergo EMT was enhanced while the movement of EPDCs within the sub-epicardium and their differentiation into smooth muscle cells were not disrupted by caHIF1α. We also showed that the transcript level of Flt-1 (VEGFR1), which can act as a VEGF signaling inhibitor, increased several fold after introducing caHIF1α into epicardial cells. Blocking the activation of the VEGF pathway in epicardial cells recapitulated the inhibition of EPDC invasion. These results suggest that caHIF1α mediated up-regulation of Flt-1, which blocks the activation of the VEGF pathway, is responsible for the inhibition of EPDC myocardial migration. In conclusion, our studies demonstrate that HIF signaling potentially regulates the degree of epicardial EMT and the extent of EPDC migration into the myocardium, both of which are likely critical in patterning the coronary vasculature during early cardiac vasculogenesis. These signals could explain why the larger coronaries appear and remain on the epicardial surface.
doi:10.1016/j.ydbio.2013.01.026
PMCID: PMC3602346  PMID: 23384563
Epithelial to mesenchymal transformation; Hypoxia inducible factor; Vascular growth factor; Epicardium; Invasion
22.  DNA methylation study of fetus genome through a genome-wide analysis 
BMC Medical Genomics  2014;7:18.
Background
DNA methylation is a crucial epigenetic modification of the genome which is involved in embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and essential for regulating temporal and spatial expression of genes controlling cell fate and differentiation. Further studies have shown that abnormal DNA methylation is associated with human diseases including the embryonic development diseases. We attempt to study the DNA methylation status of CpG islands in fetus related to fetus growth and development.
Methods
GeneChip® Human Tiling 2.0R Array set is used for analysis of methylated DNA in a whole-genome wide in 8 pairs amniotic fluid and maternal blood DNA samples.
Results
We found 1 fetus hypermethylation DNA markers and 4 fetus hypomethylation DNA markers though a Genome-wide analysis. These DNA markers all found to be associated with the critical genes for fetus growth and development (SH2D3C gene, EML3 gene, TRIM71 gene, HOXA3 gene and HOXA5 gene).
Conclusions
These genes can be used as a biomarker for association studying of embryonic development, pathological pregnancy and so on. The present study has provided new and fundamental insights into the roles that DNA methylation has in embryonic development and in the pathological pregnancy.
doi:10.1186/1755-8794-7-18
PMCID: PMC3996908  PMID: 24731722
DNA methylation; Fetus; GeneChip® human tiling 2.0R array set; Clone sequencing; Embryonic development
23.  Characterization of Constitutive Promoters for piggyBac Transposon-Mediated Stable Transgene Expression in Mesenchymal Stem Cells (MSCs) 
PLoS ONE  2014;9(4):e94397.
Multipotent mesenchymal stem cells (MSCs) can undergo self-renewal and give rise to multi-lineages under given differentiation cues. It is frequently desirable to achieve a stable and high level of transgene expression in MSCs in order to elucidate possible molecular mechanisms through which MSC self-renewal and lineage commitment are regulated. Retroviral or lentiviral vector-mediated gene expression in MSCs usually decreases over time. Here, we choose to use the piggyBac transposon system and conduct a systematic comparison of six commonly-used constitutive promoters for their abilities to drive RFP or firefly luciferase expression in somatic HEK-293 cells and MSC iMEF cells. The analyzed promoters include three viral promoters (CMV, CMV-IVS, and SV40), one housekeeping gene promoter (UbC), and two composite promoters of viral and housekeeping gene promoters (hEFH and CAG-hEFH). CMV-derived promoters are shown to drive the highest transgene expression in HEK-293 cells, which is however significantly reduced in MSCs. Conversely, the composite promoter hEFH exhibits the highest transgene expression in MSCs whereas its promoter activity is modest in HEK-293 cells. The reduced transgene expression driven by CMV promoters in MSCs may be at least in part caused by DNA methylation, or to a lesser extent histone deacetlyation. However, the hEFH promoter is not significantly affected by these epigenetic modifications. Taken together, our results demonstrate that the hEFH composite promoter may be an ideal promoter to drive long-term and high level transgene expression using the piggyBac transposon vector in progenitor cells such as MSCs.
doi:10.1371/journal.pone.0094397
PMCID: PMC3979777  PMID: 24714676
24.  Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: A meta-analysis of randomized controlled trials 
Oncology Letters  2014;7(6):1997-2002.
Breast cancer is the most common type of cancer in females worldwide. Patients with breast cancer and bone metastases may experience increased osteoclast activity, resulting in local bone destruction and skeletal complications, including pain, hypercalcemia and skeletal-related events. Intravenous bisphosphonates (BPs) are the standard treatment administered to patients with breast cancer and bone metastases to prevent skeletal-related events. However, in certain patients, BPs may cause renal toxicity, acute-phase reactions and osteonecrosis of the jaw. More effective, safer and more tolerable therapies, which prevent bone destruction and skeletal complications, are required in order to improve patient quality of life. Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor-κB ligand, which is a key mediator in the pathogenesis of a broad range of skeletal diseases, thereby inhibiting osteoclast function and bone resorption. Therefore, we conducted a meta-analysis to compare both the safety and efficacy of denosumab and BPs in the treatment of breast cancer and bone metastases. Five databases, two clinical trial registry platforms and reference lists of relevant papers were analyzed. The meta-analysis concluded that denosumab was more effective at preventing pain and skeletal-related events than BPs, in patients with breast cancer and bone metastases. Patients receiving denosumab demonstrated a higher level of clinical improvement in terms of health-related quality of life than patients receiving BPs. Compared with BPs, denosumab reduced the incidence of certain indicators of adverse events, including pyrexia, bone pain, edema and renal failure.
doi:10.3892/ol.2014.1982
PMCID: PMC4049725  PMID: 24932278
denosumab; bisphosphonates; meta-analysis; breast cancer; bone metastases
25.  pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment 
Cancer Biology & Medicine  2014;11(1):34-43.
In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles (MSNs) with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanoparticles, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.
doi:10.7497/j.issn.2095-3941.2014.01.003
PMCID: PMC3969802  PMID: 24738037
Mesoporous silica nanoparticles; pH-responsive; controlled drug release; drug delivery systems; antineoplastic protocols

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