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1.  Luteolin Inhibits Behavioral Sensitization by Blocking Methamphetamine-Induced MAPK Pathway Activation in the Caudate Putamen in Mice 
PLoS ONE  2014;9(6):e98981.
Goal
To investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogen-activated protein kinase (MAPK) signal transduction pathway activation in mice.
Methods
Mice received a single dose of MA to induce hyperactivity or repeated intermittent intraperitoneal injections of MA to establish an MA-induced behavioral sensitization mouse model. The effect of luteolin on the development and expression of MA-induced hyperactivity and behavioral sensitization was examined. The expression and activity of ΔFosB and the levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), phosphorylated c-Jun N-terminal kinase (pJNK), and phosphorylated p38 mitogen-activated protein kinase (pp38) in the caudate putamen (CPu) were measured by western blot.
Results
Luteolin significantly decreased hyperactivity as well as the development and expression of MA-induced behavioral sensitization in mice. ΔFosB, pERK1/2, and pJNK levels in the CPu were higher in MA-treated mice than in control mice, whereas the pp38 level did not change. Injection of luteolin inhibited the MA-induced increase in ΔFosB, pERK1/2, and pJNK levels, but did not affect the pp38 level.
Conclusions
Luteolin inhibits MA-induced hyperactivity and behavioral sensitization in mice through the ERK1/2/ΔFosB pathway. Furthermore, the JNK signaling pathway might be involved in MA-induced neurodegeneration in the CPu, and luteolin inhibits this process.
doi:10.1371/journal.pone.0098981
PMCID: PMC4047057  PMID: 24901319
2.  Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses 
Antiviral research  2013;98(3):432-440.
Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
doi:10.1016/j.antiviral.2013.03.023
PMCID: PMC3663898  PMID: 23578725
3.  Autophagy in stem cells 
Autophagy  2013;9(6):830-849.
Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.
doi:10.4161/auto.24132
PMCID: PMC3672294  PMID: 23486312
autophagy; embryonic stem cells; tissue stem cells; cancer stem cells
4.  Cessation of Epithelial Bmp Signaling Switches the Differentiation of Crown Epithelia to the Root Lineage in a β-Catenin-Dependent Manner 
Molecular and Cellular Biology  2013;33(23):4732-4744.
The differentiation of dental epithelia into enamel-producing ameloblasts or the root epithelial lineage compartmentalizes teeth into crowns and roots. Bmp signaling has been linked to enamel formation, but its role in root epithelial lineage differentiation is unclear. Here we show that cessation of epithelial Bmp signaling by Bmpr1a depletion during the differentiation stage switched differentiation of crown epithelia into the root lineage and led to formation of ectopic cementum-like structures. This phenotype is related to the upregulation of Wnt/β-catenin signaling and epithelial-mesenchymal transition (EMT). Although epithelial β-catenin depletion during the differentiation stage also led to variable enamel defect and precocious/ectopic formation of fragmented root epithelia in some teeth, it did not cause ectopic cementogenesis and inhibited EMT in cultured dental epithelia. Concomitant epithelial β-catenin depletion rescued EMT and ectopic cementogenesis caused by Bmpr1a depletion. These data suggested that Bmp and Wnt/β-catenin pathways interact antagonistically in dental epithelia to regulate the root lineage differentiation and EMT. These findings will aid in the design of new strategies to promote functional differentiation in the regeneration and tissue engineering of teeth and will provide new insights into the dynamic interactions between the Bmp and Wnt/β-catenin pathways during cell fate decisions.
doi:10.1128/MCB.00456-13
PMCID: PMC3838012  PMID: 24081330
5.  Pre-Clinical Characterization of Dacomitinib (PF-00299804), an Irreversible Pan-ErbB Inhibitor, Combined with Ionizing Radiation for Head and Neck Squamous Cell Carcinoma 
PLoS ONE  2014;9(5):e98557.
Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10–500 nM), both with and without IR (2–4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.
doi:10.1371/journal.pone.0098557
PMCID: PMC4031184  PMID: 24853121
6.  γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ 
The European journal of neuroscience  2013;37(10):1714-1725.
Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD.
doi:10.1111/ejn.12159
PMCID: PMC3660538  PMID: 23432732
β-amyloid; BACE1; γ-secretase; anti-Aβ therapy; AD biomarker
7.  Treatment of spontaneous ruptured hepatocellular carcinoma: A single-center study 
Objectives: Spontaneous rupture of hepatocarcinoma (HCC) is a fatal complication of advanced HCC and is associated with poor prognosis. However, there is no consensus on the best approach to treat hemoperitoneum due to ruptured HCC. In this paper, we evaluate and discuss the outcomes of different treatment methods employed at our center for ruptured HCC.
Methods: We reviewed the medical records of 132 patients diagnosed with ruptured HCC at our hospital from January 2003 to December 2012 and evaluated and compared the outcomes of five treatment methods for ruptured HCC: conservative treatment, surgical hemostasis, transarterial embolization (TAE), and one- and two-stage resections.
Results: There was no significant difference in the median survival time between the conservative treatment and surgical hemostasis groups. Patients in the TAE alone group had a better prognosis than those in the conservative treatment and surgical hemostasis groups. The survival time of the tumor resection group was obviously better than that of the conservative treatment, surgical hemostasis, and TAE alone groups, but no significant difference was observed between the one-stage and two-stage resection groups.
Conclusions: One-stage hepatectomy is a better option for patients with preserved liver function, whereas TAE is a better option for those with poorly preserved liver function.
doi:10.12669/pjms.303.4001
PMCID: PMC4048488  PMID: 24948961
Hepatocellular carcinoma; Ruptured; Treatment
8.  Soft matrix is a natural stimulator for cellular invasiveness 
Molecular Biology of the Cell  2014;25(4):457-469.
ECM softness (low stiffness comparable to soft tissues) alone is sufficient to prevent cell-to-cell adherens junction formation, up-regulate MMP secretion, promote MMP activity, and induce invadosome-like protrusion formation. Such findings suggest that cell invasion in vivo is a spontaneous cell behavior in response to ECM stiffness.
Directional mesenchymal cell invasion in vivo is understood to be a stimulated event and to be regulated by cytokines, chemokines, and types of extracellular matrix (ECM). Instead, by focusing on the cellular response to ECM stiffness, we found that soft ECM (low stiffness) itself is sufficient to prevent stable cell-to-cell adherens junction formation, up-regulate matrix metalloproteinase (MMP) secretion, promote MMP activity, and induce invadosome-like protrusion (ILP) formation. Consistently, similar ILP formation was also detected in a three-dimensional directional invasion assay in soft matrix. Primary human fibroblasts spontaneously form ILPs in a very narrow range of ECM stiffness (0.1–0.4 kPa), and such ILP formation is Src family kinase dependent. In contrast, spontaneous ILP formation in malignant cancer cells and fibrosarcoma cells occurs across a much wider range of ECM stiffness, and these tumor cell ILPs are also more prominent at lower stiffness. These findings suggest that ECM softness is a natural stimulator for cellular invasiveness.
doi:10.1091/mbc.E13-05-0260
PMCID: PMC3923638  PMID: 24336521
9.  Mining Seasonal Marine Microbial Pattern with Greedy Heuristic Clustering and Symmetrical Nonnegative Matrix Factorization 
BioMed Research International  2014;2014:189590.
With the development of high-throughput and low-cost sequencing technology, a large number of marine microbial sequences were generated. The association patterns between marine microbial species and environment factors are hidden in these large amount sequences. Mining these association patterns is beneficial to exploit the marine resources. However, very few marine microbial association patterns are well investigated in this field. The present study reports the development of a novel method called HC-sNMF to detect the marine microbial association patterns. The results show that the four seasonal marine microbial association networks have characters of complex networks, the same environmental factor influences different species in the four seasons, and the correlative relationships are stronger between OTUs (taxa) than with environmental factors in the four seasons detecting community.
doi:10.1155/2014/189590
PMCID: PMC4022257  PMID: 24877065
10.  A self-made disposable iris retractor in small pupil phacoemulsification 
AIM
To explore a simple and low-cost self-made disposable flexible iris retractor and study its clinical efficacy and safety in small pupil phacoemulsification.
METHODS
Polyproplyene suture and scalp acupuncture were used to make iris retractor. A prospective study were carried on 50 patients (50 eyes) with a maximally dilated pupil size of 2.5-4.0 mm which underwent phacoemulsification using this self-made iris retractor. Another 50 cases of phacoemulsification with normal pupil size sever as control group. The mean operation time, ultrasound time and ultrasonic power, volume of irrigation fluid were documented intraoperatively. The visual acuity, pupil size and complication were observed on 1d, 1wk, 1mo and 1y after operation. Corneal endothelial cell was measured at 1mo postoperatively.
RESULT
Pupils could be expanded to approximately 4.5-5.5 mm with our self-made iris retractor in operation. No serious postoperative complication was found. Most (88%) of the pupils returned round or oval shape, light reflex restored to varying degrees at the first day after surgery. Best corrected visual acuity stabilized in 37 eyes (74%) at one day, in 43 eyes (86%) at one week, in 44 eyes (88%) at one month and 46 eyes (92%) at one year. Compared with the control, more time was needed to complete the operation in the small pupil group. There was no significant difference of the mean ultrasound time, ultrasonic power, volume of irrigation fluid required and corneal endothelial cell loss in 1mo follow up between the two groups.
CONCLUSION
Our self-made disposable flexible iris retractor could be easy obtained preoperatively or intraoperatively. It performed both safety and efficacy in our clinical trials. This simple self-made device has shown economic and practical values, especially in primary care hospital of the less developed districts.
doi:10.3980/j.issn.2222-3959.2014.02.17
PMCID: PMC4003084  PMID: 24790872
small pupil; iris retractor; phacoemulsification
11.  A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: Similarities to and differences from the transgenic model (3xTg-AD mouse) 
Molecular neurobiology  2012;47(2):711-725.
Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP and tau genes and thus represents a model of FAD. There is an unmet need to in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.
doi:10.1007/s12035-012-8375-5
PMCID: PMC3582864  PMID: 23150171
Alzheimer’s disease; mouse model; behavioral tests; brain pathology
12.  Matrices of Physiologic Stiffness Potently Inactivate Idiopathic Pulmonary Fibrosis Fibroblasts 
Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) have been shown to differ from normal lung fibroblasts in functional behaviors that contribute to the pathogenesis of IPF, including the expression of contractile proteins and proliferation, but how such behaviors vary in matrices with stiffness matched to normal and fibrotic lung tissue remains unknown. Here, we tested whether pathologic changes in matrix stiffness control IPF and normal lung tissue–derived fibroblast functions, and compared the relative efficacy of mechanical cues to an antifibrotic lipid mediator, prostaglandin E2 (PGE2). Fibroblasts were grown on collagen I–coated glass or hydrogel substrates of discrete stiffnesses, spanning the range of normal and fibrotic lung tissue. Traction microscopy was used to quantify contractile function. The CyQuant Cell Proliferation Assay (Invitrogen, Carlsbad, CA) was used to assess changes in cell number, and PGE2 concentrations were measured by ELISA. We confirmed differences in proliferation and PGE2 synthesis between IPF and normal tissue–derived fibroblasts on rigid substrates. However, IPF fibroblasts remained highly responsive to changes in matrix stiffness, and both proliferative and contractile differences between IPF and normal fibroblasts were ablated on physiologically soft matrices. We also confirmed the relative resistance of IPF fibroblasts to PGE2, while demonstrating that decreases in matrix stiffness and the inhibition of Rho kinase both potently attenuate contractile function in IPF-derived fibroblasts. We conclude that pathologic changes in the mechanical environment control important IPF fibroblast functions. Understanding how mechanical cues control fibroblast function may offer new opportunities for targeting these cells, even when they are resistant to antifibrotic pharmacological agents or biological mediators.
doi:10.1165/rcmb.2012-0335OC
PMCID: PMC3653602  PMID: 23258227
pulmonary fibrosis; lung; extracellular matrix; fibroblast contractility
13.  Mesenchymal Progenitors Residing Close to the Bone Surface Are Functionally Distinct from Those in the Central Bone Marrow 
Bone  2012;53(2):575-586.
Long bone is an anatomically complicated tissue with trabecular-rich metaphyses at two ends and cortical-rich diaphysis at the center. The traditional flushing method only isolates mesenchymal progenitor cells from the central region of long bones and these cells are distant from the bone surface. We propose that mesenchymal progenitors residing in endosteal bone marrow that is close to the sites of bone formation, such as trabecular bone and endosteum, behave differently from those in the central bone marrow. In this report, we separately isolated endosteal bone marrow using a unique enzymatic digestion approach and demonstrated that it contained a much higher frequency of mesenchymal progenitors than the central bone marrow. Endosteal mesenchymal progenitors express traditional mesenchymal stem cell markers and are capable of multi-lineage differentiation. However, we found that mesenchymal progenitors isolated from different anatomical regions of the marrow did exhibit important functional differences. Compared to their central marrow counterparts, endosteal mesenchymal progenitors have superior proliferative ability with reduced expression of cell cycle inhibitors. They showed greater immunosuppressive activity in culture and in a mouse model of inflammatory bowel disease. Aging is a major contributing factor for trabecular bone loss. We found that old mice have a dramatically decreased number of endosteal mesenchymal progenitors compared to young mice. Parathyroid hormone (PTH) treatment potently stimulates bone formation. A single PTH injection greatly increased the number of endosteal mesenchymal progenitors, particularly those located at the metaphyseal bone, but had no effect on their central counterparts. In summary, endosteal mesenchymal progenitors are more metabolically active and relevant to physiological bone formation than central mesenchymal progenitors. Hence, they represent a biologically important target for future mesenchymal stem cell studies.
doi:10.1016/j.bone.2012.12.013
PMCID: PMC3674849  PMID: 23274348
mesenchymal progenitors; endosteal bone marrow; immunosuppression; aging; parathyroid hormone
14.  Atomic Force Microscopy Demonstration of Cytoskeleton Instability in Mouse Erythrocytes with Dematin-Headpiece and β-Adducin Deficiency 
Scanning  2011;33(6):426-436.
The pattern of disassembly of the cytoskeletal network of murine erythrocytes with deficiency of either dematin-headpiece or β-adducin or both proteins were investigated using atomic force microscopy. A heterogeneous complex structure with fine filament features and coarse features was observed in the cytoskeleton of wild type mouse erythrocytes, whereas a significant amount of rearrangement and aggregation occurred in the mutants, particularly in the cells carrying double gene mutations. These results are consistent with the cellular and biochemical phenotype of the mutant cell membranes as being more fragile due to weakened vertical connections with the plasma membrane.
doi:10.1002/sca.20246
PMCID: PMC3955161  PMID: 21638291
Atomic force microscopy; Erythrocyte; Cytoskeleton; Dematin; Adducin
15.  Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology 
The Biochemical journal  2012;448(1):141-152.
Pharmacological inhibitors of cysteine proteases have provided useful insights into the regulation of calpain activity in erythrocytes. However, the precise biological function of calpain activity in erythrocytes remains poorly understood. Erythrocytes express calpain-1, an isoform regulated by calpastatin, the endogenous inhibitor of calpains. In the present study, we investigated the function of calpain-1 in mature erythrocytes using our calpain-1-null [KO (knockout)] mouse model. The calpain-1 gene deletion results in improved erythrocyte deformability without any measurable effect on erythrocyte lifespan in vivo. The calcium-induced sphero-echinocyte shape transition is compromised in the KO erythrocytes. Erythrocyte membrane proteins ankyrin, band 3, protein 4.1R, adducin and dematin are degraded in the calcium-loaded normal erythrocytes but not in the KO erythrocytes. In contrast, the integrity of spectrin and its state of phosphorylation are not affected in the calcium-loaded erythrocytes of either genotype. To assess the functional consequences of attenuated cytoskeletal remodelling in the KO erythrocytes, the activity of major membrane transporters was measured. The activity of the K+–Cl− co-transporter and the Gardos channel was significantly reduced in the KO erythrocytes. Similarly, the basal activity of the calcium pump was reduced in the absence of calmodulin in the KO erythrocyte membrane. Interestingly, the calmodulin-stimulated calcium pump activity was significantly elevated in the KO erythrocytes, implying a wider range of pump regulation by calcium and calmodulin. Taken together, and with the atomic force microscopy of the skeletal network, the results of the present study provide the first evidence for the physiological function of calpain-1 in erythrocytes with therapeutic implications for calcium imbalance pathologies such as sickle cell disease.
doi:10.1042/BJ20121008
PMCID: PMC3955119  PMID: 22870887
calcium pump; calpain-1; deformability; erythrocyte; K+–Cl− co-transporter (KCC1); spectrin
16.  Molecular Evolution of the Vertebrate FK506 Binding Protein 25 
FK506 binding proteins (FKBPs) belong to immunophilins with peptidyl-prolyl isomerases (PPIases) activity. FKBP25 (also known as FKBP3) is one of the nuclear DNA-binding proteins in the FKBPs family, which plays an important role in regulating transcription and chromatin structure. The calculation of nonsynonymous and synonymous substitution rates suggested that FKBP25 undergoes purifying selection throughout the whole vertebrate evolution. Moreover, the result of site-specific tests showed that no sites were detected under positive selection. Only one PPIase domain was detected by searching FKBP25 sequences at Pfam and SMART domain databases. Mammalian FKBP25 possess exon-intron conservation, although conservation in the whole vertebrate lineage is incomplete. The result of this study suggests that the purifying selection triggers FKBP25 evolutionary history, which allows us to discover the complete role of the PPIase domain in the interaction between FKBP25 and nuclear proteins. Moreover, intron alterations during FKBP25 evolution that regulate gene splicing may be involved in the purifying selection.
doi:10.1155/2014/402603
PMCID: PMC3958658  PMID: 24724077
17.  Cheap, Gram-Scale Fabrication of BN Nanosheets via Substitution Reaction of Graphite Powders and Their Use for Mechanical Reinforcement of Polymers 
Scientific Reports  2014;4:4211.
As one of the most important two-dimensional (2D) materials, BN nanosheets attracted intensive interest in the past decade. Although there are many methods suitable for the preparation of BN sheets, finding a cheap and nontoxic way for their mass and high-quality production is still a challenge. Here we provide a highly effective and cheap way to synthesize gram-scale-level well-structured BN nanosheets from many common graphite products as source materials. Single-crystalline multi-layered BN sheets have a mean lateral size of several hundred nanometers and a thickness ranging from 5 nm to 40 nm. Cathodoluminescence (CL) analysis shows that the structures exhibit a near band-edge emission and a broad emission band from 300 nm to 500 nm. Utilization of nanosheets for the reinforcement of polymers revealed that the Young's modulus of BN/PMMA composite had increased to 1.56 GPa when the BN's fraction was only 2 wt.%, thus demonstrating a 20% gain compared to a blank PMMA film. It suggests that the BN nanosheet is an ideal mechanical reinforcing material for polymers. In addition, this easy and nontoxic substitution method may provide a universal route towards high yields of other 2D materials.
doi:10.1038/srep04211
PMCID: PMC3936228  PMID: 24572725
18.  Association of interleukin-10 promoter polymorphisms and corresponding plasma levels with susceptibility to laryngeal squamous cell carcinoma 
Oncology Letters  2014;7(5):1721-1727.
Interleukin (IL)-10 is critically involved in tumorigenesis. In the present study, the association between the IL-10 −1082/−819/−592 promoter polymorphisms, the plasma IL-10 levels and the risk of laryngeal squamous cell carcinoma (LSCC) was investigated in a prospective, case-control study. In total, 146 patients with LSCC, 61 with vocal leukoplakia and 119 healthy controls were genotyped for the IL-10 gene (IL-10 −1082 A/G, −819 T/C and −592 A/C) using pyrosequencing, and their plasma IL-10 levels were analyzed by ELISA. The patients with LSCC had a significantly higher frequency of AC at position −592 and −819 (OR, 1.82 and P=0.024) compared with the control, and a higher frequency of AG at position −1082 (OR, 2.20 and P=0.037). The patients with advanced LSCC had a significantly higher frequency of AG+GG at position −1082 compared with those with early-stage LSCC (OR, 3.13 and P=0.008 vs. OR, 2.06 and P=0.068). The patients with lymph node metastasis had a significantly higher frequency of AG+GG at position −1082 compared with the patients with no lymph node metastasis (OR, 2.97 and P=0.048 vs. OR, 2.23 and P=0.035). In addition, the patients with high frequencies of each genotype polymorphism had high plasma IL-10 concentrations. The present study indicates that the IL-10 −1082/−819/−592 promoter polymorphisms and corresponding high plasma IL-10 concentrations are associated with LSCC, and that variations in genotype distribution and plasma IL-10 concentrations may be associated with the stage and the lymph node metastasis status of LSCC.
doi:10.3892/ol.2014.1914
PMCID: PMC3997667  PMID: 24765208
laryngeal squamous cell carcinoma; vocal leukoplakia; cytokines; polymorphism; interleukin-10
19.  A Porphodimethene Chemical Inhibitor of Uroporphyrinogen Decarboxylase 
PLoS ONE  2014;9(2):e89889.
Uroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.
doi:10.1371/journal.pone.0089889
PMCID: PMC3934957  PMID: 24587102
20.  Casticin induces breast cancer cell apoptosis by inhibiting the expression of forkhead box protein M1 
Oncology Letters  2014;7(5):1711-1717.
Casticin is an active ingredient derived from Fructus Viticis, a traditional Chinese medicine. This study aimed to investigate the role of forkhead box O3 (FOXO3a) in breast cancer cells and examine the regulatory mechanisms of FOXO3a in response to casticin treatment of the cells by ELISA, flow cytometry, small interfering RNA (siRNA) transfection and western blot analysis. Casticin treatment induced apoptosis and reduced the expression of the transcription factor forkhead box protein M1 (FOXM1). In addition, FOXM1 repression induced by casticin treatment was associated with the activation of FOXO3a via increased dephosphorylation. Notably, silencing FOXO3a expression by siRNA-mediated gene knockdown attenuated casticin-mediated apoptosis. Collectively, these findings suggest that FOXO3a is a critical mediator of the inhibitory effects of casticin on apoptosis in breast cancer cells.
doi:10.3892/ol.2014.1911
PMCID: PMC3997681  PMID: 24765206
forkhead box O3; forkhead box protein M1; casticin; breast cancer; therapeutic targets
21.  Draft Genome Sequence of mc251, a Highly Hydrogen Peroxide-Resistant Mycobacterium smegmatis Mutant Strain 
Genome Announcements  2014;2(1):e00092-14.
Here, we report the draft genome sequence of the Mycobacterium tuberculosis-like Mycobacterium smegmatis mutant strain, mc251, compared to that of wild-type strain M. smegmatis mc2155. The draft genome sequence comprises 6,823,739 bp, revealing 6,569 coding DNA sequences (CDSs) and 50 RNA genes (4 rRNA genes and 46 tRNA genes).
doi:10.1128/genomeA.00092-14
PMCID: PMC3931361  PMID: 24558240
22.  Association of ERCC1 and ERCC2 polymorphisms with colorectal cancer risk in a Chinese population 
Scientific Reports  2014;4:4112.
The ERCC1 and ERCC2 genes are important in repairing DNA damage and genomic instability, and are involved in the nucleotide excision repair pathway. We hypothesized that single nucleotide polymorphisms (SNPs) in ERCC1 and ERCC2 are associated with the risk of colorectal cancer in a Chinese population. To test this hypothesis, we genotyped four functional SNPs (ERCC1 Asn118Asn, C8092A, ERCC2 Asp312Asn, and Lys751Gln) in a case-control study with 213 colorectal cancer cases and 240 cancer-free controls. We found that the ERCC1 C8092A polymorphism AA and CA/AA variant genotypes were associated with a significantly increased risk of colorectal cancer, compared with the CC genotype (OR = 2.50, 95% CI = 1.10–5.70 for AA versus CC, and OR = 1.58, 95% CI = 1.08–2.30 for CA/AA versus CC). Furthermore, the effect appeared to be more prominent among men, smokers, drinkers, and patients with rectal cancer. However, no other SNPs were observed for any significant association with colorectal cancer risk. These results suggest that the ERCC1 C8092A polymorphism may contribute to colorectal cancer susceptibility in the Chinese population. Further large and functional studies are needed to confirm our findings.
doi:10.1038/srep04112
PMCID: PMC3925949  PMID: 24531312
23.  VE-statin/Egfl7 expression in malignant glioma and its relevant molecular network 
This study investigated VE-statin/Egfl7 expression and its role and regulatory mechanism in malignant glioma progression. Forty-five paraffin-embedded glioma (grade I-II: n=24; grade III-IV: n=21) were examined. VE-statin/Egfl7 protein expression was detected via immunohistochemistry, and its correlation with pathological grade was evaluated. Three-dimensional cell culture was then performed to investigate the influence of VE-statin/Egfl7 on the angiogenesis of umbilical vein endothelial cells. Microarray detection was used to molecularly profile VE-statin/Egfl7 and relevant signaling pathways in malignant glioma (U251 cells). Data showed that VE-statin/Egfl7 protein was mainly expressed in the cytoplasm of cancer and vascular endothelial cells and was significantly related to the degree of malignancy (t=4.399, P<0.01). Additionally, VE-statin/Egfl7 expression was low in certain gray-matter neurons but undetectable in glial cells. VE-statin/Egfl7 gene silencing significantly inhibited angiogenesis in umbilical vein endothelial cells. The following microarray results were observed in VE-statin/Egfl7-silenced U251 cells: 1) EGFR family members showed the highest differential expression, accounting for 5.54% of differentially expressed genes; 2) cell survival-related signaling pathways changed significantly; and 3) the integrin ανβ3 signaling pathway was markedly altered. Thus, malignant glioma cells and glioma vascular endothelial cells highly express VE-statin/Egfl7, which is significantly correlated with the degree of malignancy. Moreover, VE-statin/Egfl7 plays an important role in glioma angiogenesis. Microarray results indicate that VE-statin/Egfl7 may regulate EGFR and integrins to influence the FAK activity of downstream factors, triggering the PI3K/Akt and Ras/MAPK cascades and subsequent malignant glioma development.
PMCID: PMC3971305  PMID: 24696719
Epidermal growth factor-like domain 7; glioma; pathological grade; angiogenesis; microarray
24.  Gender Differences of B Cell Signature in Healthy Subjects Underlie Disparities in Incidence and Course of SLE Related to Estrogen 
Journal of Immunology Research  2014;2014:814598.
The aim of the present study was to investigate mechanism of the gender differences of B cells. The results showed that 358 differential gene expressions (DEGs) were displayed between healthy females and males. Compared with male, 226 and 132 genes were found to be up- and downregulated in the female. 116 genes displayed possible correlation with estrogen. Moreover, the upregulated DEGs (Cav1, CD200R1, TNFRSF17, and CXCR3) and downregulated DEGs (EIF1AY and DDX3Y) in healthy female may be involved in gender predominance of some immune diseases. Furthermore, signaling pathway analysis for estrogen-relevant DEGs showed that only 26 genes were downregulated in SLE female versus SLE male, of which expressions of 8 genes had significant difference between SLE females and SLE males but are having nonsignificant difference between healthy females and healthy males. Except for the 5 Y-chromosome-related genes or varients, only 3 DEGs (LTF, CAMP, and DEFA4) were selected and qRT-PCR confirmed that the expressions of LTF and CAMP decreased significantly in B cells from female SLE patients. These data indicated that the gender differences were existent in global gene expression of B cells and the difference may be related to estrogen.
doi:10.1155/2014/814598
PMCID: PMC3987971  PMID: 24741625
25.  Genome sequence and comparative analysis of a Vibrio cholerae O139 strain E306 isolated from a cholera case in China 
Gut Pathogens  2014;6:3.
Background
Vibrio cholerae is a human intestinal pathogen and V. cholerae of the O139 serogroups are responsible for the current epidemic cholera in China. In this work, we reported the whole genome sequencing of a V. cholerae O139 strain E306 isolated from a cholera patient in the 306th Hospital of PLA, Beijing, China.
Results
We obtained the draft genome of V. cholerae O139 strain E306 with a length of 4,161,908 bps and mean G + C content of 47.7%. Phylogenetic analysis indicated that strain E306 was very close to another O139 strain, V. cholerae MO10, which was isolated during the cholera outbreak in India and Bangladesh. However, unlike MO10, strain E306 harbors the El Tor-specific RS1 element with no pre-CTX prophage (VSK), very similar to those found in some V. cholerae O1 strains. In addition, strain E306 contains a SXT/R391 family integrative conjugative element (ICE) similar to ICEVchInd4 and SXT MO10, and it carries more antibiotic resistance genes than other closest neighbors.
Conclusions
The genome sequence of the V. cholerae O139 strain E306 and its comparative analysis with other V. cholerae strains we present here will provide important information for a better understanding of the pathogenicity of V. cholerae and their molecular mechanisms to adapt different environments.
doi:10.1186/1757-4749-6-3
PMCID: PMC3923101  PMID: 24517211
Cholera toxin prophage; Integrative conjugative elements; Antibiotic resistance genes

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