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1.  Genes Underlying Positive Influence of Prenatal Environmental Enrichment and Negative Influence of Prenatal Earthquake Simulation and Corrective Influence of Chinese Herbal Medicine on Rat Offspring: Irf7 and Ninj2 
Background
Prenatal environmental enrichment (EE) has been proven to positively affect but prenatal stress negatively influence the physiological and psychological processes in animals, whose trans-generational genetic mechanism remains unclearly defined. We aimed to investigate and find out key genes underlying the positive-negative effects derived from prenatal interventions.
Materials and Methods
Pregnant rats were randomized into EE group (EEG), earthquake simulation group (ESG), herbal group (HG) received herbal supplements in feed after earthquake simulation, and control group (CG).
Results
Light Box Defecation Test (LBDT) showed EEG offspring presented less fecal pellets than CG offspring, ESG's more than CG's, and HG's less than ESG (p's<0.05). Open-field Test (OFT) score of EEG was higher than CG offspring, of ESG's was lower than CG's, and HG's higher than ESG's. Irf7 and Ninj were screened, which were up-regulated in EEG, down-regulated in ESG (FC<0.5), and were neutralized in HG. Prenatal EE could positively promote the nervous system development, prenatal earthquake simulation could retard the nervous system development and Chinese herbal remedy (JKSQW) which could correct the retardation.
Conclusion
The negative-positive prenatal effect could contribute to altered gene expression of Irf7 and Ninj2 which also could play a key role in the improving function of JKSQW for the kidneys.
PMCID: PMC4202648  PMID: 25435624
Prenatal stress; Earthquake simulation; Light Box Defecation Test; Open-field Test; Irf7; Ninj2
2.  Decision-Making for Risky Gains and Losses among College Students with Internet Gaming Disorder 
PLoS ONE  2015;10(1):e0116471.
Individuals with Internet gaming disorder (IGD) tend to exhibit disadvantageous risky decision-making not only in their real life but also in laboratory tasks. Decision-making is a complex multifaceted function and different cognitive processes are involved in decision-making for gains and losses. However, the relationship between impaired decision-making and gain versus loss processing in the context of IGD is poorly understood. The main aim of the present study was to separately evaluate decision-making for risky gains and losses among college students with IGD using the Cups task. Additionally, we further examined the effects of outcome magnitude and probability level on decision-making related to risky gains and losses respectively. Sixty college students with IGD and 42 matched healthy controls (HCs) participated. Results indicated that IGD subjects exhibited generally greater risk taking tendencies than HCs. In comparison to HCs, IGD subjects made more disadvantageous risky choices in the loss domain (but not in the gain domain). Follow-up analyses indicated that the impairment was associated to insensitivity to changes in outcome magnitude and probability level for risky losses among IGD subjects. In addition, higher Internet addiction severity scores were associated with percentage of disadvantageous risky options in the loss domain. These findings emphasize the effect of insensitivity to losses on disadvantageous decisions under risk in the context of IGD, which has implications for future intervention studies.
doi:10.1371/journal.pone.0116471
PMCID: PMC4304794  PMID: 25615595
3.  Sevoflurane Postconditioning Protects Rat Hearts against Ischemia-Reperfusion Injury via the Activation of PI3K/AKT/mTOR Signaling 
Scientific Reports  2014;4:7317.
Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway plays a key role in myocardial ischemia-reperfusion (I/R) injury. Mammalian target of rapamycin (mTOR), a downstream target of PI3K/AKT signaling, is necessary and sufficient to protect the heart from I/R injury. Inhaled anesthetic sevoflurane is widely used in cardiac surgeries because its induction and recovery are faster and smoother than other inhaled anesthetics. Sevoflurane proved capable of inducing postconditioning effects in the myocardium. However, the underlying molecular mechanisms for sevoflurane-induced postconditioning (SPC) were largely unclear. In the present study, we demonstrated that SPC protects myocardium from I/R injury with narrowed cardiac infarct focus, increased ATP content, and decreased cardiomyocyte apoptosis, which are mainly due to the activation of PI3K/AKT/mTOR signaling and the protection of mitochondrial energy metabolism. Application of dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, abolishes the up-regulation of pho-AKT, pho-GSK, pho-mTOR, and pho-p70s6k induced by SPC, hence abrogating the anti-apoptotic effect of sevoflurane and reducing SPC-mediated protection of heart from I/R injury. As such, this study proved that PI3K/AKT/mTOR pathway plays an important role in SPC induced cardiac protection against I/R injury.
doi:10.1038/srep07317
PMCID: PMC4255182  PMID: 25471136
4.  BCDP: Budget Constrained and Delay-Bounded Placement for Hybrid Roadside Units in Vehicular Ad Hoc Networks 
Sensors (Basel, Switzerland)  2014;14(12):22564-22594.
In vehicular ad hoc networks, roadside units (RSUs) placement has been proposed to improve the the overall network performance in many ITS applications. This paper addresses the budget constrained and delay-bounded placement problem (BCDP) for roadside units in vehicular ad hoc networks. There are two types of RSUs: cable connected RSU (c-RSU) and wireless RSU (w-RSU). c-RSUs are interconnected through wired lines, and they form the backbone of VANETs, while w-RSUs connect to other RSUs through wireless communication and serve as an economical extension of the coverage of c-RSUs. The delay-bounded coverage range and deployment cost of these two cases are totally different. We are given a budget constraint and a delay bound, the problem is how to find the optimal candidate sites with the maximal delay-bounded coverage to place RSUs such that a message from any c-RSU in the region can be disseminated to the more vehicles within the given budget constraint and delay bound. We first prove that the BCDP problem is NP-hard. Then we propose several algorithms to solve the BCDP problem. Simulation results show the heuristic algorithms can significantly improve the coverage range and reduce the total deployment cost, compared with other heuristic methods.
doi:10.3390/s141222564
PMCID: PMC4299028  PMID: 25436656
roadside unit; facility placement; delay bound; vehicular sensor networks
5.  Effect of epigallocatechin-3-gallate on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro 
In autologous chondrocyte implantation (ACI) to restore defective cartilage, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but their high cost and potential for tumorigenesis are major obstacles. To ensure successful ACI therapy, it is important to find an effective substitute pro-chondrogenic agent. Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, has been widely investigated in studies of interleukin-1β-induced chondrocytes. In the present study, the effects of EGCG on rabbit articular chondrocytes were investigated through the examination of cell proliferation, morphology, glycosaminoglycan synthesis and cartilage-specific gene expression. The results showed that EGCG could effectively promote chondrocyte growth and enhance the secretion and synthesis of the cartilage extracellular matrix by upregulating expression levels of aggrecan, collagen II and Sox9 genes. Expression of the collagen I gene was downregulated, which showed that EGCG effectively inhibited the dedifferentiation of chondrocytes. Hypertrophy, which may lead to chondrocyte ossification, was also undetectable in the EGCG groups. In conclusion, the recommended dose of EGCG was found to be in the range of 5 to 20 μM, with the most marked response observed with 10 μM. The present study may provide a basis for the development of a novel agent as a substitute for growth factors in the treatment of articular cartilage defects.
doi:10.3892/etm.2014.2057
PMCID: PMC4247298  PMID: 25452805
epigallocatechin-3-gallate; pro-chondrogenic agent; chondrocyte; rabbit articular cartilage; dedifferentiation
6.  Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma 
Cell reports  2013;4(6):1090-1099.
Summary
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
doi:10.1016/j.celrep.2013.08.023
PMCID: PMC3956616  PMID: 24055054
7.  The p130 Isoform of Angiomotin Is Required for Yap-Mediated Hepatic Epithelial Cell Proliferation and Tumorigenesis 
Science signaling  2013;6(291):ra77.
The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, and tumorigenesis. Members of the scaffold protein angiomotin (Amot) family interact with several Hippo pathway components, including Yap (Yes-associated protein), and either stimulate or inhibit Yap activity. We used a combination of genetic, biochemical, and transcriptional approaches to assess the functional consequences of the Amot-Yap interaction in mice and in human cells. Mice with a liver-specific Amot knockout exhibited reduced hepatic “oval cell” proliferation and tumorigenesis in response to toxin-induced injury or when crossed with mice lacking the tumor suppressor Nf2. Biochemical examination of the Amot-Yap interaction revealed that the p130 splicing isoform of Amot (Amot-p130) and Yap interacted in both the cytoplasm and nucleus, which involved binding of PPxY and LPxY motifs in Amot-p130 to WW domains of Yap. In the cytoplasm, Amot-p130 prevented the phosphorylation of Yap by blocking access of the WW domains to the kinase Lats1. Within the nucleus, Amot-p130 was associated with the transcriptional complex containing Yap and Teads (TEA domain family members) and contributed to the regulation of a subset of Yap target genes, many of which are associated with tumorigenesis. These findings indicated that Amot acts as a Yap cofactor, preventing Yap phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis.
doi:10.1126/scisignal.2004060
PMCID: PMC4175526  PMID: 24003254
8.  Preliminary experience of the robot-assisted laparoscopic excision of a retroperitoneal mass: A case report 
Oncology Letters  2014;8(6):2399-2402.
The aim of the present study was to report the initial clinical experience of adopting the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA, USA) to perform a retroperitoneal tumor resection. The patient was a 56-year-old female who presented with a five-year history of hypertension. Abdominal dynamic computed tomography (CT) and positron emission tomography-CT scans revealed a mass measuring ~6 cm in diameter that was located anterior to the abdominal aorta, and between the abdominal aorta and the inferior vena cava (at the level of the third lumbar vertebra). The tumor was excised via a five-port, robot-assisted, transperitoneal laparoscopic approach. Careful dissection of the tumor away from the abdominal aorta and the inferior vena cava was accomplished without resulting in major vascular injury. There were no complications and the patient was discharged in a good condition on the eleventh postoperative day. Pathological analysis of a tumor specimen demonstrated a benign pheochromocytoma (PHEO). During the three-month follow-up, no recurrence was identified through CT scans or measurement of the patient’s endocrine hormone levels. Thus, the da Vinci robot-assisted laparoscopic system may be safely employed in the treatment of extra-adrenal PHEOs that occur in difficult locations for which a laparoscopic surgical excision may be challenging.
doi:10.3892/ol.2014.2533
PMCID: PMC4214392  PMID: 25360164
retroperitoneal mass; pheochromocytoma; extra-adrenal; robot-assisted; laparoscopic
9.  Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer 
Journal of proteomics  2013;89:165-178.
New serological biomarkers for early detection and clinical management of ovarian cancer are urgently needed, and many candidates have been reported. A major challenge frequently encountered when validating candidates in patients is establishing quantitative assays that distinguish between highly homologous proteins. The current study tested whether multiple members of two recently discovered ovarian cancer biomarker protein families, chloride intracellular channel (CLIC) proteins and tropomyosins (TPM), were detectable in ovarian cancer patient sera. A multiplexed, label-free multiple reaction monitoring (MRM) assay was established to target peptides specific to all detected CLIC and TPM family members, and their serum levels were quantitated for ovarian cancer patients and non-cancer controls. In addition to CLIC1 and TPM1, which were the proteins initially discovered in a xenograft mouse model, CLIC4, TPM2, TPM3, and TPM4 were present in ovarian cancer patient sera at significantly elevated levels compared with controls. Some of the additional biomarkers identified in this homolog-centric verification and validation approach may be superior to the previously identified biomarkers at discriminating between ovarian cancer and non-cancer patients. This demonstrates the importance of considering all potential protein homologs and using quantitative assays for cancer biomarker validation with well-defined isoform specificity.
doi:10.1016/j.jprot.2013.06.016
PMCID: PMC3779132  PMID: 23792823
10.  Prognostic role of microvessel density in patients with renal cell carcinoma: a meta-analysis 
Microvessel density (MVD), an indicator of angiogenesis, has been proposed to predict prognosis of patients with renal cell carcinoma (RCC), but its ability to predict survival of patients with RCC remains controversial. The present study sought to address this question rigorously by systematically reviewing the literature on MVD and RCC prognosis. We identified relevant studies in PubMed, EMBASE and the Cochrane Library, and two reviewers independently assessed study quality and extracted relevant data to compare survival based on MVD stratification in patients with RCC. We identified 15 studies that satisfied the inclusion criteria; eight studies assessed MVD in surgical samples by immunohistochemistry to label factor VIII; four studies, by immunohistochemistry to label CD34; two studies, CD31; and one study, CD105. Survival meta-analysis was performed using data pooled from 10 studies: five based on factor VIII, two based on CD34, two based on CD31 and one based on CD105. The overall survival hazard ratio describing the relationship between MVD and survival in all 10 pooled studies was 0.964 (95% CI: 0.873-1.065), while the individual hazard ratios for pooled studies based on factor VIII were 1.673 (95% CI: 0.860-3.252); CD34, 0.903 (95% CI: 0.853-0.956); and CD31, 0.926 (95% CI: 0.868-0.989). The corresponding result for the sole trial based on CD105 was 0.1759 (95% CI: 0.036-0.856). These findings suggest that MVD is not reliably associated with survival time of patients with RCC, which may reflect the need to take into account whether the microvasculature is differentiated or not. MVD as currently calculated may not be an ideal prognostic factor for patients with RCC.
PMCID: PMC4203198  PMID: 25337227
Microvessel density; renal cell carcinoma; prognosis; meta-analysis
11.  Tobacco Dependence Treatment Teaching by Medical School Clerkship Preceptors: Survey Responses from more than 1,000 US Medical Students 
Preventive medicine  2013;57(2):81-86.
Objective
To determine factors associated with tobacco cessation counseling in medical school clerkships
Methods
Third-year medical students at 10 medical schools across the United States completed a 100-item survey, measuring the frequency with which they experienced their preceptors’ providing clinical teaching components: clear instruction, feedback, modeling behavior, setting clear objectives, and responding to questions about tobacco dependence counseling as well as frequency of use of tobacco prompts and office systems. Our primary dependent measure was student self-reported skill level for items of tobacco dependence treatment (e.g. “5As”).
Results
Surveys were completed by 1213 students. For both family medicine and internal medicine clerkships, modeling and providing clear instruction on ways to provide tobacco counseling were reported most commonly. In contrast, providing feedback and clear objectives for tobacco dependence treatment lagged behind. Overall, students who reported preceptors’ provision of optimal clinical teaching components and office system prompts in both family medicine and internal medicine clerkships had higher self-reported skill (p<0.001) than students with no exposure or exposure during only one of the clerkships.
Conclusions
Future educational interventions intended to help students adopt effective tobacco dependence treatment techniques should be engineered to facilitate these critical precepting components.
doi:10.1016/j.ypmed.2013.04.006
PMCID: PMC3767283  PMID: 23623894
12.  Laser-Machined Microcavities for Simultaneous Measurement of High-Temperature and High-Pressure 
Sensors (Basel, Switzerland)  2014;14(8):14330-14338.
Laser-machined microcavities for simultaneous measurement of high-temperature and high-pressure are demonstrated. These two cascaded microcavities are an air cavity and a composite cavity including a section of fiber and an air cavity. They are both placed into a pressure chamber inside a furnace to perform simultaneous pressure and high-temperature tests. The thermal and pressure coefficients of the short air cavity are ∼0.0779 nm/°C and ∼1.14 nm/MPa, respectively. The thermal and pressure coefficients of the composite cavity are ∼32.3 nm/°C and ∼24.4 nm/MPa, respectively. The sensor could be used to separate temperature and pressure due to their different thermal and pressure coefficients. The excellent feature of such a sensor head is that it can withstand high temperatures of up to 400 °C and achieve precise measurement of high-pressure under high temperature conditions.
doi:10.3390/s140814330
PMCID: PMC4178988  PMID: 25106018
high pressure sensing; high temperature sensing; laser micromachining; micro-cavity; simultaneous measurement
13.  Genomovar assignment of Pseudomonas stutzeri populations inhabiting produced oil reservoirs 
MicrobiologyOpen  2014;3(4):446-456.
Oil reservoirs are specific habitats for the survival and growth of microorganisms in general. Pseudomonas stutzeri which is believed to be an exogenous organism inoculated into oil reservoirs during the process of oil production was detected frequently in samples from oil reservoirs. Very little is known, however, about the distribution and genetic structure of P. stutzeri in the special environment of oil reservoirs. In this study, we collected 59 P. stutzeri 16S rRNA gene sequences that were identified in 42 samples from 25 different oil reservoirs and we isolated 11 cultured strains from two representative oil reservoirs aiming to analyze the diversity and genomovar assignment of the species in oil reservoirs. High diversity of P. stutzeri was observed, which was exemplified in the detection of sequences assigned to four known genomovars 1, 2, 3, 20 and eight unknown genomic groups of P. stutzeri. The frequent detection and predominance of strains belonging to genomovar 1 in most of the oil reservoirs under study indicated an association of genomovars of P. stutzeri with the oil field environments.
doi:10.1002/mbo3.179
PMCID: PMC4287174  PMID: 24890829
16S rRNA gene; Genomovar; oil reservoirs; Pseudomonas stutzeri
14.  A Correlate of HIV-1 Control Consisting of Both Innate and Adaptive Immune Parameters Best Predicts Viral Load by Multivariable Analysis in HIV-1 Infected Viremic Controllers and Chronically-Infected Non-Controllers 
PLoS ONE  2014;9(7):e103209.
HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.
doi:10.1371/journal.pone.0103209
PMCID: PMC4117509  PMID: 25078947
15.  Mutations of C-Reactive Protein (CRP) -286 SNP, APC and p53 in Colorectal Cancer: Implication for a CRP-Wnt Crosstalk 
PLoS ONE  2014;9(7):e102418.
C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.
doi:10.1371/journal.pone.0102418
PMCID: PMC4099363  PMID: 25025473
16.  Comparative studies of salinomycin-loaded nanoparticles prepared by nanoprecipitation and single emulsion method 
Nanoscale Research Letters  2014;9(1):351.
To establish a satisfactory delivery system for the delivery of salinomycin (Sal), a novel, selective cancer stem cell inhibitor with prominent toxicity, gelatinase-responsive core-shell nanoparticles (NPs), were prepared by nanoprecipitation method (NR-NPs) and single emulsion method (SE-NPs). The gelatinase-responsive copolymer was prepared by carboxylation and double amination method. We studied the stability of NPs prepared by nanoprecipitation method with different proportions of F68 in aqueous phase to determine the best proportion used in our study. Then, the NPs were prepared by nanoprecipitation method with the best proportion of F68 and single emulsion method, and their physiochemical traits including morphology, particle size, zeta potential, drug loading content, stability, and in vitro release profiles were studied. The SE-NPs showed significant differences in particle size, drug loading content, stability, and in vitro release profiles compared to NR-NPs. The SE-NPs presented higher drug entrapment efficiency and superior stability than the NR-NPs. The drug release rate of SE-NPs was more sustainable than that of the NR-NPs, and in vivo experiment indicated that NPs could prominently reduce the toxicity of Sal. Our study demonstrates that the SE-NPs could be a satisfactory method for the preparation of gelatinase-responsive NPs for intelligent delivery of Sal.
doi:10.1186/1556-276X-9-351
PMCID: PMC4134115  PMID: 25147486
Salinomycin; Nanoprecipitation method; Single emulsion method; Gelatinase; Drug delivery; Nanoparticles
17.  A Comparative Study on Inhibition of Total Astragalus Saponins and Astragaloside IV on TNFR1-Mediated Signaling Pathways in Arterial Endothelial Cells 
PLoS ONE  2014;9(7):e101504.
Background
Both total astragalus saponins (AST) and it’s main component astragaloside IV (ASIV) have been used in China as cardiovascular protective medicines. However, the anti-inflammatory activities that are beneficial for cardiovascular health have never been compared directly and the molecular mechanisms remain unresolved. This study was conducted to compare the inhibitory effects of these drugs on TNFα-induced cell responses, related signaling pathways, and the underlying mechanisms in mouse arterial endothelial cells.
Methodology/Principal Findings
Real-time qRT-PCR was performed to determine the expression of cell adhesion molecule (CAM) genes. Immunofluorescent staining was used to detect the nuclear translocation of transcription factor NF-κB-p65. Western Blot analysis was used to identify TNFα-induced NF-κB-p65 phosphorylation, IκBα degradation, and caspase-3 cleavage. Cell surface proteins were isolated and TNFα receptor-1(TNFR1) expression was determined. The results suggest that both AST and ASIV attenuate TNFα-induced up-regulation of CAMs mRNA and upstream nuclear translocation and phosphorylation of NF-κB-p65. However, TNFR1-mediated IκBα degradation, cleavage of caspase-3 and apoptosis were inhibited only by AST. These differences in the actions of AST and ASIV could be explained by the presence of other components in AST, such as ASII and ASIII, which also had an inhibitory effect on TNFR1-induced IκBα degradation. Moreover, AST, but not ASIV, was able to reduce TNFR1 protein level on the cell surface. Furthermore, mechanistic investigation demonstrated that TNFR1-mediated IκBα degradation was reversed by the use of TAPI-0, an inhibitor of TNFα converting enzyme (TACE), suggesting the involvement of TACE in the modulation of surface TNFR1 level by AST.
Conclusion
ASIV was not a better inhibitor than AST, at least on the inhibition of TNFα-induced inflammatory responses and TNFR1-mediated signaling pathways in AECs. The inhibitory effect of AST was caused by the reduction of cell surface TNFR1 level, and TACE could be involved in this action.
doi:10.1371/journal.pone.0101504
PMCID: PMC4081628  PMID: 24991819
18.  Artery Buckling: New Phenotypes, Models, and Applications 
Annals of biomedical engineering  2012;41(7):1399-1410.
Arteries are under significant mechanical loads from blood pressure, flow, tissue tethering, and body movement. It is critical that arteries remain patent and stable under these loads. This review summarizes the common forms of buckling that occur in blood vessels including cross-sectional collapse, longitudinal twist buckling, and bent buckling. The phenomena, model analyses, experimental measurements, effects on blood flow, and clinical relevance are discussed. It is concluded that mechanical buckling is an important issue for vasculature, in addition to wall stiffness and strength, and requires further studies to address the challenges. Studies of vessel buckling not only enrich vascular biomechanics but also have important clinical applications.
doi:10.1007/s10439-012-0707-0
PMCID: PMC3618579  PMID: 23192265
instability; collapsible tube; bent buckling; twist buckling; kinking; folding; blood flow; arteries; veins; blood vessels
19.  β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1 
Journal of cellular physiology  2013;228(7):1601-1609.
This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between β1 integrins and type 1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation.
doi:10.1002/jcp.24323
PMCID: PMC3749928  PMID: 23359252
TRAMP mice; Prostate cancer; Apoptosis; Insulin-like growth factor receptor
20.  Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload 
Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P < 0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.
doi:10.1155/2014/769515
PMCID: PMC4100359  PMID: 25093027
21.  Epidermal Growth Factor-Like Domain-Containing Protein 7 (EGFL7) Enhances EGF Receptor−AKT Signaling, Epithelial−Mesenchymal Transition, and Metastasis of Gastric Cancer Cells 
PLoS ONE  2014;9(6):e99922.
Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial–mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR−AKT−Snail signaling pathway. Disruption of EGFL7−EGFR−AKT−Snail signaling may a promising therapeutic strategy for gastric cancer.
doi:10.1371/journal.pone.0099922
PMCID: PMC4063792  PMID: 24945379
22.  Detection of piroplasms infection in sheep, dogs and hedgehogs in Central China 
Background
Piroplasms are kinds of tick-borne parasitic apicomplexan protozoa, which are detrimental to humans and animals in tropical and subtropical areas around the world. Up until now, there has been a limited amount of reliable information available about the prevalence of piroplasms infections in wild animals in China. Therefore, we have investigated the infections of Babesia and Theileria species in both domestic and wild animals in Xinyang city, Henan province, where tick-borne diseases have recently been reported. This study aims to analyze the distribution patterns of piroplasms infections in animals, and assess their potential threat to humans in Central China.
Methods
Blood samples were collected from sheep, dogs and hedgehogs in two regions, including Shihe District and Luoshan County, of Xinyang city, Henan province from August to December 2012. Babesia spp. and Theileria spp. were detected by polymerase chain reaction (PCR) and identified by sequencing and phylogenetic analysis. Moreover, the characteristics of detected piroplasms in different animal hosts were compared between the two study regions.
Results
A total of 227 blood samples were collected from 73 sheep, two dogs and 152 hedgehogs. Babesia spp. was only detected in the two dogs. Theileria spp. was detected both in the sheep and the hedgehogs, and the total positive rate of Theileria spp. in the sheep and the hedgehogs was 57.53% and 13.82%, respectively. Sequencing and phylogenetic analysis revealed that the Theileria spp. detected in the sheep and the hedgehogs were very close to T. lunwenshuni cloned from a small ruminant and Theileria spp. isolated from a febrile hospitalized patient in China.
Conclusion
Babesia and Theileria infections were detected in both domestic and wild animals in Xinyang city, Henan province in Central China, thus warranting further studies in these regions.
doi:10.1186/2049-9957-3-18
PMCID: PMC4051148  PMID: 24917932
Babesia spp; Theileria spp; Dogs; Sheep; Hedgehogs; China
23.  Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2 
Cancer discovery  2013;3(12):1378-1393.
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.
doi:10.1158/2159-8290.CD-13-0005
PMCID: PMC3918498  PMID: 24104062
24.  Tick-borne pathogens and associated co-infections in ticks collected from domestic animals in central China 
Parasites & Vectors  2014;7:237.
Background
Ticks can transmit a number of pathogens to humans and domestic animals. Tick borne diseases (TBDs), which may lead to organ failure and death have been recently reported in China. 98.75% of the total cases (>1000) in Henan provinces have been reported in Xinyang city. Therefore, the aims of this study were to investigate the fauna of ticks and detect the potential pathogens in ticks in Xinyang, the region of central China.
Methods
Ticks were collected from 10 villages of Xinyang from April to December 2012, from domestic animals including sheep, cattle and dogs. Then identification of ticks and detection of tick-borne pathogens, including Babesia spp., Theileria spp., Anaplasma spp., Ehrlichia spp., Rickettsia spp., tick-borne encephalitis virus (TBEV), Borrelia burgdorferi sensu lato, Leishmania infantum, were undertaken by using polymerase chain reaction assay (PCR) and sequence analysis. Moreover, the co-infection patterns of various pathogens were compared among locations where ticks were collected.
Results
A total of 308 ticks were collected. Two species of Ixodidae were found, namely Haemaphysalis longicornis (96.75%) and Rhipicephalus microplus (3.25%). Five genera of pathogens, namely Theileria spp. (3.25%), Anaplasma spp. (2.92%), Babesia spp. (1.95%), Ehrlichia spp. (2.92%) and Rickettsia spp. (0.65%), were detected in 7 villages. Co-infections by two pathogens were diagnosed in 11.11% of all infected ticks.
Conclusions
Both human and animal pathogens were abundant in ticks in the study areas. Humans and animals in these regions were at a high risk of exposure to piroplasmosis, since piroplasm had the highest rates of infection and co-infection in positive ticks.
doi:10.1186/1756-3305-7-237
PMCID: PMC4045914  PMID: 24886497
Ticks; Domestic animals; Tick-borne pathogens; Co-infections; China
25.  Trop-2 promotes prostate cancer metastasis by modulating β1 integrin functions 
Cancer research  2013;73(10):3155-3167.
The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin (FN) and signaling are affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on FN, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific since this molecule does not modulate migration on vitronectin (VN), does not associate with the major VN receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we demonstrate that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2.
doi:10.1158/0008-5472.CAN-12-3266
PMCID: PMC3655712  PMID: 23536555

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