PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (111)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  TNF-α signaling in Fanconi anemia 
Blood cells, molecules & diseases  2013;52(1):10.1016/j.bcmd.2013.06.005.
Tumor necrosis factor-alpha (TNF-α is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contribute to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA.
doi:10.1016/j.bcmd.2013.06.005
PMCID: PMC3851925  PMID: 23890415
3.  Possible Single-Nucleotide Polymorphism Loci Associated with Systemic Sclerosis Susceptibility: A Genetic Association Study in a Chinese Han Population 
PLoS ONE  2014;9(12):e113197.
Objective
The aim of this study was to confirm the association of RHOB and FAM167A-BLK gene polymorphisms with susceptibility to systemic sclerosis (SSc) in a Chinese Han population.
Methods
A total of 248 SSc patients and 251 healthy controls of Chinese Han ethnicity, which visited the department of dermatology of Peking Union Medical College Hospital, were included in the study. Six selected single nucleotide polymorphisms (SNPs) in the RHOB and FAM167A-BLK regions were selected as markers and were genotyped using a MassARRAY system, which is based on the matrix-assisted laser desorption/ionization time of flight mass spectrometry technique.
Results
Three SNPs in the coding regions of the RHOB and FAM167A-BLK genes displayed an association with SSc: (1) rs1062292T, which is a newly discovered SNP in the RHOB gene (P = 0.03, odds ratio [OR] = 1.62, 95% confidence interval (CI) = 1.05–2.50), (2) rs2736340T (P = 0.03, OR = 1.39, 95%CI = 1.03–1.85), and (3) rs13277113A (P = 0.04, OR = 1.34, 95%CI = 1.01–1.76), both in the FAM167A-BLK gene. Our results support previous findings that vaiants in the RHOB and FAM167A-BLK genes may be associated with susceptibility to SSc. However, the loci of the SNPs in RHOB region that displayed an association with SSc are quite different from the loci which were identified in studies of Caucasian populations.
Conclusion
Our results confirm that RHOB and FAM167A-BLK polymorphisms exist in Chinese Han SSc patients. Therefore, variants of the RHOB and FAM167A-BLK genes are promising genetic markers for SSc.
doi:10.1371/journal.pone.0113197
PMCID: PMC4254283  PMID: 25470816
4.  Standard b-value versus low b-value diffusion-weighted MRI in renal cell carcinoma: a systematic review and meta-analysis 
BMC Cancer  2014;14(1):843.
Background
We sought to determine the comparative diagnostic performance of standard b-value (800–1000 s/mm2) versus low b-value (400–500 s/mm2) diffusion-weighted magnetic resonance imaging (DW-MRI) in the detection of renal cell carcinoma (RCC).
Method
After a systematic review of the available literature, studies were included that reported b-values, used a histopathological reference standard, and allowed construction of 2 × 2 contingency tables for detection of RCC lesions using DW-MRI. In addition, a summary receiver operating characteristic (SROC) analysis was performed.
Results
Four articles that complied with all inclusion and exclusion criteria were selected for data extraction and analysis (n = 248 lesions in 266 patients). All four studies were high quality. Standard b-value DW-MRI displayed a pooled sensitivity of 0.59 (95% confidence interval (CI): 0.51-0.67) and a pooled specificity of 0.50 (95% CI: 0.30-0.70), while low b-value DW-MRI displayed a pooled sensitivity of 0.58 (95% CI: 0.48-0.63) and a pooled specificity of 0.23 (95% CI: 0.09-0.44). The SROC curve of standard b-value DW-MRI displayed an AUC of 0.61 and a Q*index of 0.59, while the SROC curve of low b-value DW-MRI displayed an AUC of 0.68 and a Q*index of 0.64.
Conclusion
Standard b-value DW-MRI showed a superior specificity but an approximately equivalent sensitivity to low b-value DW-MRI in detecting RCC lesions in the kidney. However, low b-value DW-MRI displayed an overall superior diagnostic accuracy over standard b-value DW-MRI.
doi:10.1186/1471-2407-14-843
PMCID: PMC4289169  PMID: 25406910
Renal cell carcinoma, RCC; Diffusion-weighted MRI, DW-MRI; b-value
5.  Restorative effect and mechanism of mecobalamin on sciatic nerve crush injury in mice 
Neural Regeneration Research  2014;9(22):1979-1984.
Mecobalamin, a form of vitamin B12 containing a central metal element (cobalt), is one of the most important mediators of nervous system function. In the clinic, it is often used to accelerate recovery of peripheral nerves, but its molecular mechanism remains unclear. In the present study, we performed sciatic nerve crush injury in mice, followed by daily intraperitoneal administration of mecobalamin (65 μg/kg or 130 μg/kg) or saline (negative control). Walking track analysis, histomorphological examination, and quantitative real-time PCR showed that mecobalamin significantly improved functional recovery of the sciatic nerve, thickened the myelin sheath in myelinated nerve fibers, and increased the cross-sectional area of target muscle cells. Furthermore, mecobalamin upregulated mRNA expression of growth associated protein 43 in nerve tissue ipsilateral to the injury, and of neurotrophic factors (nerve growth factor, brain-derived nerve growth factor and ciliary neurotrophic factor) in the L4–6 dorsal root ganglia. Our findings indicate that the molecular mechanism underlying the therapeutic effect of mecobalamin after sciatic nerve injury involves the upregulation of multiple neurotrophic factor genes.
doi:10.4103/1673-5374.145379
PMCID: PMC4283280  PMID: 25598780
nerve regeneration; peripheral nerve injury; mecobalamin; sciatic nerve; nerve repair; neurotrophic factor; neuroprotective effect; vitamin B12; molecular mechanism; gene expression; neural regeneration
6.  Comparison of genetic variation of breast cancer susceptibility genes in Chinese and German populations 
European Journal of Human Genetics  2013;21(11):1286-1292.
Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28–1.59, P=1.9 × 10−10) and rs3803662 in the German population (OR=1.43, 95% CI=1.17–1.74, P=4.01 × 10−4), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor α (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18–1.49, P=1.94 × 10−6) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations.
doi:10.1038/ejhg.2013.38
PMCID: PMC3798843  PMID: 23486537
breast cancer; single-nucleotide polymorphism (SNP); association studies; Chinese population; German population
7.  Hepatocyte Growth Factor Modification Enhances the Anti-Arrhythmic Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells 
PLoS ONE  2014;9(10):e111246.
Background/Aims
Chronic myocardial infarction (MI) results in the formation of arrhythmogenic substrates, causing lethal ventricular arrhythmia (VA). We aimed to determine whether mesenchymal stem cells (MSCs) carrying a hepatocyte growth factor (HGF) gene modification (HGF-MSCs) decrease the levels of arrhythmogenic substrates and reduce the susceptibility to developing VA compared with unmodified MSCs and PBS in a swine infarction model.
Methods
The left descending anterior artery was balloon-occluded to establish an MI model. Four weeks later, the randomly grouped pigs were administered MSCs, PBS or HGF-MSCs via thoracotomy. After an additional four weeks, dynamic electrocardiography was performed to assess heart rate variability, and programmed electrical stimulation was conducted to evaluate the risk for VA. Then, the pigs were euthanized for morphometric, immunofluorescence and western blot analyses. Results: The HGF-MSC group displayed the highest vessel density and Cx43 expression levels, and the lowest levels of apoptosis, and tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) expression. Moreover, the HGF-MSC group exhibited a decrease in the number of sympathetic nerve fibers, substantial decreases in the low frequency and the low-/high- frequency ratio and increases in the root mean square of successive differences (rMSSD) and the percentage of successive normal sinus R-R intervals longer than 50 ms (pNN50), compared with the other two groups. Finally, the HGF-MSC group displayed the lowest susceptibility to developing VA.
Conclusion
HGF-MSCs displayed potent antiarrhythmic effects, reducing the risk for VA.
doi:10.1371/journal.pone.0111246
PMCID: PMC4216066  PMID: 25360679
8.  S-1 plus gemcitabine chemotherapy followed by concurrent radiotherapy and maintenance therapy with S-1 for unresectable pancreatic cancer 
World Journal of Gastroenterology : WJG  2014;20(38):13987-13992.
AIM: To investigate the feasibility and efficacy of the combination of S-1 with gemcitabine followed by oral S-1 with concurrent radiotherapy (intensity modulated radiotherapy, IMRT) and maintenance therapy with S-1 for locally advanced pancreatic cancer.
METHODS: Subjects selected in the study were patients who had unresectable and locally advanced pancreatic cancer without distant metastases, adequate organ and marrow functions, an Eastern Cooperative Oncology Group performance status of 0-1 and no prior anticancer therapy. Initially the subjects received two cycles of chemotherapy, oral administration of S-1 40 mg/m2 twice daily from day 1 to day 14 of a 21-d cycle, with 30-min intravenous infusions of gemcitabine 1000 mg/m2 on day 1 and day 8. Two weeks after the completion of chemotherapy, S-1 was administered orally with concurrent IMRT. Oral S-1 was administered at a dose of 80 mg/m2 per day twice daily from day 1 to day 14 and from day 22 to day 35. Radiation was concurrently delivered at a dose of 50.4 Gy (1.8 Gy/d, 5 times per week, 28 fractions). One month after the completion of chemotherapy and radiotherapy, S-1 was administered orally at a dose of 80 mg/m2 per day twice daily for 14 d, followed by a 14-d rest period. This cycle was repeated as maintenance therapy, until unacceptable toxicity occurred or the disease worsened. Thirty-two patients were involved in this study. The median follow-up was 15.6 mo (range: 8.6-32.3 mo).
RESULTS: Thirty-two patients completed the scheduled course of chemotherapy, while 30 patients (93.8%) received chemoradiotherapy with two patients ceasing to continue with radiotherapy. The major toxic effects were nausea and leukopenia. There was no grade 4 toxicity or treatment-related death. According to the Response Evaluation Criteria in Solid Tumors criteria, the objective tumor response was partial response in 17 (53.1%) patients, stable disease in 9 (28.1%), and progressive disease in 6 (18.8%). The median overall survival and median progression-free survival were 15.2 mo and 9.3 mo, respectively. The survival rates at 1 year and 2 years were 75% and 34.4%, respectively.
CONCLUSION: The combination of S-1 with gemcitabine followed by oral S-1 with IMRT and maintenance therapy with S-1 alone in patients with locally advanced pancreatic cancer may be considered a well-tolerated, promising treatment regimen.
doi:10.3748/wjg.v20.i38.13987
PMCID: PMC4194583  PMID: 25320537
Chemoradiotherapy; Radiosensitizer; S-1; Pancreatic cancer; CA19-9
9.  Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages 
Aging cell  2013;12(5):794-801.
SUMMARY
Endoplasmic reticulum (ER) stress is induced by the accumulation of unfolded and misfolded proteins in the ER. Although apoptosis induced by ER stress has been implicated in several aging-associated diseases, such as atherosclerosis, it is unclear how aging modifies ER stress response in macrophages. To decipher this relationship, we assessed apoptosis in macrophages isolated from young (6–8 weeks) and aged (16–18 months) mice and exposed the cells to the ER stress inducer tunicamycin. We found that aged macrophages exhibited more apoptosis than young macrophages, which was accompanied by reduced activation of phosphorylated inositol-requiring enzyme-1 (p-IRE1α), one of the three key ER stress signal transducers. Reduced gene expression of x-box binding protein 1 (XBP1), a downstream effector of IRE1α, enhanced p-IRE1α levels and reduced apoptosis in aged, but not young macrophages treated with tunicamycin. These findings delineate a novel, age-dependent interaction by which macrophages undergo apoptosis upon ER stress, and suggest an important protective role of IRE1α in aging-associated ER stress-induced apoptosis. This novel pathway may not only be important in our understanding of longevity, but may also have important implications for pathogenesis and potential treatment of aging-associated diseases in general.
doi:10.1111/acel.12105
PMCID: PMC3773058  PMID: 23711292
Aging; macrophages; endoplasmic reticulum stress; apoptosis
10.  Identification of Essential Proteins Based on Ranking Edge-Weights in Protein-Protein Interaction Networks 
PLoS ONE  2014;9(9):e108716.
Essential proteins are those that are indispensable to cellular survival and development. Existing methods for essential protein identification generally rely on knock-out experiments and/or the relative density of their interactions (edges) with other proteins in a Protein-Protein Interaction (PPI) network. Here, we present a computational method, called EW, to first rank protein-protein interactions in terms of their Edge Weights, and then identify sub-PPI-networks consisting of only the highly-ranked edges and predict their proteins as essential proteins. We have applied this method to publicly-available PPI data on Saccharomyces cerevisiae (Yeast) and Escherichia coli (E. coli) for essential protein identification, and demonstrated that EW achieves better performance than the state-of-the-art methods in terms of the precision-recall and Jackknife measures. The highly-ranked protein-protein interactions by our prediction tend to be biologically significant in both the Yeast and E. coli PPI networks. Further analyses on systematically perturbed Yeast and E. coli PPI networks through randomly deleting edges demonstrate that the proposed method is robust and the top-ranked edges tend to be more associated with known essential proteins than the lowly-ranked edges.
doi:10.1371/journal.pone.0108716
PMCID: PMC4182551  PMID: 25268881
11.  The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function 
Protein & Cell  2014;6(1):68-78.
ABSTRACT
Pax6 and its Drosophila homolog Eyeless (Ey) play essential roles during eye development. Ey/Pax6 contains two distinct DNA binding domains, a Paired domain (PD) and a Homeodomain (HD). While Ey/Pax6 PD is required for the expression of key regulators of retinal development, relatively little is known about the HD-dependent Ey function. In this study, we used the UAS/GAL4 system to determine the functions of different Ey domains on cell growth and on retinal development. We showed that Ey can promote cell growth, which requires the HD but not the PD. In contrast, the ability of Ey to activate Ato expression and induce ectopic eye formation requires the PD but not the HD. Interestingly, deletion of the HD enhanced Ey-dependent ectopic eye induction while overexpression of the HD only Ey forms antagonizes ectopic eye induction. These studies revealed a novel function of Ey HD on cell growth and a novel antagonistic effect of Ey HD on Ey PD-dependent eye induction. We further show the third helix of the Ey HD can directly interact with the RED subdomain in Ey PD and that deletion of the HD increased the binding of Ey PD to its target. These results suggest that the direct interaction between the HD and the PD potentially mediates their antagonistic effects. Since different Ey splicing forms are expressed in overlapping regions during normal development, we speculate that the expression ratios of the different Ey splice forms potentially contribute to the regulation of growth and differentiation of these tissues.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0101-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0101-9
PMCID: PMC4286722  PMID: 25234589
Pax6; eyeless; paired domain; homeodomain; cell growth; retinal differentiation
12.  The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function 
Protein & Cell  2014;6(1):68-78.
ABSTRACT
Pax6 and its Drosophila homolog Eyeless (Ey) play essential roles during eye development. Ey/Pax6 contains two distinct DNA binding domains, a Paired domain (PD) and a Homeodomain (HD). While Ey/Pax6 PD is required for the expression of key regulators of retinal development, relatively little is known about the HD-dependent Ey function. In this study, we used the UAS/GAL4 system to determine the functions of different Ey domains on cell growth and on retinal development. We showed that Ey can promote cell growth, which requires the HD but not the PD. In contrast, the ability of Ey to activate Ato expression and induce ectopic eye formation requires the PD but not the HD. Interestingly, deletion of the HD enhanced Ey-dependent ectopic eye induction while overexpression of the HD only Ey forms antagonizes ectopic eye induction. These studies revealed a novel function of Ey HD on cell growth and a novel antagonistic effect of Ey HD on Ey PD-dependent eye induction. We further show the third helix of the Ey HD can directly interact with the RED subdomain in Ey PD and that deletion of the HD increased the binding of Ey PD to its target. These results suggest that the direct interaction between the HD and the PD potentially mediates their antagonistic effects. Since different Ey splicing forms are expressed in overlapping regions during normal development, we speculate that the expression ratios of the different Ey splice forms potentially contribute to the regulation of growth and differentiation of these tissues.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0101-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0101-9
PMCID: PMC4286722  PMID: 25234589
Pax6; eyeless; paired domain; homeodomain; cell growth; retinal differentiation
13.  Inflammation-mediated Notch signaling skews Fanconi Anemia hematopoietic stem cell differentiation 
Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Signaling pathways that regulate this choice of self-renewal versus differentiation are currently under extensive investigation. Here we report that deregulation of Notch signaling skews HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhances Notch signaling in multipotential progenitors (MPPs), which is correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found an inverse correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells. Significantly, FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-κB pathways. Genetic ablation or pharmacologic inhibition of NF-κB reduces Notch signaling in FA MPPs to near wide-type level, and blocking either NF-κB or Notch signaling partially restores FA HSC quiescence and self-renewal capacity. Taken together, these results suggest a functional crosstalk between Notch signaling and NF-κB pathway in regulation of HSC differentiation.
doi:10.4049/jimmunol.1203474
PMCID: PMC3773980  PMID: 23926327
14.  Turtle embryos move to optimal thermal environments within the egg 
Biology Letters  2013;9(4):20130337.
A recent study demonstrated that the embryos of soft-shelled turtles can reposition themselves within their eggs to exploit locally warm conditions. In this paper, we ask whether turtle embryos actively seek out optimal thermal environments for their development, as do post-hatching individuals. Specifically, (i) do reptile embryos move away from dangerously high temperatures as well as towards warm temperatures? and (ii) is such embryonic movement due to active thermoregulation, or (more simply) to passive embryonic repositioning caused by local heat-induced changes in viscosity of fluids within the egg? Our experiments with an emydid turtle (Chinemys reevesii) show that embryos avoid dangerously high temperatures by moving to cooler regions of the egg. The repositioning of embryos is an active rather than passive process: live embryos move towards a heat source, whereas dead ones do not. Overall, our results suggest that behavioural thermoregulation by turtle embryos is genuinely analogous to the thermoregulatory behaviour exhibited by post-hatching ectotherms.
doi:10.1098/rsbl.2013.0337
PMCID: PMC3730644  PMID: 23760168
behavioural thermoregulation; ectotherm; embryo; oviparity
15.  Identification of potential anticancer compounds from Oplopanax horridus 
Oplopanax horridus is a plant native to North America. Previous reports have demonstrated that this herb has antiproliferative effects on cancer cells but study mostly focused on its extract or fractions. Because there has been limited phytochemical study on this herb, its bioactive compounds are largely unknown. We recently isolated and identified 13 compounds, including six polyynes, three sesquiterpenes, two triterpenoids, and two phenolic acids, of which five are novel compounds. In this study, we systemically evaluated the anticancer effects of compounds isolated from O. horridus. Their antiproliferative effects on a panel of human colorectal and breast cancer cells were determined using the MTS assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry. The in vivo antitumor effect was examined using a xenograft tumor model. Among the 13 compounds, strong antiproliferative effects were observed from falcarindiol and a novel compound oplopantriol A. Falcarindiol showed the most potent antiproliferative effects, significantly inducing pro-apoptosis and cell cycle arrest in the S and G2/M phases. The anticancer potential of falcarindiol was further verified in vivo, significantly inhibiting HCT-116 tumor growth in an athymic nude mouse model at 15 mg/kg. We also analyzed the relationship between polyyne structures and their pharmacological activities. We observed that both the terminal hydroxyl group and double bond obviously affected their anticancer potential. Results from this study supplied valuable information for future semi-synthesis of polyyne derivatives to develop novel cancer chemopreventive agents.
doi:10.1016/j.phymed.2013.04.013
PMCID: PMC3729876  PMID: 23746754
Oplopanax horridus; Phytochemistry; Polyynes; Oplopantriol A; Falcarindiol; Anticancer; Cell cycle; Apoptosis; Structure-activity relationship
16.  A Magnetic Nanoparticle-Based Multiple-Gene Delivery System for Transfection of Porcine Kidney Cells 
PLoS ONE  2014;9(7):e102886.
Superparamagnetic nanoparticles are promising candidates for gene delivery into mammalian somatic cells and may be useful for reproductive cloning using the somatic cell nuclear transfer technique. However, limited investigations of their potential applications in animal genetics and breeding, particularly multiple-gene delivery by magnetofection, have been performed. Here, we developed a stable, targetable and convenient system for delivering multiple genes into the nuclei of porcine somatic cells using magnetic Fe3O4 nanoparticles as gene carriers. After surface modification by polyethylenimine, the spherical magnetic Fe3O4 nanoparticles showed strong binding affinity for DNA plasmids expressing the genes encoding a green (DNAGFP) or red (DNADsRed) fluorescent protein. At weight ratios of DNAGFP or DNADsRed to magnetic nanoparticles lower than or equal to 10∶1 or 5∶1, respectively, the DNA molecules were completely bound by the magnetic nanoparticles. Atomic force microscopy analyses confirmed binding of the spherical magnetic nanoparticles to stretched DNA strands up to several hundred nanometers in length. As a result, stable and efficient co-expression of GFP and DsRed in porcine kidney PK-15 cells was achieved by magnetofection. The results presented here demonstrate the potential application of magnetic nanoparticles as an attractive delivery system for animal genetics and breeding studies.
doi:10.1371/journal.pone.0102886
PMCID: PMC4105564  PMID: 25048709
17.  American ginseng attenuates azoxymethane/dextran sodium sulfate-induced colon carcinogenesis in mice 
Journal of Ginseng Research  2014;39(1):14-21.
Background
Colorectal cancer is a leading cause of cancer-related death, and inflammatory bowel disease is a risk factor for this malignancy. We previously reported colon cancer chemoprevention potential using American ginseng (AG) in a xenograft mice model. However, the nude mouse model is not a gut-specific colon carcinogenesis animal model.
Methods
In this study, an experimental colitis and colitis-associated colorectal carcinogenesis mouse model, chemically induced by azoxymethane/dextran sodium sulfate (DSS) was established and the effects of oral AG were evaluated. The contents of representative ginseng saponins in the extract were determined.
Results
AG significantly reduced experimental colitis measured by the disease activity index scores. This suppression of the experimental colitis was not only evident during DSS treatment, but also very obvious after the cessation of DSS, suggesting that the ginseng significantly promoted recovery from the colitis. Consistent with the anti-inflammation data, we showed that ginseng very significantly attenuated azoxymethane/DSS-induced colon carcinogenesis by reducing the colon tumor number and tumor load. The ginseng also effectively suppressed DSS-induced proinflammatory cytokines activation using an enzyme-linked immunosorbent assay array, in which 12 proinflammatory cytokine levels were assessed, and this effect was supported subsequently by real-time polymerase chain reaction data.
Conclusion
AG, as a candidate of botanical-based colon cancer chemoprevention, should be further investigated for its potential clinical utility.
doi:10.1016/j.jgr.2014.07.001
PMCID: PMC4268560  PMID: 25535472
American ginseng; azoxymethane; carcinogenesis; chemoprevention; dextran sodium sulfate
18.  Norcantharidin induces growth inhibition and apoptosis of glioma cells by blocking the Raf/MEK/ERK pathway 
Background
Malignant gliomas represent the most common primary brain tumors. The prognosis of patients with malignant gliomas is poor in spite of current intensive therapy and novel therapeutic modalities are needed. Here we report that norcantharidin is effective in growth inhibition of glioma cell lines in vitro.
Methods
Glioma cell lines (U87 and C6) were treated with norcantharidin. The effects of norcantharidin on the proliferation and apoptosis of glioma cells were measured by 3-[4,5-dimethylthiazol-2-thiazolyl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry. Western blotting was employed to determine the signaling pathway changes.
Results
The results showed that norcantharidin effectively inhibited cell growth and induced apoptosis in glioma cells, which was concurrent with inhibition of the expression of phospho-MEK and phospho-ERK. Furthermore, the expression anti-apoptotic proteins Bcl-2 and Mcl-1 significantly reduced, but no changes in Bcl-xL and Bax.
Conclusions
Our findings demonstrate that norcantharidin is effective for growth inhibition of glioma cell lines and suggest that norcantharidin may be a new therapeutic option for patients with glioma.
doi:10.1186/1477-7819-12-207
PMCID: PMC4114108  PMID: 25022352
Glioma; Norcantharidin; MAPK; Apoptosis
19.  Chemopreventive Effects of Oplopantriol A, a Novel Compound Isolated from Oplopanax horridus, on Colorectal Cancer 
Nutrients  2014;6(7):2668-2680.
Oplopanax horridus is a North American botanical that has received limited investigations. We previously isolated over a dozen of the constituents from O. horridus, and among them oplopantriol A (OPT A) is a novel compound. In this study, we firstly evaluated the in vivo chemoprevention activities of OPT A using the xenograft colon cancer mouse model. Our data showed that this compound significantly suppressed tumor growth with dose-related effects (p < 0.01). Next, we characterized the compound’s growth inhibitory effects in human colorectal cancer cell lines HCT-116 and SW-480. With OPT A treatment, these malignant cells were significantly inhibited in both a concentration- and time-dependent manner (both p < 0.01). The IC50 was approximately 5 µM for HCT-116 and 7 µM for SW-480 cells. OPT A significantly induced apoptosis and arrested the cell cycle at the G2/M phase. From further mechanism explorations, our data showed that OPT A significantly upregulated the expression of a cluster of genes, especially the tumor necrosis factor receptor family and caspase family, suggesting that the tumor necrosis factor-related apoptotic pathway plays a key role in OPT A induced apoptosis.
doi:10.3390/nu6072668
PMCID: PMC4113763  PMID: 25045937
Oplopanax horridus; oplopantriol A; OPT A; chemoprevention; colorectal cancer; HCT-116; SW-480; apoptosis; cell cycle; tumor necrosis factors; death receptor signaling pathway
20.  Evaluation of a novel choanoid fluidized bed bioreactor for future bioartificial livers 
AIM: To construct and evaluate the functionality of a choanoid-fluidized bed bioreactor (CFBB) based on microencapsulated immortalized human hepatocytes.
METHODS: Encapsulated hepatocytes were placed in the constructed CFBB and circulated through Dulbecco’s Modified Eagle’s Medium (DMEM) for 12 h, and then through exchanged plasma for 6 h, and compared with encapsulated cells cultivated under static conditions in a spinner flask. Levels of alanine aminotransferase (ALT) and albumin were used to evaluate the CFBB during media circulation, whereas levels of ALT, total bilirubin (TBil), and albumin were used to evaluate it during plasma circulation. Mass transfer and hepatocyte injury were evaluated by comparing the results from the two experimental conditions. In addition, the viability and microstructure of encapsulated cells were observed in the different environments.
RESULTS: The bioartificial liver model based on a CFBB was verified by in vitro experiments. The viability of encapsulated cells accounting for 84.6% ± 3.7% in CFBB plasma perfusion was higher than the 74.8% ± 3.1% in the static culture group (P < 0.05) after 6 h. ALT release from cells was 29 ± 3.5 U/L vs 40.6 ± 3.2 U/L at 12 h (P < 0.01) in the CFBB medium circulation and static medium culture groups, respectively. Albumin secretion from cells was 234.2 ± 27.8 μg/1 × 107 cells vs 167.8 ± 29.3 μg/1 × 107 cells at 6 h (P < 0.01), 274.4 ± 34.6 μg/1 × 107 cells vs 208.4 ± 49.3 μg/1 × 107 cells (P < 0.05) at 12 h, in the two medium circulation/culture groups, respectively. Furthermore, ALT and TBil levels were 172.3 ± 24.1 U/L vs 236.3 ± 21.5 U/L (P < 0.05), 240.1 ± 23.9 μmol/L vs 241.9 ± 31.4 μmol/L (P > 0.05) at 6 h in the CFBB plasma perfusion and static plasma culture groups, respectively. There was no significant difference in albumin concentration between the two experimental plasma groups at any time point. The microstructure of the encapsulated hepatocytes remained healthier in the CFBB group compared with the static culture group after 6 h of plasma perfusion.
CONCLUSION: The CFBB can function as a bioartificial liver based on a bioreactor. The efficacy of this novel bioreactor is promising for the study of liver failure.
doi:10.3748/wjg.v20.i22.6869
PMCID: PMC4051926  PMID: 24944477
Choanoid; Fluidized bed; Bioreactor; Immortalized human hepatocytes; Bioartificial liver
21.  Phosphorylation of the TOR ATP binding domain by AGC kinase constitutes a novel mode of TOR inhibition 
The Journal of Cell Biology  2013;203(4):595-604.
AGC kinase–mediated phosphorylation of the TOR kinase reduces its activity and results in physiologically significant changes in TOR signalling in both yeast and human cells.
TOR (target of rapamycin) signaling coordinates cell growth, metabolism, and cell division through tight control of signaling via two complexes, TORC1 and TORC2. Here, we show that fission yeast TOR kinases and mTOR are phosphorylated on an evolutionarily conserved residue of their ATP-binding domain. The Gad8 kinase (AKT homologue) phosphorylates fission yeast Tor1 at this threonine (T1972) to reduce activity. A T1972A mutation that blocked phosphorylation increased Tor1 activity and stress resistance. Nitrogen starvation of fission yeast inhibited TOR signaling to arrest cell cycle progression in G1 phase and promoted sexual differentiation. Starvation and a Gad8/T1972-dependent decrease in Tor1 (TORC2) activity was essential for efficient cell cycle arrest and differentiation. Experiments in human cell lines recapitulated these yeast observations, as mTOR was phosphorylated on T2173 in an AKT-dependent manner. In addition, a T2173A mutation increased mTOR activity. Thus, TOR kinase activity can be reduced through AGC kinase–controlled phosphorylation to generate physiologically significant changes in TOR signaling.
doi:10.1083/jcb.201305103
PMCID: PMC3840928  PMID: 24247430
22.  Incidence of road traffic disabilities trending upwards in transitional China: a retrospective analysis from 1980 to 2005 
BMJ Open  2014;4(5):e004297.
Objective
To evaluate the change in incidence rates of road traffic disabilities from 1980 to 2005 in China.
Methods
We employed the 2006 China National Sample Survey on Disability to derive weighted number of persons with disabilities resulting from road crashes and weighted age-gender-specific population at risk by disability occurrence year. The annual incidence rate of road traffic disabilities and corresponding 95% CI were estimated. We used the World Population Prospects (WPP) and the death rate of people with disabilities (PWD) to estimate potential earlier loss of lives before 2006. Both WPP-adjusted and PWD-adjusted incidence rates of road traffic disabilities were further adjusted using the life table analysis.
Results
The WPP-adjusted incidence rate for road traffic disabilities increased over time from 1.50 (95% CI 1.47 to 1.52) in 1980 to 11.19 (95% CI 11.13 to 11.25) per 100 000 persons in 2005. The PWD-adjusted incidence rate also increased from 1.71 (95% CI 1.68 to 1.73) to 11.51 (95% CI 11.45 to 11.57) per 100 000 persons.
Conclusions
Road crashes disable thousands of Chinese and remain a significant population health and development problem. The increasing burden of road traffic disabilities calls for more efforts and specific strategies to improve road safety in China.
doi:10.1136/bmjopen-2013-004297
PMCID: PMC4025444  PMID: 24833679
Public Health; Epidemiology
23.  Hyperactivated Wnt Signaling Induces Synthetic Lethal Interaction with Rb Inactivation by Elevating TORC1 Activities 
PLoS Genetics  2014;10(5):e1004357.
Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor.
Author Summary
Inactivation of Rb tumor suppressor is common in cancers. Therefore, identification of genes and pathways that are synthetic lethal with Rb will provide new insights into the role of Rb in cancer development and promote the development of novel therapeutic approaches. Here we identified a novel synthetic lethal interaction between Rb inactivation and hyperactivated Wnt signaling and showed that this synthetic lethal interaction is conserved in mammalian systems. We demonstrate that hyperactivated Wnt signaling activate TORC1 activity and induce excessive energy stress with inactivated Rb tumor suppressor, which underpins the evolutionarily conserved synthetic lethal interaction. This study provides novel insights into the interactions between the Rb, Wnt, and mTOR pathways in regulating cellular energy balance, cell growth, and survival.
doi:10.1371/journal.pgen.1004357
PMCID: PMC4014429  PMID: 24809668
24.  Human Body 3D Posture Estimation Using Significant Points and Two Cameras 
The Scientific World Journal  2014;2014:670953.
This paper proposes a three-dimensional (3D) human posture estimation system that locates 3D significant body points based on 2D body contours extracted from two cameras without using any depth sensors. The 3D significant body points that are located by this system include the head, the center of the body, the tips of the feet, the tips of the hands, the elbows, and the knees. First, a linear support vector machine- (SVM-) based segmentation method is proposed to distinguish the human body from the background in red, green, and blue (RGB) color space. The SVM-based segmentation method uses not only normalized color differences but also included angle between pixels in the current frame and the background in order to reduce shadow influence. After segmentation, 2D significant points in each of the two extracted images are located. A significant point volume matching (SPVM) method is then proposed to reconstruct the 3D significant body point locations by using 2D posture estimation results. Experimental results show that the proposed SVM-based segmentation method shows better performance than other gray level- and RGB-based segmentation approaches. This paper also shows the effectiveness of the 3D posture estimation results in different postures.
doi:10.1155/2014/670953
PMCID: PMC4032775  PMID: 24883422
25.  Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress 
Antioxidants & Redox Signaling  2014;20(12):1853-1865.
Abstract
Aims: A component of the base excision repair pathway, poly(ADP-ribose) polymerase-1 (PARP1) functions in multiple cellular processes, including DNA repair and programmed cell death. We previously showed that Salidroside, a phenylpropanoid glycoside isolated from medicinal plants, prevented the loss of hematopoietic stem cells (HSCs) in native mice and rescued HSCs repopulating in transplanted recipients under oxidative stress. The aim of this study was to investigate the mechanism by which PARP1 activation by Salidroside maintains HSCs under oxidative stress. Results: We found that although there were no spontaneous defects in hematopoiesis in Parp1−/− mice, oxidative stress compromised the repopulating capacity of Parp1−/− HSCs in transplanted recipient mice. A biochemical study using truncated proteins lacking the defined functional domains of PARP1 showed that the tryptophan-glycine–arginine-rich (WGR) domain of PARP1 was critical for Salidroside binding and subsequent PARP1 activation under oxidative stress. Functionally, complementation of Parp1−/− HSCs with full-length PARP1WT, but not the PARP1R591K mutant in WGR domain restored Salidroside-stimulated PARP1 activation in vitro. Mechanistically, activated PARP1 by Salidroside enhanced the repopulating capacity of the stressed HSCs by accelerating oxidative DNA damage repair. Innovations and Conclusion: Our findings reveal the action of mechanism for Salidroside in PARP1 stimulation and a novel role of PARP1 activation in maintaining HSC function under oxidative stress. Antioxid. Redox Signal. 20, 1853–1865.
doi:10.1089/ars.2013.5600
PMCID: PMC3967359  PMID: 24294904

Results 1-25 (111)