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1.  Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways 
Acta Pharmacologica Sinica  2012;33(7):861-872.
Aim:
To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect.
Methods:
Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05–10 μmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in the cortical neurons were evaluated using Western blotting analyses.
Results:
Atorvastatin (0.05–10 μmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 (30 μmol/L) and wortmannin (5 μmol/L), Akt inhibitor tricribine (1 μmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 μmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 μmol/L). Moreover, atorvastatin (10 μmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 μmol/L) significantly increased the phosphorylated GSK-3β level in the cortical neurons, which was prevented by both LY294002 and tricribine.
Conclusion:
These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3β signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons.
doi:10.1038/aps.2012.59
PMCID: PMC4011150  PMID: 22705730
statin; atorvastatin; cortical neurons; neuritogenesis; PI3-kinase; GSK-3β
2.  Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18404-18412.
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
METHODS: We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed.
RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51).
CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.
doi:10.3748/wjg.v20.i48.18404
PMCID: PMC4277979  PMID: 25561809
AT-rich interactive domain 1A; Switching defective/sucrose non-fermenting complexes; Colorectal cancer; Clinicopathologic characteristics; Prognosis
3.  A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology 
OncoTargets and therapy  2014;7:1891-1899.
Ovarian low-grade serous carcinoma (LGSC) and high-grade serous carcinoma have distinct molecular profiles, clinical behaviors, and treatment responses. The survival advantage for patients with low-grade carcinoma compared with patients with high-grade histology remains controversial. We retrospectively reviewed the medical charts of 381 patients with ovarian serous carcinoma at Peking Union Medical College Hospital from 2007 to 2010. Patients were classified into two groups according to MD Anderson two-tier system: 35 (9.2%) cases with LGSC and 346 with high-grade serous carcinoma. Patients with low-grade serous ovarian cancer had a significantly younger age at diagnosis (46 versus 56 years, P=0.046), and their median progression-free survival (PFS) and overall survival values were 35.0 and 54.0 months, respectively. A multivariate analysis showed that, for serous ovarian cancer, the histological grade was a significant prognostic factor for PFS but not for overall survival (P=0.022 and P=0.0566, respectively). When stratified by the existence of a residual disease, patients with low-grade disease who underwent cytoreductive surgery without macroscopic residual disease (>1 cm) had a significantly improved median PFS time (36.0 months) compared with that of patients with high-grade carcinoma who received optimal cytoreductive surgery (16.0 months, P=0.017). Conversely, patients with low-grade and high-grade carcinoma who were left with macroscopic residue (>1 cm) experienced a similarly shorter median PFS (10.0 and 13.0 months, respectively, P=0.871). The International Federation of Gynecology and Obstetrics stage and residual disease were significant prognostic factors of low-grade carcinoma, while positive ascites was associated with a worse PFS value. Our data showed that LGSC is a different entity from high-grade carcinoma and that LGSC was associated with improved PFS after optimal cytoreductive surgery but not suboptimal operation.
doi:10.2147/OTT.S67812
PMCID: PMC4206388  PMID: 25342912
ovarian carcinoma; low-grade serous carcinoma; high-grade serous carcinoma; prognosis
4.  The target therapy of ovarian clear cell carcinoma 
OncoTargets and therapy  2014;7:1647-1652.
Clear cell adenocarcinoma (CCC) of the ovary accounts for 10% of epithelial ovarian cancer and is a distinct entity from other epithelial ovarian carcinomas. It arises from the endometriosis. CCC has specific biological and clinical behavior. Compared with other histological types, CCC shows a chemoresistant phenotype, which leads to poorer prognosis. Thus, development of new target-based therapies remains an unmet need for these patients. Mutations in the gene ARID1A have been found to occur in high frequency in CCC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex and considered as a bona fide tumor suppressor. Upregulation of the PIK3/AKT/mTOR pathway, particularly through mutations of PIK3CA and inactivation of PTEN, is involved in tumorigenesis of CCC. Targeting angiogenesis, the Met protooncogene pathway, and HER2 are also discussed in this review.
doi:10.2147/OTT.S49993
PMCID: PMC4181630  PMID: 25285014
ARID1A; PIK3/AKT/mTOR pathway; angiogenesis; Met protooncogene pathway; HER2
5.  Women Ornament Themselves for Intrasexual Competition near Ovulation, but for Intersexual Attraction in Luteal Phase 
PLoS ONE  2014;9(9):e106407.
The present study examined women's attentional bias toward ornamental objects in relation to their menstrual phase as well as to motivations of intersexual courtship or intrasexual competition. In Experiment 1, 33 healthy heterosexual women were tested in a bias-assessment visual cuing task twice: once on a high-fertility day (during the ovulatory phase) and once on a low-fertility day (during the luteal phase). They paid greater attention to pictures of ornamental objects than to pictures of non-ornamental objects near ovulation, but not during the luteal phase, suggesting an ornamental bias during the high-fertility phase. In Experiment 2, before the visual cuing task, 40 participants viewed 10 same-sex or opposite-sex facial photographs with either high or low attractiveness as priming tasks to activate the intrasexual competition or intersexual courtship motives. Results showed that women's ornamental bias was dependent on the interaction of menstrual phase and mating motive. Specifically, the ornamental bias was observed on the high-fertility day when the subjects were primed with high-attractive same-sex images (intrasexual competition) and was observed on the low-fertility day when they were primed with high-attractive opposite-sex photographs (intersexual courtship). In conclusion, the present findings confirm the hypothesis that, during the high-fertility phase, women have an attentional bias toward ornamental objects and further support the hypothesis that the ornamental bias is driven by intrasexual competition motivation near ovulation, but driven by intersexual courtship motivation during the luteal phase.
doi:10.1371/journal.pone.0106407
PMCID: PMC4152269  PMID: 25180577
6.  Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau 
Biological psychiatry  2013;74(5):367-374.
Background
The microtubule associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease (AD). One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion.
Methods
Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the Hsp70 family in the brain, Hsc70. The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured.
Results
Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, over-expression of Hsp40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wildtype mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in from tau transgenic brain slices.
Conclusions
Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in AD and other tauopathies.
doi:10.1016/j.biopsych.2013.02.027
PMCID: PMC3740016  PMID: 23607970
tau; Alzheimer’s disease; chaperones; Hsc70; rhodocyanine; YM-01
7.  Long-term follow-up results in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents: results from a single high-volume PCI centre 
BMJ Open  2014;4(8):e004892.
Objective
To assess both short-term and long-term prognosis in consecutive patients with coronary heart disease treated with drug-eluting stents in a high-volume percutaneous coronary intervention (PCI) centre.
Design
Observational cohort study.
Setting
A hospital in the Henan province, China, between 2009 and 2011.
Participants
A total of 2533 patients were enrolled. Patients with ST-elevation myocardial infarction (STEMI) treated with urgent PCI accounted for 3.9% of cases; patients with STEMI treated with delayed PCI accounted for 20.5% of cases; patients with stable angina accounted for 16.5% of cases; and patients with non-ST elevation acute coronary syndrome (NSTE-ACS) accounted for 58.6% of cases.
Primary outcomes
Death, major adverse cardiac and cerebrovascular events (MACCE: death/myocardial infarction/stroke), and target vessel revascularisation.
Results
Follow-up after a median of 29.8 months was obtained for 2533 patients (92.6%). The mortality rate during hospitalisation was highest in the urgent PCI group (p<0.001). During follow-up, although the incidences of death and MACCE were highest in the urgent PCI group, no significant differences were observed among the different groups. The incidences of cardiac death and myocardial infarction were significantly higher in the paclitaxel-eluting stent (PES) group than in the sirolimus-eluting stent (SES) group. Independent predictors of death during follow-up were age, left ventricular ejection function <40%, diabetes mellitus, prior coronary artery bypass graft and chronic total occlusion.
Conclusions
PCI patients with STEMI had the worst hospital and long-term prognosis. The mortality rate after hospital increased markedly in patients with NSTE-ACS. SESs seem to be more effective than PESs.
doi:10.1136/bmjopen-2014-004892
PMCID: PMC4127920  PMID: 25113554
8.  Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells 
Journal of Ginseng Research  2014;39(1):22-28.
Background
Sun ginseng (SG), a specific formulation of quality-controlled red ginseng, contains approximately equal amounts of three major ginsenosides (RK1, Rg3, and Rg5), which reportedly has antitumor-promoting activities in animal models.
Methods
MTT assay was used to assess whether SG can potentiate the anticancer activity of epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells; apoptosis status was analyzed by annexin V-FITC and PI and analyzed by flow cytometry; and apoptosis pathway was studied by analysis of caspase-3, -8, and -9 activation, mitochondrial accumulation of Bax and Bak, and cytochrome c release.
Results
SG remarkably enhances cancer cell death induced by epirubicin or paclitaxel in human cervical adenocarcinoma HeLa cells, human colon cancer SW111C cells, and SW480 cells. Results of the mechanism study highlighted the cooperation between SG and epirubicin or paclitaxel in activating caspase-3 and -9 but not caspase-8. Moreover, SG significantly increased the mitochondrial accumulation of both Bax and Bak triggered by epirubicin or paclitaxel as well as the subsequent release of cytochrome c in the targeted cells.
Conclusion
SG significantly potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. Treating cancer cells by combining epirubicin and paclitaxel with SG may prove to be a novel strategy for enhancing the efficacy of the two drug types.
doi:10.1016/j.jgr.2014.08.001
PMCID: PMC4268562  PMID: 25535473
apoptosis; caspase-9; sun ginseng; synergistic effect
9.  The synthesis and characterization of monodispersed chitosan-coated Fe3O4 nanoparticles via a facile one-step solvothermal process for adsorption of bovine serum albumin 
Nanoscale Research Letters  2014;9(1):296.
Preparation of magnetic nanoparticles coated with chitosan (CS-coated Fe3O4 NPs) in one step by the solvothermal method in the presence of different amounts of added chitosan is reported here. The magnetic property of the obtained magnetic composite nanoparticles was confirmed by X-ray diffraction (XRD) and magnetic measurements (VSM). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) allowed the identification of spherical nanoparticles with about 150 nm in average diameter. Characterization of the products by Fourier transform infrared spectroscopy (FTIR) demonstrated that CS-coated Fe3O4 NPs were obtained. Chitosan content in the obtained nanocomposites was estimated by thermogravimetric analysis (TGA). The adsorption properties of the CS-coated Fe3O4 NPs for bovine serum albumin (BSA) were investigated under different concentrations of BSA. Compared with naked Fe3O4 nanoparticles, the CS-coated Fe3O4 NPs showed a higher BSA adsorption capacity (96.5 mg/g) and a fast adsorption rate (45 min) in aqueous solutions. This work demonstrates that the prepared magnetic nanoparticles have promising applications in enzyme and protein immobilization.
doi:10.1186/1556-276X-9-296
PMCID: PMC4070400  PMID: 24994954
Magnetic nanoparticles; Chitosan; Solvothermal; BSA adsorption
10.  Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway 
Acta Pharmacologica Sinica  2014;35(6):716-726.
Aim:
To investigate whether atorvastatin treatment could prevent Aβ1-42 oligomer (AβO)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin.
Methods:
SD rats were injected with AβOs (5 nmol, icv). The rats were administrated with atorvastatin (10 mg·kg−1·d−1, po) for 2 consecutive weeks (the first dose was given 5 d before AβOs injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD-95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with AβOs (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence.
Results:
The AβO-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 μmol/L) concentration-dependently attenuated the AβO-induced synaptotoxicity, including the loss of dendritic marker MAP-2, and synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 μmol/L) blocked the AβO-induced loss of synaptophysin and PSD-95.
Conclusion:
Atorvastatin prevents AβO-induced synaptotoxicity and memory dysfunction through a p38MAPK-dependent pathway.
doi:10.1038/aps.2013.203
PMCID: PMC4086387  PMID: 24793311
Alzheimer's disease; atorvastatin; hippocampus; learning and memory; synapse; amyloid-β peptide; synaptophysin; PSD-95; cytokine; p38 MAPK
11.  Dimerization Interface of 3-Hydroxyacyl-CoA Dehydrogenase Tunes the Formation of Its Catalytic Intermediate 
PLoS ONE  2014;9(4):e95965.
3-hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35) is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD) that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A) with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60–80) that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects.
doi:10.1371/journal.pone.0095965
PMCID: PMC3999109  PMID: 24763278
12.  Red Blood Cell Distribution Width and Long-Term Outcome in Patients Undergoing Percutaneous Coronary Intervention in the Drug-Eluting Stenting Era: A Two-Year Cohort Study 
PLoS ONE  2014;9(4):e94887.
Background
Previous studies suggest the higher the red blood cell distribution width (RDW) the greater the risk of mortality in patients with coronary artery disease (CAD). However, the relationship between RDW and long-term outcome in CAD patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) remains unclear. This study was designed to evaluate the long-term effect of RDW in patients treated with drug-eluting stent for CAD.
Methods
In total of 2169 non-anemic patients (1468 men, mean age 60.2±10.9 years) with CAD who had undergone successful PCI and had at least one drug-eluting stent were included in this study. Patients were grouped according to their baseline RDW: Quartile 1 (RDW<12.27%), Quartile 2 (12.27%≤RDW<13%), Quartile 3 (13%≤RDW<13.5%), and Quartile 4 (RDW≥13.5).
Results
The incidence of in-hospital mortality and death or myocardial infarction was significantly higher in Quartiles 3 and 4 compared with Quartile 1 (P<0.05). After a follow-up of 29 months, the incidence of all-cause death and stent thrombosis in Quartile 4 was higher than in Quartiles 1, 2, and 3 (P<0.05). The incidence of death/myocardial infarction/stroke and cardiac death in Quartile 4 was higher than in Quartiles 1 and 2 (P<0.05). Multivariate Cox regression analysis showed that RDW was an independent predictor of all-cause death (hazard ratio (HR) = 1.37, 95% confidence interval (CI) = 1.15–1.62, P<0.001) and outcomes of death/myocardial infarction/stroke (HR = 1.21, 95% CI = 1.04–1.39, P = 0.013). The cumulative survival rate of Quartile 4 was lower than that of Quartiles 1, 2, and 3 (P<0.05).
Conclusion
High RDW is an independent predictor of long-term adverse clinical outcomes in non-anemic patients with CAD treated with DES.
doi:10.1371/journal.pone.0094887
PMCID: PMC3983260  PMID: 24722190
13.  Ectopic Expression of Activated Notch or SOX2 Reveals Similar and Unique Roles in the Development of the Sensory Cell Progenitors in the Mammalian Inner Ear 
The Journal of Neuroscience  2013;33(41):16146-16157.
Hearing impairment or vestibular dysfunction in humans often results from a permanent loss of critical cell types in the sensory regions of the inner ear, including hair cells, supporting cells, or cochleovestibular neurons. These important cell types arise from a common sensory or neurosensory progenitor, although little is known about how these progenitors are specified. Studies have shown that Notch signaling and the transcription factor Sox2 are required for the development of these lineages. Previously we and others demonstrated that ectopic activation of Notch can direct nonsensory cells to adopt a sensory fate, indicating a role for Notch in early specification events. Here, we explore the relationship between Notch and SOX2 by ectopically activating these factors in nonsensory regions of the mouse cochlea, and demonstrate that, similar to Notch, SOX2 can specify sensory progenitors, consistent with a role downstream of Notch signaling. However, we also show that Notch has a unique role in promoting the proliferation of the sensory progenitors. We further demonstrate that Notch can only induce ectopic sensory regions within a certain time window of development, and that the ectopic hair cells display specialized stereocilia bundles similar to endogenous hair cells. These results demonstrate that Notch and SOX2 can both drive the sensory program in nonsensory cells, indicating these factors may be useful in cell replacement strategies in the inner ear.
doi:10.1523/JNEUROSCI.3150-12.2013
PMCID: PMC3792456  PMID: 24107947
14.  Bis[2,6-bis­(1H-pyrazol-1-yl)pyridine]­deca­kis­(μ2-3-nitro­benzoato)bis­(3-nitro­benzoato)tetra­dysprosium(III): a linear tetra­nuclear dysprosium compound based on mixed N- and O-donor ligands 
The title compound, [Dy4(C7H4NO4)12(C11H9N5)2] or Dy4(L1)12(L2)2, where HL1 = 3-nitro­benzoic acid and HL2 = 2,6-bis­(1H-pyrazol-1-y1)pyridine, is a linear tetra­nuclear complex possessing inversion symmetry. The two central inversion-related DyIII atoms are seven-coordinate, DyO7, with a monocapped triangular-prismatic geometry. The outer two DyIII atoms are eight-coordinate, DyO5N3, with a bicapped triangular-prismatic geometry. The outer adjacent DyIII atoms are bridged by three L1− carboxyl­ate groups, while the inner inversion-related DyIII atoms are bridged by four L1− carboxyl­ate groups. The L2 ligands are terminally coordinated to the outer DyIII atoms in a tridentate manner. In the crystal, mol­ecules are linked via C—H⋯O hydrogen bonds, forming a two-dimensional network parallel to (001). Two carboxyl­ate O atoms, and N and O atoms of three nitro groups, are disordered over two positions, with a refined occupancy ratio of 0.552 (6):0.448 (6).
doi:10.1107/S1600536814006060
PMCID: PMC4011298  PMID: 24860300
15.  p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells 
Protein & Cell  2014;5(3):224-234.
We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0027-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0027-2
PMCID: PMC3967063  PMID: 24622841
G-Rh2; Fas; p53; apoptosis
16.  p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells 
Protein & Cell  2014;5(3):224-234.
We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0027-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0027-2
PMCID: PMC3967063  PMID: 24622841
G-Rh2; Fas; p53; apoptosis
17.  Patients with Old Age or Proximal Tumors Benefit from Metabolic Syndrome in Early Stage Gastric Cancer 
PLoS ONE  2014;9(3):e89965.
Background
Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated.
Methods
Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed.
Results
Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis).
Conclusions
Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.
doi:10.1371/journal.pone.0089965
PMCID: PMC3943843  PMID: 24599168
18.  Discriminating Males and Unpredictable Females: Males Differentiate Self-Similar Facial Cues More than Females in the Judgment of Opposite-Sex Attractiveness 
PLoS ONE  2014;9(3):e90493.
Attractiveness judgment in the context of mate preferences is thought to reflect an assessment of mate quality in relation to an absolute scale of genetic fitness and a relative scale of self-similarity. In this study, subjects judged the attractiveness and trustworthiness of faces in composite images that were manipulated to produce self-similar (self-resemblance) and dissimilar (other-resemblance) images. Males differentiated between self- and other-resemblance as well as among different degrees of self-resemblance in their attractiveness ratings; females did not. Specifically, in Experiment 1, using a morphing technique, we created previously unseen face images possessing different degrees (0%, 30%, 40%, or 50%) of incorporation of the subject's images (different degrees of self-resemblance) and found that males preferred images that were closer to average (0%) rather than more self-similar, whereas females showed no preference for any degree of self-similarity. In Experiment 2, we added a pro-social question about trustworthiness. We replicated the Experiment 1 attractiveness rating results and further found that males differentiated between self- and other-resemblance for the same degree of composites; women did not. Both males and females showed a similar preference for self-resemblances when judging trustworthiness. In conclusion, only males factored self-resemblance into their attractiveness ratings of opposite-sex individuals in a manner consistent with cues of reproductive fitness, although both sexes favored self-resemblance when judging trustworthiness.
doi:10.1371/journal.pone.0090493
PMCID: PMC3940898  PMID: 24594644
19.  Domestic versus imported drug-eluting stents for the treatment of patients with acute coronary syndrome 
BACKGROUND:
The application of coronary stents, especially drug-eluting stents (DESs), has made percutaneous coronary intervention (PCI) one of important therapeutic methods for CHD. DES has reduced the in-stent restenosis to 5%–9% and significantly improved the long-term prognosis of patients with CHD. The study aimed to investigate the long-term efficacy and safety of domestic drug-eluting stents (DESs) in patients with acute coronary syndrome (ACS).
METHODS:
All patients with ACS who had undergone successful percutaneous coronary intervention (PCI) in the First Affiliated Hospital of Zhengzhou University from July 2009 to December 2010 were included in this study. Patients were excluded from the study if they were implanted with bare metal stents or different stents (domestic and imported DESs) simultaneously. The included patients were divided into two groups according to different stents implanted: domestic DESs and imported DESs.
RESULTS:
In the 1 683 patients of this study, 1 558 (92.6%) patients were followed up successfully for an average of (29.1±5.9) months. 130 (8.3%) patients had major adverse cardiovascular events (MACEs), including cardiac death in 32 (2.1%) patients, recurrent myocardial infarction in 16 (1%), and revascularization in 94 (6%). The rates of cardiac death, recurrent myocardial infarction, revascularization, in-stent restenosis, stent thrombosis and other MACEs were not significantly different between the two groups (all P>0.05). Multivarite logistic regression revealed that diabetes mellitus (OR=1.75, 95%CI: 1.09–2.82, P=0.021), vascular numbers of PCI (OR=2.16, 95%CI: 1.22–3.83, P=0.09) and PCI with left main lesion (OR=9.47, 95%CI: 2.96–30.26, P=0.01) were independent prognostic factors of MACEs. The Kaplan-Meier method revealed that there was no significant difference in cumulative survival rates and survival rates free from clinical events between the two groups (all P>0.05).
CONCLUSIONS:
The incidences of clinical events and cumulative survival rates are not statistically different between domestic DESs and imported DESs. Domestic DES is effective and safe in the treatment of patients with ACS.
doi:10.5847/wjem.j.issn.1920-8642.2014.03.003
PMCID: PMC4163808  PMID: 25225580
Acute coronary syndrome; Percutaneous coronary intervention; Drug-eluting stent; Cardiovascular adverse events
20.  Prognostic relevance of Period1 (Per1) and Period2 (Per2) expression in human gastric cancer 
Period1 (Per1) and Period2 (Per2) are members of the circadian genes. Mounting evidence suggests that the deregulation of the circadian clock plays an important role in the development of mammalian cancer. However, the expression and clinical significance of Per1 and Per2 in gastric cancer is still unexplored. Here, we evaluated the expression pattern of Per1 and Per2 in 246 gastric cancer specimens and their adjacent, non-tumorous tissues using immunohistochemical assays. Per1 expression was significantly associated with clinical stage (p < 0.001), depth invasion (p < 0.001), lymph node metastasis (p < 0.001) and pathologic differentiation (p < 0.001). On the other hand, Per2 was associated with clinical stage (p = 0.021) and depth invasion (p = 0.007). Per1 expression was positively correlated with Per2 expression in the 246 gastric cancer patients (r = 0.378, p < 0.001), and the expression levels of Per1 and Per2 were down-regulated in gastric cancer tissues when compared with adjacent, non-tumorous tissues in 45 gastric cancer samples (p < 0.001, p = 0.003). Patients with lower Per1 and Per2 tumor expression had a shorter survival time than those with higher expression. Univariate and Multivariate analyses indicated that Per2 expression is an independent prognostic factor (p = 0.023). Our results demonstrate that Per1 and Per2 may play important roles in tumor development, invasion and prognosis, and Per2 may serve as a novel prognostic biomarker of human gastric cancer.
PMCID: PMC3925906  PMID: 24551282
Circadian clock gene; Per1; Per2; gastric cancer; expression; prognostic
21.  Clear cell carcinoma of the uterine cervix: clinical characteristics and feasibility of fertility-preserving treatment 
OncoTargets and therapy  2014;7:111-116.
The objective of this retrospective study was to analyze the clinical characteristics and prognosis of clear cell adenocarcinoma (CCA) in the post-diethylstilbestrol (DES) era and to evaluate the feasibility of fertility-preserving treatment. The records of 32 patients with CCAs who were treated at Peking Union Medical College Hospital from August 1986 to June 2012 were retrospectively reviewed. Three of the patients had undergone fertility-preserving treatment. The incidence of CCA among cervical adenocarcinomas was 15.2%. The median age was 38 years: 11 patients (34.4%) were diagnosed before 30 years of age and two (6.3%) after 70 years of age. Ten patients (31.2%) were nulliparous. No patient had been exposed to DES. Twenty-nine patients (90.6%) presented with obvious symptoms, and the cervix appeared abnormal in 26 patients (81.3%). Cervical Papanicolaou (Pap) tests were abnormal in all four patients in whom they were performed (three had high-grade squamous intraepithelial lesions and one had atypical squamous cells of undetermined significance). The distribution by stage was 56.3% stage I, 34.4% stage II, 6.3% stage III, and 3.1% stage IV. Treatments mainly included surgery for patients with stage I to IIA CCA and radiochemotherapy for patients with advanced CCA. The overall 5-year progression-free survival was 72.2%. Patients with stage I to IIA CCA had better 5-year progression-free survival than did patients with stage IIB to IV CCA (81.5% versus 40.0%, P=0.003). The three patients who had undergone fertility-preserving treatment had no recurrences. CCA may also affect adolescents and children without prior DES exposure, who are often misdiagnosed as having functional uterine bleeding. Radiotherapy appears to be effective for local control but to have no effect on distant recurrences. In our study, the prognosis of patients with early-stage CCA, including those who had undergone fertility-preserving treatment, was not inferior to that of patients with other types of cervical adenocarcinoma.
doi:10.2147/OTT.S53204
PMCID: PMC3891640  PMID: 24470762
clear cell carcinoma; cervix; diagnosis; prognosis; fertility-preserving
22.  Adjuvant chemotherapy, p53, carcinoembryonic antigen expression and prognosis after D2 gastrectomy for gastric adenocarcinoma 
AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma.
METHODS: A total of 286 patients with stage II or III gastric adenocarcinoma who underwent D2 radical gastrectomy between May 2007 and December 2010 were enrolled into this study. One hundred and sixty-nine of these patients received surgery plus adjuvant chemotherapy, and 117 patients received surgery alone. Tumor expression of p53 and CEA proteins in all patients was evaluated immunohistochemically and correlated with clinicopathological parameters. The Kaplan-Meier curves for overall survival (OS) and disease-free survival (DFS) with log-rank testing were used to compare the survival difference. A Cox proportional hazard regression model was used for multivariate analysis.
RESULTS: Patients with adjuvant chemotherapy had a significantly better median OS (50.87 mo vs 30.73 mo, P = 0.000) and median DFS (36.30 mo vs 25.60 mo, P = 0.001) than patients with surgery alone in the entire cohort. Consistent results with the entire cohort were found in stage II (P = 0.006 and P = 0.047), stage III (P = 0.005 and P = 0.030), and stage IIIB/IIIC patients (P = 0.000 and P = 0.001). The median OS and DFS advantages were confirmed by multivariate analysis (P = 0.000 and P = 0.008) and maintained when the analyses were restricted to fluoropyrimidine monotherapy (P = 0.003 and P = 0.001) and fluoropyrimidine plus platinum regimen (P = 0.001 and P = 0.007), however, not the fluoropyrimidine plus taxane (P = 0.198 and P = 0.777) or platinum plus taxane (P = 0.666 and P = 0.687) regimens. Median OS and median DFS did not differ significantly between the patients with p53(+) and p53(-) tumors (P = 0.608 and P = 0.064), or between patients with CEA(+) and CEA(-) tumors (P = 0.052 and P = 0.989), which were maintained when the analyses were restricted to surgery alone (p53: P = 0.864 and P = 0.431; CEA: P = 0.142 and P = 0.948), adjuvant chemotherapy (p53: P = 0.802 and P = 0.091; CEA: P = 0.223 and P = 0.946) and even different chemotherapy regimens (P > 0.05).
CONCLUSION: Patients after D2 gastrectomy for stage II/III gastric adenocarcinoma had significantly better survival after fluoropyrimidine monotherapy and fluoropyrimidine plus platinum. p53 and CEA were not prognostic.
doi:10.3748/wjg.v20.i1.264
PMCID: PMC3886018  PMID: 24415881
Gastric adenocarcinoma; Adjuvant chemotherapy; p53; Carcinoembryonic antigen; Immunohistochemistry
23.  The Role of Non-Curative Surgery in Incurable, Asymptomatic Advanced Gastric Cancer 
PLoS ONE  2013;8(12):e83921.
Background
Although general agreement exists on palliative surgery with intent of symptom palliation in advanced gastric cancer (AGC), the role of non-curative surgery for incurable, asymptomatic AGC is hotly debated. We aim to clarify the role of non-curative surgery in patients with incurable, asymptomatic AGC under the first-line chemotherapy.
Methods
A total of 737 patients with incurable, asymptomatic advanced gastric adenocarcinoma between January 2008 and May 2012 at the Sun Yat-sen University Cancer Center were retrospectively analyzed, comprising 414 patients with non-curative surgery plus first-line chemotherapy, and 323 patients with first-line chemotherapy only. The clinicopathologic data, survival, and prognosis were evaluated, with propensity score adjustment for selection bias.
Results
The median overall survival (OS) outcomes significantly favored non-curative surgery group over first-line chemotherapy only group in entire population (28.00 versus 10.37 months, P = 0.000), stage 4 patients (23.87 versus 10.37 months, P = 0.000), young patients (28.70 versus 10.37 months, P = 0.000) and elderly patients (23.07 versus 10.27 months, P = 0.031). The median OS advantages of non-curative surgery over first-line chemotherapy only were also maintained when the analyses were restricted to single organ metastasis (P = 0.001), distant lymph node metastasis (P = 0.002), peritoneal metastasis (P = 0.000), and multi-organ metastasis (P = 0.010). Significant OS advantages of non-curative surgery over chemotherapy only were confirmed solid by multivariate analyses before and after adjustment on propensity score (P = 0.000). Small subsets of patients with surgery of single metastatic lesion after previous curative gastrectomy, and with surgery of both primary and single metastatic sites showed sound median OS.
Conclusions
There is a role for non-curative surgery plus first-line chemotherapy for incurable, asymptomatic AGC, in terms of survival. Randomized controlled trials are warranted to fill a gap in knowledge about the value of metastectomy and patient selection strategies.
doi:10.1371/journal.pone.0083921
PMCID: PMC3865283  PMID: 24358318
24.  Risk of Generalized Vitiligo is Associated with the Common 55R-94A-247H Variant Haplotype of GZMB (Encoding Granzyme B) 
Generalized vitiligo (GV) is characterized by autoimmune destruction of melanocytes by skin-homing cytotoxic T-cells (CTLs) that target melanocyte autoantigens. Two recent genomewide association studies (GWAS) of GV in European-derived whites (EUR) have demonstrated genetic association with GZMB, encoding granzyme B, a marker of activated CTLs that mediates target-cell apoptosis, as well as autoantigen activation and consequent initiation and propagation of autoimmunity. Here, we describe detailed genetic analyses of the GZMB region of chromosome 14q12 to identify genetic variation potentially causal for GV, implicating two non-synonymous SNPs in strong linkage disequilibrium that comprise part of a common multi-variant high-risk haplotype, rs8192917-C— rs11539752-C (55R-94A). To identify possible uncommon deleterious variants that might “hitchhike” on the high-risk haplotype, we then carried out “next-generation” DNA re-sequencing of GZMB in 114 EUR GV patients. Overall, our findings support a direct causal role for the GZMB rs8192917-C—rs11539752-C haplotype (55R-94A) in the pathogenesis of GV.
doi:10.1038/jid.2013.5
PMCID: PMC3634907  PMID: 23321921
Vitiligo; Autoimmune disease; granzyme B; T-cells
25.  Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation 
In Alzheimer’s disease (AD), the mechanisms of neuronal loss remain largely unknown. While tau pathology is closely correlated with neuronal loss, how its accumulation may lead to activation of neurotoxic pathways is unclear. Here we show that tau increased the levels of ubiquitinated proteins in the brain and that this triggered activation of the Unfolded Protein Response (UPR). This suggested that tau was interfering with protein quality control in the endoplasmic reticulum (ER). Consistent with this, ubiquitin was found to associate with the ER in human AD brains and rTg4510 tau transgenic mouse brains, but this was not always co-localized with tau. The increased levels of ubiquitinated protein were accompanied by increased levels of phosphorylated PERK, a marker that indicates UPR activation. Importantly, depleting soluble tau levels in cells and brain could reverse UPR activation. Tau accumulation facilitated its deleterious interaction with ER membrane and associated proteins that are essential for ER-associated degradation (ERAD), including VCP and Hrd1. Based on this, the effects of tau accumulation on ERAD efficiency were evaluated using the CD3∂ reporter, an ERAD substrate. Indeed, CD3∂ accumulated in both in vitro and in vivo models of tau over-expression and AD brains. These data suggest that soluble tau impairs ERAD, and the result is activation of the UPR. The reversibility of this process, however, suggests that tau-based therapeutics could significantly delay this type of cell death and consequently disease progression.
doi:10.1523/JNEUROSCI.5397-12.2013
PMCID: PMC3733249  PMID: 23719816

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