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1.  Temporal Genetic Dynamics of an Invasive Species, Frankliniella occidentalis (Pergande), in an Early Phase of Establishment 
Scientific Reports  2015;5:11877.
Many species can successfully colonize new areas despite their propagules having low genetic variation. We assessed whether the decreased genetic diversity could result in temporal fluctuations of genetic parameters of the new populations of an invasive species, western flower thrips, Frankliniella occidentalis, using mitochondrial and microsatellite markers. This study was conducted in eight localities from four climate regions in China, where F. occidentalis was introduced in the year 2000 and had lower genetic diversity than its native populations. We also tested the level of genetic differentiation in these introduced populations. The genetic diversity of the samples at different years in the same locality was not significantly different from each other in most localities. FST and STRUCTURE analysis also showed that most temporal population comparisons from the same sites were not significantly differentiated. Our results showed that the invasive populations of F. occidentalis in China can maintain temporal stability in genetic composition at an early phase of establishment despite having lower genetic diversity than in their native range.
PMCID: PMC4490395  PMID: 26138760
2.  Basal serum testosterone levels correlate with ovarian response but do not predict pregnancy outcome in non-PCOS women undergoing IVF 
To evaluate basal testosterone (T) levels in women undergoing in vitro fertilization (IVF) cycles and examine the association between basal T levels and ovarian response or IVF pregnancy outcome.
We retrospectively analyzed 1413 infertile Chinese women undergoing their first IVF treatment at our institution’s reproductive center from March 2011 to May 2013. The basal testosterone (T) levels in women undergoing in vitro fertilization (IVF) and the relationship between basal T levels and ovarian response or IVF pregnancy outcome were determined. These patients did not have polycystic ovary syndrome (PCOS) or endometriosis, and were treated with a long luteal down-regulation protocol. Subjects were divided into 2 groups according to basal testosterone (T) levels: Group 1, basal T values <20 ng/dl (n = 473), and Group 2, basal T values >20 ng/dl (n = 940). We evaluated the association of basal T levels with ovarian response and IVF outcome in the two groups.
In this study, BMI, basal follicle-stimulating hormone (FSH) levels, basal luteinizing hormone (LH) levels, antral follicle count (AFC), days of stimulation, total gonadotrophin dose, basal FSH/LH ratio, and the number of follicles >14 mm were significantly different (P < 0.05) between the two groups. Basal T level positively correlated with ovarian reserve function, number of follicles >14 mm on human chorionic gonadotrophin (HCG) day, and total gonadotropin dose. However, basal T levels play no role in predicting IVF pregnancy outcome.
Basal T level can be used as a good predictor for ovarian response and the number of large follicles on HCG day. Additionally, we may use basal T level as a marker to predict FSH dosage. In general women, lower level of T might relate with potential poor ovarian response. However, based on our data, basal T levels do not predict pregnancy outcome.
PMCID: PMC4096887  PMID: 24849376
IVF; Pregnancy outcomes; Basal testosterone (T) levels; Ovarian response
3.  Dietary Fiber Intake is Associated with Increased Colonic Mucosal GPR43+ Polymorphonuclear Infiltration in Active Crohn’s Disease 
Nutrients  2015;7(7):5327-5346.
G protein-coupled receptor 43/free fatty acid receptor 2 (GPR43/FFAR2) is essential for polymorphonuclear (PMN) recruitment. We investigated the expression of GPR43/FFAR2 in the colon from Crohn’s disease patients and whether dietary fiber in enteral nutrition increases GPR43+ polymorphonuclear infiltration in mucosa. Segments of ascending colon and white blood cells from peripheral blood were obtained from 46 Crohn’s disease patients and 10 colon cancer patients. The Crohn’s disease patients were grouped by the activity of disease (active or remission) and enteral nutrition with or without dietary fiber. Histological feature, expression and location of GPR43/FFAR2 and level of tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6) and myeloperoxidase were assessed. The results of hematoxylin-eosin and immunohistochemistry staining revealed that the infiltration of immune cells, including GPR43+ PMN, was more severe in active Crohn’s disease patients who consumed normal food or enteral nutrition with dietary fiber than in remission patients and colon cancer patients. This finding was supported by the results of GPR43 and myeloperoxidase expression. Active Crohn’s disease (CD) patients who consumed enteral nutrition without dietary fiber exhibited severe immune cell infiltration similar to the other active CD patients, but GPR43+ PMNs were rarely observed. The level of TNF-α mRNA in active Crohn’s disease patients was higher than those of the other patients. In conclusion, the use of dietary fiber in enteral nutrition by active Crohn’s disease patients might increase GPR43+ PMNs infiltration in colon mucosa. This effect was not observed in Crohn’s disease patients in remission.
PMCID: PMC4517000  PMID: 26140540
GPR43/FFAR2; Crohn’s disease; dietary fibre; polymorphonuclear
4.  Prognostic role of hormone receptors in endometrial cancer: a systematic review and meta-analysis 
The aim of this study was to summarize the global predicting role of hormone receptors for survival in endometrial cancer.
Eligible studies were identified and assessed for quality through multiple search strategies. Data were collected from studies comparing overall survival (OS), cancer-specific survival (CSS), or progression-free survival (PFS) in patients with elevated levels of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) with those in patients with lower levels. The combined hazard ratios of ER, PR, and HER2 for survival were calculated.
A total of 98 studies were included for meta-analysis (44 for ER, 38 for PR, and 16 for HER2). Higher levels of either ER or PR could significantly indicate better survival. The pooled hazard ratios (HRs) of ER for OS, CSS, and PFS were 0.75 (95 % CI, 0.68–0.83), 0.45 (95 % CI, 0.33–0.62), and 0.66 (95 % CI, 0.52–0.85), respectively. The combined HRs of PR for OS, CSS, and PFS reached 0.63 (95 % CI, 0.56–0.71), 0.62 (95 % CI, 0.42–0.93), and 0.45 (95 % CI, 0.30–0.68), respectively. In contrast, elevated levels of HER2 could predict worse outcome with a HR of 1.98 (95 % CI, 1.49–2.62) for OS, and a HR of 2.26 (95 % CI, 1.57–3.25) for PFS.
In patients with endometrial cancer, higher level of ER and PR predicted favorable survival, and increased level of HER2 was associated with poorer survival. All of the three hormone receptors had prognostic value for survival.
PMCID: PMC4511445  PMID: 26108802
Endometrial cancer; Estrogen receptor; Progesterone receptor; Human epidermal growth factor receptor 2; Prognosis
5.  Histone demethylase LSD1-mediated repression of GATA-2 is critical for erythroid differentiation 
The transcription factor GATA-2 is predominantly expressed in hematopoietic stem and progenitor cells and counteracts the erythroid-specific transcription factor GATA-1, to modulate the proliferation and differentiation of hematopoietic cells. During hematopoietic cell differentiation, GATA-2 exhibits dynamic expression patterns, which are regulated by multiple transcription factors.
Stable LSD1-knockdown cell lines were established by growing murine erythroleukemia (MEL) or mouse embryonic stem cells together with virus particles, in the presence of Polybrene® at 4 μg/mL, for 24–48 hours followed by puromycin selection (1 μg/mL) for 2 weeks. Real-time polymerase chain reaction (PCR)-based quantitative chromatin immunoprecipitation (ChIP) analysis was used to test whether the TAL1 transcription factor is bound to 1S promoter in the GATA-2 locus or whether LSD1 colocalizes with TAL1 at the 1S promoter. The sequential ChIP assay was utilized to confirm the role of LSD1 in the regulation of H3K4me2 at the GATA-2 locus during erythroid differentiation. Western blot analysis was employed to detect the protein expression. The alamarBlue® assay was used to examine the proliferation of the cells, and the absorbance was monitored at optical density (OD) 570 nm and OD 600 nm.
In this study, we showed that LSD1 regulates the expression of GATA-2 during erythroid differentiation. Knockdown of LSD1 results in increased GATA-2 expression and inhibits the differentiation of MEL and embryonic stem cells. Furthermore, we demonstrated that LSD1 binds to the 1S promoter of the GATA-2 locus and suppresses GATA-2 expression, via histone demethylation.
Our data revealed that LSD1 mediates erythroid differentiation, via epigenetic modification of the GATA-2 locus.
PMCID: PMC4482369  PMID: 26124638
LSD1; GATA factor switching; histone demethylation
6.  Esomeprazole regimens for reflux symptoms in Chinese patients with chronic gastritis 
AIM: To compare symptom control with esomeprazole regimens for non-erosive reflux disease and chronic gastritis in patients with a negative endoscopy.
METHODS: This randomized, open-label study was designed in line with clinical practice in China. Patients with typical reflux symptoms for ≥ 3 mo and a negative endoscopy who had a Gastroesophageal Reflux Disease Questionnaire score ≥ 8 were randomized to initial treatment with esomeprazole 20 mg once daily either for 8 wk or for 2 wk. Patients with symptom relief could enter another 24 wk of maintenance/on-demand treatment, where further courses of esomeprazole 20 mg once daily were given if symptoms recurred. The primary endpoint was the symptom control rate at week 24 of the maintenance/on-demand treatment period. Secondary endpoints were symptom relief rate, success rate (defined as patients who had symptom relief after initial treatment and after 24 wk of maintenance treatment), time-to-first-relapse and satisfaction rate.
RESULTS: Based on the data collected in the modified intention-to-treat population (MITT; patients in the ITT population with symptom relief after initial esomeprazole treatment, n = 262), the symptom control rate showed a small but statistically significant difference in favor of the 8-wk regimen (94.9% vs 87.3%, P = 0.0473). Among the secondary endpoints, based on the data collected in the ITT population (n = 305), the 8-wk group presented marginally better results in symptom relief after initial esomeprazole treatment (88.3% vs 83.4%, P = 0.2513) and success rate over the whole study (83.8% vs 72.8%, P = 0.0258). The 8-wk regimen was found to provide a 46% reduction in risk of relapse vs the 2-wk regimen (HR = 0.543; 95%CI: 0.388-0.761). In addition, fewer unscheduled visits and higher patient satisfaction supported the therapeutic benefits of the 8-wk regimen over the 2-wk regimen. Safety was comparable between the two groups, with both regimens being well tolerated.
CONCLUSION: Chinese patients diagnosed with chronic gastritis achieved marginally better control of reflux symptoms with an 8-wk vs a 2-wk esomeprazole regimen, with a similar safety profile.
PMCID: PMC4462738  PMID: 26078574
Esomeprazole; Non-erosive reflux disease regimen; Chronic gastritis regimen; Symptom control rate
7.  Mesenchymal stem cell–conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells 
Journal of Radiation Research  2015;56(4):700-708.
Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury.
PMCID: PMC4497399  PMID: 26070321
sinusoidal endothelial cell; radiation-induced liver injury; mesenchymal stem cell; apoptosis
8.  Neuron-glial antigen 2 overexpression in hepatocellular carcinoma predicts poor prognosis 
AIM: To investigate whether neuron-glial antigen 2 (NG2) could be an effective prognostic marker in hepatocellular carcinoma (HCC).
METHODS: NG2 expression was semi-quantitatively scored from the immunohistochemistry (IHC) data based on the number of positive cells and the staining intensity. A total of 132 HCC specimens and 96 adjacent noncancerous tissue samples were analyzed by IHC for NG2 protein expression. To confirm the NG2 expression levels observed by IHC, we measured NG2 expression in 30 randomly selected tumor and adjacent noncancerous tissue samples by quantitative real-time polymerase chain reaction and Western blot. The correlations between NG2 protein expression and the clinicopathological features of HCC patients were analyzed using the χ2 test. To assess the prognostic value of NG2 for HCC, the association between NG2 expression and survival was analyzed using the Kaplan-Meier method with the log-rank test. To further evaluate the prognostic value of NG2 expression, a Cox multivariate proportional hazards regression analysis was performed with all the variables to derive risk estimates related to disease-free and overall survival and to control for confounders.
RESULTS: High NG2 expression was observed in significantly more primary tumor samples (63.6%; 84/132) compared with the adjacent noncancerous tissue samples (28.1%; 27/96) (P < 0.0001). Moreover, high NG2 protein expression was closely associated with tumor differentiation (χ2 = 9.436, P = 0.0089), recurrence (χ2 = 5.769, P = 0.0163), tumor-node-metastasis (TNM) stage (χ2 = 8.976, P = 0.0027), and invasion (χ2 = 5.476, P = 0.0193). However, no significant relationship was observed between NG2 protein expression in HCC and other parameters, such as age, sex, tumor size, serum alpha fetoprotein (AFP), tumor number, or tumor capsule. The log-rank test indicated a significant difference in the overall survival of HCC patients with high NG2 expression compared with those with low NG2 expression (29.2% vs 9.5%, P < 0.001). Moreover, NG2 expression in HCC tissue significantly correlated with disease-free survival (15.2% vs 6.7%, P < 0.001). Multivariate analysis showed that NG2 expression (HR = 2.035, P = 0.002), serum AFP (HR = 1.903, P = 0.003), TNM stage (HR = 2.039, P = 0.001), and portal vein invasion (HR = 1.938, P = 0.002) were independent prognostic indicators for OS in HCC patients. Furthermore, NG2 expression (HR = 1.974, P = 0.003), serum AFP (HR = 1.767, P = 0.008), TNM stage (HR = 2.078, P = 0.001), tumor capsule (HR = 0.652, P = 0.045), and portal vein invasion (HR = 1.941, P = 0.002) were independent prognostic indicators for DFS in HCC patients.
CONCLUSION: The up-regulation of NG2 is associated with poor prognosis in HCC. Therefore, NG2 could be useful as an additional prognostic marker to increase the resolution of traditional approaches.
PMCID: PMC4458775  PMID: 26074703
Neuron-glial antigen 2; Hepatocellular carcinoma; Survival analysis; Poor prognosis; Prognostic marker
9.  Modifying Role of GSTP1 Polymorphism on the Association between Tea Fluoride Exposure and the Brick-Tea Type Fluorosis 
PLoS ONE  2015;10(6):e0128280.
Brick tea type fluorosis is a public health concern in the north-west area of China. The association between SNPs of genes influencing bone mass and fluorosis has attracted attention, but the association of SNPs with the risk of brick-tea type of fluorosis has not been reported.
To investigate the modifying roles of GSTP1 rs1695 polymorphisms on this association.
A cross-sectional study was conducted. Brick-tea water was tested by the standard of GB1996-2005 (China). Urinary fluoride was tested by the standard of WS/T 89-2006 (China). Skeletal fluorosis was diagnosed by X-ray, the part we scheduled was forearm, shank, and pelvic, then diagnosed the skeletal fluorosis by the standard of WS/192-2008 (China). Gene polymorphism was tested by Sequenom MassARRAY system.
The prevalence rate in different ethnical participants was different: Tibetan individuals had the highest prevalence rate of skeletal fluorosis. There were significant differences in genotype frequencies of GSTP1 Rs1695 among different ethnical participants (p<0.001): Tibetan, Mongolian and Han subjects with homozygous wild type (GSTP1-AA) genotype were numerically higher than Kazakh and Russian subjects (p<0.001). Compared to Tibetan participants who carried homozygous A allele of GSTP1 Rs1695, Tibetan participants who carried G allele had a significantly decreased risk of skeletal fluorosis (OR = 0.558 [95% CI, 0.326-0.955]). For Kazakh participants, a decreased risk of skeletal fluorosis among carriers of the G allele was limited to non high-loaded fluoride status (OR = 0. 166 [95% CI, 0.035–0.780] vs. OR = 1.478 [95% CI, 0.866–2.552] in participants with high-loaded fluoride status). Neither SNP-IF nor SNP-age for GSTP1 Rs1695 was observed.
The prevalence rate of the brick tea type fluorosis might have ethnic difference. For Tibetan individuals, who had the highest prevalence rate, G allele of GSTP1 Rs1695 might be a protective factor for brick tea type skeletal fluorosis.
PMCID: PMC4457801  PMID: 26046522
10.  A comparative study of mechanical strain, icariin and combination stimulations on improving osteoinductive potential via NF-kappaB activation in osteoblast-like cells 
The combination of drugs and exercise was the effective treatment in bone injure and rebuilding in clinic. As mechanical strain has potential in inducing the differentiation of osteoblasts in our previous study, the further research to investigate the combination of mechanical strain and icariin stimulation on inducing osteoblast proliferation, differentiation and the possible mechanism in MC3T3-E1 cell line.
A whole cell enzyme-linked immunosorbent assay that detects the bromodeoxyuridine incorporation during DNA synthesis was applied to evaluate the proliferation. The mRNA expression of alkaline phosphatase (ALP), osteocalcin (OCN), type I collagen (Col I), bone morphogenetic protein-2 (BMP-2) and BMP-4 was detected by real-time reverse-transcription polymerase chain reaction. The activity of ALP was analyzed by ELISA and the protein expression of OCN, Col I and BMP-2 was assessed by western blot. Moreover, the activity of nuclear transcription factor kappa-B (NF-κB) signaling pathway was investigated with the expression of inhibitor of κB (IκB) α, phosphorylation of IκB-α (P-IκB-α), p65, P-p65 by western blot.
We observed that compared to single mechanical strain or icariin stimulation, the mRNA and protein expressions of ALP (P < 0.05 or P < 0.01), OCN (P < 0.01) and Col I (P < 0.05 or P < 0.01) were increased significantly by the combination of mechanical strain and icariin stimulation. Moreover, the combination of mechanical strain and icariin stimulation could up-regulate the expression of BMP-2 (P < 0.01) and BMP-4 compared to single mechanical strain or icariin stimulation. The combination of mechanical strain and icariin stimulation could activate NF-κB signaling pathway by increasing the expression of IκB α, P-IκB-α, p65, P-p65 (P < 0.01).
The combination of mechanical strain and icariin stimulation could activate the NF-κB pathway to improve the proliferation, differentiation of osteoblast-like cells.
PMCID: PMC4455701  PMID: 25994935
Mechanical strain; Icariin; BMP-2; NF-κB; Bone remodeling
12.  Magnolia officinalis Extract Contains Potent Inhibitors against PTP1B and Attenuates Hyperglycemia in db/db Mice 
BioMed Research International  2015;2015:139451.
Protein tyrosine phosphatase 1B (PTP1B) is an established therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. The aim of this study was to investigate the inhibitory activity of Magnolia officinalis extract (ME) on PTP1B and its anti-T2DM effects. Inhibition assays and inhibition kinetics of ME were performed in vitro. 3T3-L1 adipocytes and C2C12 myotubes were stimulated with ME to explore its bioavailability in cell level. The in vivo studies were performed on db/db mice to probe its anti-T2DM effects. In the present study, ME inhibited PTP1B in a reversible competitive manner and displayed good selectivity against PTPs in vitro. Furthermore, ME enhanced tyrosine phosphorylation levels of cellular proteins, especially the insulin-induced tyrosine phosphorylations of insulin receptor β-subunit (IRβ) and ERK1/2 in a dose-dependent manner in stimulated 3T3-L1 adipocytes and C2C12 myotubes. Meanwhile, ME enhanced insulin-stimulated GLUT4 translocation. More importantly, there was a significant decrease in fasting plasma glucose level of db/db diabetic mice treated orally with 0.5 g/kg ME for 4 weeks. These findings indicated that improvement of insulin sensitivity and hypoglycemic effects of ME may be attributed to the inhibition of PTP1B. Thereby, we pioneered the inhibitory potential of ME targeted on PTP1B as anti-T2DM drug discovery.
PMCID: PMC4439476  PMID: 26064877
13.  Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice 
BioMed Research International  2015;2015:395895.
Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect.
PMCID: PMC4439479  PMID: 26064905
14.  Molecular Signatures of Major Depression 
Current Biology  2015;25(9):1146-1156.
Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.
•Amount of mtDNA is increased, and telomeric DNA is shortened in major depression•Both changes can be induced with stress but are contingent on the depressed state•Changes are tissue specific and in part due to glucocorticoid secretion•Changes are in part reversible and represent switches in metabolic strategy
Cai et al. found increases in mtDNA and a reduction in telomeric DNA in cases of major depression using whole-genome sequencing. Both changes are depression state dependent. Mice exposed to chronic stress or glucorticoids showed that these changes reflect switches in metabolic strategy and are tissue specific and partial reversible.
PMCID: PMC4425463  PMID: 25913401
15.  Aurora kinase inhibition induces PUMA via NF-κB to kill colon cancer cells 
Molecular cancer therapeutics  2014;13(5):1298-1308.
Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of PUMA, a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors.
PMCID: PMC4013266  PMID: 24563542
aurora kinase; PUMA; apoptosis; NF-κB; colon cancer
16.  Methyltransferase-Defective Avian Metapneumovirus Vaccines Provide Complete Protection against Challenge with the Homologous Colorado Strain and the Heterologous Minnesota Strain 
Journal of Virology  2014;88(21):12348-12363.
Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and is associated with swollen head syndrome in chickens. Since its discovery in the 1970s, aMPV has been recognized as an economically important pathogen in the poultry industry worldwide. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at guanine N-7 (G-N-7) and ribose 2′-O positions. In this study, we generated a panel of recombinant aMPV (raMPV) Colorado strains carrying mutations in the S-adenosyl methionine (SAM) binding site in the CR VI of L protein. These recombinant viruses were specifically defective in ribose 2′-O, but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of specific-pathogen-free (SPF) young turkeys. Importantly, turkeys vaccinated with these MTase-defective raMPVs triggered a high level of neutralizing antibody and were completely protected from challenge with homologous aMPV Colorado strain and heterologous aMPV Minnesota strain. Collectively, our results indicate (i) that aMPV lacking 2′-O methylation is highly attenuated in vitro and in vivo and (ii) that inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for aMPV and perhaps other paramyxoviruses.
IMPORTANCE Paramyxoviruses include many economically and agriculturally important viruses such as avian metapneumovirus (aMPV), and Newcastle disease virus (NDV), human pathogens such as human respiratory syncytial virus, human metapneumovirus, human parainfluenza virus type 3, and measles virus, and highly lethal emerging pathogens such as Nipah virus and Hendra virus. For many of them, there is no effective vaccine or antiviral drug. These viruses share common strategies for viral gene expression and replication. During transcription, paramyxoviruses produce capped, methylated, and polyadenylated mRNAs. Using aMPV as a model, we found that viral ribose 2′-O methyltransferase (MTase) is a novel approach to rationally attenuate the virus for vaccine purpose. Recombinant aMPV (raMPV) lacking 2′-O MTase were not only highly attenuated in turkeys but also provided complete protection against the challenge of homologous and heterologous aMPV strains. This novel approach can be applicable to other animal and human paramyxoviruses for rationally designing live attenuated vaccines.
PMCID: PMC4248898  PMID: 25122790
17.  Stratified Microbial Structure and Activity in Sulfide- and Methane-Producing Anaerobic Sewer Biofilms 
Applied and Environmental Microbiology  2014;80(22):7042-7052.
Simultaneous production of sulfide and methane by anaerobic sewer biofilms has recently been observed, suggesting that sulfate-reducing bacteria (SRB) and methanogenic archaea (MA), microorganisms known to compete for the same substrates, can coexist in this environment. This study investigated the community structures and activities of SRB and MA in anaerobic sewer biofilms (average thickness of 800 μm) using a combination of microelectrode measurements, molecular techniques, and mathematical modeling. It was seen that sulfide was mainly produced in the outer layer of the biofilm, between the depths of 0 and 300 μm, which is in good agreement with the distribution of SRB population as revealed by cryosection-fluorescence in situ hybridization (FISH). SRB had a higher relative abundance of 20% on the surface layer, which decreased gradually to below 3% at a depth of 400 μm. In contrast, MA mainly inhabited the inner layer of the biofilm. Their relative abundances increased from 10% to 75% at depths of 200 μm and 700 μm, respectively, from the biofilm surface layer. High-throughput pyrosequencing of 16S rRNA amplicons showed that SRB in the biofilm were mainly affiliated with five genera, Desulfobulbus, Desulfomicrobium, Desulfovibrio, Desulfatiferula, and Desulforegula, while about 90% of the MA population belonged to the genus Methanosaeta. The spatial organizations of SRB and MA revealed by pyrosequencing were consistent with the FISH results. A biofilm model was constructed to simulate the SRB and MA distributions in the anaerobic sewer biofilm. The good fit between model predictions and the experimental data indicate that the coexistence and spatial structure of SRB and MA in the biofilm resulted from the microbial types and their metabolic transformations and interactions with substrates.
PMCID: PMC4249016  PMID: 25192994
18.  Interferon-γ polymorphism and hepatocellular carcinoma susceptibility: a meta analysis 
Background: Interferon-gamma (IFN-γ) was first defined as an antiviral agent with potent antitumor effects in 1957 and this is supported by much subsequent research. IFN-γ rs2430561 polymorphism was found to increase IFN-γ production involved in the regulation of immune system. Previous studies of rs2430561 genotypes and hepatocellular carcinoma (HCC) susceptibility have produced inconsistent results. We thus summarized all epidemiologic and molecular data and carried out a meta-analysis to evaluate the effects of this functional polymorphism on HCC incidence. Methods: Human hospital- or population-based studies were identified by searching multiple databases (BIOSIS, Embase, PubMed, Web of Science, Chinese Biomedical Literature database). Six studies were selected for the meta-analysis. Crude ORs was calculated assuming the allele, homozygote, heterozygote, dominant and recessive model. The stability and reliability of the combined results were examined by using sensitivity analysis and publication bias tests. Results: Meta-analysis under the allele model showed that the T allele compared with the A allele showed a moderately but nonsignificantly increased risk of HCC (OR = 1.12, 95% CI = 0.92-1.35). Analyses under the remaining models revealed no evidence of a significant association. In subgroup analysis by infection type, summary ORs suggested no significantly elevated risk of HBV-infected HCC in relation to the allele or genotypes of rs2430561 polymorphism. The combined results were reliable according to sensitivity analysis and publication bias tests. Conclusion: We found no strong evidence supporting a statistically significant association between IFN-γ rs2430561 polymorphism and HCC susceptibility.
PMCID: PMC4483975  PMID: 26131150
Interferon-gamma; hepatocellular carcinoma; polymorphism; susceptibility
19.  Propofol injection combined with bone marrow mesenchymal stem cell transplantation better improves electrophysiological function in the hindlimb of rats with spinal cord injury than monotherapy 
Neural Regeneration Research  2015;10(4):636-643.
The repair effects of bone marrow mesenchymal stem cell transplantation on nervous system damage are not satisfactory. Propofol has been shown to protect against spinal cord injury. Therefore, this study sought to explore the therapeutic effects of their combination on spinal cord injury. Rat models of spinal cord injury were established using the weight drop method. Rats were subjected to bone marrow mesenchymal stem cell transplantation via tail vein injection and/or propofol injection via tail vein using an infusion pump. Four weeks after cell transplantation and/or propofol treatment, the cavity within the spinal cord was reduced. The numbers of PKH-26-positive cells and horseradish peroxidase-positive nerve fibers apparently increased in the spinal cord. Latencies of somatosensory evoked potentials and motor evoked potentials in the hindlimb were noticeably shortened, amplitude was increased and hindlimb motor function was obviously improved. Moreover, the combined effects were better than cell transplantation or propofol injection alone. The above data suggest that the combination of propofol injection and bone marrow mesenchymal stem cell transplantation can effectively improve hindlimb electrophysiological function, promote the recovery of motor funtion, and play a neuroprotective role in spinal cord injury in rats.
PMCID: PMC4424759  PMID: 26170827
nerve regeneration; bone marrow mesenchymal stem cells; propofol; spinal cord injury; cell transplantation; electrophysiology; motor function; stem cells; neuroprotection; neural regeneration
20.  Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury 
The therapeutic potential of mesenchymal stem cells (MSCs) for traumatic brain injury (TBI) is attractive. Conducting systematic review and meta-analyses based on data from animal studies can be used to inform clinical trial design. To conduct a systematic review and meta-analysis to (i) systematically review the literatures describing the effect of MSCs therapy in animal models of TBI, (ii) determine the estimated effect size of functional locomotor recovery after experimental TBI, and (iii) to provide empirical evidence of biological factors associated with greater efficacy.
We conducted a systematic search of PubMed, EMBASE, and Web of Science and hand searched related references. Studies were selected if they reported the efficacy of MSCs in animal models of TBI. Two investigators independently assessed the identified studies. We extracted the details of individual study characteristics from each publication, assessed study quality, evaluated the effect sizes of MSCs treatment, and performed stratified meta-analysis and meta-regression, to assess the influence of study design on the estimated effect size. The presence of small effect sizes was investigated using funnel plots and Egger’s tests.
Twenty-eight eligible controlled studies were identified. The study quality was modest. Between-study heterogeneity was large. Meta-analysis showed that MSCs exert statistically significant positive effects on sensorimotor and neurological motor function. For sensorimotor function, maximum effect size in studies with a quality score of 5 was found in the weight-drop impact injury TBI model established in male SD rats, to which syngeneic umbilical cord-derived MSCs intracerebrally at cell dose of (1–5) × 106 was administered r 6 hours following TBI, using ketamine as anesthetic agent. For neurological motor function, effect size was maximum for studies with a quality score of 5, in which the weight-drop impact injury TBI models of the female Wistar rats were adopted, with administration syngeneic bone marrow-derived MSCs intravenously at cell dose of 5 × 106 at 2 months after TBI, using sevofluorane as anesthetic agent.
We conclude that MSCs therapy may improve locomotor recovery after TBI. However, additional well-designed and well-reported animal studies are needed to guide further clinical studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-015-0034-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4425919  PMID: 25881229
21.  Impacts of ezetimibe on PCSK9 in rats: study on the expression in different organs and the potential mechanisms 
Previous studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated.
Thirty rats were randomly divided into two groups (n = 15 for each), which were orally administrated with ezetimibe (10 mg/kg/day) or normal saline. Blood samples were obtained at day 3 after orally administration, and the PCSK9 levels were determined by ELISA. We further analyzed the mRNA expression of PCSK9, low-density lipoprotein receptor (LDLR), sterol regulator element-binding protein 2 (SREBP2), and hepatocyte nuclear factor 1 alpha (HNF-1α) by real-time PCR, as well as the protein expression by western blot, in liver, intestine and kidney respectively.
Ezetimibe significantly increased plasma PCSK9 levels compared with control group, while there was no significant difference between the two groups with regard to lipid profile at day 3. Moreover, ezetimibe remarkably increased the expression of PCSK9, LDLR, SREBP2 and HNF-1α in liver. Enhanced expression of PCSK9, LDLR and SREBP2 protein were found in intestine and kidney, while no changes in the expression of HNF-1α were observed in intestine and kidney of rats with ezetimibe treatment.
The data demonstrated that ezetimibe increased PCSK9 expression through the SREBP2 and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats.
PMCID: PMC4365528  PMID: 25889684
Ezetimibe; PCSK9; Liver; Intestine; Kidney; Molecular mechanism
22.  Nitrooleic Acid Protects against Cisplatin Nephropathy: Role of COX-2/mPGES-1/PGE2 Cascade 
Mediators of Inflammation  2015;2015:293474.
Nitrooleic acid (OA-NO2) is an endogenous lipid product which has novel signaling properties, particularly the activation of peroxisome proliferator-activated receptors. The current study aimed to evaluate the protective effects of OA-NO2 against cisplatin-induced kidney injury in mice. Mice were pretreated with OA-NO2 for 48 h before cisplatin administration, and the cisplatin-caused nephrotoxicity was evaluated. After the cisplatin treatment (72 h), the vehicle-treated mice displayed renal dysfunction, as evidenced by the elevated plasma urea and creatinine, which was consistent with the histological damage, such as tubular necrosis, dilation, protein cast, and desquamation of epithelial cells. In contrast, the severity of the renal dysfunction and histological change were reduced in the OA-NO2 pretreated mice. The renal COX-2 and mPGES-1 mRNAs and their respective proteins expression, together with the renal PGE2 amounts, were induced by the cisplatin treatment, but their initiation was reduced by OA-NO2. Moreover, the circulating TNF-α, renal TNF-α, IL-1β, MCP-1, ICAM-1, and VACAM-1 mRNA levels were higher in the cisplatin-treated mice, compared with the controls, but they were attenuated in the OA-NO2 pretreatment group. In summary, the pretreatment with OA-NO2 remarkably ameliorated the cisplatin-induced kidney injury in mice, possibly via the inhibition of the inflammatory response, associated with the COX-2/mPGES-1/PGE2 cascade.
PMCID: PMC4377489  PMID: 25861160
23.  Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice 
PPAR Research  2015;2015:480348.
Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities.
PMCID: PMC4377523  PMID: 25861250
24.  Electroacupuncture alleviates retrieval of pain memory and its effect on phosphorylation of cAMP response element-binding protein in anterior cingulate cortex in rats 
Recent evidence suggests that persistent pain and recurrent pain are due to the pain memory which is related to the phosphorylation of cAMP response element-binding protein (p-CREB) in anterior cingulate cortex (ACC). Eletroacupuncture (EA), as a complementary Chinese medical procedure, has a significant impact on the treatment of pain and is now considered as a mind-body therapy.
The rat model of pain memory was induced by two injections of carrageenan into the paws, which was administered separately by a 14-day interval, and treated with EA therapy. The paw withdrawal thresholds (PWTs) of animals were measured and p-CREB expressions in ACC were detected by using immunofluorescence (IF) and electrophoretic mobility shift assay (EMSA). Statistical comparisons among different groups were made by one-way, repeated-measures analysis of variance (ANOVA).
The second injection of carrageenan caused the decrease of PWTs in the non-injected hind paw. EA stimulation applied prior to the second injection, increased the values of PWTs. In ACC, the numbers of p-CREB positive cells were significantly increased in pain memory model rats, which were significantly reduced by EA. EMSA results showed EA also down-regulated the combining capacity of p-CREB with its DNA. Furthermore, the co-expression of p-CREB with GFAP, OX-42, or NeuN in ACC was strengthened in the pain memory model rats. EA inhibited the co-expression of p-CREB with GFAP or OX-42, but not NeuN in ACC.
The present results suggest the retrieval of pain memory could be alleviated by the pre-treatment of EA, which is at least partially attributed to the down-regulated expression and combining capacity of p-CREB and the decreased expression of p-CREB in astrocytes and microglia cells.
PMCID: PMC4364627  PMID: 25886521
Electroacupuncture; Pain memory; Phosphorylation of cAMP response elment-binding protein; Anterior cingulate cortex; Rat
25.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer 
Cancer discovery  2014;4(9):1046-1061.
First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This monoanilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.
PMCID: PMC4315625  PMID: 24893891
EGFR mutant lung cancer; AZD9291; EGFR tyrosine kinase inhibitor

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