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1.  ZPK/DLK and MKK4 Form the Critical Gateway to Axotomy-Induced Motoneuron Death in Neonates 
The Journal of Neuroscience  2014;34(32):10729-10742.
Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.
PMCID: PMC4200111  PMID: 25100604
injury response; mitogen-activated protein kinase; programmed cell death
2.  Diminished serum repetin levels in patients with schizophrenia and bipolar disorder 
Scientific Reports  2015;5:7977.
Repetin (RPTN) protein is a member of S100 family and is known to be expressed in the normal epidermis. Here we show that RPTN is ubiquitously expressed in both mouse and human brain, with relatively high levels in choroid plexus, hippocampus and prefrontal cortex. To investigate the expression of RPTN in neuropsychiatric disorders, we determined serum levels of RPTN in patients with schizophrenia (n = 88) or bipolar disorder (n = 34) and in chronic psychostimulant users (n = 91). We also studied its expression in a mouse model of chronic unpredictable mild stress (CUMS). The results showed that serum RPTN levels were significantly diminished in patients with schizophrenia and bipolar disorder or in psychostimulant users, compared with healthy subjects (n = 115) or age-matched controls (n = 92) (p < 0.0001). In CUMS mice, RPTN expression in hippocampus and prefrontal cortex was reduced with progression of the CUMS procedure; the serum RPTN level remained unchanged. Since CUMS is a model for depression and methamphetamine (METH) abuse induced psychosis recapitulates many of the psychotic symptoms of schizophrenia, the results from this study may imply that RPTN plays a potential role in emotional and cognitive processing; its decrease in serum may indicate its involvement in the pathogenesis of schizophrenia and bipolar disorder.
PMCID: PMC4303898  PMID: 25613293
3.  Viruses and Antiviral Immunity in Drosophila 
Developmental and comparative immunology  2013;42(1):10.1016/j.dci.2013.05.002.
Viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. A wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. Studies using the powerful tools available in the model organism Drosophila have expanded our understanding of antiviral defenses against diverse viruses. In this review, we will cover three major areas. First, we will describe the tools used to study viruses in Drosophila. Second, we will survey the major viruses that have been studied in Drosophila. And lastly, we will discuss the well-characterized mechanisms that are active against these diverse pathogens, focusing on non-RNAi mediated antiviral mechanisms. Antiviral RNAi is discussed in another paper in this issue.
PMCID: PMC3826445  PMID: 23680639
4.  Forward Genetic Screening for Regulators Involved in Cholesterol Synthesis Using Validation-Based Insertional Mutagenesis 
PLoS ONE  2014;9(11):e112632.
Somatic cell genetics is a powerful approach for unraveling the regulatory mechanism of cholesterol metabolism. However, it is difficult to identify the mutant gene(s) due to cells are usually mutagenized chemically or physically. To identify important genes controlling cholesterol biosynthesis, an unbiased forward genetics approach named validation-based insertional mutagenesis (VBIM) system was used to isolate and characterize the 25-hydroxycholesterol (25-HC)-resistant and SR-12813-resisitant mutants. Here we report that five mutant cell lines were isolated. Among which, four sterol-resistant mutants either contain a truncated NH2-terminal domain of sterol regulatory element-binding protein (SREBP)-2 terminating at amino acids (aa) 400, or harbor an overexpressed SREBP cleavage-activating protein (SCAP). Besides, one SR-12813 resistant mutant was identified to contain a truncated COOH-terminal catalytic domain of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). This study demonstrates that the VBIM system can be a powerful tool to screen novel regulatory genes in cholesterol biosynthesis.
PMCID: PMC4245081  PMID: 25426949
7.  Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness 
The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.
Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.
High expression of synbindin was associated with larger tumor size (120.8 vs 44.8cm3; P = .01), advanced tumor node metastasis (TNM) stage (P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm3, 95% CI = 328.3 to 574.1 vs 726.1mm3, 95% CI = 544.2 to 908.2; P = .01).
Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.
PMCID: PMC4042874  PMID: 24104608
8.  Dynamic Comparison of Physicians’ Interaction Style with Electronic Health Records in Primary Care Settings 
Researchers have been increasingly interested in the influence of computers on physician-patient communication in consultation rooms because of the substantial growth in the use of Electronic Health Records (EHRs) in the U.S. Previous research showed that physicians have different ways of interacting with patients and EHRs; and these styles may relate to different patterns of nonverbal interaction between the physicians and patients and influence the outcomes of the clinical visit. The purpose of this study was to identify the differences of eye gaze patterns in three EHR interaction styles: the technology-centered style, the human-centered style, and the mixed interaction style. 100 primary care visits with different interaction styles were videotaped. Eye gaze behaviors were coded and described as frequencies and durations of gaze. The dynamic eye gaze patterns of the physicians and patients, in terms of how their gaze behaviors were sequentially associated, were analyzed using lag-sequential analysis. The results indicated that technology-centered group had significantly shorter amount of mutual gaze than other two groups (p=0.032; p=0.015, respectively). In addition, in technology centered style, the physicians were more likely to shift their gaze to the computer when the patients gazed at them; and when the physicians gazed at the computers, the patients were more likely to gaze somewhere else which might be an indicator of disengagement. The study implied that EHRs should be designed in a way that facilitates a positive interaction between the physicians and patients, such as maintaining mutual gaze. Training should also be provided to the physicians for establishing effective and positive interaction styles.
PMCID: PMC4233672  PMID: 25411656
EHRs; Patient centered care; Doctor-patient communication; Primary care
9.  Limonoid and Steroidal Saponin from Azadirachta indica 
A new limonoid, 17-(5-methoxy-2-oxofuran-3-yl)-28-deoxonimbolide (1), and a new C21 steroidal saponin, 2α,4α-dihydroxy-pregn-5-en-16-one-3α-O-d-glucopyranoside (2), together with 11 known compounds were isolated from the methanol extract of the leaves of Azadirachta indica. The structures were elucidated by means of spectroscopic analysis and putative biosynthetic origins. All the compounds were evaluated for their antibacterial activities against six bacterial strains.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0042-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4250567  PMID: 25381190
Azadirachta indica; Limonoid; Steroidal saponin; Antibacterial activities
10.  Fuzzy Temporal Logic Based Railway Passenger Flow Forecast Model 
Passenger flow forecast is of essential importance to the organization of railway transportation and is one of the most important basics for the decision-making on transportation pattern and train operation planning. Passenger flow of high-speed railway features the quasi-periodic variations in a short time and complex nonlinear fluctuation because of existence of many influencing factors. In this study, a fuzzy temporal logic based passenger flow forecast model (FTLPFFM) is presented based on fuzzy logic relationship recognition techniques that predicts the short-term passenger flow for high-speed railway, and the forecast accuracy is also significantly improved. An applied case that uses the real-world data illustrates the precision and accuracy of FTLPFFM. For this applied case, the proposed model performs better than the k-nearest neighbor (KNN) and autoregressive integrated moving average (ARIMA) models.
PMCID: PMC4238178  PMID: 25431586
11.  Chemical Constituents from the Stems of Ecdysanthera rosea 
One new eudesmane sesquiterpenoid (1) named ecdysantherol A and two new benzene derivatives ecdysantherols B (2) and C (3), together with five known benzene derivatives (4–8) were isolated from the stems of Ecdysanthera rosea. The structures of the new compounds were elucidated by extensive spectroscopic methods and X-ray diffraction. The known compounds were identified by the comparison of their spectroscopic data with reported literature data. Compound 1 showed moderate antibacterial activity against the Providensia smartii with MIC value of 12.5 μg/mL.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0041-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4250565  PMID: 25362577
Ecdysanthera rosea; Sesquiterpenoid; Phenolic glycoside; Absolute configuration
12.  Ten-Year Cumulative Incidence of Diabetic Retinopathy. The Beijing Eye Study 2001/2011 
PLoS ONE  2014;9(10):e111320.
To assess the cumulative 10-year incidence of diabetic retinopathy (DR) and its associated factors in a population living in Greater Beijing.
The population-based longitudinal Beijing Eye Study, which included 4439 subjects (age in 2001: 40+years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). The study participants underwent a detailed ophthalmic examination. Fundus photographs were examined for the new development of DR.
After excluding individuals with DR at baseline (n = 87) or no sufficient fundus photographs in 2011 (n = 6), the study included 2602 subjects with a mean age of 64.6±9.7 years (median: 64.0 years; range: 50 to 93 years). In the 10-year period, 109 subjects (39 men) developed new DR with an incidence of 4.2% (95% confidence interval (CI): 3.45,5.03). In multiple logistic regression analysis, incident DR was significantly associated with higher HbA1c value (P<0.001; Odds Ratio (OR): 1.73; 95% Confidence Interval (CI): 1.35,2.21), longer duration of diabetes mellitus (P<0.001; OR: 1.16; 95% CI: 1.10,1.22), higher serum concentration of creatinine (P = 0.02; OR: 1.01; 95% CI: 1.002,1.022), lower educational level (P = 0.049; OR: 0.74; 95% CI: 0.55,0.99), higher estimated cerebrospinal fluid pressure (P = 0.038; OR: 1.10; 95% CI: 1.01,1.22), and shorter axial length (P<0.001; OR: 0.48; 95% CI: 0.33,0.71).
The cumulative 10-year incidence (mean: 4.2%) of DR in a North Chinese population was significantly associated with a higher HbA1c value, longer known duration of diabetes mellitus, higher estimated CSFP and shorter axial length (P<0.001). Shorter axial length (or hyperopia) and, potentially, higher CSFP may be additional risk factors to be taken into account when counseling and treating patients with diabetes mellitus.
PMCID: PMC4210166  PMID: 25347072
13.  Cellular responses to Sindbis virus infection of neural progenitors derived from human embryonic stem cells 
BMC Research Notes  2014;7(1):757.
Sindbis virus (SINV) causes age-dependent encephalitis in mice, and therefore serves as a model to study viral encephalitis. SINV is used as a vector for the delivery of genes into selected neural stem cell lines; however, the toxicity and side effects of this vector have rarely been discussed. In this context, we investigated the cellular responses of human embryonic stem cell (hESCs) derived neural progenitors (hNPCs) to SINV infection by assessing susceptibility of the cells to SINV infection, analyzing the effect of infection on cell proliferation and cell death, and examining the impact of SINV infection on hNPCs markers of stemness.
We found that hNPCs are highly susceptible to SINV infection. Upon infection, the viruses induced apoptosis to hNPCs while not affecting the expression of cell proliferation markers. Lastly, SINV infections result in significant changes in the expression of key regulators of hNPCs’ plasticity and homeostasis.
The robust and versatile signaling, proliferation, and other cell responses of hESCs-derived hNPCs to virus infection demonstrated that it is a good model to study the pathogenesis of viral-induced neurodevelopmental and degenerative diseases. On the other hand, the toxicity of SINV to hNPCs cells cannot be ignored, and therefore extra care should be taken when using SINV as a vector to deliver genes into human stem cell lines.
PMCID: PMC4307679  PMID: 25343994
Stem cell infection; Human neural progenitors; Sindbis virus
14.  Mitochondrial Dysfunction in Obesity-Associated Nonalcoholic Fatty Liver Disease: The Protective Effects of Pomegranate with Its Active Component Punicalagin 
Antioxidants & Redox Signaling  2014;21(11):1557-1570.
Aims: Punicalagin (PU) is one of the major ellagitannins found in the pomegranate (Punica granatum), which is a popular fruit with several health benefits. So far, no studies have evaluated the effects of PU on nonalcoholic fatty liver disease (NAFLD). Our work aims at studying the effect of PU-enriched pomegranate extract (PE) on high fat diet (HFD)-induced NAFLD. Results: PE administration at a dosage of 150 mg/kg/day significantly inhibited HFD-induced hyperlipidemia and hepatic lipid deposition. As major contributors to NAFLD, increased expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukins 1, 4, and 6 as well as augmented oxidative stress in hepatocytes followed by nuclear factor (erythroid-derived-2)-like 2 (Nrf2) activation were normalized through PE supplementation. In addition, PE treatment reduced uncoupling protein 2 (UCP2) expression, restored ATP content, suppressed mitochondrial protein oxidation, and improved mitochondrial complex activity in the liver. In contrast, mitochondrial content was not affected despite increased peroxisomal proliferator-activated receptor–gamma coactivator-1α (PGC-1α) and elevated expression of genes related to mitochondrial beta-oxidation after PE treatment. Finally, PU was identified as the predominant active component of PE with regard to the lowering of triglyceride and cholesterol content in HepG2 cells, and both PU- and PE-protected cells from palmitate induced mitochondrial dysfunction and insulin resistance. Innovation: Our work presents the beneficial effects of PE on obesity-associated NAFLD and multiple risk factors. PU was proposed to be the major active component. Conclusions: By promoting mitochondrial function, eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of NAFLD. Antioxid. Redox Signal. 21, 1557–1570.
PMCID: PMC4175030  PMID: 24393106
15.  The Imprinted H19 LncRNA Antagonizes Let-7 MicroRNAs 
Molecular cell  2013;52(1):10.1016/j.molcel.2013.08.027.
Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in culture where H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs.
PMCID: PMC3843377  PMID: 24055342
16.  Targeting SHP2 for EGFR Inhibitor Resistant Non-Small Cell Lung Carcinoma 
Biochemical and biophysical research communications  2013;439(4):10.1016/j.bbrc.2013.09.028.
Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g., T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.
PMCID: PMC3822432  PMID: 24041688
SHP2; EGFR; lung cancer; drug resistance; phosphatase inhibitor
17.  Antimicrobial steroidal saponin and oleanane-type triterpenoid saponins from Paullinia pinnata 
Paullinia pinnata L. (Sapindaceae) is an African woody vine, which is widely used in traditional medicine for the treatment of human malaria, erectile dysfunction and bacterial infections. A phytochemical investigation of its methanol leaf and stem extracts led to the isolation of seven compounds which were evaluated for their antimicrobial properties.
The extracts were fractionated and compounds were isolated by chromatographic methods. Their structures were elucidated from their spectroscopic data in conjunction with those reported in literature. The antimicrobial activities of the crude extracts, fractions and compounds were evaluated against bacteria, yeasts and dermatophytes using the broth micro-dilution technique.
Seven compounds: 2-O-methyl-L-chiro-inositol (1), β-sitosterol (2), friedelin (3), 3β-(β-D-Glucopyranosyloxy) stigmast-5-ene (4), (3β)-3-O-(2′-Acetamido-2′-deoxy-β-D-glucopyranosyl) oleanolic acid (5), (3β,16α-hydroxy)-3-O-(2′-Acetamido-2′-deoxy-β-D-glucopyranosyl) echinocystic acid (6) and (3β)-3-O-[β-D-glucopyranosyl-(1″-3′)-2′-acetamido-2′-deoxy-β-D-galactopyranosyl]oleanolic acid (7) were isolated. Compounds 5 and 7 showed the best antibacterial and anti-yeast activities respectively (MIC value range of 0.78-6.25 and 1.56-6.25 μg/ml), while 6 exhibited the best anti-dermatophytic activity (MIC value range of 6.25-25 μg/ml).
The results of the present findings could be considered interesting, taking into account the global disease burden of these susceptible microorganisms, in conjunction with the search for alternative and complementary medicines.
PMCID: PMC4192449  PMID: 25277679
Paullinia pinnata; Sapindaceae; Steroidal saponin; Oleanane triterpenoid saponins; Antimicrobial activities
18.  Chemically defined serum-free and xeno-free media for multiple cell lineages 
Cell culture is one of the most common methods used to recapitulate a human disease environment in a laboratory setting. Cell culture techniques are used to grow and maintain cells of various types including those derived from primary tissues, such as stem cells and cancer tumors. However, a major confounding factor with cell culture is the use of serum and animal (xeno) products in the media. The addition of animal products introduces batch and lot variations that lead to experimental variability, confounds studies with therapeutic outcomes for cultured cells, and represents a major cost associated with cell culture. Here we report a commercially available serum-free, albumin-free, and xeno free (XF) media (Neuro-PureTM) that is more cost-effective than other commercial medias. Neuro-Pure was used to maintain and differentiate various cells of neuronal lineages, fibroblasts, as well as specific cancer cell lines; without the use of contaminants such serum, albumin, and animal products. Neuro-Pure allows for a controlled and reproducible cell culture environment that is applicable to translational medicine and general tissue culture.
PMCID: PMC4205861  PMID: 25405151
Serum-free; xeno free (XF); cell media; stem cells; drug-development
19.  Downregulation of stargazin inhibits the enhanced surface delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluR1 subunit in rat dorsal horn and ameliorates postoperative pain 
Anesthesiology  2014;121(3):609-619.
Stargazin is the first transmembrane protein known to regulate synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Yet, it is unclear whether regulation of the surface delivery of spinal AMPA receptor subunits by stargazin contributes to postoperative pain development.
Western blot analysis was used to examine changes in the surface delivery of AMPA receptor subunits GluR1 and GluR2 in rat dorsal horn. The interaction between stargazin and GluR1 and GluR2 was examined by coimmunoprecipitation. Expression of stargazin was suppressed by intrathecal administration of small interfering ribonucleic acid (siRNA)311.
Membrane-bound GluR1, but not GluR2, in ipsilateral dorsal horn was increased at 3 h (1.49±0.15-fold of β-tubulin, mean±SEM) and 1 day (1.03±0.25) after incision, as compared to that in control rats (naïve, 0.63±0.23, P < 0.05, n=6/group). The amount of GluR1 coimmunoprecipitated with stargazin was greater at 3 h after incision (1.48±0.31-fold of input) than in control animals (0.45±0.24, P < 0.05, n=6/group). Importantly, the increase in membrane GluR1 at 3 h after incision was normalized to near control level (0.72±0.20-fold of β-tubulin) by pretreatment with intrathecal stargazin siRNA311 (0.87±0.09), but not scrambled siRNA (1.48±0.24) or vehicle (1.25±0.13, P < 0.05, n=6/group). Stargazin siRNA311 pretreatment prevented the increase in stargazin–GluR1 interaction and decreased postoperative pain after incision.
This study suggests a critical role of stargazin-mediated surface delivery of GluR1 subunit in the development of postoperative pain. A better therapeutic strategy for postoperative pain may involve selectively downregulating spinal stargazin to inhibit synaptic targeting of GluR1 subunit.
PMCID: PMC4165695  PMID: 25093662
20.  Aurora kinase A suppresses metabolic stress-induced autophagic cell death by activating mTOR signaling in breast cancer cells 
Oncotarget  2014;5(17):7498-7511.
Aberrant Aur-A signaling is associated with tumor malignant behaviors. However, its involvement in tumor metabolic stress is not fully elucidated. In the present study, prolonged nutrient deprivation was conducted into breast cancer cells to mimic metabolic stress in tumors. In these cells, autophagy was induced, leading to caspase-independent cell death, which was blocked by either targeted knockdown of autophagic gene ATG5 or autophagy inhibitor 3-Methyladenine (3-MA). Aur-A overexpression mediated resistance to autophagic cell death and promoted breast cancer cells survival when exposed to metabolic stress. Moreover, we provided evidence that Aur-A suppressed autophagy in a kinase-dependent manner. Furthermore, we revealed that Aur-A overexpression enhanced the mammalian target of rapamycin (mTOR) activity under metabolic stress by inhibiting glycogen synthase kinase 3β (GSK3β). Inhibition of mTOR activity by rapamycin sensitized Aur-A-overexpressed breast cancer cells to metabolic stress-induced cell death. Consistently, we presented an inverse correlation between Aur-A expression (high) and autophagic levels (low) in clinical breast cancer samples. In conclusion, our data provided a novel insight into the cyto-protective role of Aur-A against metabolic stress by suppressing autophagic cell death, which might help to develop alternative cell death avenues for breast cancer therapy.
PMCID: PMC4202139  PMID: 25115395
aurora kinase; metabolic stress; autophagy; cell death; breast cancer
21.  Maternal Circulating Concentrations of Tumor Necrosis Factor-Alpha, Leptin, and Adiponectin in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis 
The Scientific World Journal  2014;2014:926932.
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Inflammation may play a role in the pathogenesis of GDM. We performed a systematic review and meta-analysis to determine whether maternal serum concentration of tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin were associated with GDM. A systematic search of PubMed and Medline was undertaken. In total, 27 trials were evaluated by meta-analyses using the software Review Manager 5.0. The results showed that maternal TNF-α (P = 0.0003) and leptin (P < 0.00001) concentrations were significantly higher in GDM patients versus controls. However, maternal adiponectin (P < 0.00001) concentration was significantly lower in GDM patients compared with controls. Subgroup analysis taking in consideration the effect of obesity on maternal adipokine levels showed that circulating levels of TNF-α and leptin remained elevated in GDM patients compared to their body mass index (BMI) matched controls, and adiponectin level remained depressed in GDM individuals. Our findings strengthen the clinical evidence that GDM is accompanied by exaggerated inflammatory responses.
PMCID: PMC4151523  PMID: 25202741
22.  Oncogenic mutations are associated with histological subtypes but do not have an independent prognostic value in lung adenocarcinoma 
OncoTargets and therapy  2014;7:1423-1437.
Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a rereview of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ, 20 minimally invasive adenocarcinomas, 901 invasive adenocarcinomas, 44 invasive mucinous adenocarcinomas, and three other variants. The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with fewer EGFR mutations. The ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while the KRAS mutations were more prevalent in smokers. In addition, 503 patients with stage I–IIIA tumors were analyzed for overall survival (OS) and relapse-free survival. The stage and histological pattern were independent predictors of relapse-free survival, and the pathological stage was the only independent predictor for the OS. Although patients with the EGFR mutations had better OS than those without the mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these two classifications might not increase the prognostic ability, but it provides essential information for personalized treatment.
PMCID: PMC4140237  PMID: 25152623
oncogenic mutation; IASLC/ATS/ERS classification; personalized treatment; molecular testing; prognosis
23.  MYC Expression in Concert with BCL2 and BCL6 Expression Predicts Outcome in Chinese Patients with Diffuse Large B-Cell Lymphoma, Not Otherwise Specified 
PLoS ONE  2014;9(8):e104068.
Recent studies provide convincing evidence that a combined immunohistochemical or fluorescence in situ hybridization (FISH) score of MYC, BCL2, BCL6 proteins and MYC translocations predicted outcome in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, by far, all these researches are based on Western populations. Therefore, we investigate the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression by immunohistochemistry and FISH from 336 de novo DLBCL, NOS treated with CHOP or R-CHOP. Breaks in MYC and BCL6, and fusion in IGH/BCL2 were detected in 9.7%, 20.0%, and 11.1% of the cases, respectively, and were not significantly associated with clinical outcomes. Protein overexpression of MYC (≥40%), BCL2 (≥70%) and BCL6 (≥50%) was encountered in 51%, 51% and 36% of the tumors, respectively. On the basis of MYC, BCL2 and BCL6 expression, double-hit scores (DHSs) and triple-hit score (THS) were assigned to all patients with DLBCL. Patients with high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS had multiple adverse prognostic factors including high LDH level, poor performance status, advanced clinical stage, high International Prognostic Index (IPI) score, and non-germinal center B-cell. In univariate analysis, high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS were associated with inferior OS and PFS in both CHOP and R-CHOP cohorts (P<0.05). The highly significant correlations with OS and PFS were maintained in multivariate models that controlled for IPI (P<0.05). DLBCLs with high DHSs and high THS share the clinical features and poor prognosis of double-hit lymphoma (P>0.05). These data together suggest that the immunohistochemical DHSs and THS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP or CHOP.
PMCID: PMC4121314  PMID: 25090026
24.  SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization 
Oncotarget  2014;5(16):6746-6755.
Sensitive to apoptosis gene (SAG), also known as RBX2, ROC2, or RNF7, is a RING component of SCF E3 ubiquitin ligases, which regulates cellular functions through ubiquitylation and degradation of many protein substrates. Although our previous studies showed that SAG is transcriptionally induced by redox, mitogen and hypoxia via AP-1 and HIF-1, it is completely unknown whether and how SAG is ubiquitylated and degraded. Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated degradation. Consistently, SAG protein half-life is shortened or extended by NEDD4-1 overexpression or silencing, respectively. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function.
PMCID: PMC4196160  PMID: 25216516
E3 ubiquitin ligase; NEDD4-1 E3 ligase; Protein ubiquitylation and degradation; SAG E3 ligase
25.  Crystal structure of bis­[1-(naphthalen-1-ylmeth­yl)pyridinium] bis­(2,2-di­cyano­ethene-1,1-di­thiol­ato-κ2 S,S′)nickelate(II) 
In the ion-pair complex, bis­[1-(naphthalen-1-ylmeth­yl)pyridinium] bis­(2,2-di­cyano­ethene-1,1-di­thiol­ate-κ2 S,S′)nickelate(II), C—H⋯N and C—H⋯Ni hydrogen bonds as well as π–π inter­actions between the ions result in the formation of a three-dimensional network.
A new ion-pair complex, (C16H14N)2[Ni(C4N2S2)2] or (1-NaMePy)2[Ni(imnt)2], where 1-NaMePy is 1-(4-naphthyl­methyl­ene)pyridinium and imnt is 2,2-di­cyano­ethene-1,1-di­thiol­ate, was obtained by the direct reaction of NiCl2, K2imnt and (1-NaMePy)+Br− in H2O. The asymmetric unit contains a [1-NaMePy]+ cation and one half of an Ni(imnt)2 2− anion. The NiII ion lies on an inversion centre and adopts a square-planar configuration with Ni—S bond lengths of 2.200 (1) and 2.216 (1) Å. In the [1-NaMePy]+ cation, the naphthyl ringsystem and the pyridinium ring make a dihedral angle of 90.0 (2)°. In the crystal, C—H⋯N and C—H⋯Ni hydrogen bonds, as well as π–π inter­actions between the chelate ring and the pyridinium ring [centroid–centroid distance = 3.675 (2) Å] link the ions into a three-dimensional network.
PMCID: PMC4158505  PMID: 25249870
bis­(2,2-bi­cyano­ethene-1,1-di­thiol­ato)nickel(II); pyridinium; hydrogen bonding; π–π inter­action; crystal structure.

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