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1.  Somatostatin Improved B Cells Mature in Macaques during Intestinal Ischemia-Reperfusion 
PLoS ONE  2015;10(7):e0133692.
Aims
Intestinal ischemia-reperfusion has been taken as an important pathophysiological process for multiple organ dysfunctions in critical patients. Recent studies reported that dual expression programs of the B cells receptors and Toll-like receptors on B-lymphocytes permit these ubiquitous cells to integrate both adaptive and innate immune functions. Our previous studies found that somatostatin inhibited the intestinal inflammatory injury after ischemia-reperfusion in macaques. However, the changes of B cells and the effects of somatostatin on B cells after intestinal ischemia-reperfusion were unclear.
Methods
15 macaques were divided into control, intestinal ischemia-reperfusion and somatostatin pretreatment groups. Immunohistochemistry was performed to identify the distributions of adaptive and innate immunity markers in the iliac mucosa. Hmy2.cir B lymphoblastoid cell line was cultured in vitro study. Enzyme-linked immunosorbent assay was used to measure IgM, IL-6 and SIgA, and the expressions of B cells transcription factors, PAX-5 and BLIMP-1, were detected by Western blotting.
Results
B2 lymphocytes in normal Peyer’s patches were presented the phenotype of PAX-5+CD20+CD5-. Ischemia-reperfusion increased the numbers and sizes of Peyer’s patches but with PAX-5+CD20-CD5- B cells, an unmatured set of B cells. Somatostatin partly kept the phenotype of mature B cells during ischemia-reperfusion. The innate immunity of B cells was inhibited whereas the adaptive immunity was increased in the intestinal mucosa in the somatostatin group, compared to the ischemia-reperfusion group. In vitro, somatostatin significantly inhibited IL-6 and promoted IgM by increasing the expression of both PAX-5 and BLIMP-1 in the proinflammatory condition.
Conclusion
Intestinal ischemia-reperfusion resulted in the proliferation of unmatured B cells which were involved in the augmentation of innate immunity. Somatostatin, with a bi-directional regulation function on innate as well as adaptive immunity of B cells, greatly improved B cells mature in macaques during ischemia-reperfusion. Preventive supplements of somatostatin may greatly limit intestinal injury and bacterial translocation during ischemia-reperfusion.
doi:10.1371/journal.pone.0133692
PMCID: PMC4519283  PMID: 26222793
3.  MTDH-SND1 Interaction is Essential for the Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors 
Cancer cell  2014;26(1):92-105.
SUMMARY
The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis but its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells (MECs) under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. Finally, this functional significance of MTDH-SND1 interaction is supported by clinical analysis of human breast cancer samples.
doi:10.1016/j.ccr.2014.04.027
PMCID: PMC4101059  PMID: 24981741
4.  Assessments of Drought Impacts on Vegetation in China with the Optimal Time Scales of the Climatic Drought Index 
Drought is expected to increase in frequency and severity due to global warming, and its impacts on vegetation are typically extensively evaluated with climatic drought indices, such as multi-scalar Standardized Precipitation Evapotranspiration Index (SPEI). We analyzed the covariation between the SPEIs of various time scales and the anomalies of the normalized difference vegetation index (NDVI), from which the vegetation type-related optimal time scales were retrieved. The results indicated that the optimal time scales of needle-leaved forest, broadleaf forest and shrubland were between 10 and 12 months, which were considerably longer than the grassland, meadow and cultivated vegetation ones (2 to 4 months). When the optimal vegetation type-related time scales were used, the SPEI could better reflect the vegetation’s responses to water conditions, with the correlation coefficients between SPEIs and NDVI anomalies increased by 5.88% to 28.4%. We investigated the spatio-temporal characteristics of drought and quantified the different responses of vegetation growth to drought during the growing season (April–October). The results revealed that the frequency of drought has increased in the 21st century with the drying trend occurring in most of China. These results are useful for ecological assessments and adapting management steps to mitigate the impact of drought on vegetation. They are helpful to employ water resources more efficiently and reduce potential damage to human health caused by water shortages.
doi:10.3390/ijerph120707615
PMCID: PMC4515678  PMID: 26184243
drought; SPEI; optimal time scales; NDVI; ecological assessment; China
5.  Pullulanase and Starch Synthase III Are Associated with Formation of Vitreous Endosperm in Quality Protein Maize 
PLoS ONE  2015;10(6):e0130856.
The opaque-2 (o2) mutation of maize increases lysine content, but the low seed density and soft texture of this type of mutant are undesirable. Lines with modifiers of the soft kernel phenotype (mo2) called “Quality Protein Maize” (QPM) have high lysine and kernel phenotypes similar to normal maize. Prior research indicated that the formation of vitreous endosperm in QPM might involve changes in starch granule structure. In this study, we focused on analysis of two starch biosynthetic enzymes that may influence kernel vitreousness. Analysis of recombinant inbred lines derived from a cross of W64Ao2 and K0326Y revealed that pullulanase activity had significant positive correlation with kernel vitreousness. We also found that decreased Starch Synthase III abundance may decrease the pullulanase activity and average glucan chain length given the same Zpu1 genotype. Therefore, Starch Synthase III could indirectly influence the kernel vitreousness by affecting pullulanase activity and coordinating with pullulanase to alter the glucan chain length distribution of amylopectin, resulting in different starch structural properties. The glucan chain length distribution had strong positive correlation with the polydispersity index of glucan chains, which was positively associated with the kernel vitreousness based on nonlinear regression analysis. Therefore, we propose that pullulanase and Starch Synthase III are two important factors responsible for the formation of the vitreous phenotype of QPM endosperms.
doi:10.1371/journal.pone.0130856
PMCID: PMC4482715  PMID: 26115014
6.  Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer 
Scientific Reports  2015;5:11566.
Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival-associated approach to capture a 12-gene network module based on differential co-expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer.
doi:10.1038/srep11566
PMCID: PMC4477367  PMID: 26099452
7.  Testicular metastasis from gastric carcinoma: A case report 
Gastric cancer (GC) is the most prevalent malignancy in the world, especially in China. GC has been postulated to spread via several different routes, including through hematogenous channels, lymphatic vessels, the seeding of peritoneal surfaces, direct extension through the gastric wall, and retrograde extension through the vas deferens or lymphatics. Testicular metastasis is rare. We show here a 53-year-old patient with GC who underwent a radical total gastrectomy approximately 22 mo ago after he presented with a sensation of heaviness and swelling of the right hemiscrotum. The diagnosis of metastatic adenocarcinoma was made after a right-side orchiectomy. We report the first case of testicular metastasis from gastric adenocarcinoma in mainland China and summarize the clinicopathologic features of the disease based on previously published papers.
doi:10.3748/wjg.v21.i21.6764
PMCID: PMC4458788  PMID: 26074716
Testicular cancer; Gastric carcinoma; Orchiectomy; Gastrectomy; Signet ring cell carcinoma
8.  Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations 
Scientific Reports  2015;5:10879.
Genome-wide association studies (GWASs) have revealed several genetic loci associated with HIV-1 outcome following infection (e.g., HLA-C at 6p21.33) in multi-ethnic populations with genetic heterogeneity and racial/ethnic differences among Caucasians, African-Americans, and Hispanics. To systematically investigate the inherited predisposition to modulate HIV-1 infection in Chinese populations, we performed GWASs in three ethnically diverse HIV-infected patients groups (i.e., HAN, YUN, and XIN, N = 538). The reported loci at 6p21.33 was validated in HAN (e.g., rs9264942, P = 0.0018). An independent association signal (rs2442719, P = 7.85 × 10−7, HAN group) in the same region was observed. Imputation results suggest that haplotype HLA-B*13:02/C*06:02, which can partially account for the GWAS signal, is associated with lower viral load in Han Chinese. Moreover, several novel loci were identified using GWAS approach including the top association signals at 6q13 (KCNQ5, rs947612, P = 2.15 × 10−6), 6p24.1 (PHACTR1, rs202072, P = 3.8 × 10−6), and 11q12.3 (SCGB1D4, rs11231017, P = 7.39 × 10−7) in HAN, YUN, and XIN groups, respectively. Our findings imply shared or specific mechanisms for host control of HIV-1 in ethnically diverse Chinese populations, which may shed new light on individualized HIV/AIDS therapy in China.
doi:10.1038/srep10879
PMCID: PMC4454153  PMID: 26039976
9.  Modeling Parkinson’s Disease in Monkeys for Translational Studies, a Critical Analysis 
Experimental neurology  2013;0:133-143.
The non-human primate MPTP model of Parkinson’s disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching “marked” motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson’s disease for translational studies.
doi:10.1016/j.expneurol.2013.09.014
PMCID: PMC3962841  PMID: 24070854
Parkinson’s disease; MPTP; non-human primate; model; dyskinesia
10.  HMMR Maintains the Stemness and Tumorigenicity of Glioblastoma Stem-like Cells 
Cancer research  2014;74(11):3168-3179.
Glioblastoma (GBM) stem cells (GSC) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance and tumor recurrence. Therapeutic targets in GSC are a focus of increasing interest to improve GBM therapy. Here we report that the hyaluronan-mediated motility receptor (HMMR) is highly expressed in GBM tumors where it supports the self-renewal and tumorigenic potential of GSC. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. Furthermore, HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. Conversely, HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is correlated positively with the expression of stemness-associated markers and regulators. Our findings identify HMMR as a candidate therapeutic target to GSC as a GBM treatment strategy.
doi:10.1158/0008-5472.CAN-13-2103
PMCID: PMC4059010  PMID: 24710409
Cancer stem cell; brain tumor; oncogene; self-renewal; RNA interference
11.  Hydrolysis of 2′3′-cGAMP by ENPP1 and design of non-hydrolyzable analogs 
Nature chemical biology  2014;10(12):1043-1048.
Agonists of mouse STING (TMEM173) shrink and even cure solid tumor by activating innate immunity; human STING agonists are needed to test this therapeutic hypothesis in man. The endogenous STING agonist is 2′3′-cGAMP, a 2nd messenger that signals the presence of cytosolic dsDNA. We report activity-guided partial purification and identification of ENPP1 as the dominant 2′3′-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1-/- mice. We synthesized a hydrolysis-resistant bis-phosphothioate analog of 2′3′-cGAMP (2′3′-cGsAsMP) with similar affinity for human STING in vitro and 10 times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1-/- lung fibroblasts indicate that resistance to hydrolysis contributes significantly to its higher potency. 2′3′-cGsAsMP is therefore improved over natural 2′3′-cGAMP as a model agonist, and has potential as a vaccine adjuvant and cancer therapeutic.
doi:10.1038/nchembio.1661
PMCID: PMC4232468  PMID: 25344812
12.  Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing 
Nature biotechnology  2014;32(12):1231-1240.
Active DNA demethylation in mammals involves TET-mediated iterative oxidation of 5-methylcytosine (5mC)/5-hydroxymethylcytosine (5hmC) and subsequent excision repair of highly oxidized cytosine bases 5-formylcytosine (5fC)/5-carboxylcytosine (5caC) by Thymine DNA glycosylase (TDG). However, quantitative and high-resolution analysis of active DNA demethylation activity remains challenging. Here we describe M.SssI methylase-assisted bisulfite sequencing (MAB-seq), a method that directly maps 5fC/5caC at single-base resolution. Genome-wide MAB-seq allows systematic identification of 5fC/5caC in Tdg-depleted embryonic stem cells, thereby generating a base-resolution map of active DNA demethylome. A comparison of 5fC/5caC and 5hmC distribution maps indicates that catalytic processivity of TET enzymes correlates with local chromatin accessibility. MAB-seq also reveals strong strand asymmetry of active demethylation within palindromic CpGs. Integrating MAB-seq with other base-resolution mapping methods enables quantitative measurement of cytosine modification states at key transitioning steps of active demethylation pathway, and reveals a regulatory role of 5fC/5caC excision repair in active DNA demethylation cascade.
doi:10.1038/nbt.3073
PMCID: PMC4269366  PMID: 25362244
13.  Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity 
Oncostatin M (OSM) exhibits many unique biological activities by activating Oβ receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor Oβ. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through inhibition of inositol pyrophosphate 7 (IP7) production, thus activating PI3K/Akt/BAD pathway, decreasing Bax expression while up-regulating Bcl-2 expression and decreasing the ratio of Bax to Bcl-2 in db/db mice. OSM enhanced mitochondrial biogenesis and mitochondrial function in db/db mice subjected to cardiac I/R injury. On the contrary, OSM receptor Oβ knockout exacerbated cardiac I/R injury, increased IP7 production, enhanced cardiomyocyte apoptosis, impaired mitochondrial biogenesis, glucose homoeostasis and insulin sensitivity in cardiac I/R injured diabetic mice. Inhibition of IP7 production by TNP (IP6K inhibitor) exerted similar effects of OSM. The mechanism of OSM on cardiac I/R injury in diabetic mice is partly associated with IP7/Akt and adenine mononucleotide protein kinase/PGC-1α pathway. OSM protects against cardiac I/R Injury by regulating apoptosis, insulin sensitivity and mitochondrial biogenesis in diabetic mice through inhibition of IP7 production.
doi:10.1111/jcmm.12501
PMCID: PMC4459845  PMID: 25752217
oncostatin M; ischaemia/Reperfusion injury; inositol pyrophosphate 7; diabetes
14.  Targeted Next-Generation Sequencing in Uyghur Families with Non-Syndromic Sensorineural Hearing Loss 
PLoS ONE  2015;10(5):e0127879.
The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound heterozygous mutations in TMC1, the homozygous p.V1880E mutation in MYO7A, c.1238delT frameshifting deletion in PCDH15 and c.9690+1G>A splice site mutation in MYO15A. Co-segregation of the mutations and the deafness were confirmed within each family by Sanger sequencing. No pathogenic mutations were identified in one multiplex family and one consanguineous family. Our study provided a useful piece of information for the genetic etiology of deafness in Uyghurs.
doi:10.1371/journal.pone.0127879
PMCID: PMC4444116  PMID: 26011067
15.  Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort 
AIDS (London, England)  2015;29(8):889-894.
Background:
The interferon-inducible transmembrane protein-3 (IFITM3) is a protein that restricts multiple pathogenic viruses such as influenza virus. The single-nucleotide polymorphism rs12252-C, which is rare in Caucasian populations, but much more common in the Han Chinese population, has been found in much higher homozygous frequency in patients with severe acute influenza. Until now, there has been no study on the effect of this genetic variant on the clinical control of other viral infections.
Objectives:
To investigate the impact of IFITM3-rs12252 genotypes on primary HIV-1 infection progression in an acute HIV-1-infected cohort in Beijing (PRIMO), China.
Design and methods:
We identified IFITM3-rs12252 genotypes of 178 acute HIV-1-infected patients and 196 HIV-negative candidates from the PRIMO cohort. HIV-1 viral load and CD4+ T-cell counts were monitored at multiple time points during the first year of infection, and the association between IFITM3-rs12252 genotype and disease progression was evaluated.
Results:
The current study shows that the IFITM3-rs12252 genetic variant affects the progression of HIV-1 infection, but not the acquisition. A significantly higher frequency of the CC/CT genotypes was found in rapid progressors compared to nonprogressors. Patients with CC/CT genotypes showed an elevated peak viremia level and significantly lower CD4+ T-cell count at multiple time points during the first year of primary infection, and a significantly higher risk of rapid decline of the CD4+ T-cell count to below 350 cells/μl.
Conclusion:
A novel association between IFITM3 gene polymorphism and rapid disease progression is reported in an acute HIV-1-infected MSM cohort in China.
doi:10.1097/QAD.0000000000000632
PMCID: PMC4442129  PMID: 25784441
acute infection; CD4+ T-cell count; HIV-1; interferon-inducible transmembrane protein 3; rs12252-C allele
16.  HIV-associated memory B cell perturbations 
Vaccine  2015;33(22):2524-2529.
Memory B-cell depletion, hyperimmunoglobulinemia, and impaired vaccine responses are the hallmark of B cell perturbations inhuman immunodeficiency virus (HIV) disease. Although B cells are not the targets for HIV infection, there is evidence for B cell, especially memory B cell dysfunction in HIV disease mediated by other cells or HIV itself. This review will focus on HIV-associated phenotypic and functional alterations in memory B cells. Additionally, we will discuss the mechanism underlying these perturbations and the effect of anti-retroviral therapy (ART) on these perturbations.
doi:10.1016/j.vaccine.2015.04.008
PMCID: PMC4420662  PMID: 25887082
Memory B cells; HIV; anti-retroviral therapy; vaccination
17.  A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration 
This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of −26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.
doi:10.2147/IJN.S77912
PMCID: PMC4437605  PMID: 25999718
stealth nanoparticles; dexamethasone; single-dose administration; cisplatin-induced hearing loss
18.  High-fat diet induced insulin resistance in pregnant rats through pancreatic pax6 signaling pathway 
Objective: To explore the changes in pancreas islet function of pregnant rats after consumption of high-fat diet and the underlying mechanism. Methods: Thirty pregnant Wistar rats were randomly divided into two groups: high-fat diet group and normal control group. Twenty days after gestation, fasting blood glucose concentration (FBG) and fasting serum insulin concentration (FINS) were measured. Then, oral glucose tolerance test (OGTT) and insulin release test (IRT) were performed. Finally, all the rats were sacrificed and pancreas were harvested. Insulin sensitivity index (ISI) and insulin resistance index (HOMA-IR) were calculated according to FBG and FINS. RT-PCR and Real-time PCR were performed to study the expression of paired box 6 transcription factor (Pax6) and its target genes in pancreatic tissues. Results: The body weight was significantly increased in the high-fat diet group compared with that of normal control rats (P<0.05). The fasting plasma glucose of rats in high-fat diet group was significantly increased compared with that of normal control rats (6.62 mmol/L vs. 4.96 mmol/L, P<0.05), however there was no significant difference in fasting serum insulin concentration between the two groups. OGTT and IRT were abnormal in the high-fat diet group. The high-fat diet rats were more prone to impaired glucose tolerance and insulin resistance. The level of the expression of Pax6 transcription factor and its target genes in pancreas, such as pancreatic and duodenal homeobox factor-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and glucose transporter 2 (Glut2) were decreased significantly compared with those of normal control group. Conclusion: High-fat diet feeding during pregnancy may induce insulin resistance in maternal rats by inhibiting pancreatic Pax6 and its target genes expression.
PMCID: PMC4503089  PMID: 26191217
Nutrition; gestation; rats; insulin resistance; pax6; oral glucose tolerance test; insulin sensitivity index; insulin resistance index
19.  Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer 
Cancer Biology & Therapy  2014;15(5):570-577.
Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.
doi:10.4161/cbt.28162
PMCID: PMC4026079  PMID: 24556908
crizotinib; ALK; autophagy; drug resistance; lung cancer
20.  TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway 
Scientific Reports  2015;5:9853.
Previous study revealed that the protective effect of TIGAR in cell survival is mediated through the increase in PPP (pentose phosphate pathway) flux. However, it remains unexplored if TIGAR plays an important role in DNA damage and repair. This study investigated the role of TIGAR in DNA damage response (DDR) induced by genotoxic drugs and hypoxia in tumor cells. Results showed that TIGAR was increased and relocated to the nucleus after epirubicin or hypoxia treatment in cancer cells. Knockdown of TIGAR exacerbated DNA damage and the effects were partly reversed by the supplementation of PPP products NADPH, ribose, or the ROS scavenger NAC. Further studies with pharmacological and genetic approaches revealed that TIGAR regulated the phosphorylation of ATM, a key protein in DDR, through Cdk5. The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR defines a new role of TIGAR in cancer cell survival and it suggests that TIGAR may be a therapeutic target for cancers.
doi:10.1038/srep09853
PMCID: PMC4415581  PMID: 25928429
21.  The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination 
Human Vaccines & Immunotherapeutics  2014;10(7):1985-1992.
The importance of follicular T helper (TFH) cells and the germinal center (GC) reaction in the humoral immune response has become clear in recent years, however the role of TFH cells and the GC in an HIV vaccine strategy remains unclear. In this study, we primed mice with gp120-encoding DNA and boosted with gp120 protein, a regimen previously shown to induce high titers of high affinity and cross-reactive anti-gp120 Abs. Priming with gp120 DNA caused increased TFH cell differentiation, GC B cells, and antigen-specific antibody titers, compared with priming with gp120 protein. Priming with DNA also caused more activated CD4+ T cells to become TFH cells and more GC B cells to become memory cells. Deletion of BCL6 midway through the vaccine regimen resulted in loss of TFH cells and GCs, and, unexpectedly, increased anti-gp120 IgG titers and avidity. Our data suggests vaccination with gp120-encoding DNA elicits a stronger and more rapid TFH and GC response than gp120 protein. Furthermore, we demonstrate that the GC reaction may actually limit antigen-specific IgG secretion in the context of repeated immunizations.
doi:10.4161/hv.28659
PMCID: PMC4186047  PMID: 25424808
BCL6; HIV vaccine; follicular helper T cells; germinal center; prime-boost
22.  Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress 
Archives of Medical Science : AMS  2015;11(2):427-432.
Introduction
Acute lung injury (ALI) is an acute inflammatory disease characterized by excess production of inflammatory factors in lung tissue. Quercetin, a herbal flavonoid, exhibits anti-inflammatory and anti-oxidative properties. This study was performed to assess the effects of quercetin on lipopolysaccharide (LPS)-induced ALI.
Material and methods
Sprague-Dawley rats were randomly divided into 3 groups: the control group (saline alone), the LPS group challenged with LPS (Escherichia coli 026:B6; 100 µg/kg), and the quercetin group pretreated with quercetin (50 mg/kg, by gavage) 1 h before LPS challenge. Bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected 6 h after LPS administration. Histopathological and biochemical parameters were measured.
Results
The LPS treatment led to increased alveolar wall thickening and cellular infiltration in the lung, which was markedly prevented by quercetin pretreatment. Moreover, quercetin significantly (p < 0.05) attenuated the increase in the BALF protein level and neutrophil count and lung wet/dry weight ratio and myeloperoxidase activity in LPS-challenged rats. The LPS exposure evoked a 4- to 5-fold rise in BALF levels of tumor necrosis factor-α and interleukin-6, which was significantly (p < 0.05) counteracted by quercetin pretreatment. Additionally, quercetin significantly (p < 0.05) suppressed the malondialdehyde level and increased the activities of superoxide dismutase, catalase, and glutathione peroxidase in the lung of LPS-treated rats.
Conclusions
Quercetin pretreatment effectively ameliorates LPS-induced ALI, largely through suppression of inflammation and oxidative stress, and may thus have therapeutic potential in the prevention of this disease.
doi:10.5114/aoms.2015.50975
PMCID: PMC4424260  PMID: 25995762
quercetin; acute lung injury; inflammation; oxidative stress
23.  Promiscuity Is Not Always Bad 
Molecular cell  2014;54(2):208-209.
In the recent issue of Cell, Bonham et al. reveal that the sorting adapter TIRAP regulates the assembly of the myddosome upon Toll-like receptor activation from both the cell surface and endosomes through its promiscuous binding to lipids.
doi:10.1016/j.molcel.2014.04.009
PMCID: PMC4053647  PMID: 24766883
24.  The Prognostic Significance of Pretreatment Serum CEA Levels in Gastric Cancer: A Meta-Analysis Including 14651 Patients 
PLoS ONE  2015;10(4):e0124151.
Background
Carcinoembryonic antigen (CEA) is commonly used as a serum tumor marker in clinical practice; however, its prognostic value for gastric cancer patients remains uncertain. This meta-analysis was performed to assess the prognostic value of CEA and investigate CEA as a tumor marker.
Methods
PubMed, EMBASE and other databases were searched for potentially eligible studies. Forty-one studies reporting the prognostic effect of pretreatment serum CEA expression in gastric cancer patients were selected. Data on 14651 eligible patients were retrieved for the meta-analysis. Based on the data extracted from the available literature, the hazard ratio (HR) and 95% confidence interval (CI) for an adverse prognosis were estimated for gastric cancer patients with elevated pretreatment serum levels of CEA (CEA+) relative to patients with normal pretreatment CEA levels (CEA-).
Results
The CEA+ patients had a significantly poorer prognosis than the CEA- patients in terms of overall survival (OS: HR 1.716, 95% CI 1.594 - 1.848, P< 0.001), disease-specific survival (DSS: HR 1.940, 95% CI 1.563 - 2.408, P< 0.001), and disease-free survival (DFS: HR 2.275, 95% CI 1.836 - 2.818, P< 0.001). Publication bias and an influence of different cut-off values were not observed (all P> 0.05). In the pooled analyses of multivariate-adjusted HRs, the results suggested that pretreatment serum CEA may be an independent prognostic factor in gastric cancer (OS: HR 1.681, 95% CI 1.425 - 1.982; DSS: HR 1.900, 95% CI 1.441 - 2.505; DFS: HR 2.579, 95% CI 1.935 - 3.436).
Conclusion/Significance
The meta-analysis based on the available literature supported the association of elevated pretreatment serum CEA levels with a poor prognosis for gastric cancer and a nearly doubled risk of mortality in gastric cancer patients. CEA may be an independent prognostic factor for gastric cancer patients and may aid in determining appropriate treatment which may preferentially benefit the CEA+ patients.
doi:10.1371/journal.pone.0124151
PMCID: PMC4400039  PMID: 25879931
25.  Temporal and Spatial Regulation of Epsin Abundance and VEGFR3 Signaling are Required for Lymphatic Valve Formation and Function 
Science signaling  2014;7(347):ra97.
Lymphatic valves prevent the backflow of the lymph fluid and ensure proper lymphatic drainage throughout the body. Local accumulation of lymphatic fluid in tissues, a condition called lymphedema, is common in individuals with malformed lymphatic valves. The vascular endothelial growth factor receptor 3 (VEGFR3) is required for the development of lymphatic vascular system. The abundance of VEGFR3 in collecting lymphatic trunks is high before valve formation and, except at valve regions, decreases after valve formation. We found that in mesenteric lymphatics, the abundance of epsin 1 and 2, which are ubiquitin-binding adaptor proteins involved in endocytosis, was low at early stages of development. After lymphatic valve formation, the initiation of steady shear flow was associated with an increase in the abundance of epsin 1 and 2 in collecting lymphatic trunks, but not in valve regions. Epsin 1 and 2 bound to VEGFR3 and mediated the internalization and degradation of VEGFR3, resulting in termination of VEGFR3 signaling. Mice with lymphatic endothelial cell-specific deficiency of epsin 1 and 2 had dilated lymphatic capillaries, abnormally high VEGFR3 abundance in collecting lymphatics, immature lymphatic valves, and defective lymph drainage. Deletion of a single Vegfr3 allele or pharmacological suppression of VEGFR3 signaling restored normal lymphatic valve development and lymph drainage in epsin-deficient mice. Our findings establish a critical role for epsins in the temporal and spatial regulation of VEGFR3 abundance and signaling in collecting lymphatic trunks during lymphatic valve formation.
doi:10.1126/scisignal.2005413
PMCID: PMC4226761  PMID: 25314967

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