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1.  Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis 
AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats.
METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10 μL/kg body weight, i.p), 3 times a week for 4 wk. The rats in the 3 treatment groups including a high-dose DMN group (10 mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4 mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type IV collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy.
RESULTS: Compared with the model control group, the serum levels of HA, LN, type IV collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P < 0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P < 0.05).
CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis.
doi:10.3748/wjg.14.3569
PMCID: PMC2716622  PMID: 18567088
Liver fibrosis; Qianggan-Rongxian Decoction; Prevention; Rat model; Dimethylnitrosamine
2.  Intercalated Disc Protein, mXinα, Suppresses p120-Catenin-Induced Branching Phenotype via Its Interactions with p120-Catenin and Cortactin 
The Xin repeat-containing proteins, Xinα (Xirp1) and Xinβ (Xirp2), localize to the intercalated discs (ICDs) of mammalian hearts. Mouse Xinα (mXinα) directly interacts with β-catenin and actin filaments, potentially coupling the N-cadherin/β-catenin complexes to the underlying actin cytoskeleton and modulating ICD integrity and function. Supporting this possibility, mXinα-null hearts develop ICD structural defects and cardiomyopathy with conduction defects. However, the underlying mechanisms leading to these defects remain unclear. Here, we showed that mXinα also interacted with p120-catenin and cortactin. Different from the β-catenin binding domain, there existed multiple p120-catenin binding sites on mXinα, while only the extreme N-terminus of mXinα containing a SH3-binding motif could interact with cortactin. In mouse heart, a significant fraction of cortactin was co-localized with N-cadherin to ICDs, whereas in mXinα-null heart, this fraction of cortactin was drastically reduced. Therefore, mXinα may modulate ICD integrity and function through its interactions with catenins and cortactin. Analyses of the in vivo consequence of p120-catenin and mXinα interaction revealed that force-expressed mXinα or its fragments significantly suppressed the p120-catenin-induced branching phenotypes. It is known that p120-catenin directly regulates Rho GTPases, leading to the branching phenotype. Thus, mXinα may sequester the p120-catenin from inhibiting RhoA activity and/or from activating Rac1 activity.
doi:10.1016/j.abb.2012.12.018
PMCID: PMC3640673  PMID: 23296090
3.  Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer 
Molecular Cancer  2014;13:156.
Background
Protein coding genes account for only about 2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs including long non-coding RNAs. A growing volume of literature has proposed that lncRNAs are important players in cancer. HOTAIR was previously shown to be an oncogene and negative prognostic factor in a variety of cancers. However, the factors that contribute to its upregulation and the interaction between HOTAIR and miRNAs are largely unknown.
Methods
A computational screen of HOTAIR promoter was conducted to search for transcription-factor-binding sites. HOTAIR promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the HOTAIR promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The association of c-Myc with the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay and Electrophoretic mobility shift assay. A search for miRNAs with complementary base paring with HOTAIR was performed utilizing online software program. Gain and loss of function approaches were employed to investigate the expression changes of HOTAIR or miRNA-130a. The expression levels of HOTAIR, c-Myc and miRNA-130a were examined in 65 matched pairs of gallbladder cancer tissues. The effects of HOTAIR and miRNA-130a on gallbladder cancer cell invasion and proliferation was tested using in vitro cell invasion and flow cytometric assays.
Results
We demonstrate that HOTAIR is a direct target of c-Myc through interaction with putative c-Myc target response element (RE) in the upstream region of HOTAIR in gallbladder cancer cells. A positive correlation between c-Myc and HOTAIR mRNA levels was observed in gallbladder cancer tissues. We predicted that HOTAIR harbors a miRNA-130a binding site. Our data showed that this binding site is vital for the regulation of miRNA-130a by HOTAIR. Moreover, a negative correlation between HOTAIR and miRNA-130a was observed in gallbladder cancer tissues. Finally, we demonstrate that the oncogenic activity of HOTAIR is in part through its negative regulation of miRNA-130a.
Conclusion
Together, these results suggest that HOTAIR is a c-Myc-activated driver of malignancy, which acts in part through repression of miRNA-130a.
doi:10.1186/1476-4598-13-156
PMCID: PMC4085645  PMID: 24953832
Long non-coding RNA; HOTAIR; miRNA-130a; c-Myc; Gallbladder cancer
4.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
5.  An Invertebrate Warburg Effect: A Shrimp Virus Achieves Successful Replication by Altering the Host Metabolome via the PI3K-Akt-mTOR Pathway 
PLoS Pathogens  2014;10(6):e1004196.
In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.
Author Summary
The Warburg effect (or aerobic glycolysis) is a metabolic shift that was first found in cancer cells, but has also recently been discovered in vertebrate cells infected by viruses. The Warburg effect facilitates the production of more energy and building blocks to meet the enormous biosynthetic requirements of cancerous and virus-infected cells. To date, all of our knowledge of the Warburg effect comes from vertebrate cell systems and our previous paper was the first to suggest that the Warburg effect may also occur in invertebrates. Here, we use a state-of-the-art systems biology approach to show the global metabolomic and proteomic changes that are triggered in shrimp hemocytes by a shrimp virus, white spot syndrome virus (WSSV). We characterize several critical metabolic properties of the invertebrate Warburg effect and show that they are similar to the vertebrate Warburg effect. WSSV triggers aerobic glycolysis via the PI3K-Akt-mTOR pathway, and during the WSSV genome replication stages, we show that the Warburg effect is essential for the virus, because even when the TCA cycle is boosted in mTOR-inactivated shrimp, this fails to provide enough energy and materials for successful viral replication. Our study provides new insights into the rerouting of the host metabolome that is triggered by an invertebrate virus.
doi:10.1371/journal.ppat.1004196
PMCID: PMC4055789  PMID: 24945378
6.  Tgif1 Regulates Quiescence and Self-Renewal of Hematopoietic Stem Cells 
Molecular and Cellular Biology  2013;33(24):4824-4833.
TG-interacting factor 1 (TGIF1) is a transcriptional repressor that can modulate retinoic acid and transforming growth factor β signaling pathways. It is required for myeloid progenitor cell differentiation and survival, and mutations in the TGIF1 gene cause holoprosencephaly. Furthermore, we have previously observed that acute myelogenous leukemia (AML) patients with low TGIF1 levels had worse prognoses. Here, we explored the role of Tgif1 in murine hematopoietic stem cell (HSC) function. CFU assays showed that Tgif1−/− bone marrow cells produced more total colonies and had higher serial CFU potential. These effects were also observed in vivo, where Tgif1−/− bone marrow cells had higher repopulation potential in short- and long-term competitive repopulation assays than wild-type cells. Serial transplantation and replating studies showed that Tgif1−/− HSCs exhibited greater self-renewal and were less proliferative and more quiescent than wild-type cells, suggesting that Tgif1 is required for stem cells to enter the cell cycle. Furthermore, HSCs from Tgif1+/− mice had a phenotype similar to that of HSCs from Tgif1−/− mice, while bone marrow cells with overexpressing Tgif1 showed increased proliferation and lower survival in long-term transplant studies. Taken together, our data suggest that Tgif1 suppresses stem cell self-renewal and provide clues as to how reduced expression of TGIF1 may contribute to poor long-term survival in patients with AML.
doi:10.1128/MCB.01076-13
PMCID: PMC3889555  PMID: 24100014
7.  Efficacy and safety of vildagliptin, Saxagliptin or Sitagliptin as add-on therapy in Chinese patients with type 2 diabetes inadequately controlled with dual combination of traditional oral hypoglycemic agents 
Background
The oral DPP-4 inhibitors are new incretin-based therapies for treatment of type 2 diabetes. To assess the efficacy and safety of three DPP-4 inhibitors (Saxagliptin, Sitagliptin and Vildagliptin) as add-on therapy to dual combination of traditional oral hypoglycemic agents in Chinese type 2 diabetes patients.
Methods
In this 24-week, randomized, open-label, parallel clinical trial, we enrolled inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7.5% to ≤10%) patients with type 2 diabetes, who were treated by dual combination of metformin and another traditional oral hypoglycemic agent (glimepiride, acarbose or pioglitazone). 207 patients had been randomized to add-on 5 mg saxagliptin group or 100 mg sitagliptin once daily group, or 50 mg vildagliptin twice daily group for 24 weeks. HbA1c, fasting and postprandial blood glucose (FBG and P2hBG), body weight, body mass index (BMI), episodes of hypoglycemia and adverse events were evaluated.
Result
After 24 weeks, HbA1c, FBG, and P2hBG of each group were significantly decreased. (saxagliptin vs vildagliptin vs sitagliptin: HbA1c: -1.2% vs -1.3% vs -1.1%; FBG: -1.8 mmol/l vs -2.4 mmol/l vs -1.5 mmol/l; P2hBG: -3.4 mmol/l vs -3.7 mmol/l vs -3.2 mmol/l). The changes of HbA1c and P2hBG among the three groups had no significance. However, vildagliptin-added group showed the greatest reduction (p < 0.001), while, sitagliptin-added group showed the lowest reduction (p < 0.001) in terms of FPG changes. Proportions of patients achieving HbA1c < 7% at the end were similar in three groups (saxagliptin 59%, vildagliptin 65%, sitagliptin 59%). Mild hypoglycemia was commonly reported among the three groups (saxagliptin 6%, vildagliptin 2%, sitagliptin 3%). No significant between-group difference was shown in other AEs.
Conclusion
The three gliptins showed almost similar glycemic control and incidence of adverse events. However, for FBG control, saxagliptin demonstrated superiority to sitagliptin, while, inferiority to vildagliptin.
doi:10.1186/1758-5996-6-69
PMCID: PMC4050987  PMID: 24917890
Type 2 diabetes mellitus; Glycemic control; DPP-4 inhibitors; OHAs
8.  Pharmacokinetics, clearance, and biosafety of polyethylene glycol-coated hollow gold nanospheres 
Objective
Gold nanoparticles have attracted enormous interest as potential theranostic agents. However, little is known about the long-term elimination and systemic toxicity of gold nanoparticles in the literature. Hollow gold nanospheres (HAuNS) is a class of photothermal conducting agent that have shown promises in photoacoustic imaging, photothermal ablation therapy, and drug delivery. It’s very necessary to make clear the biosafety of HAuNS for its further application.
Methods
We investigated the cytotoxicity, complement activation, and platelet aggregation of polyethylene glycol (PEG)-coated HAuNS (PEG-HAuNS, average diameter of 63 nm) in vitro and their pharmacokinetics, biodistribution, organ elimination, hematology, clinical chemistry, acute toxicity, and chronic toxicity in mice.
Results
PEG-HAuNS did not induce detectable activation of the complement system and did not induce detectable platelet aggregation. The blood half-life of PEG-HAuNS in mice was 8.19 ± 1.4 hr. The single effective dose of PEG-HAuNS in photothermal ablation therapy was determined to be 12.5 mg/kg. PEG-HAuNS caused no adverse effects after 10 daily intravenous injections over a 2-week period at a dose of 12.5 mg/kg per injection (accumulated dose: 125 mg/kg). Quantitative analysis of the muscle, liver, spleen, and kidney revealed that the levels of Au decreased 45.2%, 28.6%, 41.7%, and 40.8%, respectively, from day 14 to day 90 after the first intravenous injection, indicating that PEG-HAuNS was slowly cleared from these organs in mice.
Conclusion
Our data support the use of PEG-HAuNS as a promising photothermal conducting agent.
doi:10.1186/1743-8977-11-26
PMCID: PMC4082425  PMID: 24886070
Hollow gold nanospheres; Toxicity; Photothermal ablation therapy
9.  IRGM rs13361189 polymorphism may contribute to susceptibility to Crohn’s disease: A meta-analysis 
The aim of the present meta-analysis was to evaluate the correlation between a common polymorphism, rs13361189 C>T in the immunity-related GTPase M (IRGM) gene, and susceptibility to Crohn’s disease (CD). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were investigated from database inception through to October 1, 2013 without the application of any language restrictions. The meta-analysis was performed using STATA 12.0 software and the relative risk (RR) with a 95% confidence interval (CI) was calculated. Seven case-control studies were included with a total of 3,093 CD patients and 3,227 healthy control subjects. The results of the meta-analysis revealed that the IRGM rs13361189 polymorphism correlates with an increased risk of CD (T allele versus C allele: RR=1.25 with 95% CI, 1.04–1.50; P=0.016 and CT + TT versus CC: RR=1.21 with 95% CI, 1.03–1.42; P=0.018). A subgroup analysis conducted using a genotyping method indicated that the IRGM rs13361189 polymorphism was correlated with an increased risk of CD in the TaqMan® (T allele versus C allele: RR=1.32 with 95% CI, 1.01–1.73; P=0.042) and the polymerase chain reaction-restriction fragment length polymorphism subgroups (T allele versus C allele: RR=1.80 with 95% CI, 1.32–2.45; P<0.001 and CT + TT versus CC: RR=1.61 with 95% CI, 1.19–2.18; P=0.018). However, no correlation was observed in the direct sequencing subgroup (P>0.05). Further subgroup analysis by sample size demonstrated significant correlations between the IRGM rs13361189 polymorphism and an increased risk of CD in the large sample-size subgroup (T allele versus C allele: RR=1.46 with 95% CI, 1.26–1.68; P<0.001 and CT + TT versus CC: RR=1.40 with 95% CI, 1.21–1.62; P<0.001). However, no correlation was identified between the IRGM rs13361189 polymorphism and CD risk in the small sample-size subgroup (P>0.05). The present meta-analysis indicated that the IRGM rs13361189 polymorphism may contribute to susceptibility to CD. Thus, IRGM rs13361189 polymorphism may be a potential biomarker for the early diagnosis of CD.
doi:10.3892/etm.2014.1736
PMCID: PMC4079410
IRGM; Crohn’s disease; polymorphism; meta-analysis
10.  The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis 
Current opinion in pharmacology  2011;11(6):670-675.
The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote steroidogenesis, and PDE5 modulates this process. Finally, PDE mutations may lead to several human diseases characterized by abnormal steroid levels.
doi:10.1016/j.coph.2011.09.003
PMCID: PMC4034742  PMID: 21962440
11.  Draft Genome Sequence of Burkholderia sp. Strain MP-1, a Methyl Parathion (MP)-Degrading Bacterium from MP-Contaminated Soil 
Genome Announcements  2014;2(3):e00344-14.
Burkholderia sp. strain MP-1 was isolated from pesticide-contaminated soil. Herein, we report the draft genome sequence of strain MP-1, which contains 168 contigs of 8,611,053 bp, with a G+C content of 62.55% and 7,631 protein-coding genes.
doi:10.1128/genomeA.00344-14
PMCID: PMC4031332  PMID: 24855293
12.  Humanin Rescues Cultured Rat Cortical Neurons from NMDA-Induced Toxicity Not by NMDA Receptor 
The Scientific World Journal  2014;2014:341529.
Excitatory neurotoxicity has been implicated in many pathological situations and there is no effective treatment available. Humanin is a 24-aa peptide cloned from the brain of patients with Alzheimer's disease (AD). In the present study, excitatory toxicity was induced by N-methyl-D-aspartate (NMDA) in primarily cultured rat cortical neurons. MTT assessment, lactate dehydrogenase (LDH) release, and calcein staining were employed to evaluate the protective activity of humanin on NMDA induced toxicity. The results suggested that NMDA (100 μmol/L, 2.5 hr) triggered neuronal morphological changes, lactate dehydrogenase (LDH) release (166% of the control), reduction of cell viability (about 50% of the control), and the decrease of living cell density (about 50% of the control). When pretreated with humanin, the toxicity was suppressed. The living cells' density of humanin treated group was similar to that of control. The cell viability was attenuated dose-dependently (IC50 = 0.132 nmol/L). The LDH release was also neutralized in a dose-dependent manner. In addition, the intracellular Ca2+ overloading triggered by NMDA reverted quickly and humanin could not inhibit it. These findings indicate that humanin can rescue cortical neurons from NMDA-induced toxicity in rat but not through interfering with NMDA receptor directly.
doi:10.1155/2014/341529
PMCID: PMC4052483  PMID: 24959608
13.  CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model 
C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 play key roles in the initiation and development of acute transplant rejection. Previously, higher levels of RANTES expression and secretion were demonstrated in retransplantation or T-cell memory-transfer models. In the present study, the effect of the chemokines, CXCL9 and CXCL10, were investigated in a mouse retransplantation model. BALB/c mice were used as donors, while C57BL/6 mice were used as recipients. In the experimental groups, a heterotopic heart transplantation was performed six weeks following skin grafting. In the control groups, a heterotopic heart transplantation was performed without skin grafting. Untreated mice served as blank controls. The mean graft survival time of the heterotopic heart transplantations was 7.7 days in the experimental group (n=6), as compared with 3.25 days in the control group (n=6; P<0.001). On day three following cardiac transplantation, histological evaluation of the grafts revealed a higher International Society for Heart & Lung Transplantation grade in the experimental group as compared with the control group. In addition, gene expression and serum concentrations of CXCL9, CXCL10, interferon-γ, and interleukin-2 were markedly higher in the experimental group when compared with the control group. Differences between the levels of CXCL9 and CXCL10 in the pre- and post-transplant mice indicated that the chemokines may serve as possible biomarkers to predict acute rejection. The results of the present study demonstrated that CXCL9 and CXCL10 play a critical role in transplantation and retransplantation. High levels of these cytokines during the pre-transplant period may lead to extensive acute rejection. Thus, the observations enhance the understanding of the mechanism underlying the increased expression and secretion of CXCL9 and CXCL10 by alloreactive memory T cells.
doi:10.3892/etm.2014.1714
PMCID: PMC4061216  PMID: 24944628
C-X-C motif chemokine ligand 9; C-X-C motif chemokine ligand 10; retransplantation; memory T cells; heart transplantation
14.  Developmental Toxicity of Diclofenac and Elucidation of Gene Regulation in zebrafish (Danio rerio) 
Scientific Reports  2014;4:4841.
Environmental pollution by emerging contaminants, e.g. pharmaceuticals, has become a matter of widespread concern in recent years. We investigated the membrane transport of diclofenac and its toxic effects on gene expression and the development of zebrafish embryos. The association of diclofenac with the embryos conformed to the general partition model at low concentration, the partition coefficient being 0.0033 ml per embryo. At high concentration, the interaction fitted the Freundlich model. Most of the diclofenac remained in the extracellular aqueous solution with less than 5% interacting with the embryo, about half of which was adsorbed on the membranes while the rest entered the cytoplasm. Concentrations of diclofenac over 10.13 μM were lethal to all the embryos, while 3.78 μM diclofenac was teratogenic. The development abnormalities at 4 day post treatment (dpt) include shorter body length, smaller eye, pericardial and body edema, lack of liver, intestine and circulation, muscle degeneration, and abnormal pigmentation. The portion of the diclofenac transferred into the embryo altered the expression of certain genes, e.g. down-regulation of Wnt3a and Gata4 and up-regulation of Wnt8a. The alteration of expression of such genes or the regulation of downstream genes could cause defects in the cardiovascular and nervous systems.
doi:10.1038/srep04841
PMCID: PMC4007093  PMID: 24788080
15.  Annexin A5-Functionalized Nanoparticle for Multimodal Imaging of Cell Death 
Molecular imaging  2013;12(3):182-190.
Techniques for visualizing cell death can provide noninvasive assessment of both disease states and response to therapeutic intervention. The purpose of this study was to develop and evaluate a multimodal imaging nanoplatform for the detection of cell death.
Method
In this study, we evaluated 111In-labeled Annexin A5-conjugated core-crosslinked polymeric micelles (CCPM) for multimodal imaging of cell death in various disease models. Three different models were conducted, including tumor apoptosis, hepatic apoptosis and inflammation. Both micro-single photon emission tomography/computed tomography (µSPECT/CT) and fluorescence molecular tomography (FMT) were performed. Biodistribution and immunohistochemistry assays were carried out to validate selectivity of cell death imaging.
Result
In all disease models, cell death was clearly visualized by both µSPECT/CT and FMT. In contrast, there was relatively low signal in the corresponding tissues of control mice. Moreover, the radioactive signal from 111In-labeled annexin A5-CCPM colocalized with its fluorescence signal, and both signals were confined to regions of dying cells.
Conclusion
111In-labeled annexin A5-CCPM allows visualization of cell death by both nuclear and optical techniques at whole-body level as well as at microscopic level. It has the potential to aid diagnosis of disease states or tissue responses involving abnormal cell death.
PMCID: PMC3893065  PMID: 23490444
Cell Death; Annexin A5; Polymeric Micelles; Nuclear Imaging; Fluorescence Optical Imaging
16.  Cyclodepsipeptides and Other O-Containing Heterocyclic Metabolites from Beauveria felina EN-135, a Marine-Derived Entomopathogenic Fungus 
Marine Drugs  2014;12(5):2816-2826.
Bioassay-guided fractionation of a culture extract of Beauveria felina EN-135, an entomopathogenic fungus isolated from a marine bryozoan, led to the isolation of a new cyclodepsipeptide, iso-isariin D (1); two new O-containing heterocyclic compounds that we have named felinones A and B (2 and 3); and four known cyclodepsipeptides (4–7). The structures were elucidated via spectroscopic analysis, and the absolute configurations of 1 and 2 were determined using single-crystal X-ray diffraction and CD, respectively. All isolated compounds were evaluated for antimicrobial activity and brine-shrimp (Artemia salina) lethality.
doi:10.3390/md12052816
PMCID: PMC4052318  PMID: 24828289
marine fungus; bryozoan; Beauveria felina; secondary metabolites; bioactivity
17.  Mangiferin Facilitates Islet Regeneration and β-Cell Proliferation through Upregulation of Cell Cycle and β-Cell Regeneration Regulators 
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7–14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes.
doi:10.3390/ijms15059016
PMCID: PMC4057772  PMID: 24853132
islet regeneration; partial pancreatectomy; mangiferin; cell cycle; β-cell
18.  Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis 
Arthritis Research & Therapy  2014;16(2):R105.
Introduction
Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.
Methods
A three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.
Results
In the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (Phet = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.
Conclusion
The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.
doi:10.1186/ar4554
PMCID: PMC4075243  PMID: 24779919
19.  Do Changes in Electrical Skin Resistance of Acupuncture Points Reflect Menstrual Pain? A Comparative Study in Healthy Volunteers and Primary Dysmenorrhea Patients 
Electrical skin resistance (ESR) measurements were performed with a four-electrode impedance detector at 10 points bilaterally on the first day of and the third day after menstruation in 48 healthy volunteers and 46 primary dysmenorrhea (PD) patients, to assess whether ESR changes of acupuncture points can reflect menstrual pain or not. The results showed statistical reductions in ESR imbalance ratio between left and right side that were detected at SP8 (Diji) and GB39 (Xuanzhong) (P < 0.05), and a statistical increase was detected at SP6 (Sanyinjiao) (P = 0.05) on the first day of menstruation compared with those values on the third day after menstruation in dysmenorrhea group. No significant differences were detected at other points within and between two groups (P > 0.05). This study showed that the imbalance of ESR at uterine-relevant points in PD patients is not significantly different from those of healthy women on both the 1st day of and the 3rd day after menstruation. The ESR imbalance ratio of certain points can either be lower or higher during menstruation in PD patients. The ESR property of acupuncture points needs to be investigated in further clinical trials with appropriate points, diseases, larger sample sizes, and optimal device.
doi:10.1155/2014/836026
PMCID: PMC4020393  PMID: 24876879
20.  Cell-Permeable 99mTc(CO3)-Labeled Fluorogenic Caspase 3 Substrate for Dual-Modality Detection of Apoptosis 
doi:10.1002/chem.200900766
PMCID: PMC3998829  PMID: 19637160
Apoptosis; Caspase 3; Dual Modality; DEVD; Technetium99m; Gamma imaging; Optical Imaging
21.  Hacking on decoy-state quantum key distribution system with partial phase randomization 
Scientific Reports  2014;4:4759.
Quantum key distribution (QKD) provides means for unconditional secure key transmission between two distant parties. However, in practical implementations, it suffers from quantum hacking due to device imperfections. Here we propose a hybrid measurement attack, with only linear optics, homodyne detection, and single photon detection, to the widely used vacuum + weak decoy state QKD system when the phase of source is partially randomized. Our analysis shows that, in some parameter regimes, the proposed attack would result in an entanglement breaking channel but still be able to trick the legitimate users to believe they have transmitted secure keys. That is, the eavesdropper is able to steal all the key information without discovered by the users. Thus, our proposal reveals that partial phase randomization is not sufficient to guarantee the security of phase-encoding QKD systems with weak coherent states.
doi:10.1038/srep04759
PMCID: PMC3996487  PMID: 24755767
22.  A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk 
Background
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.
Methods
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.
Results
Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10−4) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10−22). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10−24).
Conclusions
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
doi:10.1093/jnci/djt018
PMCID: PMC3627644  PMID: 23411593
23.  Antilymphocyte Antibodies in Systemic Lupus Erythematosus: Association with Disease Activity and Lymphopenia 
Journal of Immunology Research  2014;2014:672126.
Purpose. We analyzed the prevalence, clinical correlation, and the functional significance of ALA in patients with systemic lupus erythematosus (SLE). Methods. ALA IgG was detected by indirect immunofluorescence in the serum of 130 SLE patients, 75 patients with various rheumatic diseases, and 45 healthy controls (HC). Results. The sensitivity and specificity of ALA IgG in SLE were 42.3% and 96.7%, respectively. ALA was observed in 55.6% (50/90) of patients with lymphopenia, which was significantly higher than in patients with normal lymphocytes (5/40, 12.5%; P < 0.001). Patients with active SLE showed higher ALA positivity (60.9%) than those with inactive disease (24.2%; χ2 = 17.925; P < 0.001). ALA correlated significantly with hypocomplementemia, anti-dsDNA antibodies, and higher SLEDAI scores. The incidences of ALA in SLE patients who were seronegative for anti-dsDNA, anti-Sm, or both antibodies were 32.9% (26/79), 41.0% (43/105), and 32.4% (22/68), respectively. The ALA-positive group also had higher incidences of neuropsychiatric SLE (NPSLE) and lupus nephritis (LN). In multivariate analyses, ALA was independently associated with lymphopenia, higher SLEDAI scores, and increased risk for LN. ALA titers significantly decreased as clinical disease was ameliorated following treatment. Conclusions. ALA occurred more frequently in patients with active SLE and was independently associated with lymphopenia, disease activity, and LN.
doi:10.1155/2014/672126
PMCID: PMC4016860  PMID: 24860837
24.  Risk stratification and prognostic performance of the predisposition, infection, response, and organ dysfunction (PIRO) scoring system in septic patients in the emergency department: a cohort study 
Critical Care  2014;18(2):R74.
Introduction
The predisposition, infection, response and organ dysfunction (PIRO) staging system was designed as a stratification tool to deal with the inherent heterogeneity of septic patients. The present study was conducted to assess the performance of PIRO in predicting multiple organ dysfunction (MOD), intensive care unit (ICU) admission, and 28-day mortality in septic patients in the emergency department (ED), and to compare this scoring system with the Mortality in Emergency Department Sepsis (MEDS) and Acute Physiology and Chronic Health Evaluation (APACHE II) scores.
Methods
Consecutive septic patients (n = 680) admitted to the ED of Beijing Chao-Yang Hospital were enrolled. PIRO, MEDS, and APACHE II scores were calculated for each patient on ED arrival. Organ function was reassessed within 3 days of enrollment. All patients were followed up for 28 days. Outcome criteria were the development of MOD within 3 days, ICU admission or death within 28 days after enrollment. The predictive ability of the four components of PIRO was analyzed separately. Receiver operating characteristic (ROC) curve and logistic regression analysis were used to assess the prognostic and risk stratification value of the scoring systems.
Results
Organ dysfunction independently predicted ICU admission, MOD, and 28-day mortality, with areas under the ROC curve (AUC) of 0.888, 0.851, and 0.816, respectively. The predictive value of predisposition, infection, and response was weaker than that of organ dysfunction. A negative correlation was found between the response component and MOD, as well as mortality. PIRO, MEDS, and APACHE II scores significantly differed between patients who did and did not meet the outcome criteria (P < 0.001). PIRO and APACHE II independently predicted ICU admission and MOD, but MEDS did not. All three systems were independent predictors of 28-day mortality with similar AUC values. The AUC of PIRO was 0.889 for ICU admission, 0.817 for MOD, and 0.744 for 28-day mortality. The AUCs of PIRO were significantly greater than those of APACHE II and MEDS (P < 0.05) in predicting ICU admission and MOD.
Conclusions
The study indicates that PIRO is helpful for risk stratification and prognostic determinations in septic patients in the ED.
doi:10.1186/cc13832
PMCID: PMC4056311  PMID: 24739219
25.  Relationship of renin-angiotensin-aldosterone system polymorphisms and phenotypes to mortality in Chinese coronary atherosclerosis patients 
Scientific Reports  2014;4:4600.
We performed a large, long-term cohort study to evaluate the association of renin-angiotensin-aldosterone system gene polymorphisms and baseline phenotypes to all-cause mortality among patients with angiographically confirmed coronary atherosclerosis. The study included 1075 subjects who underwent coronary angiography. Patients were genotyped for eight polymorphisms (rs4343, rs5186, rs5182, rs5049, rs5051, rs699, rs4762, and rs1799998), and their baseline plasma angiotensin II and aldosterone levels were measured. The interval between baseline and follow-up time-points ranged from 6.39 to 9.59 years. The results of multivariate regression analysis further indicated that high baseline angiotensin II levels (1.226 (1.024–1.468), p = 0.027) were independently associated with all-cause death. Therefore, we found that an increased baseline plasma angiotensin II level was associated with higher long-term all-cause mortality, even after correcting for established cardiovascular risk factors.
doi:10.1038/srep04600
PMCID: PMC3983573  PMID: 24722536

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