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1.  Biological Properties of Acidic Cosmetic Water from Seawater 
This current work was to investigate the biological effects of acidic cosmetic water (ACW) on various biological assays. ACW was isolated from seawater and demonstrated several bio-functions at various concentration ranges. ACW showed a satisfactory effect against Staphylococcus aureus, which reduced 90% of bacterial growth after a 5-second exposure. We used cultured human peripheral blood mononuclear cells (PBMCs) to test the properties of ACW in inflammatory cytokine release, and it did not induce inflammatory cytokine release from un-stimulated, normal PBMCs. However, ACW was able to inhibit bacterial lipopolysaccharide (LPS)-induced inflammatory cytokine TNF-α released from PBMCs, showing an anti-inflammation potential. Furthermore, ACW did not stimulate the rat basophilic leukemia cell (RBL-2H3) related allergy response on de-granulation. Our data presented ACW with a strong anti-oxidative ability in a superoxide anion radical scavenging assay. In mass spectrometry information, magnesium and zinc ions demonstrated bio-functional detections for anti-inflammation as well as other metal ions such as potassium and calcium were observed. ACW also had minor tyrosinase and melanin decreasing activities in human epidermal melanocytes (HEMn-MP) without apparent cytotoxicity. In addition, the cell proliferation assay illustrated anti-growth and anti-migration effects of ACW on human skin melanoma cells (A375.S2) indicating that it exerted the anti-cancer potential against skin cancer. The results obtained from biological assays showed that ACW possessed multiple bioactivities, including anti-microorganism, anti-inflammation, allergy-free, antioxidant, anti-melanin and anticancer properties. To our knowledge, this was the first report presenting these bioactivities on ACW.
PMCID: PMC3382787  PMID: 22754342
acidic cosmetic water (ACW); antioxidant activity; anti-microorganism; anti-inflammation; allergy-free; skin-whitening; anti-melanoma
2.  Copy Number Variation in Bronchopulmonary Dysplasia 
PMCID: PMC4167221  PMID: 24975634
copy number variation; genome-wide association study (GWAS); chronic lung disease of infancy; bronchopulmonary dysplasia; genetic predisposition to disease; premature; very low birth weight infant
3.  Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome 
Genome Biology  2015;16:211.
DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited.
We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population. We find that postnatal DNA methylation increases at 3′ CpG islands (CGIs) correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation. To directly test whether 3′ CGI methylation regulates transcription, we conditionally disrupted two major DNA methyltransferases, Dnmt1 or Dnmt3a, in fetal and adult intestine. Deficiency of Dnmt1 causes severe intestinal abnormalities in neonates and disrupts crypt homeostasis in adults, whereas Dnmt3a loss was compatible with intestinal development. These studies reveal that 3′ CGI methylation is functionally involved in the regulation of transcriptional activation in vivo, and that Dnmt1 is a critical regulator of postnatal epigenetic changes in intestinal stem cells. Finally, we show that postnatal 3′ CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by germ-free conditions.
Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0763-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4589031  PMID: 26420038
4.  Rapid HIV antibody testing among men who have sex with men who visited a gay bathhouse in Hangzhou, China: a cross-sectional study 
BMJ Open  2015;5(9):e008661.
To understand the prevalence and correlates of rapid HIV antibody testing (RHT) among men who have sex with men (MSM) clients of gay bathhouses.
Cross-sectional questionnaire survey.
This study was conducted in a gay bathhouse in Hangzhou, China.
354 MSM were validly recruited from October to December 2012. Inclusion criteria were (1) men who visited the gay bathhouse, (2) men who had engaged in sex with men during the previous 6 months, (3) first-time participants in this survey and (4) men who were HIV-negative if already tested.
Sociodemographic measures included factors related to sexual behaviour and HIV risk perception, and the scales of HIV-related knowledge and behavioural intervention that each participant received.
Of the 354 participants, 222 (62.7%) were rapid tested during the previous 6 months; of them, 66.2% were tested at the Centers for Disease Prevention and Control (CDC), and 46.8% at gay venues. The following factors were independently associated with rapid testing within the previous 6 months: sexual initiation at 20–29 years of age, ever having undergone standard testing, ever having seen a sexually transmitted disease doctor, consistent use of condom during the past 6 months, familiarity with RHT and perception of possible HIV infection.
Publicity of RHT and risk education for HIV infection are necessary to promote RHT among MSM who visit gay bathhouses. The characteristics of sexual behaviours among those who do and do not undergo RHT should be taken into consideration while promoting the service in this group.
PMCID: PMC4563263  PMID: 26346876
5.  Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients 
Usher syndrome (USH) is the most common disease causing combined deafness and blindness. It is predominantly an autosomal recessive genetic disorder with occasionally digenic cases. Molecular diagnosis of USH patients is important for disease management. Few studies have tried to find the genetic cause of USH in Chinese patients. This study was designed to determine the mutation spectrum of Chinese USH patients.
We applied next generation sequencing to characterize the mutation spectrum in 67 independent Chinese families with at least one member diagnosed with USH. Blood was collected at Peking Union Medical College Hospital. This cohort is one of the largest USH cohorts reported. We utilized customized panel and whole exome sequencing, variant analysis, Sanger validation and segregation tests to find disease causing mutations in these families.
We identified biallelic disease causing mutations in known USH genes in 70 % (49) of our patients. As has been previously reported, MYO7A is the most frequently mutated gene in our USH type I patients while USH2A is the most mutated gene in our USH type II patients. In addition, we identify mutations in CLRN1, DFNB31, GPR98 and PCDH15 for the first time in Chinese USH patients. Together, mutations in CLRN1, DNFB31, GPR98 and PCDH15 account for 11.4 % of disease in our cohort. Interestingly, although the spectrum of disease genes is quite similar between our Chinese patient cohort and other patient cohorts from different (and primarily Caucasian) ethnic backgrounds, the mutations themselves are dramatically different. In particular, 76 % (52/68) of alleles found in this study have never been previously reported. Interestingly, we observed a strong enrichment for severe protein truncating mutations expected to have severe functional consequence on the protein in USH II patients compared to the reported mutation spectrum in RP patients, who often carry partial protein truncating mutations.
Our study provides the first comprehensive genetic characterization of a large collection of Chinese USH patients. Up to 90 % of USH patients have disease caused by mutations in known USH disease genes. By combining NGS-based molecular diagnosis and patient clinical information, a more accurate diagnosis, prognosis and personalized treatment of USH patients can be achieved.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0329-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4559966  PMID: 26338283
6.  Impaired Spatial Learning Memory after Isoflurane Anesthesia or Appendectomy in Aged Mice is Associated with Microglia Activation 
Journal of Cell Death  2015;8:9-19.
Postoperative cognitive dysfunction (POCD) has been one of the most common problems in elderly patients following surgery. But the specific mechanism of POCD is still not clear. To further understand the reason of these postoperative behavioral deficits, we evaluated the spatial learning memory of both adult (3 months) and aged (18 months) male mice, 3 or 28 days after isoflurane (Iso) exposure for two hours or appendectomy (App). Hippocampal microglia activation and IL-1β, TNF-α, and IFN-γ expression were also evaluated at day 3, day 14 and day 28 after Iso exposure or appendectomy. Results showed that spatial learning memory of aged, but not adult, mice was impaired after Iso exposure or appendectomy, accompanied with more hippocampal microglia activation and IL-1β, TNF-α, and IFN-γ overexpression. These findings suggest that the cognitive deficits of elderly patients who have undergone surgeries are quite possibly caused by hippocampal microglia overactivation and the subsequent inflammation.
PMCID: PMC4560456  PMID: 26380557
postoperative cognitive dysfunction; microglia; surgery; isoflurane
7.  Angiotensin-(1–7) induces cerebral ischaemic tolerance by promoting brain angiogenesis in a Mas/eNOS-dependent pathway 
British Journal of Pharmacology  2014;171(18):4222-4232.
Background and Purpose
As a newer component of the renin–angiotensin system, angiotensin-(1–7) [Ang-(1–7) ] has been shown to facilitate angiogenesis and protect against ischaemic damage in peripheral tissues. However, the role of Ang-(1–7) in brain angiogenesis remains unclear. The aim of this study was to investigate whether Ang-(1–7) could promote angiogenesis in brain, thus inducing tolerance against focal cerebral ischaemia.
Experimental Approach
Male Sprague-Dawley rats were i.c.v. infused with Ang-(1–7), A-779 (a Mas receptor antagonist), L-NIO, a specific endothelial NOS (eNOS) inhibitor, endostatin (an anti-angiogenic compound) or vehicle, alone or simultaneously, for 1–4 weeks. Capillary density, endothelial cell proliferation and key components of eNOS pathway in the brain were evaluated. Afterwards, rats were subjected to permanent middle cerebral artery occlusion (pMCAO), and regional cerebral blood flow (rCBF), infarct volume and neurological deficits were measured 24 h later.
Key Results
Infusion of Ang-(1–7) for 4 weeks significantly increased brain capillary density via promoting endothelial cell proliferation, which was accompanied by eNOS activation and up-regulation of NO and VEGF in brain. These effects were abolished by A-779 or L-NIO. More importantly, Ang-(1–7) improved rCBF and decreased infarct volume and neurological deficits after pMCAO, which could be reversed by A-779, L-NIO or endostatin.
Conclusions and Implications
This is the first evidence that Ang-(1–7) promotes brain angiogenesis via a Mas/eNOS-dependent pathway, which enhances tolerance against subsequent cerebral ischaemia. These findings highlight brain Ang-(1–7)/Mas signalling as a potential target in stroke prevention.
PMCID: PMC4241089  PMID: 24824997
8.  Vibrio cholerae Represses Polysaccharide Synthesis To Promote Motility in Mucosa 
Infection and Immunity  2015;83(3):1114-1121.
The viscoelastic mucus layer of gastrointestinal tracts is a host defense barrier that a successful enteric pathogen, such as Vibrio cholerae, must circumvent. V. cholerae, the causative agent of cholera, is able to penetrate the mucosa and colonize the epithelial surface of the small intestine. In this study, we found that mucin, the major component of mucus, promoted V. cholerae movement on semisolid medium and in liquid medium. A genome-wide screen revealed that Vibrio polysaccharide (VPS) production was inversely correlated with mucin-enhanced motility. Mucin adhesion assays indicated that VPS bound to mucin. Moreover, we found that vps expression was reduced upon exposure to mucin. In an infant mouse colonization model, mutants that overexpressed VPS colonized less effectively than wild-type strains in more distal intestinal regions. These results suggest that V. cholerae is able to sense mucosal signals and modulate vps expression accordingly so as to promote fast motion in mucus, thus allowing for rapid spread throughout the intestines.
PMCID: PMC4333447  PMID: 25561707
9.  Next-Generation Sequencing and Novel Variant Determination in a Cohort of 92 Familial Exudative Vitreoretinopathy Patients 
Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment.
Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants.
Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS.
We were able to determine probable disease-causing variants in a large number of FEVR patients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR.
We were able to determine probable disease-causing variants in 45 of 92 FEVR patients, the majority of which were novel. To our knowledge, this is the largest study of a FEVR cohort using NGS. Knowledge of these variants will help to further characterize and diagnose FEVR.
PMCID: PMC4365990  PMID: 25711638
next-generation sequencing; FEVR; novel alleles; familial segregation
10.  Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy 
Cancer Biology & Therapy  2014;15(9):1226-1238.
Recombinant Newcastle disease virus (rNDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. In this study, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of inserting both interleukin-2 (IL-2) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) delivered by rNDV. We demonstrated that rNDV expressing TRAIL (rNDV-TRAIL) or both human IL-2 and TRAIL (rNDV-IL-2-TRAIL) significantly enhanced inherent anti-neoplastic of rNDV by inducing apoptosis. And we showed that apoptosis-related genes mRNA expression was increased after treated with rNDV-TRAIL or rNDV-IL-2-TRAIL compared with rNDV and rNDV-IL-2. We also demonstrated that both rNDV-IL-2 and rNDV-IL-2-TRAIL induced proliferation of the CD4+ and CD8+ in treated mice and elicited expression of TNF-α and IFN-γ antitumor cytokines. These mice treated with oncolytic agents exhibited significant reduction in tumor development compared with mice treated with the parental virus. In addition, experiments in both hepatocellular carcinoma and melanoma-bearing mice demonstrated that the genetically engineered rNDV-IL-2-TRAIL exhibited prolonged animals’ survival compared with rNDV, rNDV-IL-2, and rNDV-TRAIL. In conclusion, the immunotherapy and oncolytic virotherapy properties of NDV can be enhanced by the introduction of IL-2 and TRAIL genes, whose products initiated a broad cascade of immunological affects and induced tumor cells apoptosis in the microenvironment of the immune system.
PMCID: PMC4128865  PMID: 24971746
rNDV; cancer therapy; IL-2; TRAIL; rNDV-IL-2-TRAIL; immunotherapy and oncolytic virotherapy; oncolytic agent
11.  The Effects of TiO2 Nanodot Films with RGD Immobilization on Light-Induced Cell Sheet Technology 
BioMed Research International  2015;2015:582359.
Cell sheet technology is a new strategy in tissue engineering which could be possible to implant into the body without a scaffold. In order to get an integrated cell sheet, a light-induced method via UV365 is used for cell sheet detachment from culture dishes. In this study, we investigated the possibility of cell detachment and growth efficiency on TiO2 nanodot films with RGD immobilization on light-induced cell sheet technology. Mouse calvaria-derived, preosteoblastic (MC3T3-E1) cells were cultured on TiO2 nanodot films with (TR) or without (TN) RGD immobilization. After cells were cultured with or without 5.5 mW/cm2 UV365 illumination, cell morphology, cell viability, osteogenesis related RNA and protein expression, and cell detachment ability were compared, respectively. Light-induced cell detachment was possible when cells were cultured on TR samples. Also, cells cultured on TR samples showed better cell viability, alongside higher protein and RNA expression than on TN samples. This study provides a new biomaterial for light-induced cell/cell sheet harvesting.
PMCID: PMC4568331  PMID: 26417596
12.  Mother root of Aconitum carmichaelii Debeaux exerts antinociceptive effect in Complet Freund’s Adjuvant-induced mice: roles of dynorpin/kappa-opioid system and transient receptor potential vanilloid type-1 ion channel 
Processed Chuanwu (PCW), the mother root of Aconitum carmichaeliiDebeauxv, has been widely used as a classic Traditional Chinese Medicine for pain relieve for over two millennia clinically. However, its action on chronic inflammatory pain has not been clarified. Here, we investigated the antinociceptive effect of PCW in complete freund’s adjuvant (CFA)-induced mice and its possible mechanisms associated with opioid system and TRPV1 ion channel.
Male ICR mice were intraplantarly injected with CFA. PCW (0.34, 0.68 and 1.35 g/kg) was orally given to mice once a day for 7 days. Von frey hairs and planter test were assessed to evaluate the antinociceptive effect of PCW. To investigate the participation of dynorphin/opioid system in PCW antinociception, subtype-specific opioid receptor antagonists or anti-dynorphin A antiserum were used. To eliminate other central mechanisms that contribute to PCW antinociception, hot plate (50 °C) test were performed. Further, involvements of TRPV1 in PCW antinociception were evaluated in CFA-induced TRPV1−/− and TRPV1+/+ C57BL/6 male mice, and in capsaicin-induced nociception ICR naive mice pretreated with nor-BNI. Meanwhile, calcium imaging was performed in HEK293T-TRPV1 cells. Finally, rotarod, open-field tests and body temperature measurement were carried out to assess side effects of PCW.
PCW dose-dependently attenuated mechanical and heat hypersensitivities with no tolerance, which could be partially attenuated by coadministration of k-opioid receptor antagonist nor-binaltorphimine (nor-BNI) or anti-dynorphin A (1–13) antiserum. And PCW antinociception was totally erased by pretreatment with nor-BNI in the hot plate test. In addition, PCW antinociception was decreased in TRPV1−/− mice compared to TRPV1+/+ group. And PCW still manifested inhibitory effects in capsaicin-induced nociception with nor-BNI pretreatment. PCW significantly inhibited capsaicin-induced calcium influx in HEK293T-TRPV1 cells. Finally, no detectable side effects were found in naive mice treated with PCW.
This study shows PCW’s potent antinociceptive effect in inflammatory conditions without obvious side effects. This effect may result from the activation of κ-opioid receptor via dynorpin release and the inhibition of TRPV1. These findings indicate that PCW might be a potential agent for the management of chronic inflammatory pain.
PMCID: PMC4553211  PMID: 26320055
Processed mother root of Aconitum carmichaelii; CFA-induced inflammatory pain; Dynorpin/kappa-opioid system; TRPV1
13.  High quality draft genomic sequence of Arenimonas donghaensis DSM 18148T 
Arenimonas donghaensis is the type species of genus Arenimonas which belongs to family Xanthomonadaceae within Gammaproteobacteria. In this study, a total of five type strains of Arenimonas were sequenced. The draft genomic information of A. donghaensis DSM 18148T is described and compared with other four genomes of Arenimonas. The genome size of A. donghaensis DSM 18148T is 2,977,056 bp distributed in 51 contigs, containing 2685 protein-coding genes and 49 RNA genes.
PMCID: PMC4572611  PMID: 26380644
Arenimonas; Arenimonas donghaensis; Comparative genomics; Genome sequence; Xanthomonadaceae
14.  Defining the Molecular Basis of Amyloid Inhibitors: Human Islet Amyloid Polypeptide–Insulin Interactions 
Journal of the American Chemical Society  2014;136(37):12912-12919.
Human islet amyloid polypeptide (hIAPP or Amylin) is a 37 residue hormone that is cosecreted with insulin from the pancreatic islets. The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts. Despite considerable effort, little is known about the mode of action of IAPP amyloid inhibitors, and this has limited rational drug design. Insulin is one of the most potent inhibitors of hIAPP fibril formation, but its inhibition mechanism is not understood. In this study, the aggregation of mixtures of hIAPP with insulin, as well as with the separate A and B chains of insulin, were characterized using ion mobility spectrometry-based mass spectrometry and atomic force microscopy. Insulin and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform, an aggregation-prone conformation, and thus inhibit hIAPP from forming β-sheets and subsequently amyloid fibrils. All-atom molecular modeling supports these conclusions.
PMCID: PMC4183647  PMID: 25144879
15.  Triage of high-risk human papillomavirus-positive women by methylated POU4F3 
Clinical Epigenetics  2015;7(1):85.
Insufficient specificity of the high-risk human papillomavirus (hrHPV) assay in primary cervical cancer screening results in unnecessary referral. Additional assays to triage hrHPV-positive women are needed to improve molecular cervical cancer screening. DNA methylation is a promising biomarker in cervical cancer. We evaluated the clinical performance of potentially methylated genes as a triage assay for hrHPV-positive women.
We conducted a retrospective hospital-based case–control study in Taiwan. Cervical scrapings were collected before colposcopy for hrHPV testing and quantitative methylation-specific PCR (QMSP) of 16 genes. Five genes, POU4F3, HS3ST2, AJAP1, PAX1, and SOX1, were prioritized for the clinical performance to triage hrHPV-positive women. Two hundred cervical scrapings were randomly classified into a training set (n = 111) and testing set (n = 89). All samples were tested for hrHPV using a Hybrid Capture II (HCII) assay. HrHPV-positive women were subjected to DNA methylation analysis by QMSP. In the training set, the receiver operating characteristic (ROC) curves defined the optimal methylation index (M-index) cutoff values for discriminating CIN3+ from CIN1/normal, which then were applied to the testing set. Among the five genes, POU4F3 revealed the highest area under the ROC curve (AUC) (0.86; 95 % CI, 0.78–0.95) in detecting CIN3+. In the testing set, POU4F3 revealed the best clinical performance in triage of hrHPV-positive women with a sensitivity of 74 % and specificity of 89 % for detecting CIN3+.
POU4F3 methylation analysis is a potential molecular tool for triage in detecting CIN3+ in hrHPV-positive women. The combined use of broad-spectrum HPV assay and POU4F3 methylation analysis as a new generation of molecular cervical cancer screening warrants further population-based study.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0122-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4546171  PMID: 26300990
DNA methylation; HrHPV test; QMSP; Biomarker; Cervical intraepithelial neoplasia (CIN); Cervical cancer screening
16.  Rationally Designed, Nontoxic, Nonamyloidogenic Analogues of Human Islet Amyloid Polypeptide with Improved Solubility 
Biochemistry  2014;53(37):5876-5884.
Human islet amyloid polypeptide (hIAPP or amylin) is a polypeptide hormone produced in the pancreatic β-cells that plays a role in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes and is a promising adjunct to insulin therapy. However, hIAPP rapidly forms amyloid, and its strong tendency to aggregate limits its usefulness. The process of hIAPP amyloid formation is toxic to cultured β-cells and islets, and islet amyloid formation in vivo has been linked to β-cell death and islet graft failure. An analogue of hIAPP with a weakened tendency to aggregate, denoted pramlintide (PM), has been approved for clinical applications, but suffers from poor solubility, particularly at physiological pH, and its unfavorable solubility profile prevents coformulation with insulin. We describe a strategy for rationally designing analogues of hIAPP with improved properties; key proline mutations are combined with substitutions that increase the net charge of the molecule. An H18R/G24P/I26P triple mutant and an H18R/A25P/S28P/S29P quadruple mutant are significantly more soluble at neutral pH than hIAPP or PM. They are nonamyloidogenic and are not toxic to rat INS β-cells. The approach is not limited to these examples; additional analogues can be designed using this strategy. To illustrate this point, we show that an S20R/G24P/I26P triple mutant and an H18R/I26P double mutant are nonamyloidogenic and significantly more soluble than human IAPP or PM. These analogues and second-generation derivatives are potential candidates for the coformulation of IAPP with insulin and other polypeptides.
PMCID: PMC4172205  PMID: 25140605
17.  A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy 
Science translational medicine  2014;6(218):218ra4.
The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA–mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.
PMCID: PMC4539009  PMID: 24401939
18.  Cross-vendor validation of liver magnetic resonance elastography 
Abdominal imaging  2015;40(4):789-794.
To evaluate and validate the reproducibility of MR Elastography (MRE) derived liver stiffness values on two different MR vendor platforms performed on the same subject on the same day.
This investigation was approved by the hospital IRB. MRE exams were performed twice in identical fashion in eight volunteers and in five clinical patients on two different 1.5T MR scanners – once on a Philips MR scanner and immediately afterward in back-to-back fashion on a General Electric MR scanner, or vice versa. All scan parameters were kept identical on the two platforms to the best extent possible. After the MRE magnitude and phase images were obtained, the data was converted into quantitative images displaying the stiffness of the liver parenchyma. Mean liver stiffness values between the two platforms were compared using interclass correlation with a p-value < 0.05 considered statistically significant.
Interclass correlation coefficient (ICC) value of 0.994 was obtained for 13 subjects with p-value <0.001 indicating a significantly positive correlation.
As MRE gains in acceptance and as its availability becomes more widespread, it is important to ascertain and confirm that liver stiffness values obtained on different MRE vendor platforms are consistent and reproducible. In this small pilot investigation, we demonstrate that liver stiffness measurement with MRE is reproducible and has very good consistency across two vendor platforms.
PMCID: PMC4523216  PMID: 25476489
MRE; Liver Elastography; MRE validation
19.  Evolution of Carbapenem-Resistant Acinetobacter baumannii Revealed through Whole-Genome Sequencing and Comparative Genomic Analysis 
Acinetobacter baumannii is a globally important nosocomial pathogen characterized by an evolving multidrug resistance. A total of 35 representative clinical A. baumannii strains isolated from 13 hospitals in nine cities in China from 1999 to 2011, including 32 carbapenem-resistant and 3 carbapenem-susceptible A. baumannii strains, were selected for whole-genome sequencing and comparative genomic analysis. Phylogenetic analysis revealed that the earliest strain, strain 1999BJAB11, and two strains isolated in Zhejiang Province in 2004 were the founder strains of carbapenem-resistant A. baumannii. Ten types of AbaR resistance islands were identified, and a previously unreported AbaR island, which comprised a two-component response regulator, resistance-related proteins, and RND efflux system proteins, was identified in two strains isolated in Zhejiang in 2004. Multiple transposons or insertion sequences (ISs) existed in each strain, and these gradually tended to diversify with evolution. Some of these IS elements or transposons were the first to be reported, and most of them were mainly found in strains from two provinces. Genome feature analysis illustrated diversified resistance genes, surface polysaccharides, and a restriction-modification system, even in strains that were phylogenetically and epidemiologically very closely related. IS-mediated deletions were identified in the type VI secretion system region, the csuE region, and core lipooligosaccharide (LOS) loci. Recombination occurred in the heme utilization region, and intrinsic resistance genes (blaADC and blaOXA-51-like variants) and three novel blaOXA-51-like variants (blaOXA-424, blaOXA-425, and blaOXA-426) were identified. Our results could improve the understanding of the evolutionary processes that contribute to the emergence of carbapenem-resistant A. baumannii strains and help elucidate the molecular evolutionary mechanism in A. baumannii.
PMCID: PMC4335871  PMID: 25487793
20.  Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland 
Human genetics  2014;134(2):217-230.
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.
PMCID: PMC4347882  PMID: 25472526
21.  A better experimental method to detect the sensitivity of cancer cells to anticancer drugs after adenovirus-mediated introduction of two kinds of p53 in vivo 
Anti-Cancer Drugs  2015;26(8):852-859.
p53 plays an important role in drug responses by regulating cell cycle progression and inducing programmed cell death. The C-terminal of p53 self-regulates the protein negatively; however, whether it affects the sensitivity of cancer cells to anticancer drugs is unclear. In this study, two experimental methods were used to compare the sensitivity to anticancer drugs of human lung 801D cancer cells transfected with adenovirus bearing either full-length p53 or the deleted-C-terminal p53 in vivo. Adenovirus-mediated deliveries of full-length or deleted-C-terminal p53 were performed after development of tumors (the first method) or by infection into cells before xenotransplantation (the second method). The results showed that infection with the deleted-C-terminal p53 increased 801D cell sensitivity to anticancer drugs in the second, but not in the first method, as indicated by greater tumor-inhibition rates. In addition, compared with the first method, the second method resulted in viruses with more uniformly infected cells and the infection rates between groups were similar. This yielded smaller within-group variations and greater uniformity among transplanted tumors. The second method could circumvent the difficulties associated with intratumoral injection.
PMCID: PMC4521903  PMID: 26164152
drug sensitivity; experimental method; in vivo; p53
22.  Synthesis and Structure–Activity Relationships of Pteridine Dione and Trione Monocarboxylate Transporter 1 Inhibitors 
Journal of Medicinal Chemistry  2014;57(17):7317-7324.
Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these compounds as inhibitors of lactate transport was confirmed using a 14C-lactate transport assay, and their potency against MCT1-expressing human tumor cells was established using MTT assays. The four most potent compounds showed substantial anticancer activity (EC50 37–150 nM) vs MCT1-expressing human Raji lymphoma cells.
PMCID: PMC4161152  PMID: 25068893
23.  Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer 
Scientific Reports  2015;5:12495.
Activation of hypoxia-inducible factor 1α (HIF1α) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1α at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1α level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1α expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1α protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1α were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1α could result in a sustained activation of HIF1α pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.
PMCID: PMC4513346  PMID: 26205124
24.  Comparative proteomics analysis provide novel insight into laminitis in Chinese Holstein cows 
BMC Veterinary Research  2015;11:161.
Laminitis is considered as the most important cause of hoof lameness in dairy cows, which causes abundant economic losses in husbandry. Through intense efforts in past decades, the etiology of laminitis is preliminarily considered to be subacute ruminal acidosis; however, the pathogenesis of laminitis needs further research. The differentially expressed proteins (DEP) were detected in plasma of healthy cows and clinical laminitis cows by two-dimensional gel electrophoresis (2-DE) and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Nineteen protein spots were differentially expressed, and 16 kinds of proteins were identified after peptide mass fingerprint search and bioinformatics analysis. Of these, 12 proteins were differentially up-regulated and 4 down-regulated. Overall, these differential proteins were involved in carbohydrate metabolism, lipids metabolism, molecular transport, immune regulation, inflammatory response, oxidative stress and so on.
The DEPs were closely related to the occurrence and development of laminitis and the lipid metabolic disturbance may be a new pathway to cause laminitis in dairy cows. The results provide the theory foundation for further revealing the mechanism of laminitis and screening the early diagnostic proteins and therapeutic target.
PMCID: PMC4511986  PMID: 26202328
Comparative proteomics; 2-DE; Laminitis; Plasma; Dairy cow
25.  Yindanxinnaotong, a Chinese compound medicine, synergistically attenuates atherosclerosis progress 
Scientific Reports  2015;5:12333.
Yindanxinnaotong (YD), a traditional Chinese medicine, has been introduced to clinical medicine for more than a decade, while its pharmacological properties are still not to be well addressed. This report aimed to explore the anti-atherosclerosis properties and underlying mechanisms of YD. We initially performed a computational prediction based on a network pharmacology simulation, which clued YD exerted synergistically anti-atherosclerosis properties by vascular endothelium protection, lipid-lowering, anti-inflammation, and anti-oxidation. These outcomes were then validated in atherosclerosis rats. The experiments provided evidences indicating YD’s contribution in this study included, (1) significantly reduced the severity of atherosclerosis, inhibited reconstruction of the artery wall and regulated the lipid profile; (2) enhanced antioxidant power, strengthened the activity of antioxidant enzymes, and decreased malondialdhyde levels; (3) significantly increased the viability of umbilical vein endothelial cells exposed to oxidative stress due to pretreatment with YD; (4) significantly reduced the level of pro-inflammatory cytokines; (5) significantly down-regulated NF-kB/p65 and up-regulated IkB in the YD-treated groups. Overall, these results demonstrated that YD intervention relieves atherosclerosis through regulating lipids, reducing lipid particle deposition in the endothelial layer of artery, enhancing antioxidant power, and repressing inflammation activity by inhibiting the nuclear factor-kappa B signal pathway.
PMCID: PMC4508829  PMID: 26196108

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