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1.  Whole-transcriptome analyses of the Sapsaree, a Korean natural monument, before and after exercise-induced stress 
The Sapsaree (Canis familiaris) is a Korean native dog that is very friendly, protective, and loyal to its owner, and is registered as a natural monument in Korea (number: 368). To investigate large-scale gene expression profiles and identify the genes related to exercise-induced stress in the Sapsaree, we performed whole-transcriptome RNA sequencing and analyzed gene expression patterns before and after exercise performance.
We identified 525 differentially expressed genes in ten dogs before and after exercise. Gene Ontology classification and KEGG pathway analysis revealed that the genes were mainly involved in metabolic processes, such as programmed cell death, protein metabolic process, phosphatidylinositol signaling system, and cation binding in cytoplasm. The ten Sapsarees could be divided into two groups based on the gene expression patterns before and after exercise. The two groups were significantly different in terms of their basic body type (p ≤ 0.05). Seven representative genes with significantly different expression patterns before and after exercise between the two groups were chosen and characterized.
Body type had a significant effect on the patterns of differential gene expression induced by exercise. Whole-transcriptome sequencing is a useful method for investigating the biological characteristics of the Sapsaree and the large-scale genomic differences of canines in general.
Electronic supplementary material
The online version of this article (doi:10.1186/s40781-016-0097-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4832554  PMID: 27087983
NGS; Bioinformatics; RNA-Seq; Transcriptome; Exercise; Physical stress; Sapsaree
2.  Sex-specific Immune Modulation of Primary Hypertension 
Cellular immunology  2014;294(2):95-101.
It is well known that the onset of essential hypertension occurs earlier in men than women. Numerous studies have shown sex differences in the vasculature, kidney and sympathetic nervous system contribute to this sex difference in the development of hypertension. The immune system also contributes to the development of hypertension; however, sex differences in immune system modulation of blood pressure (BP) and the development of hypertension has only recently begun to be explored. Here we review findings on the effect of one's sex on the immune system and specifically how these effects impact BP and the development of primary hypertension. We also propose a hypothesis for why mechanisms underlying inflammation-induced hypertension are sex-specific. These studies underscore the value of and need for studying both sexes in the basic science exploration of the pathophysiology of hypertension as well as other diseases.
PMCID: PMC4380543  PMID: 25498375
Sex differences; inflammation; T-cells; hypertension; kidney; subfornical organ
3.  Dry Eye Disease in Patients with Functioning Filtering Blebs after Trabeculectomy 
PLoS ONE  2016;11(3):e0152696.
The aim of this study was to analyze dry eye disease (DED) in patients with functioning filtering blebs and to explore the relationship between the morphology of filtering blebs and ocular surface instability.
This was a cross-sectional, case-comparison study. Seventy glaucomatous patients (70 eyes) with functioning blebs who had undergone trabeculectomy more than 6 months prior (study group) and 35 control subjects (35 eyes) (control group) were included. All subjects completed an ocular symptom questionnaire that referred to the Shihpai Eye Study. Evaluation of meibomian gland obstruction, a tear film break-up time test (TFBUT), fluorescein corneal staining and a Schirmer’s tear test were then performed. Filtering bleb morphology was analyzed using Wuerzburg bleb classification scoring criteria in the study group. The presence of DED was defined as the concomitant presence of TFBUT <10 seconds and the presence of superficial punctate keratitis.
The patients with functioning blebs presented higher corneal staining scores (P = 0.012) and lower TFBUT values (P = 0.043) than the control group. DED was present in 28/70 patients in the study group and 6/35 patients in the control group (P = 0.018). More patients in the study group complained of dryness (P = 0.001), a gritty or sandy sensation (P < 0.001) and redness (P = 0.048). In the study group, the patients with DED were significantly different from the patients without DED in both TFBUT (P < 0.001) and corneal staining (P < 0.001). More patients in the DED group were likely to report dryness (P = 0.013) and watery or teary eyes (P = 0.012). The differences in meibomian gland obstruction scores between the study and the control group, the DED and the non-DED group were not significant (P = 0.105 and P = 0.077, respectively). The values for microcysts and bleb heights were significantly higher in the DED group (P = 0.040 and P = 0.011, respectively). A Spearman’s rank correlation showed that microcysts were positively correlated with corneal staining (r = 0.270, P = 0.024). Bleb height was negatively correlated with TFBUT (r = -0.299, P = 0.012) and positively correlated with corneal staining (r = 0.275, P = 0.021). The relationships between DED and microcysts and between DED and bleb height were significant (r = 0.247, P = 0.039 and r = 0.307, P = 0.010, respectively).
DED is relatively common in patients with functioning filtering blebs following trabeculectomy. In DED patients, dryness and watery are common symptoms. Microcysts and bleb height are related to ocular surface instability and DED.
PMCID: PMC4816306  PMID: 27032098
4.  PtrA/NINV, an alkaline/neutral invertase gene of Poncirus trifoliata, confers enhanced tolerance to multiple abiotic stresses by modulating ROS levels and maintaining photosynthetic efficiency 
BMC Plant Biology  2016;16:76.
Alkaline/neutral invertase (A/N-INV), an enzyme that hydrolyzes sucrose irreversibly into glucose and fructose, is essential for normal plant growth,development, and stress tolerance. However, the physiological and/or molecular mechanism underpinning the role of A/N-INV in abiotic stress tolerance is poorly understood.
In this report, an A/N-INV gene (PtrA/NINV) was isolated from Poncirus trifoliata, a cold-hardy relative of citrus, and functionally characterized. PtrA/NINV expression levels were induced by cold, salt, dehydration, sucrose, and ABA, but decreased by glucose. PtrA/NINV was found to localize in both chloroplasts and mitochondria. Overexpression of PtrA/NINV conferred enhanced tolerance to multiple stresses, including cold, high salinity, and drought, as supported by lower levels of reactive oxygen species (ROS), reduced oxidative damages, decreased water loss rate, and increased photosynthesis efficiency, relative to wild-type (WT). The transgenic plants exhibited higher A/N-INV activity and greater reducing sugar content under normal and stress conditions.
PtrA/NINV is an important gene implicated in sucrose decomposition, and plays a positive role in abiotic stress tolerance by promoting osmotic adjustment, ROS detoxification and photosynthesis efficiency. Thus, PtrA/NINV has great potential to be used in transgenic breeding for improvement of stress tolerance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-016-0761-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4812658  PMID: 27025596
Poncirus trifoliata; Abiotic stress; Alkaline/neutral invertase; Photosynthetic efficiency; Sucrose metabolism; ROS homeostasis
5.  Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats 
Scientific Reports  2016;6:22374.
The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction.
PMCID: PMC4780085  PMID: 26947764
6.  Amygdala NRG1–ErbB4 Is Critical for the Modulation of Anxiety-Like Behaviors 
Neuropsychopharmacology  2014;40(4):974-986.
Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1–ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1–ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia.
PMCID: PMC4330511  PMID: 25308353
7.  A novel M2e-multiple antigenic peptide providing heterologous protection in mice 
Journal of Veterinary Science  2016;17(1):71-78.
Swine influenza viruses (SwIVs) cause considerable morbidity and mortality in domestic pigs, resulting in a significant economic burden. Moreover, pigs have been considered to be a possible mixing vessel in which novel strains loom. Here, we developed and evaluated a novel M2e-multiple antigenic peptide (M2e-MAP) as a supplemental antigen for inactivated H3N2 vaccine to provide cross-protection against two main subtypes of SwIVs, H1N1 and H3N2. The novel tetra-branched MAP was constructed by fusing four copies of M2e to one copy of foreign T helper cell epitopes. A high-yield reassortant H3N2 virus was generated by plasmid based reverse genetics. The efficacy of the novel H3N2 inactivated vaccines with or without M2e-MAP supplementation was evaluated in a mouse model. M2e-MAP conjugated vaccine induced strong antibody responses in mice. Complete protection against the heterologous swine H1N1 virus was observed in mice vaccinated with M2e-MAP combined vaccine. Moreover, this novel peptide confers protection against lethal challenge of A/Puerto Rico/8/34 (H1N1). Taken together, our results suggest the combined immunization of reassortant inactivated H3N2 vaccine and the novel M2e-MAP provided cross-protection against swine and human viruses and may serve as a promising approach for influenza vaccine development.
PMCID: PMC4808646  PMID: 27051342
H3N2; M2e-multiple antigenic peptide; high-yield; inactivated vaccine; swine influenza virus
8.  The contributions of the tissue inhibitor of metalloproteinase-1 genotypes to triple negative breast cancer risk 
BioMedicine  2016;6(1):4.
The tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins which have been shown to be upregulated in various types of cancers. However, the contribution of TIMPs in breast cancer is not fully understood, not to mention triple negative breast cancer (TNBC). This study’s aim was to evaluate the contribution of TIMP-1 rs4898, rs6609533, and rs2070584 genotypes to the risk of breast cancer, especially the subtype of TNBC. The contributions of these TIMP-1 genotypes to cancer risk were examined among 1232 breast cancer patients and 1232 healthy controls, and several clinicopathologic factors were also analyzed. The results showed that the percentages of CC, CT, and TT of TIMP-1 rs4898 were differentially distributed at 28.5%, 33.1% and 38.4% in the breast cancer patient group and 34.5%, 41.0% and 24.5% in the control group, respectively (P for trend = 7.99*10-13). It was also found that the CC genotype carriers were of increased risk for breast cancer (odds ratio = 1.90, 95% confidence interval = 1.55-2.33, P = 0.0001) than the TT genotype carriers. In addition, we analyzed the allelic frequency distributions of all three TIMP-1s, and the results showed that the C allele of TIMP-1 rs4898 contributes to an increase in breast cancer susceptibility (P = 2.41*10-12). On the other hand, there was no difference found in the distribution of genotypic or allelic frequencies among the patients and the controls for TIMP-1 rs6609533 and rs2070584. Thus, it is our conclusion that the CC genotype of TIMP-1 rs4898 compared to the TT wild-type genotype may increase the risk for breast cancer, especially TNBC in Taiwan, and may serve as an early detective and predictive marker.
PMCID: PMC4752549  PMID: 26872812
Breast cancer; Genotype; MMP; Polymorphism; Taiwan; TIMP-1; Triple negative breast cancer
9.  Antimicrobial activity of a quaternary ammonium methacryloxy silicate-containing acrylic resin: a randomised clinical trial 
Scientific Reports  2016;6:21882.
Quaternary ammonium methacryloxy silicate (QAMS)-containing acrylic resin demonstrated contact-killing antimicrobial ability in vitro after three months of water storage. The objective of the present double-blind randomised clinical trial was to determine the in vivo antimicrobial efficacy of QAMS-containing orthodontic acrylic by using custom-made removable retainers that were worn intraorally by 32 human subjects to create 48-hour multi-species plaque biofilms, using a split-mouth study design. Two control QAMS-free acrylic disks were inserted into the wells on one side of an orthodontic retainer, and two experimental QAMS-containing acrylic disks were inserted into the wells on the other side of the same retainer. After 48 hours, the disks were retrieved and examined for microbial vitality using confocal laser scanning microscopy. No harm to the oral mucosa or systemic health occurred. In the absence of carry-across effect and allocation bias (disks inserted in the left or right side of retainer), significant difference was identified between the percentage kill in the biovolume of QAMS-free control disks (3.73 ± 2.11%) and QAMS-containing experimental disks (33.94 ± 23.88%) retrieved from the subjects (P ≤ 0.001). The results validated that the QAMS-containing acrylic exhibits favourable antimicrobial activity against plaque biofilms in vivo. The QAMS-containing acrylic may also be used for fabricating removable acrylic dentures.
PMCID: PMC4763235  PMID: 26903314
10.  How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies 
Scientific Reports  2016;6:20872.
Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.–)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.–-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.
PMCID: PMC4757858  PMID: 26887346
11.  Analysis of drug resistance in 1,861 strains of Acinetobacter baumannii 
Biomedical Reports  2016;4(4):463-466.
Acinetobacter baumannii is an emerging human pathogen that causes hospital-acquired infections. The trend in increased antimicrobial resistance limits the choice of effective antimicrobial agents. The present study reports the resistance to Acinetobacter baumannii and analyzes the associations between antibiotic use and resistance rates at a general hospital between 2010 and 2014. A total of 1,861 isolates were obtained from clinical cultures, accounting for 10.33% of all detected bacteria (1,861/18,016). The strains were mainly from respiratory samples (1,628 isolates, 87.5%) and the intensive care unit (696 isolates, 37.4%). The resistance rates of Acinetobacter baumannii to the majority of antibiotics were >50%, particularly the resistance rate to cefoperazone/sulbactam increased from 47.37 in 2011 to 89.25% in 2014. However, the rates of imipenem and cilastatin sodium decreased from 81.03 to 69.44% due to the antibiotic policy. There were Pearson significant associations between the use of three antibiotics and resistance in Acinetobacter baumannii to this drug, piperacillin/tazobactam (r=0.976, P<0.01), gentamicin (r=0.870, P<0.01) and cefoxitin (r=0.741, P<0.05). Therefore, a combination of drugs should be adopted to treat Acinetobacter baumannii infections. Microbiology laboratory support and surveillance policies are essential to control the emergence of multidrug-resistance Acinetobacter baumannii.
PMCID: PMC4812292  PMID: 27073633
drug resistance; Acinetobacter baumannii; antibiotics usage
12.  Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma 
Neurobiology of disease  2014;74:167-179.
Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss. We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP. Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs.
PMCID: PMC4523228  PMID: 25478814
retinal ganglion cell; glaucoma; mitochondrial DNA; mutation
13.  Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector 
The Hippo pathway plays a stage-specific role in regeneration and fibrogenesis after ischaemia/reperfusion-induced acute kidney injury. The proper modulation of this pathway might be the key point of transition from acute kidney injury to chronic kidney disease.
Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI–CKD transition after I/R injury.
PMCID: PMC4727597  PMID: 26574480
acute kidney injury; chronic kidney disease; fibrogenesis; Hippo pathway; repair; Yes-associated protein (YAP)
14.  Collaborative effects between the TNFα-TNFR1-macrophage axis and the VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis 
Oncoimmunology  2015;4(3):e989777.
Although inflammation and metastasis are two well-known hallmarks of malignant disease, the relationship between inflammation and lymphatic metastasis is an unexplored research area. We recently elucidated a sophisticated mechanism by which TNFα-induced tumor inflammation conscripts macrophage-mediated VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis.
PMCID: PMC4404838  PMID: 25949904
TNF-α; macrophage; inflammation; lymphangiogenesis; metastasis
15.  A Mutation in Plant-Specific SWI2/SNF2-Like Chromatin-Remodeling Proteins, DRD1 and DDM1, Delays Leaf Senescence in Arabidopsis thaliana 
PLoS ONE  2016;11(1):e0146826.
Leaf senescence is a finely regulated complex process; however, evidence for the involvement of epigenetic processes in the regulation of leaf senescence is still fragmentary. Therefore, we chose to examine the functions of DRD1, a SWI2/SNF2 chromatin remodeling protein, in epigenetic regulation of leaf senescence, particularly because drd1-6 mutants exhibited a delayed leaf senescence phenotype. Photosynthetic parameters such as Fv/Fm and ETRmax were decreased in WT leaves compared to leaves of drd1-6 mutants after dark treatment. The WT leaves remarkably lost more chlorophyll and protein content during dark-induced senescence (DIS) than the drd1-6 leaves did. The induction of senescence-associated genes was noticeably inhibited in the drd1-6 mutant after 5-d of DIS. We compared changes in epigenetic regulation during DIS via quantitative expression analysis of 180-bp centromeric (CEN) and transcriptionally silent information (TSI) repeats. Their expression levels significantly increased in both the WT and the drd1-6 mutant, but did much less in the latter. Moreover, the delayed leaf senescence was observed in ddm1-2 mutants as well as the drd1-6, but not in drd1-p mutants. These data suggest that SWI2/SNF2 chromatin remodeling proteins such as DRD1 and DDM1 may influence leaf senescence possibly via epigenetic regulation.
PMCID: PMC4709239  PMID: 26752684
16.  Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1α Activation 
Scientific Reports  2016;6:18928.
Prolyl hydroxylase domain protein 2 (PHD2) belongs to an evolutionarily conserved superfamily of 2-oxoglutarate and Fe(II)-dependent dioxygenases that mediates homeostatic responses to oxygen deprivation by mediating hypoxia-inducible factor-1α (HIF-1α) hydroxylation and degradation. Although oxidative stress contributes to the inactivation of PHD2, the precise molecular mechanism of PHD2 inactivation independent of the levels of co-factors is not understood. Here, we identified disulfide bond-mediated PHD2 homo-dimer formation in response to oxidative stress caused by oxidizing agents and oncogenic H-rasV12 signalling. Cysteine residues in the double-stranded β-helix fold that constitutes the catalytic site of PHD isoforms appeared responsible for the oxidative dimerization. Furthermore, we demonstrated that disulfide bond-mediated PHD2 dimerization is associated with the stabilization and activation of HIF-1α under oxidative stress. Oncogenic H-rasV12 signalling facilitates the accumulation of HIF-1α in the nucleus and promotes aerobic glycolysis and lactate production. Moreover, oncogenic H-rasV12 does not trigger aerobic glycolysis in antioxidant-treated or PHD2 knocked-down cells, suggesting the participation of the ROS-mediated PHD2 inactivation in the oncogenic H-rasV12-mediated metabolic reprogramming. We provide here a better understanding of the mechanism by which disulfide bond-mediated PHD2 dimerization and inactivation result in the activation of HIF-1α and aerobic glycolysis in response to oxidative stress.
PMCID: PMC4703963  PMID: 26740011
17.  Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells 
Induced pluripotent stem cells (iPSCs) hold tremendous potential, both as a biological tool to uncover the pathophysiology of disease by creating relevant human cell models, and as a source of cells for cell-based therapeutic applications. Studying the reprogramming process will also provide significant insight into tissue development.
We sought to characterize the derivation of iPSC lines from nasal epithelial cells isolated from the nasal mucosa samples of children, a highly relevant and easily accessible tissue for pediatric populations.
We performed detailed comparative analysis on the transcriptomes and methylomes of nasal epithelial cells, iPSCs derived from nasal epithelial cells (NEC-iPSCs), and ESCs.
NEC-iPSCs express pluripotent cell markers, can differentiate into all three germ layers in vivo and in vitro, and have a transcriptome and methylome remarkably similar to ESCs. However, residual DNA methylation marks exist, which are differentially methylated between NEC-iPSCs and ESCs. A subset of these methylation markers related to epithelium development and asthma and specific to iPSCs generated from nasal epithelial cells persisted after several passages in vitro, suggesting the retention of an epigenetic memory of their tissue of origin. Our analysis also identified novel candidate genes with dynamic gene expression and DNA methylation changes during reprogramming, indicative of possible roles in airway epithelium development.
Nasal epithelial cells are an excellent tissue source to generate iPSCs in pediatric asthmatics, and detailed characterization of the resulting iPSC lines would help us better understand the reprogramming process and retention of epigenetic memory.
PMCID: PMC4289122  PMID: 25441642
induced pluripotent stem cells; nasal epithelial cells; DNA methylation; gene expression; epigenetic memory; asthma
18.  CPT-cGMP Is A New Ligand of Epithelial Sodium Channels 
Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2'-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption.
PMCID: PMC4807156  PMID: 27019621
amiloride-sensitive sodium channel; cyclic guanosine nucleotides; molecular docking; lung edema.
19.  Mean platelet volume in young children with urinary tract infection 
Scientific Reports  2015;5:18072.
Mean platelet volume (MPV) has not yet been well-established in urinary tract infection (UTI). The purpose of this study was to evaluate the role of MPV as an acute phase reactant in children with UTI. Data from 118 young children (<2 years) with UTI between 2012 and 2013 were grouped as acute pyelonephritis (APN) and lower UTI according to the dimercaptosuccinic acid (DMSA) scan abnormalities. MPV, platelet distribution width (PDW) platelet count, and other infection markers (white blood cell [WBC] count, erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]) were measured. WBC (P = 0.001), ESR (P = 0.005), CRP (P < 0.001) and MPV levels (P = 0.011) were significantly higher in the APN group than those in the lower UTI group. MPV positively correlated with PDW, CRP and negatively with platelet count. Multiple logistic regression analyses showed that CRP and MPV were independent predictive factors for APN patients. However, the area under the Receiver Operating Characteristic (ROC) curve analysis for MPV was lower than CRP. Our results suggest that MPV can be an inflammatory marker in UTI, but the predictive value of MPV was not superior to CRP in the diagnosis of APN.
PMCID: PMC4678298  PMID: 26666588
20.  Association between Interleukin-8-251A/T polymorphism and gastric cancer susceptibility: a meta-analysis based on 5286 cases and 8000 controls 
Objectives: Published data on the association between Interleukin-8-251A/T polymorphism and gastric cancer (GC) risk are inconclusive. Thus, we conducted a meta-analysis to evaluate the relationship between cyclin D1 G870A polymorphism and GC risk. Methods: We searched PubMed, EMBASE, Web of science and the Cochrane Library up to July 12, 2015 for relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Results: Twenty-six studies published from 2004 to 2015, with a total of 5286 cases and 8000 controls, were included in this meta-analysis. The pooled results showed that there was significant association between Interleukin-8-251A/T polymorphism and GC risk in any genetic model. In the subgroup analysis by ethnicity, the effects remained in Asians. However, no genetic models reached statistical association in Europeans. The subgroup analysis stratified by Source of controls showed an increased breast cancer risk in hospital-based (HB) studies in any genetic model except recessive model. However, there was no association in any genetic model in population based (PB) studies. When stratifying by Genotyping method, we found statistical association in Non-RFLP (restriction fragment length polymorphism) in any genetic model except heterozygote comparison, the effect was remain in PCR-RFLP in dominant model and heterozygote comparison. Conclusions: This meta-analysis suggests that Interleukin-8-251A/T polymorphism is a risk factor for susceptibility to GC in overall population, especially in Asians, in hospital populations and in Non-RFLP. While, there was no association in Europeans and in general population. Further large scale multicenter epidemiological studies are warranted to confirm this finding.
PMCID: PMC4730005  PMID: 26885219
Interleukin-8-251A/T; polymorphism; gastric cancer; susceptibility; meta-analysis
21.  Pediatric asthma and autism—genomic perspectives 
High-throughput technologies, ranging from microarrays to NexGen sequencing of RNA and genomic DNA, have opened new avenues for exploration of the pathobiology of human disease. Comparisons of the architecture of the genome, identification of mutated or modified sequences, and pre-and post- transcriptional regulation of gene expression as disease specific biomarkers are revolutionizing our understanding of the causes of disease and are guiding the development of new therapies. There is enormous heterogeneity in types of genomic variation that occur in human disease. Some are inherited, while others are the result of new somatic or germline mutations or errors in chromosomal replication. In this review, we provide examples of changes that occur in the human genome in two of the most common chronic pediatric disorders, autism and asthma. The incidence and economic burden of both of these disorders are increasing worldwide. Genomic variations have the potential to serve as biomarkers for personalization of therapy and prediction of outcomes.
PMCID: PMC4678135  PMID: 26668064
Genomic variation; Transcription; Pathobiology; Pediatric disorders; Autism; Asthma
22.  Study of a High-Yield Cellulase System Created by Heavy-Ion Irradiation-Induced Mutagenesis of Aspergillus niger and Mixed Fermentation with Trichoderma reesei 
PLoS ONE  2015;10(12):e0144233.
The aim of this study was to evaluate and validate the efficiency of 12C6+ irradiation of Aspergillus niger (A. niger) or mutagenesis via mixed Trichoderma viride (T. viride) culturing as well as a liquid cultivation method for cellulase production via mixed Trichoderma reesei (T. reesei) and A. niger culture fermentation. The first mutagenesis approach was employed to optimize yield from a cellulase-producing strain via heavy-ion mutagenesis and high-throughput screening, and the second was to effectively achieve enzymatic hydrolysis of cellulase from a mixed culture of mutant T. viride and A. niger. We found that 12C6+-ion irradiation induced changes in cellulase biosynthesis in A. niger but had no effect on the time course of the synthesis. It is notable that the exoglucanases (CBH) activities of A. niger strains H11-1 and H differed (6.71 U/mL vs. 6.01 U/mL) and were significantly higher than that of A. niger mutant H3-1. Compared with strain H, the filter paper assay (FPA), endoglucanase (EG) and β-glucosidase (BGL) activities of mutant strain H11-1 were increased by 250.26%, 30.26% and 34.91%, respectively. A mixed culture system was successfully optimized, and the best ratio of T. reesei to A. niger was 5:1 for 96 h with simultaneous inoculation. The BGL activity of the mixed culture increased after 72 h. At 96 h, the FPA and BGL activities of the mixed culture were 689.00 and 797.15 U/mL, respectively, significantly higher than those of monocultures, which were 408.70 and 646.98 U/mL for T. reesei and 447.29 and 658.89 U/mL for A. niger, respectively. The EG activity of the mixed culture was 2342.81 U/mL, a value that was significantly higher than that of monocultures at 2206.57 U/mL for T. reesei and 1727.62 U/mL for A. niger. In summary, cellulose production and hydrolysis yields were significantly enhanced by the proposed combination scheme.
PMCID: PMC4686103  PMID: 26656155
23.  Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits 
To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status.
Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining.
Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant.
Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.
PMCID: PMC4639523  PMID: 26604693
VEGF-C; retroperitoneal lymph nodes; VX2; cisplatin; lymphatic metastasis; peripheral blood
24.  Biochar-amended potting medium reduces the susceptibility of rice to root-knot nematode infections 
BMC Plant Biology  2015;15:267.
Biochar is a solid coproduct of biomass pyrolysis, and soil amended with biochar has been shown to enhance the productivity of various crops and induce systemic plant resistance to fungal pathogens. The aim of this study was to explore the ability of wood biochar to induce resistance to the root-knot nematode (RKN) Meloidogyne graminicola in rice (Oryza sativa cv. Nipponbare) and examine its histochemical and molecular impact on plant defense mechanisms.
A 1.2 % concentration of biochar added to the potting medium of rice was found to be the most effective at reducing nematode development in rice roots, whereas direct toxic effects of biochar exudates on nematode viability, infectivity or development were not observed. The increased plant resistance was associated with biochar-primed H2O2 accumulation as well as with the transcriptional enhancement of genes involved in the ethylene (ET) signaling pathway. The increased susceptibility of the Ein2b-RNAi line, which is deficient in ET signaling, further confirmed that biochar-induced priming acts at least partly through ET signaling.
These results suggest that biochar amendments protect rice plants challenged by nematodes. This priming effect partially depends on the ET signaling pathway and enhanced H2O2 accumulation.
PMCID: PMC4632470  PMID: 26537003
Biochar; Meloidogyne graminicola; Hydrogen peroxide; Lignin; Callose
25.  Wound Healing Effects of Rose Placenta in a Mouse Model of Full-Thickness Wounds 
Archives of Plastic Surgery  2015;42(6):686-694.
Rosa damascena, a type of herb, has been used for wound healing in Eastern folk medicine. The goal of this study was to evaluate the effectiveness of rose placenta from R. damascena in a full-thickness wound model in mice.
Sixty six-week-old C57BL/6N mice were used. Full-thickness wounds were made with an 8-mm diameter punch. Two wounds were made on each side of the back, and wounds were assigned randomly to the control and experimental groups. Rose placenta (250 µg) was injected in the experimental group, and normal saline was injected in the control group. Wound sizes were measured with digital photography, and specimens were harvested. Immunohistochemical staining was performed to assess the expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and CD31. Vessel density was measured. Quantitative analysis using an enzyme-linked immunosorbent assay (ELISA) for EGF was performed. All evaluations were performed on postoperative days 0, 2, 4, 7, and 10. Statistical analyses were performed using the paired t-test.
On days 4, 7, and 10, the wounds treated with rose placenta were significantly smaller. On day 2, VEGF and EGF expression increased in the experimental group. On days 7 and 10, TGF-β1 expression decreased in the experimental group. On day 10, vessel density increased in the experimental group. The increase in EGF on day 2 was confirmed with ELISA.
Rose placenta was found to be associated with improved wound healing in a mouse full-thickness wound model via increased EGF release. Rose placenta may potentially be a novel drug candidate for enhancing wound healing.
PMCID: PMC4659980  PMID: 26618114
Wound healing; Rosa; Epidermal growth factor; Mice

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