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1.  The influence of scaffold material on chondrocytes in inflammatory conditions 
Acta biomaterialia  2013;9(5):6563-6575.
Cartilage tissue engineering aims to repair damaged cartilage tissue in arthritic joints. As arthritic joints have significantly higher levels of pro-inflammatory cytokines (such as IL-1β and TNFα that cause cartilage destruction, it is critical to engineer stable cartilage in an inflammatory environment. Biomaterial scaffolds constitute an important component of the microenvironment for chondrocytes in engineered cartilage. However, it remains unclear how scaffold material influences the response of chondrocytes seeded in these scaffolds under inflammatory stimuli. Here, we compared the response of articular chondrocytes seeded within three different polymeric scaffolding materials (silk, collagen and polylactic acid (PLA)) to IL-1β and TNFα. These scaffolds have different physical characteristics and yielded significant differences in the expression of genes associated with cartilage matrix production and degradation, cell adhesion and cell death. Silk and collagen scaffolds released pro-inflammatory cytokines faster and had higher uptake water abilities than PLA scaffolds. Correspondingly, chondrocytes cultured in silk and collagen scaffolds maintained higher levels of cartilage matrix than those in PLA, suggesting that these biophysical properties of scaffolds may regulate gene expression and response to inflammatory stimuli in chondrocytes. Based on this study, we concluded that selecting the proper scaffolding material will aid in the engineering of more stable cartilage tissues for cartilage repair; and that silk and collagen are the more optimal scaffolds in supporting the stability of 3D cartilage under inflammatory conditions.
doi:10.1016/j.actbio.2013.01.004
PMCID: PMC3713500  PMID: 23333441
cartilage matrix production; scaffold; pro-inflammatory cytokines; cytokine release; water uptake
2.  Syphilis and Its Correlates among Heterosexual Males Attending Sexually Transmitted Infection Clinics – Observation from a Multicity Cohort in Jiangsu Province, China 
PLoS ONE  2014;9(4):e95289.
Objectives
To estimate the prevalence of HIV and syphilis, incidence of syphilis and to identify the correlates of syphilis infection among heterosexual male attendees of sexually transmitted infection (STI) clinics (MSC).
Methods
A cohort study of one-year duration was conducted in Yangzhou and Changzhou cities in Jiangsu province of China. The baseline survey commenced in June 2009, recruited 1225 consenting adult MSCs (609 in Yangzhou and 617 in Changzhou) through STI-clinic based convenience sampling.
Results
Baseline HIV and syphilis prevalence were 0.49% and 17.29% respectively. Syphilis incidence rate was 7.22 per 100 person-years (6.53 in Yangzhou and 7.76 in Changzhou) during the 6-month follow-up with retention fractions of 27.38% and 35.15% for Yangzhou and Changzhou respectively. Majority of the participants were middle-aged, high school educated, married, living with partners and non-migrants. Very few subjects reported recent and consistent condom-use with regular partners. Although considerable number of MSCs reported recent sexual exposure with female sex workers (FSW) and non-FSW casual partners, the proportion of reported condom use was very low during those exposures. In multivariate analyses higher age, having recent sex with FSWs and being HIV-positive were associated with higher syphilis sero-positivity while higher education was protective. In bivariate analyses, being married, divorced/widowed, official residency of the study cities and non-use of condom with regular partners predicted higher risk.
Conclusions
Considering the potential bridging role of MSCs between high and low-risk populations, effective intervention strategies among them targeting the correlates of syphilis infection are urgently called for in Jiangsu province of China.
doi:10.1371/journal.pone.0095289
PMCID: PMC3990697  PMID: 24743839
3.  Prognostic significance of heart rate turbulence parameters in patients with chronic heart failure 
Background
This study is aimed to evaluate the clinical significance of heart rate turbulence (HRT) parameters in predicting the prognosis in patients with chronic heart failure (CHF).
Methods
From June 2011 to December 2012, a total of 104 CHF patients and 30 healthy controls were enrolled in this study. We obtained a 24-hour Holter ECG recording to assess the HRT parameters, included turbulence onset (TO), turbulence slope (TS), standard deviation of N-N intervals (SDNN), and resting heart rate (RHR). The relationships between HRT parameters and the prognosis of CHF patients were determined.
Results
The assessment follow-up period lasted until January 31, 2013. The overall mortality of CHF patients was 9.6% (10/104). Our results revealed that CHF patients had higher levels of TO than those of healthy subjects, but the TS levels of CHF patients were lower than that of the control group. CHF patients with NYHA grade IV had higher HRT1/2 rate than those with NYHA grade II/III. There were statistical differences in TS, LVEF, SDNN and RHR between the non-deteriorating group and the non-survivor group. Significant differences in TS among the three groups were also found. Furthermore, CHF patients in the non-survivor group had lower levels of TS than those in the deteriorating group. Correlation analyses indicated that TO negatively correlate with SDNN, while TS positively correlated with SDNN and left ventricular ejection fraction (LVEF). We also observed negative correlations between TS and left ventricular end-diastolic cavity dimension (LVEDD), RHR, homocysteine (Hcy) and C-reactive protein (CRP). Multivariate Cox regression analysis further confirmed that LVEF (≤30%), HRT2, SDNN and RHR were independent risk factors which can indicate poor prognosis in CHF patients.
Conclusions
Our findings indicate that HRT may have good clinical predictive value in patients with CHF. Thus, quantifying HRT parameters could be a useful tool for predicting mortality in CHF patients.
doi:10.1186/1471-2261-14-50
PMCID: PMC3996196  PMID: 24725657
Heart rate turbulence; Chronic heart failure; Prognosis
4.  ALOX5 Is Associated with Tuberculosis in a Subset of the Pediatric Population of North China 
Background: Genetic factors are involved in the etiology of Mycobacterium tuberculosis infection. Recently, ALOX5 has been identified as a candidate gene for tuberculosis (TB) susceptibility. We investigated whether an association between ALOX5 and TB exists in a Chinese pediatric population from northern China. Methods: We conducted a case–control study comprising 488 individuals aged 2 months to 17 years by genotyping 18 tag-single-nucleotide polymorphisms (SNPs) from the ALOX5 gene. The tag-SNPs were selected from the international HapMap project. An Illumina BeadXpress Scanner was utilized for genotyping, supported by the high-density BeadArray technology in combination with an allele-specific extension, adapter ligation, and amplification assay. Statistical analyses were performed to determine correlations between genetic variation and disease. Results: Our study is the first to show that ALOX5 is associated with susceptibility to pediatric TB in a subset of children in northern China. The rs2115819 T allele of ALOX5 presents a risk factor for childhood TB disease.
doi:10.1089/gtmb.2012.0426
PMCID: PMC3609609  PMID: 23448388
5.  A 3'UTR Polymorphism of IL-6R Is Associated with Chinese Pediatric Tuberculosis 
BioMed Research International  2014;2014:483759.
Background. IL-6 is a proinflammatory cytokine that plays a critical role in host defense against tuberculosis (TB). Genetic polymorphisms of IL-6 and its receptor IL-6R had been discussed in adult TB recently. However, their role in pediatric TB is still unclear. Due to the obvious differences in TB pathophysiology in children, which may also reflect differences in genetic background, further association studies in pediatric populations are needed. Methods. A case-control study was carried out in a Chinese pediatric population including 353 TB patients and 400 healthy controls. Tag-SNPs of IL-6 and IL-6R genes were selected by Haploview software, genotyped using MassArray, and analyzed statistically. Results. One polymorphism, rs2229238, in the 3'UTR region of IL-6R was observed to be associated with increased resistance to TB (adjusted P = 0.03). The rs2229238 T allele contributed to a reduced risk to TB in recessive heritable model (OR, 0.53; 95% CI, 0.35–0.78). Conclusions. By tag-SNP genotyping based case-control study, we identified a genetic polymorphism in the IL-6R 3'UTR that regulates host resistance to pediatric TB in a Chinese population.
doi:10.1155/2014/483759
PMCID: PMC3977562  PMID: 24772425
6.  Genetic Contribution of CISH Promoter Polymorphisms to Susceptibility to Tuberculosis in Chinese Children 
PLoS ONE  2014;9(3):e92020.
Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16–2.74) and 1.86-fold (95% CI, 1.26–2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C−809451-T−414171-C−622502 haplotype (OR 3.66, 95% CI:2.12–6.32). The G−809451-A−414171-C−622502-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C−809451-T−414171-C−622502-containing counterpart in Hela cell lines (P = 0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.
doi:10.1371/journal.pone.0092020
PMCID: PMC3954833  PMID: 24632804
7.  Identification of Salmonella enterica Serovar Pullorum Antigenic Determinants Expressed In Vivo 
Infection and Immunity  2013;81(9):3119-3127.
Salmonella enterica serovar Pullorum affecting poultry causes pullorum disease and results in severe economic loss in the poultry industry. Currently, it remains a major threat in countries with poor poultry surveillance and no efficient control measures. As S. Pullorum could induce strong humoral immune responses, we applied an immunoscreening technique, the in vivo-induced antigen technology (IVIAT), to identify immunogenic bacterial proteins expressed or upregulated during S. Pullorum infection. Convalescent-phase sera from chickens infected with S. Pullorum were pooled, adsorbed against antigens expressed in vitro, and used to screen an S. Pullorum genomic expression library. Forty-five proteins were screened out, and their functions were implicated in molecular biosynthesis and degradation, transport, metabolism, regulation, cell wall synthesis and antibiotic resistance, environmental adaptation, or putative functions. In addition, 11 of these 45 genes were assessed for their differential expression by quantitative real-time reverse transcription-PCR (RT-PCR), revealing that 9 of 11 genes were upregulated to different degrees under in vivo conditions, especially the regulator of virulence determinants, phoQ. Then, four in vivo-induced proteins (ShdA, PhoQ, Cse3, and PbpC) were tested for their immunoreactivity in 28 clinical serum samples from chickens infected with S. Pullorum. The rate of detection of antibodies against ShdA reached 82% and was the highest among these proteins. ShdA is a host colonization factor known to be upregulated in vivo and related to the persistence of S. Typhimurium in the intestine. Furthermore, these antigens identified by IVIAT warrant further evaluation for their contributions to pathogenesis, and more potential roles, such as diagnostic, therapeutic, and preventive uses, need to be developed in future studies.
doi:10.1128/IAI.00145-13
PMCID: PMC3754199  PMID: 23774596
8.  A ‘hidden’ 18O-enriched reservoir in the sub-arc mantle 
Scientific Reports  2014;4:4232.
Plate subduction continuously transports crustal materials with high-δ18O values down to the mantle wedge, where mantle peridotites are expected to achieve the high-δ18O features. Elevated δ18O values relative to the upper mantle value have been reported for magmas from some subduction zones. However, peridotites with δ18O values significantly higher than the well-defined upper mantle values have never been observed from modern subduction zones. Here we present in-situ oxygen isotope data of olivine crystals in Sailipu mantle xenoliths from South Tibet, which have been subjected to a long history of Tethyan subduction before the India-Asia collision. Our data identify for the first time a metasomatized mantle that, interpreted as the sub-arc lithospheric mantle, shows anomalously enriched oxygen isotopes (δ18O = +8.03 ± 0.28 ‰). Such a high-δ18O mantle commonly does not contribute significantly to typical island arc basalts. However, partial melting or contamination of such a high-δ18O mantle is feasible to account for the high-δ18O signatures in arc basalts.
doi:10.1038/srep04232
PMCID: PMC3937801  PMID: 24577190
9.  One family cluster of avian influenza A(H7N9) virus infection in Shandong, China 
Background
The first case of human infection with avian influenza A (H7N9) virus was identified in March, 2013 and the new H7N9 virus infected 134 patients and killed 45 people in China as of September 30, 2013. Family clusters with confirmed or suspected the new H7N9 virus infection were previously reported, but the family cluster of H7N9 virus infection in Shandong Province was first reported.
Case presentation
A 36-year-old man was admitted to Zaozhuang City Hospital with progressive respiratory distress and suspicion of impending acute respiratory distress syndrome on April 21. The chest radiography revealed bilateral ground-glass opacities and pulmonary lesions. The second case, the first case’s 4 year old son, was admitted to the same hospital on April 28 with fever and multiple patchy shadows in the bilateral lungs. Both of the two cases were confirmed to infect with H7N9 virus by the results of real-time reverse transcriptase-polymerase-chain reaction (rRT-PCR), virus isolation and serum antibody titer. At the same time, one environment samples was detected positive for H7N9 virus in the living poultry market in Zaozhuang. The homologous analysis of the full genome sequence indicated that both viruses from the patients were almost genetically identical. The field epidemiology investigation showed that the two cases had no recognized exposure to poultry, but had the exposure to the environment. The second case had substantial unprotected close exposure to his ill father and developed symptoms seven days after his last contact with his father. After surgery, the index case and his son were discharged on May 16 and May 6, respectively. 11 close contacts of both patients were identified and tested negative both the throat swabs and the serum antibody.
Conclusion
The infection of the index case probably resulted from contact with environmentally contaminated material. For the son, the probable infection source was from the index case during unprotected exposure, but the possibility from the environment or other sources could not be completely ruled out.
doi:10.1186/1471-2334-14-98
PMCID: PMC3974040  PMID: 24559386
Avian Influenza A (H7N9) virus; Epidemiology; Infectious source
10.  A Glimpse of the Pathogenetic Mechanisms of Wnt/β-Catenin Signaling in Diabetic Nephropathy 
BioMed Research International  2013;2013:987064.
The Wnt family of proteins belongs to a group of secreted lipid-modified glycoproteins with highly conserved cysteine residues. Prior results indicate that Wnt/β-catenin signaling plays a prominent role in cell differentiation, adhesion, survival, and apoptosis and is involved in organ development, tumorigenesis, and tissue fibrosis, among other functions. Accumulating evidence has suggested that Wnt/β-catenin exhibits a pivotal function in the progression of diabetic nephropathy (DN). In this review, we focused on discussing the dual role of Wnt/β-catenin in apoptosis and epithelial mesenchymal transition (EMT) formation of mesangial cells. Moreover, we also elucidated the effect of Wnt/β-catenin in podocyte dysfunction, tubular EMT formation, and renal fibrosis under DN conditions. In addition, the molecular mechanisms involved in this process are introduced. This information provides a novel molecular target of Wnt/β-catenin for the protection of kidney damage and in delay of the progression of DN.
doi:10.1155/2013/987064
PMCID: PMC3886614  PMID: 24455745
11.  Direct-Write Assembly of 3D Silk/Hydroxyapatite Scaffolds for Bone Co-Cultures 
Advanced healthcare materials  2012;1(6):729-735.
doi:10.1002/adhm.201200057
PMCID: PMC3739986  PMID: 23184824
Direct-write; gradient; silk; bone formation; vascularization
12.  Development of a Fluorescence Polarization Based High-Throughput Assay to Identify Casitas B-Lineage Lymphoma RING Domain Regulators 
PLoS ONE  2013;8(10):e78042.
The E3 ubiquitin protein ligase Casitas B-lineage Lymphoma (Cbl) proteins and their binding partners play an important role in regulating signal transduction pathways. It is important to utilize regulators to study the protein-protein interactions (PPIs) between these proteins. However, finding specific small-molecule regulators of PPIs remains a significant challenge due to the fact that the interfaces involved in PPIs are not well suited for effective small molecule binding. We report the development of a competitive, homogeneous, high-throughput fluorescence polarization (FP) assay to identify small molecule regulators of Cbl (RING) domain. The FP assay was used to measure binding affinities and inhibition constants of UbCH7 peptides and small molecule regulators of Cbl (RING) domains, respectively. In order to rule out promiscuous, aggregation-based inhibition, two assay conditions were developed and compared side by side. Under optimized conditions, we screened a 10,000 natural compound library in detergent-free and detergent-present (0.01% Triton X-100) systems. The results indicate that the detergent-present system is more suitable for high-throughput screens. Three potential compounds, methylprotodioscin, leonuride and catalpol, have been identified that bind to Cbl (RING) domain and interfere with the Cbl (RING)-UbCH7 protein-protein interaction.
doi:10.1371/journal.pone.0078042
PMCID: PMC3814989  PMID: 24205080
13.  Oncogenic Features of PHF8 Histone Demethylase in Esophageal Squamous Cell Carcinoma 
PLoS ONE  2013;8(10):e77353.
Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. It has been reported that histone demethylases are involved in the carcinogenesis of certain types of tumors. Here, we studied the role of one of the histone lysine demethylases, plant homeodomain finger protein 8 (PHF8), in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). Using short hairpin RNA via lentiviral infection, we established stable ESCC cell lines with constitutive downregulation of PHF8 expression. Knockdown of PHF8 in ESCC cells resulted in inhibition of cell proliferation and an increase of apoptosis. Moreover, there were reductions of both anchorage-dependent and -independent colony formation. In vitro migration and invasion assays showed that knockdown of PHF8 led to a reduction in the number of migratory and invasive cells. Furthermore, downregulation of PHF8 attenuated the tumorigenicity of ESCC cells in vivo. Taken together, our study revealed the oncogenic features of PHF8 in ESCC, suggesting that PHF8 may be a potential diagnostic marker and therapeutic target for ESCC.
doi:10.1371/journal.pone.0077353
PMCID: PMC3795633  PMID: 24146981
14.  Correction: Norcantharidin Inhibits Renal Interstitial Fibrosis by Blocking the Tubular Epithelial-Mesenchymal Transition 
PLoS ONE  2013;8(10):10.1371/annotation/84e623b5-d1a7-47b7-96d7-4f5464b6f4b3.
doi:10.1371/annotation/84e623b5-d1a7-47b7-96d7-4f5464b6f4b3
PMCID: PMC3794066
15.  Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology 
Kidney international  2013;83(4):568-581.
Mitochondria are a class of dynamic organelles that constantly undergo fission and fusion. Mitochondrial dynamics is governed by a complex molecular machinery and finely tuned by regulatory proteins. During cell injury or stress, the dynamics is shifted to fission, resulting in mitochondrial fragmentation, which contributes to mitochondrial damage and consequent cell injury and death. Emerging evidence has suggested a role of mitochondrial fragmentation in the pathogenesis of renal diseases including acute kidney injury and diabetic nephropathy. A better understanding of the regulation of mitochondrial dynamics and its pathogenic changes may unveil novel therapeutic strategies.
doi:10.1038/ki.2012.441
PMCID: PMC3612360  PMID: 23325082
16.  In Vitro Sensitivities of Plasmodium falciparum Isolates from the China-Myanmar Border to Piperaquine and Association with Polymorphisms in Candidate Genes 
The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.
doi:10.1128/AAC.02306-12
PMCID: PMC3623367  PMID: 23357760
17.  Role of Cartilage Forming Cells in Regenerative Medicine for Cartilage Repair 
Orthopedic research and reviews  2010;2010(2):85-94.
Currently, cartilage repair remains a major challenge for researchers and physicians due to its limited healing capacity. Cartilage regeneration requires suitable cells; these must be easily obtained and expanded, able to produce hyaline matrix with proper mechanical properties, and demonstrate sustained integration with native tissue. At present, there is a wide variety of possible cell sources for cartilage regeneration; this review explores the diversity of sources for cartilage forming cells and the distinctive characteristics, advantages, limitations, and potential applications of each cell source. We place emphasis on cell sources used for in vitro and clinical studies.
doi:10.2147/ORR.S7194
PMCID: PMC3773876  PMID: 24049462
cell sources; cartilage regeneration; stem cells; chondrocytes
18.  Predicting enhancer transcription and activity from chromatin modifications 
Nucleic Acids Research  2013;41(22):10032-10043.
Enhancers play a pivotal role in regulating the transcription of distal genes. Although certain chromatin features, such as the histone acetyltransferase P300 and the histone modification H3K4me1, indicate the presence of enhancers, only a fraction of enhancers are functionally active. Individual chromatin marks, such as H3K27ac and H3K27me3, have been identified to distinguish active from inactive enhancers. However, the systematic identification of the most informative single modification, or combination thereof, is still lacking. Furthermore, the discovery of enhancer RNAs (eRNAs) provides an alternative approach to directly predicting enhancer activity. However, it remains challenging to link chromatin modifications to eRNA transcription. Herein, we develop a logistic regression model to unravel the relationship between chromatin modifications and eRNA synthesis. We perform a systematic assessment of 24 chromatin modifications in fetal lung fibroblast and demonstrate that a combination of four modifications is sufficient to accurately predict eRNA transcription. Furthermore, we compare the ability of eRNAs and H3K27ac to discriminate enhancer activity. We demonstrate that eRNA is more indicative of enhancer activity. Finally, we apply our fibroblast trained model to six other cell-types and successfully predict eRNA synthesis. Thus, we demonstrate the learned relationships are general and independent of cell-type. We provided a powerful tool to identify active enhancers and reveal the relationship between chromatin modifications, eRNA production and enhancer activity.
doi:10.1093/nar/gkt826
PMCID: PMC3905895  PMID: 24038352
19.  Changes in expression of four molecular marker proteins and one microRNA in mesothelial cells of the peritoneal dialysate effluent fluid of peritoneal dialysis patients 
The aim of this study was to detect the expression of microRNA-200c and epithelial-mesenchymal transition (EMT) in the mesothelial cells of the peritoneal dialysate effluent fluid of peritoneal dialysis (PD) patients, and to investigate the association between microRNA-200c and peritoneal mesothelial cell EMT. Twelve patients who had recently started continuous ambulatory peritoneal dialysis (PD start group) and 16 patients who had been undergoing peritoneal dialysis for >6 months (PD >6 months group) were randomly chosen for the isolation, culture and identification of effluent cells. qPCR and western blot analysis were used to detect the expression levels of microRNA-200c and the levels of four cellular marker proteins, E-cadherin, vimentin, fibronectin (FN) and COL-1, in effluent cells. The results showed that the effluent cells in peritoneal dialysis were peritoneal mesothelial cells. The level of E-cadherin protein expression was significantly lower in the PD >6 months group than in the PD start group, while vimentin, FN and COL-1 protein expression levels were significantly increased in the PD >6 months group. microRNA-200c in the PD >6 months group was significantly downregulated. The E-cadherin protein expression level was significantly decreased and vimentin, FN and COL-1 protein expression levels were significantly increased in the PD >6 months group. The level of microRNA-200c was significantly reduced in the PD > 6 months group, suggesting that microRNA-200c may be associated with EMT.
doi:10.3892/etm_2013.1281
PMCID: PMC3820727  PMID: 24223642
peritoneal dialysis; peritoneal fibrosis; microRNA-200c
20.  A Novel Application of Furazolidone: Anti-Leukemic Activity in Acute Myeloid Leukemia 
PLoS ONE  2013;8(8):e72335.
Acute myeloid leukemia (AML) is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA) has been successfully introduced to treat acute promyelocytic leukemia (APL), it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA) were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA). Furazolidone (FZD) was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.
doi:10.1371/journal.pone.0072335
PMCID: PMC3739762  PMID: 23951311
21.  A Functional Promoter Polymorphism of IFITM3 Is Associated with Susceptibility to Pediatric Tuberculosis in Han Chinese Population 
PLoS ONE  2013;8(7):e67816.
A susceptibility locus for tuberculosis, a re-emerging infectious disease throughout the world, was previously discovered to exist on chromosome 11p15. IFITM3 gene encoding for interferon inducible transmembrane protein 3, is located at 11p15. It acts as an effector molecule for interferon-gamma, which is essential for anti-tuberculosis immune response. In order to investigate the association between susceptibility to TB and genetic polymorphisms of the IFITM3 core promoter, a case-control study including 368 TB patients and 794 healthy controls was performed in Han Chinese children in northern China. The rs3888188 polymorphism showed significant association with susceptibility to TB. The rs3888188 G allele, acting recessively, was more frequent in TB patients (95% confidence interval: 1.08–1.56, Bonferroni P-value: 0.039). We further assessed the effect of rs3888188 polymorphism on IFITM3 transcription in vitro. As based on luciferase promoter assays, the promoter activity of haplotypes with rs3888188 G allele was lower than that of haplotypes with rs3888188 T allele. Moreover, peripheral-blood mononuclear cells carrying rs3888188 GG genotype showed a reduced IFITM3 mRNA level compared to cells carrying TT or GT genotype. In conclusion, rs3888188, a functional promoter polymorphism of IFITM3, was identified to influence the risk for pediatric TB in Han Chinese population.
doi:10.1371/journal.pone.0067816
PMCID: PMC3706438  PMID: 23874452
22.  A Glimpse of Various Pathogenetic Mechanisms of Diabetic Nephropathy 
Annual review of pathology  2011;6:395-423.
Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor β and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney.
doi:10.1146/annurev.pathol.4.110807.092150
PMCID: PMC3700379  PMID: 21261520
hyperglycemia; advanced glycation products; protein kinase C; GTP-binding proteins; reactive oxygen species; hypertension; tubulointerstitial fibrosis
23.  Discovery of Genes Related to Diabetic Nephropathy in Various Animal Models by Current Techniques 
Contributions to nephrology  2011;169:161-174.
One of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy. The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD. With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with up-to-date innovative measures. In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies. Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome-wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) coupled with mass spectroscopic analysis. Several genes, such as Tim44 (translocase of inner mitochondrial membrane-44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase-3β isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents. Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy. Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histone-methylation profiling, metabolomic approaches (e.g. metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies.
doi:10.1159/000313951
PMCID: PMC3697089  PMID: 21252517
24.  In silico Analysis of TCR Vβ7 of Two Patients with Type 1 Diabetes Mellitus 
Objective:
To compare the sequences and crystal structures of variable region of beta chain 7 (Vβ7) of T cell receptor (TCR) of two patients with type 1 diabetes mellitus (T1DM).
Patients and Methods:
The skewness of TCR Vβ7 of two T1DM patients were detected with real-time florescence quantitative polymerase chain reaction (FQ-PCR) and deoxyribonucleic acid (DNA) melting curve analysis technique followed by being sequenced, the crystal structures of them were simulated according to CPH models 2.0 Server, IMGT database, and RasMol 2 software.
Results:
The whole sequences of TCR Vβ7 of T1DM patient-1 were “CASRTAGQYEQYFGPGTR”, that of patient-2 were “CASRTAGQYEQFFGPGTR”; the only difference between them lied on the 12th amino acid. The crystal structures of Vβ7 of the two patients simulated with backbone model were rather similar, while that with sphere model were obviously different.
Conclusion:
Although the TCR Vβ7 of the T1DM patients share the similar gene sequences, their crystal structures simulated with sphere model are different, and the mechanism needs further study.
doi:10.4103/0974-2727.119845
PMCID: PMC3968635  PMID: 24701098
Beta chain; crystal structure; T cell receptor; type 1 diabetes mellitus; variable region
25.  Norcantharidin Inhibits Renal Interstitial Fibrosis by Blocking the Tubular Epithelial-Mesenchymal Transition 
PLoS ONE  2013;8(6):e66356.
Epithelial–mesenchymal transition (EMT) is thought to contribute to the progression of renal tubulointerstitial fibrosis. Norcantharidin (NCTD) is a promising agent for inhibiting renal interstitial fibrosis. However, the molecular mechanisms of NCTD are unclear. In this study, a unilateral ureteral obstruction (UUO) rat model was established and treated with intraperitoneal NCTD (0.1 mg/kg/day). The UUO rats treated with NCTD showed a reduction in obstruction-induced upregulation of α-SMA and downregulation of E-cadherin in the rat kidney (P<0.05). Human renal proximal tubule cell lines (HK-2) stimulated with TGF-β1 were treated with different concentrations of NCTD. HK-2 cells stimulated by TGF-β1 in vitro led to downregulation of E-cadherin and increased de novo expression of α-SMA; co-treatment with NCTD attenuated all of these changes (P<0.05). NCTD reduced TGF-β1-induced expression and phosphorylation of Smad2/3 and downregulated the expression of Snail1 (P<0.05). These results suggest that NCTD antagonizes tubular EMT by inhibiting the Smad pathway. NCTD may play a critical role in preserving the normal epithelial phenotype and modulating tubular EMT.
doi:10.1371/journal.pone.0066356
PMCID: PMC3692527  PMID: 23825538

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