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1.  Clinical value of endoluminal ultrasonography in the diagnosis of rectovaginal fistula 
BMC Medical Imaging  2016;16:29.
Background
Rectovaginal fistula (RVF) refers to a pathological passage between the rectum and vagina, which is a public health challenge. This study was aimed to explore the clinical value of endoluminal biplane ultrasonography in the diagnosis of rectovaginal fistula (RVF).
Methods
Thirty inpatients and outpatients with suspected RVF from January 2006 to June 2013 were included in the study, among whom 28 underwent surgical repair. All 28 patients underwent preoperative endoluminal ultrasonography, and the obtained diagnostic results were compared with the corresponding surgical results.
Results
All of the internal openings located at the anal canal and rectum of the 28 patients and confirmed during surgery were revealed by preoperative endosonography, which showed a positive predictive value of 100 %. Regarding the 30 internal openings located in the vagina during surgery, the positive predictive value of preoperative endosonography was 93 %. The six cases of simple fistulas confirmed during surgery were revealed by endosonography; for the 22 cases of complex fistula confirmed during surgery, the positive predictive value of endosonography was 90 %. Surgery confirmed 14 cases of anal fistula and 14 cases of RVF, whereas preoperative endoluminal ultrasonography suggested 16 cases of anal fistula and 12 cases of RVF, resulting in positive predictive values of 92.3 and 93 %, respectively.
Conclusion
The use of endoluminal biplane ultrasonography in the diagnosis of RVF can accurately determine the internal openings in the rectum or vagina and can relatively accurately identify concomitant branches and abscesses located in the rectovaginal septum. Thus, it is a good imaging tool for examining internal and external anal sphincter injuries and provides useful information for preoperative preparation and postoperative evaluation.
doi:10.1186/s12880-016-0131-2
PMCID: PMC4823858  PMID: 27053063
Endoluminal ultrasonography; Diagnosis; Rectovaginal fistula (RVF)
2.  A novel dinuclear iridium(III) complex as a G-quadruplex-selective probe for the luminescent switch-on detection of transcription factor HIF-1α 
Scientific Reports  2016;6:22458.
A novel dinuclear Ir(III) complex 5 was discovered to be specific to G-quadruplex DNA, and was utilized in a label-free G-quadruplex-based detection platform for transcription factor activity. The principle of this assay was demonstrated by using HIF-1α as a model protein. Moreover, this HIF-1α detection assay exhibited potential use for biological sample analysis.
doi:10.1038/srep22458
PMCID: PMC4773817  PMID: 26932240
3.  Type III Secretion System Translocon Component EseB Forms Filaments on and Mediates Autoaggregation of and Biofilm Formation by Edwardsiella tarda 
Applied and Environmental Microbiology  2015;81(17):6078-6087.
The type III secretion system (T3SS) of Edwardsiella tarda plays an important role in infection by translocating effector proteins into host cells. EseB, a component required for effector translocation, is reported to mediate autoaggregation of E. tarda. In this study, we demonstrate that EseB forms filamentous appendages on the surface of E. tarda and is required for biofilm formation by E. tarda in Dulbecco's modified Eagle's medium (DMEM). Biofilm formation by E. tarda in DMEM does not require FlhB, an essential component for assembling flagella. Dynamic analysis of EseB filament formation, autoaggregation, and biofilm formation shows that the formation of EseB filaments occurs prior to autoaggregation and biofilm formation. The addition of an EseB antibody to E. tarda cultures before bacterial autoaggregation prevents autoaggregation and biofilm formation in a dose-dependent manner, whereas the addition of the EseB antibody to E. tarda cultures in which biofilm is already formed does not destroy the biofilm. Therefore, EseB filament-mediated bacterial cell-cell interaction is a prerequisite for autoaggregation and biofilm formation.
doi:10.1128/AEM.01254-15
PMCID: PMC4551241  PMID: 26116669
4.  American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma 
In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.
doi:10.1016/j.bbmt.2015.09.016
PMCID: PMC4757494  PMID: 26428082
Myeloma; Stem cell transplantation; Salvage therapy
5.  Follicular thyroid carcinoma with NRAS Q61K and GNAS R201H mutations that had a good 131I treatment response 
Summary
We report a case of follicular thyroid carcinoma with concomitant NRAS p.Q61K and GNAS p.R201H mutations, which manifested as a 13.5 cm thyroid mass with lung, humerus and T9 spine metastases, and exhibited good response to radioactive iodine treatment.
Learning points
GNAS p.R201H somatic mutation is an activating or gain-of-function mutation resulting in constitutively activated Gs-alpha protein and downstream cAMP cascade, independent of TSH signaling, causing autonomously functioning thyroid nodules. NRAS p.Q61K mutations with GNAS p.R201H mutations are known for a good radioactive iodine treatment response.Further exploration of the GNAS-activating pathway may provide therapeutic insights into the treatment of metastatic follicular carcinoma.
doi:10.1530/EDM-15-0067
PMCID: PMC4716662  PMID: 26788326
6.  Relationship between Lipids Levels of Serum and Seminal Plasma and Semen Parameters in 631 Chinese Subfertile Men 
PLoS ONE  2016;11(1):e0146304.
Objective
This prospective study was designed to investigate the relationship between lipids levels in both serum and seminal plasma and semen parameters.
Methods
631 subfertile men were enrolled. Their obesity-associated markers were measured, and semen parameters were analyzed. Also, seminal plasma and serum TC, TG, HDL and LDL and serum FFA, FSH, LH, total testosterone (TT), estradiol (E2) and SHBG levels were detected.
Results
Seminal plasma and serum TG, TC and LDL levels were positively related to age. Serum TC, TG and LDL were positively related to obesity-associated markers (P < 0.001), while only seminal plasma TG was positively related to them (P < 0.05). For lipids levels in serum and seminal plasma, only TG level had slightly positive correlation between them (r = 0.081, P = 0.042). There was no significant correlation between serum lipids levels and semen parameters. However, seminal plasma TG, TC, LDL and HDL levels were negatively related to one or several semen parameters, including semen volume (SV), sperm concentration (SC), total sperm count (TSC), sperm motility, progressive motility (PR) and total normal-progressively motile sperm counts (TNPMS). Moreover, seminal plasma TG, TC, LDL and HDL levels in patients with oligospermatism, asthenospermia and teratozoospermia were higher than those with normal sperm concentration, motility or morphology. After adjusting age and serum LH, FSH, TT, E2 and SHBG levels, linear regression analysis showed that SV was still significantly correlated with seminal plasma LDL (P = 0.012), both of SC and TSC with seminal plasma HDL (P = 0.028 and 0.002), and both of PR and sperm motility with seminal plasma TC (P = 0.012 and 0.051).
Conclusion
The abnormal metabolism of lipids in male reproductive system may contribute to male factor infertility.
doi:10.1371/journal.pone.0146304
PMCID: PMC4699695  PMID: 26726884
7.  Accuracy Evaluation of The Depth of Six Kinds of Sperm Counting Chambers for both Manual and Computer-Aided Semen Analyses 
Background
Although the depth of the counting chamber is an important factor influencing sperm counting, no research has yet been reported on the measurement and comparison of the depth of the chamber. We measured the exact depths of six kinds of sperm counting chambers and evaluated their accuracy.
Materials and Methods
In this prospective study, the depths of six kinds of sperm counting chambers for both manual and computer-aided semen analyses, including Makler (n=24), Macro (n=32), Geoffrey (n=34), GoldCyto (n=20), Leja (n=20) and Cell-VU (n=20), were measured with the Filmetrics F20 Spectral Reflectance Thin-Film Measurement System, then the mean depth, the range and the coefficient of variation (CV) of each chamber, and the mean depth, relative deviation and acceptability of each kind of chamber were calculated by the closeness to the nominal value. Among the 24 Makler chambers, 5 were new and 19 were used, and the other five kinds were all new chambers.
Results
The depths (mean ± SD, μm) of Makler (new), Macro and Geoffrey chambers were 11.07 ± 0.41, 10.19 ± 0.48 and 10.00 ± 0.28, respectively, while those of GoldCyto, Leja and Cell-VU chambers were 23.76 ± 2.15, 20.49 ± 0.22 and 24.22 ± 2.58, respectively. The acceptability of Geoffrey chambers was the highest (94.12%), followed by Macro (65.63%), Leja (35%) and Makler (20%), while that of the other two kinds and the used Makler chamber was zero.
Conclusion
There existed some difference between the actual depth and the corresponding nominal value for sperm counting chambers, and the overall acceptability was very low. Moreover, the abrasion caused by the long use, as of Makler chamber, for example, may result in unacceptability of the chamber. In order to ensure the accuracy and repeatability of sperm concentration results, the depth of the sperm counting chamber must be checked regularly.
PMCID: PMC4793174  PMID: 26985341
Depth; Measurement; Sperm Counting Chamber
8.  Two patients with small chromosome 22q11.21 alterations and central nervous system abnormalities 
Background
Central nervous system features have been rarely described to be associated with the small deletion or duplication of chromosome 22q11.21.
Case presentation
We report two patients with chromosome 22q11.21 alterations and central nervous system abnormalities. Features described include semilobar holoprosencephaly in the patient with the small deletion and Chiari I malformation in the patient with the small duplication.
Conclusions
This report will aid in the characterization of the clinical significance of interstitial duplications and deletions on the long-arm of chromosome 22. Areas of future research would benefit from additional analysis of the described regions with inclusion of the phenotypic findings described in this case report to provide additional insight into the pathogenicity of the described alterations.
doi:10.1186/s13039-015-0200-1
PMCID: PMC4696335  PMID: 26719767
Semilobar holoprosencephaly; Chiari I malformation; Central nervous system abnormalities; Microarray; Array CGH; Chromosome 22q11; Deletion; Duplication
9.  Glycyrrhetinic acid induces cytoprotective autophagy via the inositol-requiring enzyme 1α-c-Jun N-terminal kinase cascade in non-small cell lung cancer cells 
Oncotarget  2015;6(41):43911-43926.
Glycerrhetinic acid (GA), one of the main bioactive constituents of Glycyrrhiza uralensis Fisch, exerts anti-cancer effects on various cancer cells. We confirmed that GA inhibited cell proliferation and induced apoptosis in non-small cell lung cancer A549 and NCI-H1299 cells. GA also induced expression of autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and punta formation of green fluorescent protein microtubule-associated protein light-chain 3. We further proved that expression of GA-increased autophagy marker was attributed to activation instead of suppression of autophagic flux. The c-jun N-terminal kinase (JNK) pathway was activated after incubation with GA. Pretreatment with the JNK inhibitor SP600125 or silencing of the JNK pathway by siRNA of JNK or c-jun decreased GA-induced autophagy. The endoplasmic reticulum (ER) stress responses were also apparently stimulated by GA by triggering the inositol-requiring enzyme 1α (IRE1α) pathway. The GA-induced JNK pathway activation and autophagy were decreased by IRE1α knockdown, and inhibition of autophagy or the JNK cascade increased GA-stimulated IRE1α expression. In addition, GA-induced cell proliferative inhibition and apoptosis were increased by inhibition of autophagy or the JNK pathway. Our study was the first to demonstrate that GA induces cytoprotective autophagy in non-small cell lung cancer cells by activating the IRE1α-JNK/c-jun pathway. The combined treatment of autophagy inhibitors markedly enhances the anti-neoplasmic activity of GA. Such combination shows potential as a strategy for GA or GA-contained prescriptions in cancer therapy.
PMCID: PMC4791276  PMID: 26549806
glycyrrhetinic acid; autophagy; JNK; IRE1α; protective
10.  Orphan nuclear receptor NR4A2 inhibits hepatic stellate cell proliferation through MAPK pathway in liver fibrosis 
PeerJ  2015;3:e1518.
Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown. NR4A2 expression was examined by real-time polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence analyses. NR4A2 expression was significantly lower in fibrotic liver tissues and PDGF BB or TGF-β stimulated HSCs compared with control group. After NR4A2 knockdown α-smooth muscle actin and Col1 expression increased. In addition, NR4A2 silencing led to the promotion of cell proliferation, increase of cell percentage in S phase and reduced phosphorylation of ERK1/2, P38 and JNK in HSCs. These results indicate that NR4A2 can inhibit HSC proliferation through MAPK pathway and decrease extracellular matrix in liver fibrogenesis. NR4A2 may be a promising therapeutic target for liver fibrosis.
doi:10.7717/peerj.1518
PMCID: PMC4690364  PMID: 26713258
Fibrosis; Hepatic stellate cell; MAPK; NR4A2; Proliferation
11.  Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells 
Acta Pharmacologica Sinica  2015;36(12):1503-1513.
Aim:
Platycodin D, the main saponin isolated from Chinese herb Platycodonis Radix, exhibits anticancer activities against various cancer cell lines. Here we evaluated its anticancer action against human hepatocellular carcinoma cells in vitro and in vivo, and elucidated the relationship between platycodin D-induced apoptosis and autophagy.
Methods:
The viability of human hepatocellular carcinoma BEL-7402 cells was evaluated with MTT assay, and the apoptosis was examined using Annexin V/PI and Hoechst 33342 staining assays. Monodansylcadaverine (MDC) staining was used to label autophagic vacuoles. The proteins were detected using Western blot analysis. For studying its anticancer action in vivo, platycodin D (5 and 10 mg· kg−1·d−1) was intraperitoneally injected to BEL-7402-bearing mice for 21 days.
Results:
Platycodin D (5–40 μmol/L) inhibited the cell proliferation in vitro with IC50 values of 37.70±3.99, 24.30±2.30 and 19.70±2.36 μmol/L at 24, 48 and 72 h, respectively. Platycodin D (5–20 μmol/L) dose-dependently increased BEL-7402 cell apoptosis, increased the Bax/Bcl-2 ratio and the levels of cleaved PARP and cleaved caspase-3, and decreased the level of Bcl-2. Furthermore, platycodin D (5–20 μmol/L) induced autophagy in BEL-7402 cells, as evidenced by formation of cytoplasmic vacuoles, increased amounts of LC3-II, and increased numbers of MDC-positive cells. Pretreatment with the autophagy inhibitor chloroquine (5 μmol/L) or BAF (50 nmol/L) significantly enhanced platycodin D-induced proliferation inhibition and apoptosis. Moreover, platycodin D (20 μmol/L) activated the ERK and JNK pathways in BEL-7402 cells, and simultaneous blockage of the two pathways effectively suppressed platycodin D-induced autophagy and enhanced platycodin D-induced apoptosis. In BEL-7402-bearing mice, platycodin D (10 mg·kg−1•d−1) significantly reduced relative tumor volume with decreased body weight.
Conclusion:
Platycodin D not only inhibits the proliferation of BEL-7402 cells but also suppresses BEL-7402 xenograft tumor growth. Platycodin D-induced cell proliferation inhibition and apoptosis are amplified by co-treatment with autophagy inhibitors
doi:10.1038/aps.2015.99
PMCID: PMC4816242  PMID: 26592509
platycodin D; human hepatocellular carcinoma; BEL-7402 cells; apoptosis; autophagy; ERK; JNK; U0126; SP600125; chloroquine; BAF
12.  Glycyrrhetinic Acid Triggers a Protective Autophagy by Activation of Extracellular Regulated Protein Kinases in Hepatocellular Carcinoma Cells 
Glycyrrhetinic acid (GA), one of the main constituents of the famous Chinese medicinal herb and food additive licorice (Glycyrrhiza uralensis Fisch), has been indicated to possess potential anticancer effects and is widely utilized in hepatocellular carcinoma (HCC) targeted drug delivery systems (TDDS) due to the highly expressed target binding sites of GA on HCC cells. This study found that GA reduced the cell viability, increased the release of lactate dehydrogenase, and enhanced the expression of Bax, cleaved caspase-3, and LC3-II in HCC cells. The GA-triggered autophagy has been further confirmed by monodansylcadaverine staining as well as transmission electron microscopy analysis. The cell viability was obviously decreased whereas the expression of cleaved caspases was significantly increased when inhibition of autophagy by choloroquine or bafilomycin A1, suggesting that GA triggered a protective autophagy. Extracellular regulated protein kinase (ERK) was activated after treatment with GA in HepG2 cells and pretreatment with U0126 or PD98059, the MEK inhibitors, reversed GA-triggered autophagy as evidenced by decreased expression of LC3-II and formation of autophagosomes, respectively. Furthermore, GA-induced cell death and apoptosis were enhanced after pretreatment with PD98059. This is the first report that GA triggers a protective autophagy in HCC cells via activation of ERK, which might attenuate the anticancer effects of GA or chemotherapeutic drugs loaded with GA-modified TDDS.
doi:10.1021/jf503968k
PMCID: PMC4264863  PMID: 25403108
glycyrrhetinic acid; autophagy; hepatocellular carcinoma; ERK; protective
13.  The Applicability of the International Staging System in Chinese Patients with Multiple Myeloma Receiving Bortezomib or Thalidomide-Based Regimens as Induction Therapy: A Multicenter Analysis 
BioMed Research International  2015;2015:856704.
The International Staging System (ISS) is the most important prognostic system for multiple myeloma (MM). It was identified in the era of conventional agents. The outcome of MM has significantly changed by novel agents. Thus the applicability of ISS system in the era of novel agents in Chinese patients needs to be demonstrated. We retrospectively analyzed the clinical outcomes and prognostic significance of ISS system in 1016 patients with newly diagnosed multiple myeloma in Chinese patients between 2008 and 2012, who received bortezomib- or thalidomide-based regimens as first-line therapy. The median overall survival (OS) of patients for ISS stages I/II/III was not reached/55.4 months/41.7 months (p < 0.001), and the median progression-free survival (PFS) was 30/29.5/25 months (p = 0.072), respectively. Statistically significant difference in survival was confirmed among three ISS stages in thalidomide-based group, but not between ISS stages I and II in bortezomib-based group. These findings suggest that ISS system can predict the survival in the era of novel agents in Chinese MM patients, and bortezomib may have the potential to partially overcome adverse effect of risk factors on survival, especially in higher stage of ISS system.
doi:10.1155/2015/856704
PMCID: PMC4658402  PMID: 26640799
14.  Trophectoderm morphology predicts outcomes of pregnancy in vitrified-warmed single-blastocyst transfer cycle in a Chinese population 
Purpose
In this study, we estimated the effect of blastocoele expansion, ICM and TE quality after warming and culture on the rates of clinical pregnancy, live birth and miscarriage in vitrified-warmed single-blastocyst transfer cycle in a Chinese population.
Methods
A retrospective analysis of 263 cycles of vitrified-warmed single-blastocyst transfers was performed.
Results
The blastocysts with higher TE grade significantly increased the rates of clinical pregnancy (OR = 0.59, 95 % CI, 0.35–0.99, P = 0.045, grade (A + B) vs grade C) and live birth (OR = 0.55, 95 % CI, 0.32–0.94, P = 0.029, grade (A + B) vs grade C). And the association between TE grade and the rate of live birth didn’t change after the number of repeated cycles was adjusted (OR = 0.55, 95 % CI, 0.32–0.95, P = 0.033, grade (A + B) vs grade C). The number of repeated cycles was a confounding factor significantly different between the live birth and no live birth groups. By contrast, neither blastocoele expansion nor inner cell mass was statistically related to the rates of clinical pregnancy, live birth and miscarriage.
Conclusions
Our data firstly provided the evidence that TE grading, but not ICM grading, was significantly associated with the clinical pregnancy rate and live birth rate in vitrified-warmed blastocyst transfer cycles in a Chinese population. TE morphology may help predict outcomes of pregnancy in single-blastocyst transfer.
doi:10.1007/s10815-014-0317-x
PMCID: PMC4389933  PMID: 25123128
Blastocyst grading; Trophectoderm; Vitrified-warmed single-blastocyst transfer; Clinical pregnancy; Live birth
15.  A Pilot Comparative Study of 26 Biochemical Markers in Seminal Plasma and Serum in Infertile Men 
BioMed Research International  2015;2015:805328.
Introduction. The relationships of the biochemical components in seminal plasma and serum, and their origins and physiological effects in male reproductive system have been poorly understood. Methods. Based on the calibration and quality control measures, 26 biochemical markers, in seminal plasma and serum samples from 36 male infertility patients with nonazoospermia were detected and compared. Results. Only PA was undetectable in all seminal plasma samples. There were significant differences of all other 24 biochemical markers in seminal plasma and serum (P < 0.05) except for UA (P = 0.214). There were rich proteins in seminal plasma, and globulin accounted for about 90%. There were also abundant enzymes in seminal plasma, and the activities of ALT, AST, AKP, GGT, LDH, CK, and αHBDH in seminal plasma were significantly higher than those in serum while ADA was inversely lower. There were relatively low levels of Glu, TG, TC, and hsCRP in seminal plasma, but Glu was undetectable in 8 of 36 cases. Conclusions. The differences of the levels of biochemical markers in seminal plasma and serum might be associated with the selective secretion of testis, epididymis and male accessory glands, and the specific environment needed for sperm metabolism and function maintenance.
doi:10.1155/2015/805328
PMCID: PMC4619868  PMID: 26539526
16.  Identification and Functional Characterization of the Novel Edwardsiella tarda Effector EseJ 
Infection and Immunity  2015;83(4):1650-1660.
Edwardsiella tarda is a Gram-negative enteric pathogen that causes hemorrhagic septicemia in fish and gastro- and extraintestinal infections in humans. The type III secretion system (T3SS) of E. tarda has been identified as a key virulence factor that contributes to pathogenesis in fish. However, little is known about the associated effectors translocated by this T3SS. In this study, by comparing the profile of secreted proteins of the wild-type PPD130/91 and its T3SS ATPase ΔesaN mutant, we identified a new effector by matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry. This effector consists of 1,359 amino acids, sharing high sequence similarity with Orf29/30 of E. tarda strain EIB202, and is renamed EseJ. The secretion and translocation of EseJ depend on the T3SS. A ΔeseJ mutant strain adheres to epithelioma papillosum of carp (EPC) cells 3 to 5 times more extensively than the wild-type strain does. EseJ inhibits bacterial adhesion to EPC cells from within bacterial cells. Importantly, the ΔeseJ mutant strain does not replicate efficiently in EPC cells and fails to replicate in J774A.1 macrophages. In infected J774A.1 macrophages, the ΔeseJ mutant elicits higher production of reactive oxygen species than wild-type E. tarda. The replication defect is consistent with the attenuation of the ΔeseJ mutant in the blue gourami fish model: the 50% lethal dose (LD50) of the ΔeseJ mutant is 2.34 times greater than that of the wild type, and the ΔeseJ mutant is less competitive than the wild type in mixed infection. Thus, EseJ represents a novel effector that contributes to virulence by reducing bacterial adhesion to EPC cells and facilitating intracellular bacterial replication.
doi:10.1128/IAI.02566-14
PMCID: PMC4363441  PMID: 25667268
17.  Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity 
Scientific Reports  2015;5:14544.
Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 μM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus.
doi:10.1038/srep14544
PMCID: PMC4586517  PMID: 26416333
18.  Mitochondrial energy metabolism disorder and apoptosis: a potential mechanism of postoperative ileus 
Aim: To explore whether mitochondrial energy metabolism disorder and apoptosis of smooth muscle cells in intestinal muscularis are participated in pathogenesis of postoperative ileus (POI). Methods: Rats were randomized into three groups: naive controls (NC) group, sham controls (SC) group and intestinal manipulation (IM) group. Gastrointestinal transits were analyzed. Reactive oxygen species (ROS), malondialdehyde (MDA) and adenosine triphosphatases (ATPases) activity in intestinal muscularis were determined. The levels of aldehyde dehydrogenase 2 (ALDH2), Bcl-2 and Bax in intestinal muscularis were measured by real-time PCR assays and western blot analysis. The levels of ATP, ADP and AMP in intestinal muscularis were determined by high performance liquid chromatography. Transmission electron microscopic was used to observe ultrastructure of smooth muscle cells and mitochondria in intestinal muscularis. Results: Delayed gastrointestinal transitoccurred only in IM groups. After IM, increased levels of ROS and MDA were observed in intestinal muscularis. In IM groups, we also observed decreased levels of ALDH2 and Bcl-2/Bax ratio. The levels of ATP and ADP were decreased and level of AMP was increased in IM groups. The activity of ATPases was decreased in IM groups. Abnormal morphological architecture of smooth muscle cells and mitochondria were found in intestinal muscularis of IM groups. Conclusion: Our results suggest that mitochondrial energy metabolism disorder and apoptosis of smooth muscle cells in intestinal muscularis may participate in the development of POI.
PMCID: PMC4658859  PMID: 26628970
Postoperative ileus; oxidative stress; mitochondria; energy metabolism; apoptosis
19.  Impact of different surgical traumas on postoperative ileus in rats and the mechanisms involved 
The degree of postoperative ileus and the underlying pathophysiological mechanism among different types of surgical traumas have not been examined. The aim of this study was to investigate the inflammatory and oxidative stress changes in rat intestinal muscularis and gastrointestinal transit among three types of surgical traumas. Rats were randomized assigned to four groups: control group, intestinal manipulation (IM) group, intestinal ischemia/reperfusion injury (IR) group and peritoneal air exposure (AE) group. Gastrointestinal transit was measured 24 hours after surgery. Malondialdehyde (MDA), glutathione (GSH) and inflammatory mediators in intestinal muscularis were measured. Influx of neutrophil in intestinal muscularis was also determined. The degree of gastrointestinal motility impairment was equal between the IM and AE groups. However, the IR group was subject to a less impairment of gastrointestinal motility compared with the IM and AE groups. The IM group showed the most significant increase of inflammatory response, while the AE group showed the most significant increase of oxidative stress. The IR group showed a moderate increase of inflammatory response and oxidative stress. Rats subjected to IM, IR and AE could all develop into POI. We speculate that oxidative stress should be an equally important pathophysiological mechanism of POI as inflammation.
PMCID: PMC4659108  PMID: 26629220
Postoperative ileus; oxidative stress; inflammation; surgical trauma
20.  Electroacupuncture versus Moxibustion for Irritable Bowel Syndrome: A Randomized, Parallel-Controlled Trial 
Objective. To compare the impacts of electroacupuncture (EA) and mild moxibustion (Mox) on patients with irritable bowel syndrome (IBS). Method. Eighty-two IBS patients were randomly allocated into EA group (n = 41) and Mox group (n = 41) and received corresponding interventions for four weeks. Before and after the treatment, the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS) was used to evaluate the gastrointestinal symptoms and mental well-being; and the expression of serotonin (5-hydroxytryptamine, 5-HT), 5-HT3 receptor (5-HT3R), and 5-HT4 receptor (5-HT4R) in sigmoid mucosal tissue were detected. Results. Both EA and Mox can radically improve the total VAS-IBS score (P < 0.05), and EA was found to be more effective in ameliorating the symptom of constipation, while Mox was found to be more effective in ameliorating the symptom of diarrhoea. The abnormal expressions of 5-HT, 5-HT3R, and 5-HT4R in both groups were significantly improved after the treatments (all P < 0.05), and EA was superior to Mox in regulating the abnormally decreased 5-HT4R expression in IBS patients with constipation (P < 0.05). Conclusion. Electroacupuncture and mild moxibustion were both effective in improving IBS symptoms and modulate abnormal expressions of 5-HT, 5-HT3R, and 5-HT4R in the colonic tissue.
doi:10.1155/2015/361786
PMCID: PMC4534607  PMID: 26294923
21.  Cardamonin Regulates miR-21 Expression and Suppresses Angiogenesis Induced by Vascular Endothelial Growth Factor 
BioMed Research International  2015;2015:501581.
Cardamonin has promising potential in cancer prevention and therapy by interacting with proteins and modifying the expressions and activities, including factors of cell survival, proliferation, and angiogenesis. In our precious study, we have demonstrated that cardamonin suppressed vascular endothelial growth factor- (VEGF-) induced angiogenesis as evaluated in the mouse aortic ring assay. It is also known that microRNAs (miRNAs) play important roles in angiogenesis. Herein, we hypothesized whether antiangiogenesis effect of cardamonin in human umbilical vein endothelial cells (HUVECs) triggered by VEGF was associated with miRNAs. We found that cardamonin reduced the miR-21 expression induced by VEGF in HUVECs. Treatment with miR-21 mimics abolished the effects of cardamonin on VEGF-induced cell proliferation, migration, and angiogenesis in HUVECs. However, treatment with miR-21 inhibitors presented the opposite effects, indicating the vital role of miR-21 in this process. Our study provides a new insight of the preliminary mechanism of anti-VEGF-induced angiogenesis by cardamonin in HUVECs.
doi:10.1155/2015/501581
PMCID: PMC4523674  PMID: 26266258
22.  Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study 
Nature Communications  2015;6:7633.
Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
Graves' disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
doi:10.1038/ncomms8633
PMCID: PMC4506516  PMID: 26151496
23.  Genome-wide analysis, expression profile of heat shock factor gene family (CaHsfs) and characterisation of CaHsfA2 in pepper (Capsicum annuum L.) 
BMC Plant Biology  2015;15:151.
Background
Heat shock factors (Hsfs) play crucial roles in plant developmental and defence processes. The production and quality of pepper (Capsicum annuum L.), an economically important vegetable crop, are severely reduced by adverse environmental stress conditions, such as heat, salt and osmotic stress. Although the pepper genome has been fully sequenced, the characterization of the Hsf gene family under abiotic stress conditions remains incomplete.
Results
A total of 25 CaHsf members were identified in the pepper genome by bioinformatics analysis and PCR assays. They were grouped into three classes, CaHsfA, B and C, based on highly conserved Hsf domains, were distributed over 11 of 12 chromosomes, with none found on chromosome 11, and all of them, except CaHsfA5, formed a protein–protein interaction network. According to the RNA-seq data of pepper cultivar CM334, most CaHsf members were expressed in at least one tissue among root, stem, leaf, pericarp and placenta. Quantitative real-time PCR assays showed that all of the CaHsfs responded to heat stress (40 °C for 2 h), except CaHsfC1 in thermotolerant line R9 leaves, and that the expression patterns were different from those in thermosensitive line B6. Many CaHsfs were also regulated by salt and osmotic stresses, as well as exogenous Ca2+, putrescine, abscisic acid and methyl jasmonate. Additionally, CaHsfA2 was located in the nucleus and had transcriptional activity, consistent with the typical features of Hsfs. Time-course expression profiling of CaHsfA2 in response to heat stress revealed differences in its expression level and pattern between the pepper thermosensitive line B6 and thermotolerant line R9.
Conclusions
Twenty-five Hsf genes were identified in the pepper genome and most of them responded to heat, salt, osmotic stress, and exogenous substances, which provided potential clues for further analyses of CaHsfs functions in various kinds of abiotic stresses and of corresponding signal transduction pathways in pepper.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0512-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0512-7
PMCID: PMC4472255  PMID: 26088319
Pepper; Identification of CaHsfs family; Abiotic stress; CaHsfA2; Gene expression
24.  Rutin ameliorates renal fibrosis and proteinuria in 5/6-nephrectomized rats by anti-oxidation and inhibiting activation of TGFβ1-smad signaling 
Objectives: Rutin, a polyphenolic flavonoid, was reported to have beneficial effect on drug induced nephropathy. The present study aimed to introduce 5/6 nephrectomized rat model to further evaluate its renal protective effect. Methods: Adult Wistar rats were induced to develop chronic renal failure through 5/6 nephrectomy (5/6 Nx). After that, animals were treated orally with saline, rutin at 15 and 45 mg/kg, and losartan (10 mg/kg) daily for 20 weeks; sham-operated animals were also involved as control. After treatment for 8 and 20 weeks, blood and urine samples were collected for biochemical examination; all the kidney remnants were collected for histological examination. The protein levels of TGF-β1, smad2 and phosphorylated-smad2 (p-smad2) in kidney were measured. Immunohistochemistry was used to analyze the expression of TGF-β1, fibronectin and collagen IV in kidney tissues. Results: Results suggested that rutin could reduce the proteinurea, blood urine nitrogen and blood creatinine in 5/6 Nx animals significantly, as well as oxidation stress in the kidney. By histological examination, rutin administration alleviated glomerular sclerosis scores and tubulointerstitial injuries in a dose-dependent manner (P<0.01). Immunohistochemistry also suggested rutin could reduce the expression of TGF-β1, fibronectin and collagen IV in kidney tissues. By western blot, we found the rutin could reduce the TGF-β1, p-smad2 expression in the kidney tissues of rats. Conclusions: This study suggests that the rutin can improve renal function in 5/6 Nx rats effectively. Its effect may be due to its anti-oxidation and inhibiting TGFβ1-Smad signaling.
PMCID: PMC4503034  PMID: 26191162
Rutin; 5/6 nephrectomy; TGF-β1; chronic renal failure
25.  Potent natural products and herbal medicines for treating liver fibrosis 
Chinese Medicine  2015;10:7.
Liver fibrosis is a wound-healing response to chronic liver injury characterized by progressive inflammation and deposition of extracellular matrix components. The pathological condition of liver fibrosis involves secretion of extracellular matrix proteins and formation of scar tissue. The major regulators involved in hepatic fibrogenesis are the transforming growth factor (TGF)-β1/SMAD and toll-like receptor 4 (TLR4)-initiated myeloid differentiation primary response 88 gene (MyD88)/NF-ĸB cell signaling pathways. This article reviews natural products and herbal medicines that have demonstrated activity against liver fibrosis through different mechanisms of action, including anti-hepatitis B and C virus activity, anti-inflammation, inhibition of cytokine production and nuclear receptor activation, and free radical scavenging.
doi:10.1186/s13020-015-0036-y
PMCID: PMC4403904  PMID: 25897319

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