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1.  Development and In Vitro Release of Isoniazid and Rifampicin-Loaded Bovine Serum Albumin Nanoparticles 
Background
Bovine serum albumin nanoparticles loaded with isoniazid and rifampicin (INH-RFP-BSA-NPs) were prepared and their release characteristics were studied in vitro.
Material/Methods
The INH-RFP-BSA-NPs were prepared by a modified self-emulsion solvent diffusion method, with albumin and polylactic acid used as carriers and to form the nanoparticles structure. Transmission electron microscopy was used to observe the morphology of the INH-RFP-BSA-NPs. The size distribution of the INH-RFP-BSA-NPs were assessed using a submicron particle-size analyzer for drug loadings, and the coating rate of the INH-RFP-BSA-NPs was measured by high-performance liquid chromatography. A dynamic membrane dialysis method was used to study the in vitro release characteristics of the INH-RFP-BSA-NPs.
Results
The INH-RFP-BSA-NPs were smooth, sphere-like, relatively uniform in size, and well-dispersed, and the average diameter was 60.5±4.6 nm. Drug loading and entrapment efficiencies were high, at 19.8% and 87.8% for isoniazid, respectively, and 20.1% and 98.0% for rifampicin, respectively. Drug release was slow and sustained with 97.02% INH cumulative release at 6 days, and full release of RFP requiring 5 days.
Conclusions
INH-RFP-BSA-NPs exhibit uniform NP diameter, good dispersion, high drug loading and encapsulation rates, and have sustained release properties.
doi:10.12659/MSM.905581
PMCID: PMC5791387  PMID: 29364864
Albumins; In Vitro; Isoniazid; Nanoparticles
2.  MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47 
Molecular Cancer  2018;17:12.
Immunoevasion is a hallmark of cancer progression, and immune checkpoint blockade has emerged as a promising strategy for cancer treatment. microRNAs (miRNAs) are important negative regulators of gene expression in the immune system. Here, we demonstrate that miR-708 regulates CD47, a transmembrane protein that inhibits phagocytosis in T cell acute lymphoblastic leukemia. miR-708 directly targeted CD47 through binding to 3’UTR and is inversely correlated with CD47 expression. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo. Together, our findings suggest that miR-708 is a key negative regulator of CD47 and may serve as an attractive candidate for immunotherapy of T-ALL.
Electronic supplementary material
The online version of this article (10.1186/s12943-018-0768-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-018-0768-2
PMCID: PMC5782377  PMID: 29368647
miR-708; CD47; T-cell acute lymphoblastic leukemia; Targeted therapies
3.  miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease 
Circulation research  2016;120(2):354-365.
Rationale
Endothelial-to-mesenchymal transition (EndoMT) is implicated in myofibroblast-like cell-mediated damage to the coronary arterial wall in acute Kawasaki disease (KD) patients, as evidenced by positive staining for connective tissue growth factor (CTGF) and EndoMT markers in KD autopsy tissues. However, little is known about the molecular basis of EndoMT involved in KD.
Objective
We investigated the microRNA (miRNA) regulation of CTGF and the consequent EndoMT in KD pathogenesis. As well, the modulation of this process by statin therapy was studied.
Methods and Results
Sera from healthy children and KD subjects were incubated with human umbilical vein endothelial cells (HUVECs). Cardiovascular disease-related miRNAs, CTGF, and EndoMT markers were quantified using RT-qPCR, ELISA, and Western blotting. Compared to healthy controls, HUVEC incubated with sera from acute KD patients had decreased miR-483, increased CTGF, and increased EndoMT markers. Bioinformatics analysis followed by functional validation demonstrated that Krüppel-like factor 4 (KLF4) transactivates miR-483, which in turn targets the 3′ untranslated region of CTGF mRNA. Overexpression of KLF4 or pre-miR-483 suppressed, whereas knockdown of KLF4 or anti-miR-483 enhanced, CTGF expression in ECs in vitro and in vivo. Furthermore, atorvastatin, currently being tested in a Phase I/IIa clinical trial in KD children, induced KLF4-miR-483, which suppressed CTGF and EndoMT in ECs.
Conclusions
KD sera suppress the KLF4-miR-483 axis in ECs leading to increased expression of CTGF and induction of EndoMT. This detrimental process in the endothelium may contribute to coronary artery abnormalities in KD patients. Statin therapy may benefit acute KD patients, in part through the restoration of KLF4-miR-483 expression.
Clinical Trial Registration
NCT01431105
doi:10.1161/CIRCRESAHA.116.310233
PMCID: PMC5391835  PMID: 27923814
Kawasaki disease; miR-483; CTGF; EndoMT; atorvastatin; microRNA; endothelial dysfunction; Pediatrics; Translational Studies; Endothelium/Vascular Type/Nitric Oxide; Fibrosis; Vascular Disease
4.  Enhancer-associated long non-coding RNA LEENE regulates endothelial nitric oxide synthase and endothelial function 
Nature Communications  2018;9:292.
The optimal expression of endothelial nitric oxide synthase (eNOS), the hallmark of endothelial homeostasis, is vital to vascular function. Dynamically regulated by various stimuli, eNOS expression is modulated at transcriptional, post-transcriptional, and post-translational levels. However, epigenetic modulations of eNOS, particularly through long non-coding RNAs (lncRNAs) and chromatin remodeling, remain to be explored. Here we identify an enhancer-associated lncRNA that enhances eNOS expression (LEENE). Combining RNA-sequencing and chromatin conformation capture methods, we demonstrate that LEENE is co-regulated with eNOS and that its enhancer resides in proximity to eNOS promoter in endothelial cells (ECs). Gain- and Loss-of-function of LEENE differentially regulate eNOS expression and EC function. Mechanistically, LEENE facilitates the recruitment of RNA Pol II to the eNOS promoter to enhance eNOS nascent RNA transcription. Our findings unravel a new layer in eNOS regulation and provide novel insights into cardiovascular regulation involving endothelial function.
eNOS expression is dynamically regulated both transcriptionally and post-transcriptionally by various stimuli. Here the authors identify an enhancer-associated lncRNA (LEENE) that is co-regulated with, and enhances eNOS expression.
doi:10.1038/s41467-017-02113-y
PMCID: PMC5773557  PMID: 29348663
5.  Association between KIF6 rs20455 polymorphism and the risk of coronary heart disease (CHD): a pooled analysis of 50 individual studies including 40,059 cases and 64,032 controls 
Background
The KIF6 rs20455 polymorphism has been verified as an important genetic factor of coronary heart disease (CHD), but with controversial results. The aim of this study was to explore the association between KIF6 rs20455 polymorphism and susceptibility to CHD.
Methods
All eligible studies were identified by searching Medline (mainly PubMed), EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure, Wanfang Database and China Biological Medicine up to October 5, 2016.Odds ratios (ORs) with 95% confidence interval (CI) were used to explore the association between KIF6 rs20455 polymorphism and CHD risk. Begg’s and Egger’s tests were used to examine the publication bias. Subgroup analysis and sensitivity analysis were performed to test the reliability and stability of the results. All the analyses were carried out by Stata 12.0 software.
Results
A total of 28 publications including 50 individual studies were analyzed in this present work. There are no significant association found between KIF6 rs20455 polymorphism and CHD risk (Homozygote model: OR = 1.007, 95% CI =0.952–1.066, P = 0.801; Heterozygote model: OR = 1.009, 95% CI = 0.968–1.052, P = 0.636; Dominant model: OR = 1.007, 95% CI = 0.966–1.048, P = 0.753; Recessive model: OR = 0.989, 95% CI = 0.943–1.037, P = 0.655; Allele comparison model: OR = 1.00, 95% CI = 0.971–1.030, P = 0.988). Furthermore, subgroup analyses were performed by ethnicity, source of control.
Conclusions
Our result suggests that KIF6 rs20455 polymorphism may not be associated with CHD susceptibility. However, additional very well-designed large-scale studies are warranted to confirm our results.
doi:10.1186/s12944-017-0651-y
PMCID: PMC5755295  PMID: 29304815
Coronary heart disease; KIF6 rs20455; Polymorphism; Meta-analysis
6.  Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an interrater agreement study 
Objective
To determine agreement of endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI) and histopathology, viewed sequentially.
Design
Interrater agreement study
Setting
Five urban surgical centers
Population
Women, aged 18–44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 without a postoperative endometriosis diagnosis was obtained from the ENDO Study.
Methods
Laparoscopies were diagnosed, digitally recorded, and reassessed.
Main Outcome Measures
Interobserver agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias adjusted kappas (κ) were calculated for diagnosis and weighted κ were calculated for staging.
Results
Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n=148) (mean κ=0.67, range: 0.61–0.69; mean κ=0.64, range: 0.53–0.78, respectively) and after additionally viewing operative reports (n=148) (mean κ=0.88, range: 0.85–0.89; mean κ=0.85, range: 0.84–0.86, respectively). While additionally viewing MRI findings (n=36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n=67) with expert reviewers changing their assessment from a positive to negative diagnosis in up to 20% of cases.
Conclusions
While these findings suggest that misclassification bias in diagnosis or staging of endometriosis via visualized disease is minimal, they should alert gynecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments.
Tweetable abstract
Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.
doi:10.1111/1471-0528.13711
PMCID: PMC4821828  PMID: 26435386
endometriosis; epidemiology; reliability; laparoscopy; histology; magnetic resonance imaging
7.  Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis 
Nature Communications  2017;8:2168.
Aberrant activation of NLRP3 inflammasome has an important function in the pathogenesis of various inflammatory diseases. Although many components and mediators of inflammasome activation have been identified, how NLRP3 inflammasome is regulated to prevent excessive inflammation is unclear. Here we show NLRP3 inflammasome stimulators trigger Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocation to the mitochondria, to interact with and dephosphorylate adenine nucleotide translocase 1 (ANT1), a central molecule controlling mitochondrial permeability transition. This mechanism prevents collapse of mitochondrial membrane potential and the subsequent release of mitochondrial DNA and reactive oxygen species, thus preventing hyperactivation of NLRP3 inflammasome. Ablation or inhibition of SHP2 in macrophages causes intensified NLRP3 activation, overproduction of proinflammatory cytokines IL-1β and IL-18, and increased sensitivity to peritonitis. Collectively, our data highlight that, by inhibiting ANT1 and mitochondrial dysfunction, SHP2 orchestrates an intrinsic regulatory loop to limit excessive NLRP3 inflammasome activation.
The NLRP3 inflammasome is central to a variety of inflammatory diseases, but how it is regulated to prevent excessive inflammation is not clear. Here the authors show that NLRP3 activation causes SHP2 translocation to the mitochondria to interact with and dephosphorylate ANT1, thus stabilizing the mitochondria and preventing release of proinflammatory mitochondrial DNA and ROS.
doi:10.1038/s41467-017-02351-0
PMCID: PMC5735095  PMID: 29255148
8.  Production of C2–C4 diols from renewable bioresources: new metabolic pathways and metabolic engineering strategies 
C2–C4 diols classically derived from fossil resource are very important bulk chemicals which have been used in a wide range of areas, including solvents, fuels, polymers, cosmetics, and pharmaceuticals. Production of C2–C4 diols from renewable resources has received significant interest in consideration of the reducing fossil resource and the increasing environmental issues. While bioproduction of certain diols like 1,3-propanediol has been commercialized in recent years, biosynthesis of many other important C2–C4 diol isomers is highly challenging due to the lack of natural synthesis pathways. Recent advances in synthetic biology have enabled the de novo design of completely new pathways to non-natural molecules from renewable feedstocks. In this study, we review recent advances in bioproduction of C2–C4 diols, focusing on new metabolic pathways and metabolic engineering strategies being developed. We also discuss the challenges and future trends toward the development of economically competitive processes for bio-based diol production.
doi:10.1186/s13068-017-0992-9
PMCID: PMC5727944
Diols; Bioresource; Pathway design; New metabolic pathway; Metabolic engineering
9.  Characterization of a novel bioflocculant from a marine bacterium and its application in dye wastewater treatment 
BMC Biotechnology  2017;17:84.
Background
The identification of microorganisms with excellent flocculant-producing capability and optimization of the fermentation process are necessary for the wide-scale application of bioflocculants. Thus, we evaluated the flocculant-producing ability of a novel strain identified by the screening of marine bacteria, and we report for the first time the properties of the bioflocculant produced by Alteromonas sp. in the treatment of dye wastewater.
Results
A bioflocculant-producing bacterium was isolated from seawater and identified as Alteromonas sp. CGMCC 10612. The optimal carbon and nitrogen sources for the strain were 30 g/L glucose and 1.5 g/L wheat flour. In a 2-L fermenter, the flocculating activity and bioflocculant yield reached maximum values of 2575.4 U/mL and 11.18 g/L, respectively. The bioflocculant was separated and showed good heat and pH stability. The purified bioflocculant was a proteoglycan consisting of 69.61% carbohydrate and 21.56% protein (wt/wt). Infrared spectrometry further indicated the presence of hydroxyl, carboxyl and amino groups preferred for flocculation. The bioflocculant was a nanoparticle polymer with an average mass of 394,000 Da. The purified bioflocculant was able to remove Congo Red, Direct Black and Methylene Blue at efficiencies of 98.5%, 97.9% and 72.3% respectively.
Conclusions
The results of this study indicated that the marine strain Alteromonas sp. is a good candidate for the production of a novel bioflocculant and suggested its potential industrial utility for biotechnological processes.
Electronic supplementary material
The online version of this article (10.1186/s12896-017-0404-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12896-017-0404-z
PMCID: PMC5693566  PMID: 29149843
Bioflocculant; Alteromonas sp.; Marine bacterium; Dye wastewater
10.  Comparisons of health-related quality of life among surgery and radiotherapy for localized prostate cancer: a systematic review and meta-analysis 
Oncotarget  2017;8(58):99057-99065.
The objective of this study is to compare health-related quality of life (QOL) outcomes between radical prostatectomy (RP) and external beam radiation therapy (EBRT) for localized prostate cancer. PubMed, EMBASE, the Cochrane Library and Web of Science (to July 2017) were searched. Pooled analysis of each domain-specific score was calculated in relevant studies, and its change with follow-up time was explored by sub-group analysis. A total of six studies containing 4423 patients were included. Men underwent RP was associated with worse urinary and sexual domain score than EBRT (standardized mean difference (SMD) = –0.59, –0.58; 95% confidence interval (CI) = –0.73 to –0.45, –0.72 to –0.44). In contrast, EBRT group had lower bowel domain score than RP group (SMD = 0.42, 95% CI = 0.33 to 0.52). The sub-group analysis revealed the most severe urinary and sexual QOL in RP as well as bowel QOL in EBRT group all happened in the first month post operation. The different performance of two treatments in three QOL domains diminished afterwards. Health-related QOL should be considered comprehensively when planning follow-up for men after RP or EBRT for localized prostate cancer.
doi:10.18632/oncotarget.21519
PMCID: PMC5716791
prostatic neoplasms; prostatectomy; radiotherapy; quality of life
11.  Prognostic value of pretreatment serum carbohydrate antigen 19-9 level in patients with colorectal cancer: A meta-analysis 
PLoS ONE  2017;12(11):e0188139.
Background
Carbohydrate antigen 19–9 (CA 19–9) is one of the most frequently used tumor markers for gastrointestinal cancer, particularly for diagnostic purposes. However, its value in predicting prognosis remains controversial. In this study, we sought to clarify this by conducting a meta-analysis of relevant studies.
Methods
We systematically searched several databases, including PubMed, EMBASE and Web of Science for articles pertaining to the relationship between pretreatment serum CA 19–9 levels and prognosis in patients with colorectal cancer (CRC). The reported hazard ratios (HR) of overall survival (OS), disease-free survival (DFS), pooled progression-free survival (PFS) and recurrence-free survival (RFS) in the analyzed studies were compared by fixed effects/random effects models.
Results
Seventeen studies involving 6434 patients with CRC were included in our meta-analysis. A comprehensive analysis of the collected data revealed that high serum CA 19–9 levels before treatment were significantly associated with poor OS (HR: 1.58, 95% CI: 1.36–1.83, P<0.001), DFS (HR: 1.71, 95% CI: 1.38–2.13, P<0.001), PFS (HR: 1.30,95%CI:0.93–1.82, P = 0.121) and RFS (HR: 1.43, 95% CI: 1.11–1.83, P = 0.006). This association between high pretreatment serum CA 19–9 levels and poor survival held true across different geographical regions, analysis types, methods used for HR determination, sample size, and treatment methods.
Conclusions
The results of this study indicate that pretreatment serum CA 19–9 level can be used as a prognostic indicator for patients with CRC.
doi:10.1371/journal.pone.0188139
PMCID: PMC5687748  PMID: 29141049
12.  The Impact of Heat Treatment on Porcine Heart Valve Leaflets 
The purpose of this study was to determine the impact of elevated temperature exposure in tissue banking on soft tissues. A secondary objective was to determine the relative ability of various assays to detect changes in soft tissues due to temperature deviations. Porcine pulmonary heart valve leaflets exposed to 37 °C were compared with those incubated at 52 and 67 °C for 10, 30 and 100 min. The analytical methods consisted of (1) viability assessment using the resazurin assay, (2) collagen content using the Sircol assay, and (3) permeability assessment using an electrical conductivity assay. Additionally, histology and two photon microscopy were used to reveal mechanisms of cell and tissue damage. Viability, collagen content, and permeability all decreased following heat treatment. In terms of statistical significance with respect to treatment temperature, cell viability was most affected (p < 0.0001), followed by permeability (p < 0.0001), and then collagen content (p = 0.13). After heat treatment, histology indicated increased apoptosis and two photon microscopy revealed a decrease in collagen fiber organization and an increase in elastin density. These results suggest that measures of cell viability would be best for assessing tissues where the cells are alive and that permeability may be best where cell viability is not intentionally maintained.
doi:10.1007/s13239-017-0334-x
PMCID: PMC5797199  PMID: 29134471
Heart valve; Heat treatment; Tissue banking; Cell viability; Collagen content; Matrix permeability
13.  Characterization of a beta-glucosidase from Bacillus licheniformis and its effect on bioflocculant degradation 
AMB Express  2017;7:197.
Bacillus licheniformis CGMCC 2876, an aerobic spore-forming bacterium, produces a polysaccharide bioflocculant that is biodegradable and harmless. The present study determined that β-glucosidase played a negative role in bioflocculant synthesis. The gene encoding β-glucosidase was cloned and expressed in Escherichia coli BL21. This gene consists of 1437 bp and encodes 478 amino acid residues. The recombinant β-glucosidase (Bgl.bli1) was purified and showed a molecular mass of 53.4 kDa by SDS-PAGE. The expression and reaction conditions of Bgl.bli1 were optimized; the activity of β-glucosidase reached a maximum at 45.44 U/mL. Glucose clearly inhibited the activity of β-glucosidase. The purified recombinant Bgl.bli1 hydrolysed polysaccharide bioflocculant in vitro and synergised with other cellulases. The ability of Bgl.bli1 to hydrolyse polysaccharide bioflocculant was the reason for the decrease in flocculating activity and indicated the utility of this enzyme for diverse industrial processes.
doi:10.1186/s13568-017-0501-3
PMCID: PMC5673865  PMID: 29110104
β-Glucosidase; Heterologous expression; Polysaccharide bioflocculant; Bacillus licheniformis
14.  Treatment of hypertension by increasing impaired endothelial TRPV4‐KCa2.3 interaction 
EMBO Molecular Medicine  2017;9(11):1491-1503.
Abstract
The currently available antihypertensive agents have undesirable adverse effects due to systemically altering target activity including receptors, channels, and enzymes. These effects, such as loss of potassium ions induced by diuretics, bronchospasm by beta‐blockers, constipation by Ca2+ channel blockers, and dry cough by ACEI, lead to non‐compliance with therapies (Moser, 1990). Here, based on new hypertension mechanisms, we explored a new antihypertensive approach. We report that transient receptor potential vanilloid 4 (TRPV4) interacts with Ca2+‐activated potassium channel 3 (KCa2.3) in endothelial cells (ECs) from small resistance arteries of normotensive humans, while ECs from hypertensive patients show a reduced interaction between TRPV4 and KCa2.3. Murine hypertension models, induced by high‐salt diet, N(G)‐nitro‐l‐arginine intake, or angiotensin II delivery, showed decreased TRPV4‐KCa2.3 interaction in ECs. Perturbation of the TRPV4‐KCa2.3 interaction in mouse ECs by overexpressing full‐length KCa2.3 or defective KCa2.3 had hypotensive or hypertensive effects, respectively. Next, we developed a small‐molecule drug, JNc‐440, which showed affinity for both TRPV4 and KCa2.3. JNc‐440 significantly strengthened the TRPV4‐KCa2.3 interaction in ECs, enhanced vasodilation, and exerted antihypertensive effects in mice. Importantly, JNc‐440 specifically targeted the impaired TRPV4‐KCa2.3 interaction in ECs but did not systemically activate TRPV4 and KCa2.3. Together, our data highlight the importance of impaired endothelial TRPV4‐KCa2.3 coupling in the progression of hypertension and suggest a novel approach for antihypertensive drug development.
doi:10.15252/emmm.201707725
PMCID: PMC5666316  PMID: 28899928
artery; endothelium; hypertension; KCa2.3; TRPV4; Cardiovascular System; Vascular Biology & Angiogenesis
15.  Europium (III) chelate microparticle-based lateral flow immunoassay strips for rapid and quantitative detection of antibody to hepatitis B core antigen 
Scientific Reports  2017;7:14093.
Quantitative hepatitis B core antigen (anti-HBc) measurements could play an important role in evaluating therapeutic outcomes and optimizing the antiviral therapy of chronic hepatitis B infection. In this study, we have developed a simple and rapid fluorescence point-of-care test based on a lateral flow immunoassay (LFIA) method integrated with Eu (III) chelate microparticles to quantitatively determine anti-HBc concentrations in serum. This assay is based on a direct competitive immunoassay performed on lateral flow test strips with an assay time of 15 min. The Eu (III) chelate microparticle-based LFIA assay could quantitatively detect anti-HBc levels with a limit of detection of 0.31 IU mL−1, and exhibited a wide linear range (0.63–640 IU mL−1). The intra- and inter-assay coefficients of variation for anti-HBc were both less than 10% and a satisfactory dilution test and accuracy were demonstrated. There were no statistically significant differences in sensitivity or specificity in serum samples between the Eu (III) chelate microparticle-based LFIA strips and the Abbott Architect kit. A simple, rapid and effective quantitative detection of anti-HBc was possible using the Eu (III) chelate microparticle-based LFIA strips. The strips will provide diagnostic value for clinical application.
doi:10.1038/s41598-017-14427-4
PMCID: PMC5658374  PMID: 29074971
16.  Effect of Hua Yu Xiao Zheng decoction on the expression levels of vascular endothelial growth factor and angiopoietin-2 in rats with endometriosis 
The aims of the present study were to investigate the effects of a traditional Chinese medicine, Hua Yu Xiao Zheng (HYXZ) decoction, on surgically induced endometriosis in a rat model and to determine the possible underlying regulatory mechanisms. A total of 108 female Sprague-Dawley rats were divided into the control group (n=12) and endometriosis group (EM group; n=96), in which endometriosis was surgically induced in model rats by autotransplantation of endometrial tissues and 72 rats survived. After 3 weeks, the EM model rats were randomly divided into four subgroups (n=18), including the untreated model group, and three groups administered 7, 14 or 21 g/kg HYXZ decoction. Following 28 days of treatment, the associated proteins and genes of ectopic endometrial tissues were analyzed using immunohistochemistry, western blotting and quantitative polymerase chain reaction to investigate the underlying mechanisms. Compared with the model group, the size of the endometriotic implants decreased significantly in the HYXZ-treated groups. Furthermore, the expression levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were significantly decreased in HYXZ-treated groups compared with the model group. These results indicate that HYXZ affected the inhibition of angiogenesis and decreased the endometriotic implant volumes and histopathological scores. The effectiveness of HYXZ may be partially attributed to the decrease of VEGF and Ang-2 expression levels in the ectopic endometrium.
doi:10.3892/etm.2017.5280
PMCID: PMC5740754
endometriosis; vascular endothelial growth factor; angiopoietin-2; Hua Yu Xiao Zheng decoction; western blotting
17.  Women's Reproductive History Before the Diagnosis of Incident Endometriosis 
Journal of Women's Health  2016;25(10):1021-1029.
Abstract
Background: Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction.
Materials and Methods: The study sample comprised 473 women (aged 18–44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007–2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity.
Results: Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46–1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1.
Conclusions: Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.
doi:10.1089/jwh.2015.5712
PMCID: PMC5111831  PMID: 27379997
endometriosis; epidemiology; fertility
18.  Increasing the bioflocculant production and identifying the effect of overexpressing epsB on the synthesis of polysaccharide and γ-PGA in Bacillus licheniformis 
Background
Polysaccharides and poly-γ-glutamic acid (γ-PGA) are biomacromolecules that have been reported as bioflocculants, and they exhibit high flocculating activity in many industrial applications. Bacillus licheniformis CGMCC 2876 can produce polysaccharide and γ-PGA bioflocculants under different culture conditions. Several key genes are involved in the metabolic pathway of polysaccharides in B. licheniformis, but the impacts of the regulation of these genes on the production of polysaccharide bioflocculants have not been illustrated completely. To increase the bioflocculant production and identify the correlation between the synthesis of polysaccharides and γ-PGA in B. licheniformis, a few key genes were investigated to explore their influence on the synthesis of the bioflocculants.
Results
Overexpressing epsB from the eps gene cluster not only improved the bioflocculant crude yield by 13.98% but also enhanced the flocculating activity by 117.92%. The composition of the bioflocculant from the epsB recombinant strain was 28.95% total sugar, 3.464% protein and 44.03% γ-PGA, while in the original strain, these components represented 53.67%, 3.246% and 34.13%, respectively. In combination with an analysis of the transcriptional levels of several key genes involved in γ-PGA synthesis in B. licheniformis, we inferred that epsB played a key role in the synthesis of both polysaccharide and γ-PGA. The bioflocculant production of the epsB recombinant strain was further evaluated during batch fermentation in a 2 L fermenter; the flocculating activity reached 9612.75 U/mL, and the bioflocculant yield reached 10.26 g/L after 72 h, representing increases of 224% and 36.62%, respectively, compared with the original strain. Moreover, we found that the tandem expression of phosphoglucomutase (pgcA) and UTP-glucose-1-phosphate uridylyltransferase (gtaB1) could enhance the crude yield of the bioflocculant by 20.77% and that the overexpression of epsA could enhance the bioflocculant yield by 23.70% compared with the original strain.
Conclusions
This study provides a new method to greatly increase the bioflocculant production in B. licheniformis, and it demonstrates the correlation between the biosynthesis of polysaccharide and γ-PGA during EPS fermentation by regulating the expression of EpsB.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-017-0775-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12934-017-0775-9
PMCID: PMC5615475  PMID: 28950882
Bacillus licheniformis; Polysaccharide; epsB; γ-PGA; Gene overexpression
19.  Chiral platinum (II)-4-(2,3-dihydroxypropyl)- formamide oxo-aporphine (FOA) complexes promote tumor cells apoptosis by directly targeting G-quadruplex DNA in vitro and in vivo 
Oncotarget  2017;8(37):61982-61997.
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(–)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells. Moreover, our in vivo studies showed that complex 6 can effectively inhibit tumor growth in the BEL-7404 and BEL-7402 xenograft mouse models and is less toxic than 5-fluorouracil and cisplatin. The effective inhibition of tumor growth is attributed to its interactions with 53BP1, TRF1, c-myc, TRF2, and hTERT. Thus, complex 6 can serve as a novel lead compound and a potential drug candidate for anticancer chemotherapy.
doi:10.18632/oncotarget.18778
PMCID: PMC5617480
chiral platinum(II) complex; oxoaporphine; G-quadruplex DNA; telomerase; antitumor activity
20.  LYTAK1 attenuates proliferation of retinal pigment epithelial cells through TGF-β-mediated epithelial-mesenchymal transition via the ERK/AKT signaling pathway 
Retinal pigment epithelial (RPE) cells have crucial roles in the initiation and development of human ophthalmic diseases. Our previous study suggested that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a potential target in the progression and pathogenesis of human proliferative vitreoretinopathy disease. The present study further analyzed the role of TAK1 inhibitor, LYTAK1, in human RPE cells and explored the potential molecular mechanism of LYTAK1-mediated proliferation of human RPE cells. Proliferation of human RPE cells was investigated following treatment with LYTAK1 and knockdown of TGF-β. TGF-β-mediated epithelial-mesenchymal transition (EMT) through regulation of the extracellular signal-regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was also explored to analyze the LYTAK1-mediated mechanism of proliferation in human RPE cells. The present results demonstrated that LYTAK1 administration suppressed TAK1 gene and protein expression in human RPE cells. LYTAK1 administration also inhibited proliferation and migration of human RPE cells in vitro. Outcomes indicated that LYTAK1 treatment downregulated expression levels of TGF-β1 and EMT markers, including cadherin, fibronectin and α-smooth muscle actin in human RPE cells. Notably, results demonstrated that the ERK/AKT signal pathway was blocked by LYTAK1 in human RPE cells. Knockdown of TGF-β markedly inhibited phosphorylation and activity of TAK1 and suppressed the LYTAK1-mediated ERK/AKT signaling pathway in RPE cells, which further canceled inhibition of RPE cell proliferation by LYTAK1. In conclusion, these findings indicated that LYTAK1 may inhibit RPE cell proliferation through the TGF-β-mediated EMT/ERK/AKT signaling pathway, suggesting that TAK1 may be a potential target for the treatment of RPE diseases.
doi:10.3892/etm.2017.5187
PMCID: PMC5704344
retinal pigment epithelial; transforming growth factor-β-activated kinase 1; LYTAK1; transforming growth factor-β; epithelial-mesenchymal transition; extracellular signal-regulated kinase/protein kinase B
21.  The lncRNA PDIA3P Interacts with miR-185-5p to Modulate Oral Squamous Cell Carcinoma Progression by Targeting Cyclin D2 
Long noncoding RNAs (lncRNAs) are emerging as important regulators during tumorigenesis by serving as competing endogenous RNAs (ceRNAs). In this study, the qRT-PCR results indicated that the lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) was overexpressed in oral squamous cell carcinoma (OSCC) and decreased the survival rate of OSCC patients. CCK-8 and clonal colony formation assays were used to detect the effects of PDIA3P on proliferation. Results revealed that silencing PDIA3P by small interfering RNA (siRNA) inhibited OSCC cell proliferation and repressed tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Furthermore, the interaction between PDIA3P and miRNAs was then analyzed by qRT-PCR and luciferase reporter gene assay. We found that PDIA3P negatively regulated miR-185-5p in OSCC cells. Simultaneously, we found that silencing PDIA3P by siRNA suppressed proliferation via miR-185-5p in OSCC cells. Moreover, silencing PDIA3P by siRNA inhibited CCND2 protein (no influence on mRNA levels) expression via miR-185-5p in OSCC cells, and CCND2 facilitated cell proliferation of SCC4 and SCC15 cells induced by sh-PDIA3P#1. Therefore, our study demonstrated that PDIA3P may be a therapeutic target for the treatment of OSCC.
doi:10.1016/j.omtn.2017.08.015
PMCID: PMC5626923
protein disulfide isomerase family A member 3 pseudogene 1; PDIA3P; miR-185-5p; cyclin D2; oral squamous cell carcinoma; OSCC; tumorigenesis
22.  Comparison and Evaluation of Biomechanical, Electrical, and Biological Methods for Assessment of Damage to Tissue Collagen 
Cell and tissue banking  2016;17(3):531-539.
In regard to evaluating tissue banking methods used to preserve or otherwise treat (process) soft allograft tissue, current tests may not be sufficiently sensitive to detect potential damage inflicted before, during, and after processing. Using controlled parameters, we aim to examine the sensitivity of specific biomechanical, electrical, and biological tests in detecting mild damage to collagen. Fresh porcine pulmonary heart valves were treated with an enzyme, collagenase, and incubated using various times. Controls received no incubation. All valves were cryopreserved and stored at −135°C until being rewarmed for evaluation using biomechanical, permeability, and cell viability tests. Statistically significant time dependent changes in leaflet ultimate stress, (p=0.006), permeability (p=0.01), and viability (p≤0.02, 4 different days of culture) were found between heart valves subjected to 0–15 minutes of collagenase treatment (ANOVA). However, no statistical significance was found between the tensile modulus of treated and untreated valves (p=0.07). Furthermore, the trends of decreasing and increasing ultimate stress and viability, respectively, were somewhat inconsistent across treatment times. These results suggest that permeability tests may offer a sensitive, quantitative assay to complement traditional biomechanical and viability tests in evaluating processing methods used for soft tissue allografts, or when making changes to current validated methods. Multiple test evaluation may also offer insight into the mechanism of potential tissue damage such as, as is the case here, reduced collagen content and increased tissue porosity.
doi:10.1007/s10561-016-9560-y
PMCID: PMC5010934  PMID: 27130199
Soft Tissue; Heart Valve; Cryopreservation; Cell Viability; Tensile Modulus; Matrix Permeability
23.  Differences in Quality of Life between American and Chinese Breast Cancer Survivors 
Objective
It has been speculated that cancer survivors in Asia may have lower quality of life (QOL) compared with their western counterparts. However, no studies made international comparisons in QOL using a comprehensive measure. This study aimed to compare Chinese breast cancer survivors’ QOL with United States (US) counterparts and examine if demographic and medical factors were associated with QOL across groups.
Method
The sample consisted of 159 breast cancer patients (97 Chinese and 62 US) who completed the Functional Assessment for Cancer Therapy Breast Cancer Scale (FACT-B) before the start of radiotherapy in Shanghai, China and Houston, US.
Results
Higher income was associated with higher QOL total scores in both Chinese and American cancer patients, but QOL was not significantly associated with other factors including age, education, disease stage, mastectomy and chemotherapy. Consistent with hypotheses, compared to their US counterparts, Chinese breast cancer survivors reported lower QOL including FACT-G total scores and all four sub-dimensions including Functional Well-being (FWB), Physical Well-being (PWB), Emotional Well-being (EWB) and Social Well-being (SWB); they also reported more breast cancer specific concerns (BCS). Differences were also clinically significant for FACT-G total scores and the FWB subscale. After controlling for demographic and medical covariates, these differences remained except for the SWB and BCS. Furthermore, Chinese breast cancer survivors receiving chemotherapy reported significantly lower FACT-G scores than those who did not, but this difference did not emerge among US breast cancer survivors.
Discussion
Chinese breast cancer survivors reported poorer QOL on multiple domains compared to US women. Findings indicate that better strategies are needed to help improve the QOL of Chinese breast cancer survivors, especially those who underwent chemotherapy.
doi:10.1007/s00520-016-3195-1
PMCID: PMC5421630  PMID: 27048455
quality of life; breast cancer; culture; country
24.  Facile total synthesis of lysicamine and the anticancer activities of the RuII, RhIII, MnII and ZnII complexes of lysicamine 
Oncotarget  2017;8(35):59359-59375.
Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1–4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.
doi:10.18632/oncotarget.19584
PMCID: PMC5601738  PMID: 28938642
lysicamine; metal complexes; antitumor activity; apoptosis
25.  Unraveling the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis: expanding the phenotypic variability of RAX mutations 
Scientific Reports  2017;7:9064.
Ocular coloboma is a common eye malformation arising from incomplete closure of the human optic fissure during development. Multiple genetic mutations contribute to the disease process, showing extensive genetic heterogeneity and complexity of coloboma spectrum diseases. In this study, we aimed to unravel the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis. The subjects were recruited and underwent specialized ophthalmologic clinical examination. A combination of whole exome sequencing (WES), homozygosity mapping, and comprehensive variant analyses was performed to uncover the causative mutation. Only one homozygous mutation (c.113 T > C, p.I38T) in RAX gene survived our strict variant filtering process, consistent with an autosomal recessive inheritance pattern. This mutation segregated perfectly in the family and is located in a highly conserved functional domain. Crystal structure modeling indicated that I38T affected the protein structure. We describe a patient from a consanguineous Chinese family with unusual coloboma, proven to harbor a novel RAX mutation (c.113 T > C, p.I38T, homozygous), expanding the phenotypic variability of ocular coloboma and RAX mutations.
doi:10.1038/s41598-017-09276-0
PMCID: PMC5567291  PMID: 28831107

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