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1.  Liraglutide attenuates high glucose-induced abnormal cell migration, proliferation, and apoptosis of vascular smooth muscle cells by activating the GLP-1 receptor, and inhibiting ERK1/2 and PI3K/Akt signaling pathways 
Background
As a new anti-diabetic medicine, Liraglutide (LIRA), one of GLP-1 analogues, has been found to have an anti-atherosclerotic effect. Since vascular smooth muscle cells (VSMCs) play pivotal roles in the occurrence of diabetic atherosclerosis, it is important to investigate the role of LIRA in reducing the harmful effects of high-glucose (HG) treatment in cultured VSMCs, and identifying associated molecular mechanisms.
Methods
Primary rat VSMCs were exposed to low or high glucose-containing medium with or without LIRA. They were challenged with HG in the presence of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK)1/2, or glucagon-like peptide receptor (GLP-1R) inhibitors. Cell proliferation and viability was evaluated using a Cell Counting Kit-8. Cell migration was determined by Transwell migration and scratch wound assays. Flow cytometry and Western blotting were used to determine apoptosis and protein expression, respectively.
Results
Under the HG treatment, VSMCs exhibited increased migration, proliferation, and phosphorylation of protein kinase B (Akt) and ERK1/2, along with reduced apoptosis (all p < 0.01 vs. control). These effects were significantly attenuated with LIRA co-treatment (all p < 0.05 vs. HG alone). Inhibition of PI3K kinase and ERK1/2 similarly attenuated the HG-induced effects (all p < 0.01 vs. HG alone). GLP-1R inhibitors effectively reversed the beneficial effects of LIRA on HG treatment (all p < 0.05).
Conclusions
HG treatment may induce abnormal phenotypes in VSMCs via PI3K and ERK1/2 signaling pathways activated by GLP-1R, and LIRA may protect cells from HG damage by acting on these same pathways.
doi:10.1186/s12933-015-0177-4
PMCID: PMC4327797
Akt; ERK1/2; Glucagon-like peptide receptor; High glucose; Liraglutide; Vascular smooth muscle cells
2.  Three Clustered Cases of Candidemia Caused by Candida quercitrusa and Mycological Characteristics of This Novel Species 
Journal of Clinical Microbiology  2014;52(8):3044-3048.
We investigated three nosocomial Candida quercitrusa candidemia cases occurring within 2 months in a Chinese hospital. Isolates were identifiable only by DNA sequencing of the rRNA genes. Genetic (via random amplified polymorphic DNA [RAPD]) and protein mass spectral (via matrix-assisted laser desorption ionization–time of flight mass spectrometry [MALDI-TOF MS]) analyses yielded identical profiles suggesting an outbreak. The fluconazole MICs of all the strains were 16 to 32 μg/ml.
doi:10.1128/JCM.00246-14
PMCID: PMC4136143  PMID: 24696025
3.  Evaluation of Immune Responses in Mice after DNA Immunization with Putative Toxoplasma gondii Calcium-Dependent Protein Kinase 5 
Toxoplasma gondii can cause serious public health problems and economic losses worldwide. Calcium-dependent protein kinases (CDPKs) are key mediators of T. gondii signaling pathways and are implicated as important virulence factors. In the present study, we cloned a novel T. gondii CDPK gene, named TgCDPK5, and constructed the eukaryotic expression vector pVAX-CDPK5. Then, we evaluated the immune protection induced by pVAX-CDPK5 in Kunming mice. After injection of pVAX-CDPK5 intramuscularly, immune responses, determined with lymphoproliferative assays and cytokine and antibody measurements, were monitored, and mouse survival times and brain cyst formation were evaluated following challenges with the T. gondii RH strain (genotype I) and the PRU strain (genotype II). pVAX-CDPK5 effectively induced immune responses with increased specific antibodies, a predominance of IgG2a production, and a strong lymphocyte proliferative response. The levels of gamma interferon (IFN-γ), interleukin 2 (IL-2), and IL-12(p70) and the percentages of CD3+ CD4+ and CD3+ CD8+ cells in mice vaccinated with pVAX-CDPK5 were significantly increased. However, IL-4 and IL-10 were not produced in the vaccinated mice. These results demonstrate that pVAX-CDPK5 can elicit strong humoral and cellular Th1 immune responses. The survival time of immunized mice challenged with the T. gondii RH strain (8.67 ± 4.34 days) was slightly, but not significantly, longer than that in the control groups within 7 days (P > 0.05). The numbers of brain cysts in the mice in the pVAX-CDPK5 group were reduced by ∼40% compared with those in the control groups (P < 0.05), which provides a foundation for the further development of effective subunit vaccines against T. gondii.
doi:10.1128/CVI.00059-14
PMCID: PMC4097438  PMID: 24789795
4.  Liriodenine induces the apoptosis of human laryngocarcinoma cells via the upregulation of p53 expression 
Oncology Letters  2014;9(3):1121-1127.
Laryngocarcinoma is one of the most aggressive cancers that affects the head and neck region. The survival rate of patients with laryngocarcinoma is low due to late metastases and the resistance of the disease to chemotherapy and radiotherapy. Liriodenine, an alkaloid extracted from a number of plant species, has demonstrated antitumor effects on multiple types of cancer. However, the effects of liriodenine upon laryngocarcinoma, and the underlying mechanisms, are yet to be elucidated. The present study therefore investigated the potential antitumor effects of liriodenine on HEp-2 human laryngocarcinoma cells in vitro and HEp-2-implanted nude mice in vivo. Liriodenine induced significant apoptosis and inhibition of cell migration in the HEp-2 cells. Furthermore, the rate of tumor growth in the HEp-2-implanted nude mice was inhibited by the administration of liriodenine. The potential mechanism underlying the antitumor effects of liriodenine may result from an upregulative effect upon p53 expression, which ultimately induces cellular apoptosis. By contrast, the downregulation of p53 significantly reduced the antitumor effects of liriodenine. Together, these results suggest that liriodenine exhibits potent antitumor activities in laryngocarcinoma HEp-2 cells, in vitro and in vivo, via the upregulation of p53 expression. Liriodenine may therefore be a potential therapy for the treatment of laryngocarcinoma.
doi:10.3892/ol.2014.2834
PMCID: PMC4314988  PMID: 25663867
laryngocarcinoma; liriodenine; p53; HEp-2 cells; nude mice
5.  Epidemiological, Clinical and Histological Characteristics of HBV/HDV Co-Infection: A Retrospective Cross-Sectional Study in Guangdong, China 
PLoS ONE  2014;9(12):e115888.
Background
The epidemiology of hepatitis D virus (HDV) in China is fairly unknown. The mechanisms whereby HDV leads to accelerated liver disease in hepatitis B virus (HBV)/HDV co-infected patients and the histological characteristics of chronic hepatitis D (CHD) patients need further investigation.
Methods
The prevalence of HDV was retrospectively evaluated in all consecutive hospitalized patients with chronic HBV infection from May 2005 to October 2011. HBV/HDV co-infected patients and HBV mono-infected patients were compared clinically and histologically. Significant histological abnormality was defined as significant necroinflammation (grade ≥A2) and/or significant fibrosis (stage ≥ F2).
Results
6.5% of patients (426/6604) tested positive for IgM anti-HDV. HDV was more common in patients over 50 years old than those under 50 (11.7% vs. 5.1%, P<0.001). HBV/HDV co-infected patients had higher frequencies of end-stage liver disease (ESLD) than HBV mono-infected patients, and HDV co-infection was an independent risk factor for ESLD (OR: 1.428, 95%CI: 1.116–1.827; P = 0.005). The HBV DNA levels in the HBV/HDV group were significantly lower than the HBV group in chronic hepatitis patients (median: 6.50 log10copies/mL vs 6.80 log10copies/mL, P = 0.003), but higher than the HBV group in ESLD patients (median: 5.73 log10copies/mL vs 5.16 log10copies/mL, P<0.001). When stratified by alanine aminotransferase (ALT) level, 46.7%, 56.5% and 80.5% of CHD patients had significant necroinflammation and 86.7%, 87.0% and 90.3% had significant fibrosis with ALT 1–2×upper limit normal (ULN), 2–5×ULN and>5×ULN respectively.
Conclusion
The prevalence of HDV is not low in patients with chronic HBV infection. HDV may contribute to progression to ESLD through late-phase HBV DNA reactivation.
doi:10.1371/journal.pone.0115888
PMCID: PMC4274124  PMID: 25532128
6.  The Widely Used ATB FUNGUS 3 Automated Readings in China and Its Misleading High MICs of Candida spp. to Azoles: Challenges for Developing Countries' Clinical Microbiology Labs 
PLoS ONE  2014;9(12):e114004.
The rapid development in the clinical microbiology diagnostic assays presents more challenges for developing countries than for the developed world, especially in the area of test validation before the introduction of new tests. Here we report on the misleading high MICs of Candida spp. to azoles using the ATB FUNGUS 3 (bioMérieux, La Balme-les Grottes, France) with automated readings in China to highlight the dangers of introducing a diagnostic assay without validation. ATB FUNGUS 3 is the most commonly used commercial antifungal susceptibility testing method in China. An in-depth analysis of data showed higher levels of resistance to azoles when ATB FUNGUS 3 strips were read automatically than when read visually. Based on this finding, the performance of ATB FUNGUS 3, read both visually and automatically, was evaluated by testing 218 isolates of five clinically important Candida species, using broth microdilution (BMD) following CLSI M27-A3 as the gold-standard. The overall essential agreement (EA) between ATB visual readings and BMD was 99.1%. In contrast, the ATB automated readings showed higher discrepancies with BMD, with overall EA of 86.2%, and specifically lower EA was observed for fluconazole (80.7%), voriconazole (77.5%), and itraconazole (73.4%), which was most likely due to the trailing effect of azoles. The major errors in azole drug susceptibilities by ATB automated readings is a concern in China that can result in misleading clinical antifungal drug selection and pseudo high rates of antifungal resistance. Therefore, the ATB visual reading is generally recommended. In the meantime, we propose a practical algorithm to be followed for ATB FUNGUS 3 antifungal susceptibility for Candida spp. before the improvement in the automated reading system.
doi:10.1371/journal.pone.0114004
PMCID: PMC4252076  PMID: 25460351
7.  Achyranthes bidentata extract exerts osteoprotective effects on steroid-induced osteonecrosis of the femoral head in rats by regulating RANKL/RANK/OPG signaling 
Background
Steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) presents great challenges due to the various effects of steroids on multi-system pathways involved into osteoblast differentiation, osteoblast and osteoclast apoptosis, lipid metabolism, calcium metabolism and coagulation. As one of the most frequently used herbs in Traditional Chinese Medicine formulas that are prescribed for the regulation of bone and mineral metabolism, the therapeutic effects of Achyranthes bidentata on steroid-induced ONFH remain unclear. Thus, the aim of the current study was to verify whether Achyranthes bidentata extract (ABE) can be used to prevent steroid-induced ONFH and to investigate its underlying pharmacological mechanisms.
Methods
Steroid-induced ONFH rat models were established to evaluate the effects of ABE treatment on osteonecrotic changes and repair processes. Microfocal computed tomography (Micro-CT) was performed to assess the effects of ABE treatment on bone mass, microstructure, and vascularization. Then, the effects of ABE treatment on osteoclast differentiation and bone formation were also evaluated in vivo and in vitro. In addition, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) expression in sera, femoral heads and bone marrow-derived mesenchymal stem cells (BMSCs) were detected at both protein and mRNA levels.
Results
The ratio of empty lacuna, adipose tissue area, and adipocyte perimeter in the bone marrow were markedly lower in the ABE treatment groups than in the model group. Micro-CT evaluation indicated that ABE treatment could improve the microstructure of the trabecular bone, increase bone mineral density and promote vascularization in steroid-induced ONFH rats. Moreover, ABE treatment inhibited osteoclast differentiation and activated bone formation markers. Interestingly, OPG downregulation, RANK and RANKL upregulation, and an increased ratio of RANKL to OPG in sera and necrotic femoral head could be reversed by ABE treatment, which also effectively inhibited RANKL-induced osteoclast differentiation and regulated RANKL and OPG expression of in vitro.
Conclusion
ABE may prevent steroid-induced ONFH and alleviate steroid-induced bone deterioration by regulating the RANKL/RANK/OPG signaling pathway.
doi:10.1186/s12967-014-0334-7
PMCID: PMC4256888  PMID: 25471933
Achyranthes bidentata extract; Steroid-induced osteonecrosis; Femoral head; Osteoprotective; RANKL/RANK/OPG signaling pathway
8.  Which is the best postoperative chemotherapy regimen in patients with rectal cancer after neoadjuvant therapy? 
BMC Cancer  2014;14(1):888.
Background
There is no general agreement about whether patients who have already received neoadjuvant chemoradiotherapy need further postoperative chemotherapy based on 5-fluorouracil(5-FU) or 5-FU plus oxaliplatin.
Methods
Medicare beneficiaries from 1992 to 2008 with Union for International Cancer Control ypStages I to III primary carcinoma of the rectum who underwent 5-FU-based neoadjuvant chemoradiotherapy and surgery for curative intent were identified through the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. A Cox proportional hazards model and propensity score-matched techniques were used to evaluate the effect of treatment on survival.
Results
For patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, postoperative 5-FU-based chemotherapy did not prolong cancer-specific survival (CSS) in ypStage I (P = 0.960) and ypStage II (P = 0.134); however, it significantly improved the CSS in ypStage III (hazard ratio = 1.547, 95% CI = 1.101-2.173, P = 0.012). No significant differences in survival between the 5-FU group and oxaliplatin group were observed.
Conclusions
For patients with resected rectal cancer who have already received 5-FU-based neoadjuvant chemoradiotherapy, postoperative 5-FU-based chemotherapy prolongs the CSS of groups in ypStage III. Adding oxaliplatin to fluoropyrimidines in the postoperative chemotherapy did not improve the CSS for patients who received neoadjuvant chemoradiotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-888) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-888
PMCID: PMC4255436  PMID: 25428401
Rectal neoplasms; SEER program; Chemotherapy; Neoadjuvant therapy
9.  A Rare Fungal Species, Quambalaria cyanescens, Isolated from a Patient after Augmentation Mammoplasty – Environmental Contaminant or Pathogen? 
PLoS ONE  2014;9(10):e106949.
Some emerging but less common human fungal pathogens are known environmental species and could be of low virulence. Meanwhile, some species have natural antifungal drug resistance, which may pose significant clinical diagnosis and treatment challenges. Implant breast augmentation is one of the most frequently performed surgical procedures in China, and fungal infection of breast implants is considered rare. Here we report the isolation of a rare human fungal species, Quambalaria cyanescens, from a female patient in China. The patient had undergone bilateral augmentation mammoplasty 11 years ago and was admitted to Peking Union Medical College Hospital on 15 September 2011 with primary diagnosis of breast infection. She underwent surgery to remove the implant and fully recovered thereafter. During surgery, implants and surrounding tissues were removed and sent for histopathology and microbiology examination. Our careful review showed that there was no solid histopathologic evidence of infection apart from inflammation. However, a fungal strain, which was initially misidentified as “Candida tropicalis” because of the similar appearance on CHROMagar Candida, was recovered. The organism was later on re-identified as Q. cyanescens, based on sequencing of the rDNA internal transcribed spacer region rather than the D1/D2 domain of 26S rDNA. It exhibited high MICs to 5-flucytosine and all echinocandins, but appeared more susceptible to amphotericin B and azoles tested. The possible pathogenic role of Q. cyanescens in breast implants is discussed in this case, and the increased potential for misidentification of the isolate is a cause for concern as it may lead to inappropriate antifungal treatment.
doi:10.1371/journal.pone.0106949
PMCID: PMC4203675  PMID: 25330078
10.  Intravitreal bevacizumab and Ahmed glaucoma valve implantation in patients with neovascular glaucoma 
AIM
To explore the efficacy of preoperative intravitreal bevacizumab (IVB) injection combined with Ahmed glaucoma valve (AGV) implantation in the treatment of neovascular glaucoma (NVG).
METHODS
This retrospective study included 35 eyes from 35 patients who underwent preoperative IVB and AGV implantation for treatment of NVG. Findings such as intraocular pressure (IOP) number of anti-glaucoma medications, visual acuity (VA), surgical success rates, and complications were recorded.
RESULTS
After AGV implantation, IOP was 18.2±4.0 mm Hg, 15.5±3.3 mm Hg and 9.8±2.6 mm Hg at 6, 12 and 36mo, significantly decreased compared with pre-IOP (P<0.01). The number of anti-glaucoma medications was 0.9±0.5, 0.8±0.9 and 0.8±0.6 at 6, 12 and 36mo, significantly decreased compared to pre-treatment (P<0.01). At last visit, there were 19 eyes with stable VA, 4 with VA improvement, 12 with diminished VA and 3 with complete loss light perception. There were 7 cases that failed during 3-year fellow up period. Cumulative probabilities of valve survival by Kaplan-Meier analysis were 82.9%, 74.1% and 71.0% at 12, 24 and 36mo, respectively. Cox stepwise regression analysis found that the survival time was significant associated with the pre-visual acuity <2/400 (P<0.05). Post-operative complications occurred in 8 eyes, of which hyphema presented in 2 eyes, choroidal effusion in 2 eyes.
CONCLUSION
The procedure of preoperative IVB and AGV implantation should be one of treatments for NVG because of its safety and effectiveness.
doi:10.3980/j.issn.2222-3959.2014.05.18
PMCID: PMC4206891  PMID: 25349803
Ahmed glaucoma valve; bevacizumab; intravitreal injection; neovascular glaucoma
11.  Coadministration of Pinellia ternata Can Significantly Reduce Aconitum carmichaelii to Inhibit CYP3A Activity in Rats 
Chuanwu (CW), the mother root of Aconitum carmichaelii Debx., is a traditional Chinese medicine (TCM) for treating traumatic injuries, rheumatoid arthritis, and tumors. CW coadministered with banxia (BX), the root of Pinellia ternata, is also widely prescribed in clinical practice. However, the mechanism of this combination is yet deciphered. Current study aimed to investigate the effects of CW, including raw chuanwu (RCW) and processed chuanwu (PCW) alone, as well as CW coadministered with BX on CYP3A activity. Buspirone (BP) and testosterone (Tes) were used as specific probe substrates in vivo and ex vivo, respectively. CYP3A activity was determined by the metabolites formation ratios from the substrates. Compared with those in the control group, the metabolites formation ratios significantly decreased in the RCW and PCW alone groups, accompanied by a marked decrease in CYP3A protein and mRNA levels. However, there was a significant increase in those ratios in the RCW-BX and PCW-BX groups compared to the RCW and PCW alone groups. The results indicated that both RCW and PCW can inhibit CYP3A activity in rats because of downregulation of CYP3A protein and mRNA levels. Decreases in CYP3A activity can be reversed by coadministration with BX.
doi:10.1155/2014/734867
PMCID: PMC4211167  PMID: 25371696
12.  Treatment with SiMiaoFang, an Anti-Arthritis Chinese Herbal Formula, Inhibits Cartilage Matrix Degradation in Osteoarthritis Rat Model 
Rejuvenation Research  2013;16(5):364-376.
Abstract
A Chinese herbal preparation, SiMiaoFang (SMF), has been used clinically for treating arthralgia by virtue of its anti-inflammatory and pain-relieving activities. However, no evidence base links SMF to anti-osteoarthritis (OA), particularly its link to inhibiting cartilage matrix degradation. In this study, we undertook a characterization of anti-OA activity of SMF using an in vivo rat model induced by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) together with in vitro studies with chondrocytes for further molecular characterization. ACLT+MMx rats were treated with SMF at doses of 0.63, 1.25, and 2.5 grams/kg per day for 6 weeks. SMF treatments significantly inhibited cartilage matrix degradation, as indicated by increasing proteoglycan and collagen content, particularly type II collagen expression in articular cartilage, decreasing CTX-II (collagen type II degradation marker), and increasing CPII (collagen type II synthesis marker) in circulation. Moreover, SMF suppressed synovial inflammation and inhibited release of interleukin-1β (IL-1β) and tumor necrosis factor-α in serum. The levels of serum prostaglandin E2 and nitric oxide productions were decreased via suppression of the production of cyclooxygenase-2 and inducible nitric oxide synthase, respectively. Importantly, SMF interfered with OA-augmented expression of matrix metalloproteinases (MMPs) -3 and -13 and aggrecanases (ADAMTS) -4 and -5, which are considered to be key enzymes in cartilage matrix degradation, and simultaneously augmented OA-reduced tissue inhibitors of metalloproteinases (TIMPs) -1 and -3 expression in the joints. The largest changes in these parameters were found at the highest dose. Meanwhile, SMF significantly decreased MMP-3 and -13 and increased TIMP-1 and -3 at mRNA and protein levels in IL-1β–induced chondrocytes. These findings provide the first evidence that SMF effectively treats OA by inhibiting cartilage matrix degradation.
doi:10.1089/rej.2013.1439
PMCID: PMC3804322  PMID: 23799821
13.  Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study 
BMC Nephrology  2014;15(1):158.
Background
Acute rejection (AR) and acute tubular necrosis (ATN) are main causes of early renal allograft dysfunction. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) and Diffusion weighted (DW) MRI can provide valuable information about changes of oxygen bioavailability and water diffusion by measuring R2* or apparent diffusion coefficient (ADC) respectively. We aimed to determine the value of BOLD MRI and DW MRI in detecting causes for early allograft dysfunction in renal allograft recipients.
Methods
Fifty patients received renal allografts from deceased donors were analyzed, including 35 patients with normal renal function (control group), 10 AR patients and 5 ATN patients. Cortical R2* (CR2*) and medullary R2* (MR2*) were measured by BOLD MRI. Ten diffusion gradient b values (0, 5, 10, 20, 50, 100, 200, 400, 800, 1200s/mm2) were used in DW MRI. ADC values were measured in renal cortex (CADC) and medulla (MADC). CADCl and MADCl were measured under low b values (b ≤ 200 s/mm2), while CADCh and MADCh were measured under high b values (b > 200 s/mm2).
Results
MR2* was significantly lower in AR group (18.2 ± 1.5/s) than control group (23.8 ± 5.0/s, p = 0.001) and ATN group (25.8 ± 5.0/s, p = 0.004). There was a tendency of lower levels on CADCl, MADCl, CADCh or MADCh in AR group than in control group. There were no differences on ADC values between AR group and ATN group.
Conclusions
BOLD MRI was a valuable method in detection of renal allografts with acute rejection.
doi:10.1186/1471-2369-15-158
PMCID: PMC4192395  PMID: 25270976
14.  Radioprotective effects of valproic acid, a histone deacetylase inhibitor, in the rat brain 
Biomedical Reports  2014;3(1):63-69.
Radiotherapy is commonly used in the treatment of brain tumors but can cause significant damage to surrounding normal brain. The radioprotective effects of valproic acid (VPA) on normal tissue in the rat brain were evaluated following irradiation. Male Wistar rats were used in the present study and 48 rats were randomly divided into four groups consisting of 12 rats each. The whole-brain irradiation (WBI) was delivered by X-ray and the rats received the following treatment once a day for 5 days. The control group (sham-exposed group) received sham irradiation plus physiological saline. The VPA group received sham irradiation plus 150 mg VPA/kg. The X-ray group received WBI plus physiological saline. The combined group received WBI plus 150 mg/kg intraperitoneally VPA. A total of 6 months post-irradiation, the rats were sacrificed and the brains were harvested. Cell apoptosis in the cortex was determined by immunohistochemistry 24 h post-irradiation using an antibody for protein caspase-3. Transmission electron microscope (TEM) analyses were used to assess the effects of VPA on the radioprotection of rat normal brain cells 6 months post-irradiation. The weights of the animals in the TEM group measured over the two weeks after the first injection of VPA were also observed. Histological findings demonstrated that apoptosis occurred on the cortex 1 day after treatment, peaking in the X-ray group. The cells of the combined group showed a moderate caspase-3 staining compared to the X-ray group. There was a trend towards a lower body weight of the X-ray group following irradiation compared to either no-irradiation or rats of the combined group, although there was no significant difference in the average weight between the combined group and irradiated rats. Mild swelling of the capillary endothelial cells in the irregular lumen was observed in the combined group, whereas the X-ray group showed a severe structural disorder. In conclusion, VPA supplementation during radiotherapy may be beneficial for radioprotection following WBI by reducing normal brain cell injury.
doi:10.3892/br.2014.367
PMCID: PMC4251104  PMID: 25469249
fractionated radiotherapy; valproic acid; brain injury; radioprotection
15.  Identification of Essential Proteins Based on Ranking Edge-Weights in Protein-Protein Interaction Networks 
PLoS ONE  2014;9(9):e108716.
Essential proteins are those that are indispensable to cellular survival and development. Existing methods for essential protein identification generally rely on knock-out experiments and/or the relative density of their interactions (edges) with other proteins in a Protein-Protein Interaction (PPI) network. Here, we present a computational method, called EW, to first rank protein-protein interactions in terms of their Edge Weights, and then identify sub-PPI-networks consisting of only the highly-ranked edges and predict their proteins as essential proteins. We have applied this method to publicly-available PPI data on Saccharomyces cerevisiae (Yeast) and Escherichia coli (E. coli) for essential protein identification, and demonstrated that EW achieves better performance than the state-of-the-art methods in terms of the precision-recall and Jackknife measures. The highly-ranked protein-protein interactions by our prediction tend to be biologically significant in both the Yeast and E. coli PPI networks. Further analyses on systematically perturbed Yeast and E. coli PPI networks through randomly deleting edges demonstrate that the proposed method is robust and the top-ranked edges tend to be more associated with known essential proteins than the lowly-ranked edges.
doi:10.1371/journal.pone.0108716
PMCID: PMC4182551  PMID: 25268881
16.  Evaluation of immuno-efficacy of a novel DNA vaccine encoding Toxoplasma gondii rhoptry protein 38 (TgROP38) against chronic toxoplasmosis in a murine model 
BMC Infectious Diseases  2014;14(1):525.
Background
Toxoplasma gondii is an obligate intracellular parasite which can infect almost all mammalian animals, leading to toxoplasmosis. T. gondii rhoptry protein 38 (TgROP38) is an active rhoptry protein kinase which is involved in the inhibitory effect on host cell transcription by down-regulating the MAPK signaling track.
Methods
TgROP38 gene was amplified and inserted into eukaryotic vector pVAX I and formed the DNA vaccine pVAX-ROP38. Mice in the experimental group were intramuscularly immunized with pVAX-ROP38 and those injected with pVAX I, PBS or nothing were treated as controls. After three injections at two week intervals, all mouse groups were challenged intraperitoneally with 1000 tachyzoites of the virulent T. gondii RH strain (Type I, ToxoDB #10) and 10 cysts of the PRU strain (Type II, ToxoDB #1), respectively.
Results
Mice inoculated with pVAX-ROP38 vaccine had a higher level of IgG antibodies (P < 0.01) and T lymphoproliferative response. The high ratio of IgG2a/IgG1 and the increasing levels of IFN-γ and IL-2 (P < 0.05) indicated an activated Th1 cell-mediated immune responses. Furthermore, the CD4+ and CD8+ proportions in vaccinated mice were also increased significantly compared with that in mice of the three control groups (P < 0.01). In the model of acute infection, the average survival time of mice in the pVAX-ROP38 group (8.1 days ± 0.75) was no statistically different compared to that in the PBS, pVAX I and blank control groups which died within 7 days. However, in the model of chronic infection, the brain cyst reduction in the pVAX-ROP38 group reached 76.6%, compared to controls (P < 0.01).
Conclusions
The present study revealed that the pVAX-ROP38 vaccine could elicit strong humoral and cell immunity response against chronic T. gondii infection in mice, resulting in the reduction of the brain cyst formation effectively, which suggests that TgROP38 is a desirable vaccine candidate against chronic T. gondii infection.
doi:10.1186/1471-2334-14-525
PMCID: PMC4261603  PMID: 25267356
Toxoplasma gondii; Toxoplasmosis; TgROP38; DNA vaccine; Protective immunity; Mouse
17.  Novel Therapeutic Targets in Depression and Anxiety: Antioxidants as a Candidate Treatment 
Current Neuropharmacology  2014;12(2):108-119.
There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway. The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.
doi:10.2174/1570159X11666131120231448
PMCID: PMC3964743  PMID: 24669206
Oxidative stress; Antioxidants; Depression and anxiety; Oxidative stress pathway; Antidepressants.
18.  Drug Allergy and the Risk of Lymph Node Metastasis in Rectal Cancer 
PLoS ONE  2014;9(8):e106123.
Background
Previous epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. However, no information is available for the association between allergy and the risk of lymph node metastasis. Our study was designed to determine this association in rectal cancer.
Methods
Patients who were treated at our hospital in the period from January 2003 to June 2011, and with a pathologically hospital discharge diagnosis of rectal adencarcinoma, were included. The clinical, laboratory, and pathologic parameters were analyzed. A multivariate logistic regression model was used to determine the association. Moreover, for type of allergic drug, sub-group analysis was performed.
Results
469 patients were included, including 231 with pathological lymph node metastasis (pLNM) (49.3%) and 238 without pLNM. Univariate analysis showed, compared with patients without pLNM, patients with pLNM had a younger age (60.6±12.8 yr vs. 63.6±12.2 yr, P = 0.012), a lower percentage of drug allergy (8.7% vs. 16.0%, P = 0.016), an increased CEA (median/interquartile-range 5.40/2.40–13.95 vs. 3.50/2.08–8.67, P = 0.009), and a lower serum sodium (141±3.1 mmol/L vs. 142±2.9 mmol/L, P = 0.028). Multivariate analysis showed that drug allergy was associated with a reduced risk of pLNM (OR = 0.553; 95% CI, 0.308–0.994; P = 0.048). In addition, our results showed that: (1) for tumor classification, patients with drug allergy had a higher percentage of group patients with pT1/pT2; and (2) for type of allergic drug, this inverse association was found for penicillins, not for other allergic drugs.
Conclusion
Drug allergy is associated with a reduced risk of pLNM in rectal cancer.
doi:10.1371/journal.pone.0106123
PMCID: PMC4146592  PMID: 25162236
19.  An image-based multi-label human protein subcellular localization predictor (iLocator) reveals protein mislocalizations in cancer tissues 
Bioinformatics  2013;29(16):2032-2040.
Motivation: Human cells are organized into compartments of different biochemical cellular processes. Having proteins appear at the right time to the correct locations in the cellular compartments is required to conduct their functions in normal cells, whereas mislocalization of proteins can result in pathological diseases, including cancer.
Results: To reveal the cancer-related protein mislocalizations, we developed an image-based multi-label subcellular location predictor, iLocator, which covers seven cellular localizations. The iLocator incorporates both global and local image descriptors and generates predictions by using an ensemble multi-label classifier. The algorithm has the ability to treat both single- and multiple-location proteins. We first trained and tested iLocator on 3240 normal human tissue images that have known subcellular location information from the human protein atlas. The iLocator was then used to generate protein localization predictions for 3696 protein images from seven cancer tissues that have no location annotations in the human protein atlas. By comparing the output data from normal and cancer tissues, we detected eight potential cancer biomarker proteins that have significant localization differences with P-value < 0.01.
Availability: http://www.csbio.sjtu.edu.cn/bioinf/iLocator/
Contact: hbshen@sjtu.edu.cn or zhng@umich.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt320
PMCID: PMC3722518  PMID: 23740749
20.  An intensity ratio of interlocking loops determines circadian period length 
Nucleic Acids Research  2014;42(16):10278-10287.
Circadian clocks allow organisms to orchestrate the daily rhythms in physiology and behaviors, and disruption of circadian rhythmicity can profoundly affect fitness. The mammalian circadian oscillator consists of a negative primary feedback loop and is associated with some ‘auxiliary’ loops. This raises the questions of how these interlocking loops coordinate to regulate the period and maintain its robustness. Here, we focused on the REV-ERBα/Cry1 auxiliary loop, consisting of Rev-Erbα/ROR-binding elements (RORE) mediated Cry1 transcription, coordinates with the negative primary feedback loop to modulate the mammalian circadian period. The silicon simulation revealed an unexpected rule: the intensity ratio of the primary loop to the auxiliary loop is inversely related to the period length, even when post-translational feedback is fixed. Then we measured the mRNA levels from two loops in 10-mutant mice and observed the similar monotonic relationship. Additionally, our simulation and the experimental results in human osteosarcoma cells suggest that a coupling effect between the numerator and denominator of this intensity ratio ensures the robustness of circadian period and, therefore, provides an efficient means of correcting circadian disorders. This ratio rule highlights the contribution of the transcriptional architecture to the period dynamics and might be helpful in the construction of synthetic oscillators.
doi:10.1093/nar/gku701
PMCID: PMC4176327  PMID: 25122753
21.  Yeast Identification Algorithm Based on Use of the Vitek MS System Selectively Supplemented with Ribosomal DNA Sequencing: Proposal of a Reference Assay for Invasive Fungal Surveillance Programs in China 
Journal of Clinical Microbiology  2014;52(2):572-577.
Sequence analysis of the internal transcribed spacer (ITS) region was employed as the gold standard method for yeast identification in the China Hospital Invasive Fungal Surveillance Net (CHIF-NET). It has subsequently been found that matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) is potentially a more practical approach for this purpose. In the present study, the performance of the Vitek MS v2.0 system for the identification of yeast isolates collected from patients with invasive fungal infections in the 2011 CHIF-NET was evaluated. A total of 1,243 isolates representing 31 yeast species were analyzed, and the identification results by the Vitek MS v2.0 system were compared to those obtained by ITS sequence analysis. By the Vitek MS v2.0 system, 96.7% (n = 1,202) of the isolates were correctly assigned to the species level and 0.2% (n = 2) of the isolates were identified to the genus level, while 2.4% (n = 30) and 0.7% (n = 9) of the isolates were unidentified and misidentified, respectively. After retesting of the unidentified and misidentified strains, 97.3% (n = 1,209) of the isolates were correctly identified to the species level. Based on these results, a testing algorithm that combines the use of the Vitek MS system with selected supplementary ribosomal DNA (rDNA) sequencing was developed and validated for yeast identification purposes. By employing this algorithm, 99.7% (1,240/1,243) of the study isolates were accurately identified with the exception of two isolates of Candida fermentati and one isolate of Cryptococcus gattii. In conclusion, the proposed identification algorithm could be practically implemented in strategic programs of fungal infection surveillance.
doi:10.1128/JCM.02543-13
PMCID: PMC3911352  PMID: 24478490
22.  Sanmiao formula inhibits chondrocyte apoptosis and cartilage matrix degradation in a rat model of osteoarthritis 
Sanmiao formula (SM) is a basic prescription for the treatment of gouty and rheumatoid arthritis that has been used in China over a long period of history. However, there is no evidence associating SM with the treatment of osteoarthritis (OA). In this study, a characterization of the anti-OA effect of SM was conducted using an in vivo rat model induced by anterior cruciate ligament transection and medial meniscus resection (ACLT plus MMx), together with in vitro studies using chondrocytes for further molecular characterization. Rats subjected to ACLT plus MMx were treated with SM at doses of 0.63, 1.25 and 2.5 g/kg per day for three or six weeks. SM treatment significantly inhibited the histopathological changes of articular cartilage damage and synovial inflammation in the rats following ACLT plus MMx. SM (2.5 g/kg) clearly inhibited chondrocyte apoptosis and prevented cartilage matrix degradation, which was indicated by the increased proteoglycan and collagen content, particularly with regard to type II collagen expression in articular cartilage. Furthermore, SM (2.5 g/kg) markedly inhibited the release of interleukin (IL)-1β, tumor necrosis factor-α and nitric oxide in serum, while simultaneously increasing the levels of bone morphogenetic protein-2 and transforming growth factor-β in the circulation. Notably, SM (2.5 g/kg) clearly attenuated the OA-augmented expression of matrix metalloproteinase (MMP)-13 and augmented the OA-reduced expression of tissue inhibitor of metalloproteinase (TIMP)-1 in the knee joints. In addition, SM significantly reduced the proportion of early and late apoptotic and sub-G1 phase cells, and clearly decreased the expression of MMP-13 and increased that of TIMP-1 at the mRNA and protein levels in IL-1β-induced chondrocytes. These findings provide the first evidence that SM effectively treats OA by inhibiting chondrocyte apoptosis, cartilage matrix degradation and the inflammatory response.
doi:10.3892/etm.2014.1862
PMCID: PMC4151698  PMID: 25187798
Sanmiao formula; chondrocytes; proteoglycan; collagen; inflammatory cytokines; metalloproteinases; tissue inhibitors of metalloproteinase
23.  Targeting complement anaphylatoxin C5a receptor in hyperoxic lung injury in mice 
Molecular Medicine Reports  2014;10(4):1786-1792.
Receptor binding of complement anaphylatoxin C5a results in proinflammatory activation of numerous diseases, but the role of receptor-mediated action during hyperoxic lung injury has, to the best of our knowledge, not yet been investigated. The contribution of the C5a receptor (C5aR) to hyperoxic lung injury in mice was investigated in this study. The effect of C5aR on hyperoxic lung injury in Balb/c mice was examined employing a C5aR antagonist (C5aRA). The mice were ventilated with 100% oxygen for 36 h with or without the administration of C5aRA. C5aR expression levels in non-treated or 100% oxygen-treated mice were assessed by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The body weight and the relative lung weight of the mice, and the morphological changes in the lung were then determined. The total cell counts and the number of macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) were determined using cytocentrifuge slides and a hemocytometer. The levels of interleukin-6 (IL-6), monocyte chemotactic protein (MCP-1) and tumor necrosis factor-α (TNF-α) in BALF and the myeloperoxidase (MPO) activity in the lung tissue were measured by enzyme-linked immunosorbent assay. The relative levels of CD68 and F4/80 messenger ribonucleic acid (mRNA) expression in the lung tissue were detected by RT-PCR. The TNF-α, IL-6 and MCP-1 protein expression levels in the lung tissue were assessed by western blot analysis. The results revealed hyperoxia-induced morphological changes, lung injury and increased expression levels of C5aR in lung tissue. The hyperoxia-induced increases in the total cell count and the number of macrophages, neutrophils and lymphocytes in the BALF were all significantly reduced in the mice receiving C5aRA. Treatment with C5aRA also attenuated the morphological changes and reduced MPO activity, and CD68 and F4/80 mRNA expression levels in the lung tissue, as well as the levels of IL-6, MCP-1 and TNF-α in BALF and lung tissue. In conclusion, C5a-C5aR action accelerated hyperoxia-induced lung injury, but this hyperoxic lung injury was attenuated by treatment with C5aRA.
doi:10.3892/mmr.2014.2394
PMCID: PMC4148369  PMID: 25050483
hyperoxic lung injury; complement anaphylatoxin C5a; receptor antagonist; macrophage
24.  Sequence Variation in Toxoplasma gondii rop17 Gene among Strains from Different Hosts and Geographical Locations 
The Scientific World Journal  2014;2014:349325.
Genetic diversity of T. gondii is a concern of many studies, due to the biological and epidemiological diversity of this parasite. The present study examined sequence variation in rhoptry protein 17 (ROP17) gene among T. gondii isolates from different hosts and geographical regions. The rop17 gene was amplified and sequenced from 10 T. gondii strains, and phylogenetic relationship among these T. gondii strains was reconstructed using maximum parsimony (MP), neighbor-joining (NJ), and maximum likelihood (ML) analyses. The partial rop17 gene sequences were 1375 bp in length and A+T contents varied from 49.45% to 50.11% among all examined T. gondii strains. Sequence analysis identified 33 variable nucleotide positions (2.1%), 16 of which were identified as transitions. Phylogeny reconstruction based on rop17 gene data revealed two major clusters which could readily distinguish Type I and Type II strains. Analyses of sequence variations in nucleotides and amino acids among these strains revealed high ratio of nonsynonymous to synonymous polymorphisms (>1), indicating that rop17 shows signs of positive selection. This study demonstrated the existence of slightly high sequence variability in the rop17 gene sequences among T. gondii strains from different hosts and geographical regions, suggesting that rop17 gene may represent a new genetic marker for population genetic studies of T. gondii isolates.
doi:10.1155/2014/349325
PMCID: PMC4121216  PMID: 25126596
25.  Exposure to Silica Nanoparticles Causes Reversible Damage of the Spermatogenic Process in Mice 
PLoS ONE  2014;9(7):e101572.
Environmental exposure to nanomaterials is inevitable, as nanomaterials have become part of our daily life now. In this study, we firstly investigated the effects of silica nanoparticles on the spermatogenic process according to their time course in male mice. 48 male mice were randomly divided into control group and silica nanoparticle group with 24 mice per group, with three evaluation time points (15, 35 and 60 days after the first dose) per group. Mice were exposed to the vehicle control and silica nanoparticles at a dosage of 20 mg/kg every 3 days, five times over a 13-day period, and were sacrificed at 15, 35 and 60 days after the first dose. The results showed that silica nanoparticles caused damage to the mitochondrial cristae and decreased the levels of ATP, resulting in oxidative stress in the testis by days 15 and 35; however, the damage was repaired by day 60. DNA damage and the decreases in the quantity and quality of epididymal sperm were found by days 15 and 35; but these changes were recovered by day 60. In contrast, the acrosome integrity and fertility in epididymal sperm, the numbers of spermatogonia and sperm in the testes, and the levels of three major sex hormones were not significantly affected throughout the 60-day period. The results suggest that nanoparticles can cause reversible damage to the sperms in the epididymis without affecting fertility, they are more sensitive than both spermatogonia and spermatocytes to silica nanoparticle toxicity. Considering the spermatogenesis time course, silica nanoparticles primarily influence the maturation process of sperm in the epididymis by causing oxidative stress and damage to the mitochondrial structure, resulting in energy metabolism dysfunction.
doi:10.1371/journal.pone.0101572
PMCID: PMC4086902  PMID: 25003337

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