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1.  Induction of ROS generation and NF-κB activation in MARC-145 cells by a novel porcine reproductive and respiratory syndrome virus in Southwest of China isolate 
BMC Veterinary Research  2015;11:232.
Porcine reproductive and respiratory syndrome virus (PRRSV) is the cause of an economically important swine disease that has devastated the swine industry since the late 1980s. The aim of the present study was to investigate the interaction between reactive oxygen species (ROS) and NF-κB by PRRSV infection.
We isolated the local strain of PRRSV from southwest China, designated YN-2011, then sequenced and analyzed the genome. YN-2011 was then used to evaluate the interaction of ROS and NF-κB. In PRRSV infected MARC-145 cells, there was a time-dependent increase in ROS and Maleic Dialdehyde (MDA). Accordingly, NF-κB activation was also increased as PRRSV infection progressed. Degradation of IκB mRNA was detected late in PRRSV infection, and overexpression of the dominant negative form of IκBα significantly suppressed NF-κB induced by PRRSV.
The results indicate that the generation of ROS is involved in PRRSV replication and this progression is associated with the alteration in NF-κB activity induced by ROS. These results should extend our better understanding the interaction between PRRSV and host MARC-145 cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12917-015-0480-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4565009  PMID: 26358082
PRRSV; ROS; NF-κB; MARC-145 cells
3.  Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells 
eLife  null;4:e07687.
Eukaryotic cells possess a variety of signaling pathways that prevent accumulation of unfolded and misfolded proteins. Chief among these is the heat shock response (HSR), which is assumed to respond to unfolded proteins in the cytosol and nucleus alike. In this study, we probe this axiom further using engineered proteins called ‘destabilizing domains’, whose folding state we control with a small molecule. The sudden appearance of unfolded protein in mammalian cells elicits a robust transcriptional response, which is distinct from the HSR and other known pathways that respond to unfolded proteins. The cellular response to unfolded protein is strikingly different in the nucleus and the cytosol, although unfolded protein in either compartment engages the p53 network. This response provides cross-protection during subsequent proteotoxic stress, suggesting that it is a central component of protein quality control networks, and like the HSR, is likely to influence the initiation and progression of human pathologies.
eLife digest
The majority of cellular proteins must be folded into a precise shape to work correctly. But when cells experience stressful conditions such as high temperatures and harmful chemicals, proteins start misfolding or even completely unfold. Misfolded proteins can be highly toxic. As a result, cells use several different groups of molecules that work together in pathways to both detect and then refold incorrectly folded proteins.
Protein misfolding has mainly been studied under extreme experimental conditions that cause hundreds of different proteins to misfold at the same time. In 2006, researchers developed a technique that can be used to switch a protein between a folded and an unfolded state. Now, Miyazaki et al.—including several of the researchers involved in the 2006 work—have used this technique to investigate how a cell responds when a single protein unfolds. The sudden appearance of the unfolded protein increased the expression of several genes. Some of these genes are part of known pathways, but the majority were not known to respond to protein-folding stress. The cell also reacts differently depending on whether the unfolded protein is made in the cell nucleus, or the cytosol (the fluid that surrounds the nucleus and other cellular components).
Miyazaki et al. discovered that a network of molecules controlled, in part, by a protein called p53 activates the response to unfolded proteins in either the nucleus or the cytosol. Cells that activated this network were also better able to protect themselves from further stress. This newly discovered pathway is likely to play an important role in monitoring the quality of the proteins made in the cell. The next step involves identifying the cellular sensor(s) that recognize the unfolded protein as well as the transcription factors that are responsible for increasing gene expression. With a more complete picture of this new response, it will be possible to knock-out specific pathways to determine their roles.
PMCID: PMC4566031  PMID: 26314864
unfolded protein response; protein quality control; chaperone; cellular stress response; neurodegenerative disease; mouse
4.  Comparison of posterior capsule opacification at 360-degree square edge hydrophilic and sharp edge hydrophobic acrylic intraocular lens in diabetic patients 
To compare posterior capsule opacification (PCO) degree and visual functions after phacoemulsification in eyes implanted with 360-degree square edge hydrophilic acrylic intraocular lens (IOL) (570C C-flex, Rayner) and sharp edge hydrophobic acrylic IOL (Sensar AR40e, AMO) in diabetic patients.
Sixty diabetic patients underwent uneventful phacoemulsification and randomly implanted one of the two IOLs. The PCO value was measured by retroillumination photographs and Evaluation of Posterior Capsule Opacification (EPCO) 2000 image-analysis software at 1, 6, 12, and 24mo after surgery. Visual acuity, and contrast sensitivity in photopic and mesopic conditions were also examined at each follow up time point. The incidence of eye that required Nd:YAG laser posterior capsulotomy were also compared.
There was not any statistically significant difference in PCO scores between Rayner C-flex 570C group and Sensar AR40e group at each follow up time point. Visual acuity, Nd:YAG capsulotomy incidence and contrast sensitivity also had no significant difference during the 24mo follow-up.
For diabetic patients, Rayner 570C C-flex and Sensar AR40e IOLs are same effective for prevent PCO. The 360-degree square edge design maybe is a good alternative technique to improve PCO prevention.
PMCID: PMC4539619  PMID: 26309870
hydrophilic acrylic intraocular lens; posterior capsule opacification; visual functions; diabetic patients
5.  Cognitive Impairments in LRRK2-Related Parkinson's Disease: A Study in Chinese Individuals 
Behavioural Neurology  2015;2015:621873.
Background. LRRK2 S1647T has been identified as a polymorphic risk variant for Parkinson's disease (PD) in Chinese individuals. As LRRK2 is the most common genetic cause for PD, it has drawn great interest regarding whether cognitive impairments in PD are related with LRRK2. Purpose. This study aimed to explore the effects of LRRK2 S1647T polymorphism on cognitive function in PD. Method. 90 PD patients were randomly recruited. They underwent a series of clinical evaluations and genetic testing for the LRRK2 S1647T polymorphism. Global intellect and five cognitive domains (language fluency, visuospatial function, attention, memory, and executive function) were compared between S1647T carriers and noncarriers. Results. No differences in motor features were found between two groups, but the executive function evaluation showed that Stroop word colour test time (SWCT-TIME) scores were lower in LRRK2 S1647T carriers than in noncarriers (P = 0.017). However, multiple linear regression analysis indicated that the correlation between S1647T polymorphism and SWCT-TIME scores did not reach significant level (P = 0.051). Conclusion. Our findings suggest that cognitive impairments are not correlated with different LRRK2 S1647T polymorphisms in Chinese PD individuals.
PMCID: PMC4544948  PMID: 26346174
6.  Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke 
Neurobiology of disease  2014;68:91-103.
Stroke is a devastating neurological disorder and one of the leading causes of death and serious disability. After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke. In the present study, we tested the hypothesis that post-stroke angiogenesis would be enhanced by omega-3 polyunsaturated fatty acids (n-3 PUFAs), a major component of dietary fish oil. To this end, we found that transgenic fat-1 mice that overproduce n-3 PUFAs exhibited long-term behavioral and histological protection against transient focal cerebral ischemia (tFCI). Importantly, fat-1 transgenic mice also exhibited robust improvements in revascularization and angiogenesis compared to wild type littermates, suggesting a potential role for n-3 fatty acids in post-stroke cerebrovascular remodeling. Mechanistically, n-3 PUFAs induced upregulation of angiopoietin 2 (Ang 2) in astrocytes after tFCI and stimulated extracellular Ang 2 release from cultured astrocytes after oxygen and glucose deprivation. Ang 2 facilitated endothelial proliferation and barrier formation in vitro by potentiating the effects of VEGF on phospholipase Cγ1 and Src signaling. Consistent with these findings, blockade of Src activity in post-stroke fat-1 mice impaired n-3 PUFA-induced angiogenesis and exacerbated long-term neurological outcomes. Taken together, our findings strongly suggest that n-3 PUFA supplementation is a potential angiogenic treatment capable of augmenting brain repair and improving long-term functional recovery after cerebral ischemia.
PMCID: PMC4121733  PMID: 24794156
angiogenesis; angiopoietin 2; astrocyte; neuroprotection; omega-3 polyunsaturated fatty acids; stroke; VEGF
7.  Heterozygote of TAP1 Codon637 decreases susceptibility to HPV infection but increases susceptibility to esophageal cancer among the Kazakh populations 
The role of human papillomavirus (HPV) may be involved in the development of esophageal cancer (EC) and the polymorphic immune response gene transporter associated with antigen processing (TAP) may be involved in HPV persistence and subsequent cancer carcinogenesis. The current study aims to provide association evidence for HPV with EC, to investigate TAP1 polymorphisms in EC and assess its association with HPV statuses and EC in Kazakhs.
The HPV genotypes in 361 patients with EC and 66 controls selected from Kazakh population were evaluated using PCR. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect two SNPs of TAP1 in 150 cases comprised of 75 HPV+ and 75 HPV- patients and 283 pure ethnic population of Kazakh and evaluate their associations with susceptibility to EC. A case-to-case comparison based on the genotyping results was conducted to address the function of TAP1 variants in the involvement of HPV.
The presence of four HPV genotypes in EC tissues ― including HPV 16, 18, 31, 45 ― was significantly higher at 64.6 % than those in controls at 18.2 % (P < 0.001). Such presence was strongly associated with increased risk of EC (OR 8.196; 95 % CI 4.280–15.964). The infection of HPV16, and multi-infection of 16 and 18 significantly increase the risk for developing EC (OR 4.616, 95 % CI 2.099–10.151; and OR 6.029, 95 % CI 1.395–26.057 respectively). Heterozygote of TAP1 D637G had a significantly higher risk for developing EC (OR 1.626; 95 % CI 1.080–2.449). The odds ratio for HPV infection was significantly lower among carriers of TAP1 D637G polymorphism (OR 0.281; 95 % CI 0.144–0.551).
HPV infection exhibits a strong positive association with the risk of EC in Kazakhs. Heterozygote of TAP1 D637G decreases susceptibility to HPV infection in patients with EC but increases susceptibility to EC among the Kazakh populations.
PMCID: PMC4514451  PMID: 26205887
Esophageal squamous cell carcinoma; Human papillomavirus; Transporter associated with antigen processing; Single nucleotide polymorphism
8.  Interleukin-6 as a Prognostic Biomarker in Ruptured Intracranial Aneurysms 
PLoS ONE  2015;10(7):e0132115.
Interleukin-6 (IL-6), a proinflammatory cytokine, was found to surge in the cerebral spinal fluid after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the plasma level of IL-6 could be an independent biomarker in predicting clinical outcome of patients with ruptured intracranial aneurysm.
We prospectively included 53 consecutive patients treated with platinum coil embolization of the ruptured intracranial aneurysm. Plasma IL-6 levels were measured in the blood samples at the orifices of the aneurysms and from peripheral veins. The outcome measure was the modified Rankin Scale one month after SAH. Multiple logistic regression analyses were used to evaluate the associations between the plasma IL-6 levels and the neurological outcome.
Significant risk factors for the poor outcome were old age, low Glasgow Coma Scale (GCS) on day 0, high Fisher grades, and high aneurysmal and venous IL-6 levels in univariate analyses. Aneurysmal IL-6 levels showed modest to moderate correlations with GCS on day 0, vasospasm grade and Fisher grade. A strong correlation was found between the aneurysmal and the corresponding venous IL-6 levels (ρ = 0.721; P<0.001). In the multiple logistic regression models, the poor 30-day mRS was significantly associated with high aneurysmal IL-6 level (OR, 17.97; 95% CI, 1.51–214.33; P = 0.022) and marginally associated with high venous IL-6 level (OR, 12.71; 95% CI, 0.90–180.35; P = 0.022) after adjusting for dichotomized age, GCS on day 0, and vasospasm and Fisher grades.
The plasma level of IL-6 is an independent prognostic biomarker that could be used to aid in the identification of patients at high-risk of poor neurological outcome after rupture of the intracranial aneurysm.
PMCID: PMC4503596  PMID: 26176774
9.  Identification of low miR-105 expression as a novel poor prognostic predictor for human glioma 
Glioma is the most common and aggressive brain tumor with poor clinical outcome. Identification and development of new biomarkers could be beneficial for diagnosis and prognosis of glioma patients. Recent studies have showed evidences that dysregulation of microRNAs (miRNAs) is involved in glioma tumorigenesis. Therefore, we attempted to identify specific miRNAs as prognostic and predictive markers for glioma. We statistically compared expression profile of 365 miRNAs between WHO grade IV and grade III gliomas, by qRT-PCR. MiR-105 was identified as a remarkably decreased miRNA in grade IV gliomas compared with grade III gliomas (P=0.012, fold change =0.04). We subsequently examined its expression levels in an independent series of gliomas, and statistically analyzed the associations between miR-105 expression and clinicopathological characteristics and survivals of these glioma patients. MiR-105 showed remarkably decreased expression in gliomas as compared to non-neoplastic brains. And grade IV gliomas had significantly lower miR-105 expression compared with grade III and II gliomas (both P<0.001). Additionally, low miR-105 expression was statistically associated with advanced tumor grade, advanced patient’s age and low pre-operative Karnofsky performance score (all P<0.001). Furthermore, patients with low miR-105 expression had significantly poorer survival by Kaplan-Meier method (P<0.001). Multivariate analysis indicated miR-105 as an independent prognostic indicator for glioma patients (P=0.018, risk ratio =4.2). Our results suggested that low expression of miR-105 may correlate with unfavorable clinical outcome and be involved in tumorigenesis and aggressive progression of glioma. And miR-105 may be a novel biomarker in prognostic prediction for glioma.
PMCID: PMC4565262  PMID: 26379879
microRNA; miR-105; glioma; glioblastoma; down-regulation; prognosis
10.  Efficacy and safety of oral branched-chain amino acid supplementation in patients undergoing interventions for hepatocellular carcinoma: a meta-analysis 
Nutrition Journal  2015;14:67.
Most hepatocellular carcinoma (HCC) patients have complications, including cirrhosis and malnutrition. The efficacy of dietary supplementation with oral branched-chain amino acids (BCAAs) in HCC patients undergoing interventions has not been confirmed. Relevant publications on the efficacy and safety of oral BCAA supplementation for HCC patients undergoing anti-HCC interventions through September, 2014 were searched for identification in the PubMed, Embase, Web of Science, and the Cochrane Library databases. The pooled risk ratio (RR) and standardized mean difference (SMD) were used to assess the supplementation effects. A total of 11 eligible studies (974 patients in total) were evaluated and included in our analysis. Oral BCAA supplementation helped to maintain liver reserve with higher serum albumin (SMD = 0.234, 95 % CI: 0.033–0.435, P = 0.022), and lower rates of ascites (RR = 0.545, 95 % CI: 0.316–0.938, P = 0.029) and edema (RR = 0.494, 95 % CI: 0.257–0.952, P = 0.035) than in the control group. BCAA supplementation seemed to be effective in improving mortality, especially in Child-Pugh class B patients, but the efficacy was not confirmed. Apparent effects were not found in improving HCC recurrence, total bilirubin, ALT, or AST. BCAA supplementation was relatively safe without serious adverse events. BCAA supplementation may be clinically applied in improving liver functional reserve for HCC patients and further improving the quality of life.
Electronic supplementary material
The online version of this article (doi:10.1186/s12937-015-0056-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4496824  PMID: 26155840
Branched-chain amino acids; Hepatocellular carcinoma; Meta-analysis
11.  Identification, Characterization and Down-Regulation of Cysteine Protease Genes in Tobacco for Use in Recombinant Protein Production 
PLoS ONE  2015;10(7):e0130556.
Plants are an attractive host system for pharmaceutical protein production. Many therapeutic proteins have been produced and scaled up in plants at a low cost compared to the conventional microbial and animal-based systems. The main technical challenge during this process is to produce sufficient levels of recombinant proteins in plants. Low yield is generally caused by proteolytic degradation during expression and downstream processing of recombinant proteins. The yield of human therapeutic interleukin (IL)-10 produced in transgenic tobacco leaves was found to be below the critical level, and may be due to degradation by tobacco proteases. Here, we identified a total of 60 putative cysteine protease genes (CysP) in tobacco. Based on their predicted expression in leaf tissue, 10 candidate CysPs (CysP1-CysP10) were selected for further characterization. The effect of CysP gene silencing on IL-10 accumulation was examined in tobacco. It was found that the recombinant protein yield in tobacco could be increased by silencing CysP6. Transient expression of CysP6 silencing construct also showed an increase in IL-10 accumulation in comparison to the control. Moreover, CysP6 localizes to the endoplasmic reticulum (ER), suggesting that ER may be the site of IL-10 degradation. Overall results suggest that CysP6 is important in determining the yield of recombinant IL-10 in tobacco leaves.
PMCID: PMC4493103  PMID: 26148064
12.  Trends in Relative Survival for Ovarian Cancer From 1975 to 2011 
Obstetrics and gynecology  2015;125(6):1345-1352.
To examine relative survival (a metric that incorporates changes in survival within a population) in women with ovarian cancer from 1975 to 2011.
Women diagnosed with ovarian cancer from 1975 to 2011 and recorded in the National Cancer Institute’s Surveillance, Epidemiology, and End Results database were examined. Relative survival, estimated as the ratio of the observed survival of cancer patients (all-cause mortality) to the expected survival of a comparable group from the general population, was matched to the patients with the main factors that are considered to affect patient survival such as age, calendar time, and race. Hazard ratios were adjusted for age, race, year of diagnosis, time since diagnosis, and the interaction of age and years since diagnosis (except for stage II).
A total of 49,932 women were identified. For stage I ovarian cancer, the adjusted excess hazard ratio for death in 2006 was 0.51 (95% confidence interval [CI] 0.41–0.63) compared with those diagnosed in 1975. The reduction in excess mortality remained significant when compared with 1980 and 1985. For women with stage III–IV tumors, the excess hazard of mortality was lower in 2006 compared with all other years of study ranging from 0.49 (95% CI 0.44–0.55) compared with 1975 to 0.93 (95% CI 0.87–0.99) relative to 2000. For women aged 50–59 years, 10-year relative survival was 0.85 (99% CI 0.61–0.95) for stage I disease and 0.18 (99% CI 0.10–0.27) for stage III–IV tumors. For women aged 60–69 years, the corresponding 10-year relative survival estimates were 0.89 (99% CI 0.58–0.98) and 0.15 (99% CI 0.09–0.21).
Relative survival has improved for all stages of ovarian cancer from 1975 to 2011.
PMCID: PMC4484269  PMID: 26000505
13.  Scientific migration of junior scientists to China 
Genome Biology  2014;15(6):119.
PMCID: PMC4072958  PMID: 25001910
14.  Spatiotemporal Distribution, Sources, and Photobleaching Imprint of Dissolved Organic Matter in the Yangtze Estuary and Its Adjacent Sea Using Fluorescence and Parallel Factor Analysis 
PLoS ONE  2015;10(6):e0130852.
To investigate the seasonal and interannual dynamics of dissolved organic matter (DOM) in the Yangtze Estuary, surface and bottom water samples in the Yangtze Estuary and its adjacent sea were collected and characterized using fluorescence excitation-emission matrices (EEMs) and parallel factor analysis (PARAFAC) in both dry and wet seasons in 2012 and 2013. Two protein-like components and three humic-like components were identified. Three humic-like components decreased linearly with increasing salinity (r>0.90, p<0.001), suggesting their distribution could primarily be controlled by physical mixing. By contrast, two protein-like components fell below the theoretical mixing line, largely due to microbial degradation and removal during mixing. Higher concentrations of humic-like components found in 2012 could be attributed to higher freshwater discharge relative to 2013. There was a lack of systematic patterns for three humic-like components between seasons and years, probably due to variations of other factors such as sources and characteristics. Highest concentrations of fluorescent components, observed in estuarine turbidity maximum (ETM) region, could be attributed to sediment resuspension and subsequent release of DOM, supported by higher concentrations of fluorescent components in bottom water than in surface water at two stations where sediments probably resuspended. Meanwhile, photobleaching could be reflected from the changes in the ratios between fluorescence intensity (Fmax) of humic-like components and chromophoric DOM (CDOM) absorption coefficient (a355) along the salinity gradient. This study demonstrates the abundance and composition of DOM in estuaries are controlled not only by hydrological conditions, but also by its sources, characteristics and related estuarine biogeochemical processes.
PMCID: PMC4479555  PMID: 26107640
15.  Interferon Treatment of Hepatitis C Reinfection after Liver Transplantation: A Meta-Analysis 
Background. Graft reinfection with hepatitis C (HCV) after liver transplantation is a significant problem in transplant hepatology. This meta-analysis was performed to compare the effectiveness and risk of adverse events of interferon-based therapy with no treatment after liver transplantation. Methods. We searched electronic databases up to July 31, 2013, to obtain relevant research reports that satisfied the inclusion criteria. Meta-analyses were done on randomized controlled trials (RCTs) and nonrandomized trials. Results. A meta-analysis was performed on 2 RCTs and 2 cohort studies comprising a total of 326 patients (171 of whom accepted interferon-based antiviral therapy). The treatment group was found to have higher virological response (VR) rates than controls at 12, 24, 48, and 72 weeks. Patients in the antiviral group had higher sustained virological response (SVR) rates and lower mean alanine aminotransferase levels relative to controls at 48 weeks, but more total serious adverse events (AEs) than controls. Conclusions. Interferon-based treatment has some efficacy in the treatment of HCV graft reinfection following liver transplantation.
PMCID: PMC4488578  PMID: 26167174
16.  Preoperative Serum Albumin Is Associated With Mortality and Complications After Radical Cystectomy 
BJU international  2014;113(6):918-923.
To determine the association between preoperative serum albumin and mortality and postoperative complications after radical cystectomy and urinary diversion.
Patients and Methods
We conducted a retrospective review of 1097 radical cystectomies performed for the treatment of bladder cancer between 1992 and 2005.
All data were entered prospectively into a hospital-based complications database.
We used multivariable logistic regression to assess the association between preoperative serum albumin and complications and mortality within 90 days of surgery, while controlling for preoperative patient and disease characteristics.
Low preoperative serum albumin was identified in 14% of the cohort.
Preoperative serum albumin was a predictor of postoperative complications (adjusted odds ratio [OR] per unit increase in albumin: 0.61, 95% confidence interval [CI] 0.42–0.90) and 90-day mortality (OR 0.33, 95% CI 0.14–0.75) when controlling for sex, race, age-adjusted Charlson score, body mass index, prior history of abdominal surgery, clinical stage, and neoadjuvant chemotherapy.
As serum albumin decreased, the risk of complications and mortality increased.
In addition to age-adjusted Charlson score, low preoperative serum albumin is a significant predictor of complications and mortality after radical cystectomy.
Serum albumin testing can be used to identify individuals at high-risk for morbidity and mortality.
PMCID: PMC4203702  PMID: 24053616
hypoalbuminemia; postoperative complications; urinary bladder neoplasms
17.  High miR-196a and low miR-367 cooperatively correlate with unfavorable prognosis of high-grade glioma 
Identification of microRNAs (miRNAs) could be beneficial for the diagnosis and prognosis of glioma. Therefore, we attempted to identify and develop specific miRNAs as prognostic and predictive markers for glioma patients. We compared the expression profiles of 365 miRNAs between 4 glioblastomas (GBMs, WHO grade IV) and 4 anaplastic astrocytomas (AAs, WHO grade III) using miRNA qPCR Array. MiR-196a (P = 0.004, fold change = 289.86) and miR-367 (P = 0.044, fold change = 0.03) were identified as the most up-regulated and down-regulated miRNAs in GBMs compared with AAs, respectively. We subsequently examined miR-196a and miR-367 expression levels in an independent series of 63 gliomas including 50 GBMs and 13 AAs, as well as 10 non-neoplastic brain tissues, and statistically analyzed the associations between miRNA expression and clinicopathological characteristics and survivals of these glioma patients. MiR-196a and miR-367 showed significant increased and decreased expression in high-grade gliomas relative to non-neoplastic brains, as well as in GBMs versus AAs, respectively. Additionally, high-miR-196a and low-miR-367 expression, alone or in combination, statistically correlated with aggressive clinicopathological features of gliomas. Furthermore, overall survivals of glioma patients with high-miR-196a, low-miR-367 and high-miR-196a/low-miR-367 expression tended to be shorter than the corresponding control groups (all P ≤ 0.001). Moreover, multivariate analysis indicated high-miR-196a/low-miR-367 as an independent prognostic indicator for glioma patients (P = 0.005, risk ratio = 1.8). Our results suggested that both high-miR-196a and low-miR-367 expression may be associated with aggressive progression and unfavorable clinical outcome in glioma patients. And combination of high-miR-196a and low-miR-367 expression may be a novel biomarker in identifying a poor prognosis group of high-grade glioma.
PMCID: PMC4525873  PMID: 26261539
microRNA; miR-196a; miR-367; high-grade glioma; glioblastoma; prognosis
18.  Impact of acute and chronic stress hormone on male albino rat brain 
The present investigation aimed to evaluate the acute and chronic effect of stress (stress hormone) in male albino rat brain. Nor-epinephrine was used for the treatment and saline used for the control. Nor-epinephrine was dissolved in the saline and administered orally to the rats. Following nor-epinephrine administration, the brain was removed surgically at 6 h, 12 h and 45 days. Alanine tansaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) were significantly altered in the rats. Lipid peroxidation was measured as malondialdehyde (MDA), showed altered lipid peroxidation. Hematological markers such as packed cell volume (PCV), white blood cells (WBC), neutrophil, lymphocytes and hemoglobin were significantly altered compared to controls. Altered serum biochemical and hematological markers, lipid peroxidation and enzyme activities leads to adverse effect in the cellular metabolism and physiological activities of rats.
PMCID: PMC4525905  PMID: 26261571
Rat; brain; enzymes; lipid peroxidation; WBC
19.  Comparison of Bone Mineral Density in Lumbar Spine and Fracture Rate among Eight Drugs in Treatments of Osteoporosis in Men: A Network Meta-Analysis 
PLoS ONE  2015;10(5):e0128032.
The preferred treatment for osteoporosis in men is debated, and pairwise meta-analysis cannot obtain hierarchies of these treatments.
The objective of this study was to integrate the evidence and provide hierarchies of eight drugs based on their effect on the bone mineral density in the lumbar spine (BMD in LS) and the fracture rate.
Data Sources
Eligible studies were identified by searching Amed, British Nursing Index, EMBASE, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, SIGLE, the National Technical Information Service, the National Research Register (UK), and the Current Controlled Trials databases.
Study Selection
RCTs or quasi-RCTs reporting at least two drugs (two active drugs or one active drug and a placebo) used to treat osteoporosis in men were selected by two authors.
Data Extraction
Two authors independently extracted the data.
Data Synthesis
Thirteen studies involving 3647 patients were included. Compared with placebo therapy, zoledronate (SMDs 13.48, 95% credible intervals 11.88-15.08) yielded the most significant effect on increasing the BMD in LS, followed by alendronate (11.04, 9.68-12.41), teriparatide (20mcg) + risedronate (10.98, 8.55-13.48), risedronate (10.33, 8.68-12.01), teriparatide (20mcg) (9.33, 6.87-11.76), strontium ranelate (8.88, 7.51-10.24), ibandronate (5.49, 3.82-7.16), parathyroid hormone (1-84) (4.89, 3.12-6.62) and alfacalcidol (3.42, 1.7-5.2). Placebo therapy had a significantly higher fracture rate in contrast to risedronate (OR 2.51, 95% CrI 1.23-4.24) or zoledronate (2.92, 1.29-5.62) or teriparatide (20mcg) (4.04, 1.36-8.49) or teriparatide (40mcg) (3.5, 1.14-8.34). Zoledronate ranked first for increasing the BMD in LS, and teriparatide (20mg) was ranked first for decreasing the fracture rate.
Zoledronate might be the best choice to increase the BMD in LS and teriparatide (20mg) might lead to the lowest fracture rate.
PMCID: PMC4444106  PMID: 26010450
20.  miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling 
Scientific Reports  2015;5:9930.
Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation.
PMCID: PMC4441322  PMID: 26001136
21.  Transcriptome sequencing of three Ranunculus species (Ranunculaceae) reveals candidate genes in adaptation from terrestrial to aquatic habitats 
Scientific Reports  2015;5:10098.
Adaptation to aquatic habitats is a formidable challenge for terrestrial angiosperms that has long intrigued scientists. As part of a suite of work to explore the molecular mechanism of adaptation to aquatic habitats, we here sequenced the transcriptome of the submerged aquatic plant Ranunculus bungei, and two terrestrial relatives R. cantoniensis and R. brotherusii, followed by comparative evolutionary analyses to determine candidate genes for adaption to aquatic habitats. We obtained 126,037, 140,218 and 114,753 contigs for R. bungei, R. cantoniensis and R. brotherusii respectively. Bidirectional Best Hit method and OrthoMCL method identified 11,362 and 8,174 1:1:1 orthologous genes (one ortholog is represented in each of the three species) respectively. Non-synonymous/synonymous (dN/dS) analyses were performed with a maximum likelihood method and an approximate method for the three species-pairs. In total, 14 genes of R. bungei potentially involved in the adaptive transition from terrestrial to aquatic habitats were identified. Some of the homologs to these genes in model plants are involved in vacuole protein formation, regulating ‘water transport process’ and ‘microtubule cytoskeleton organization’. Our study opens the door to understand the molecular mechanism of plant adaptation from terrestrial to aquatic habitats.
PMCID: PMC4438715  PMID: 25993393
22.  Resection is an effective treatment for recurrent follicular dendritic cell sarcoma from retroperitoneum: unusual presentation of a rare tumor 
Retroperitoneum follicular dendritic cell sarcoma (FDCS) is an extremely rare neoplasm. The treatment of this disease is not clear. A 49-year-old Chinese female who had been found a 4.4×4 cm retroperitoneum mass by routine physical examination was received radical resection. Pathology revealed an inflammatory pseudotumor-like follicular dendritic cell tumor. After five years follow-up, a new nodule was noted on the tail of pancreas by routine CT evaluation. Re-resection was performed and pathological examination found a spindle-cell tumor with a great quantity of froth histiocytes. Immunohistochemical stains were positive for CD35 and CD21 which suggested it was a recurrent FDCS. Retroperitoneum FDCS is a very rare tumor. Surgical resection may be the first choice for this disease, even for recurrent tumor, if feasible. A relatively good prognosis often is achieved when compared with other malignancy.
PMCID: PMC4509342  PMID: 26221397
FDCS; retroperitoneum; recurrent; resection; pancreas
23.  Upregulation of NLRP3 Inflammasome in the Tears and Ocular Surface of Dry Eye Patients 
PLoS ONE  2015;10(5):e0126277.
To evaluate the mRNA and protein expressions of NLRP3 inflammasome and its downstream inflammatory factors in human dry eye.
We recruited 54 patients with Sjögren’s syndrome dry eye (SSDE), 50 patients with non-Sjögren’s syndrome dry eye (NSSDE), and 46 healthy controls. Tear film breakup time (TBUT), Schirmer I test, and fluorescein staining (FL) were performed on all subjects. Tear samples were obtained to analyze the inflammatory cytokine levels of IL-1β and IL-18 via enzyme-linked immunosorbent (ELISA). Conjunctival impression cytology (CIC) specimens were collected to detect the mRNA expression of NLRP3, caspase-1, IL-1β, and IL-18 using quantitative RT-PCR, and the protein expression of NLRP3 and caspase-1 by Western blotting.
NLRP3 mRNA expression showed higher levels in both dry eye groups compared with controls, with a comparably significant elevation in the SSDE group (relative 2.47-fold upregulation, p<0.05). NLRP3 protein expression was also increased in SSDE group (relative1.94-fold upregulation) compared with the controls. mRNA expression of caspase-1 was significantly upregulated in both SSDE (relative 1.44-fold upregulation, p<0.05) and NSSDE (relative 1.32-fold upregulation, p<0.05). Procaspase-1 protein level was increased in SSDE (relative 1.84-fold upregulation) and NSSDE (relative 1.12-fold upregulation) versus controls; and caspase-1 protein expression was also increased in SSDE (relative 1.49-fold upregulation) and NSSDE (relative 1.17-fold upregulation) compared with the controls. The patients with SSDE and NSSDE had higher IL-1β and IL-18 mRNA values and protein expressions than the controls did. The relative mRNA expression of IL-1β upregulated 3.59-fold (p<0.001) in SSDE and 2.13-fold (p<0.01) in NSSDE compared with the controls. IL-1β protein level also showed significant upregulation in SSDE (p=0.01; vs. controls groups). IL-18 mRNA expression levels were significantly upregulated in the SSDE (relative 2.97-fold upregulation, p=0.001) and NSSDE (relative 2.05-fold upregulation, p=0.001) groups compared with the controls; tear IL-18 concentrations were also significantly increased in the SSDE (p<0.001) and NSSDE (p<0.05) groups.
In the current study, we found that mRNA and protein expressions of NLRP3 inflammasome were upregulated in human dry eyes, especially in SSDE; the downstream inflammatory factors caspase-1, IL-1β, and IL-18 were also elevated in dry eye patients. These observations suggest the involvement of NLRP3 inflammasome in the onset and development of the inflammation in dry eye.
PMCID: PMC4427105  PMID: 25962072
24.  CART treatment improves memory and synaptic structure in APP/PS1 mice 
Scientific Reports  2015;5:10224.
Major characteristics of Alzheimer’s disease (AD) include deposits of β-amyloid (Aβ) peptide in the brain, loss of synapses, and cognitive dysfunction. Cocaine- and amphetamine-regulated transcript (CART) has recently been reported to attenuate Aβ-induced toxicity. In this study, CART localization in APP/PS1 mice was characterized and the protective effects of exogenous CART treatment were examined. Compared to age-matched wild type mice, 8-month-old APP/PS1 mice had significantly greater CART immunoreactivity in the hippocampus and cortex. A strikingly similar pattern of Aβ plaque-associated CART immunoreactivity was observed in the cortex of AD cases. Treatment of APP/PS1 mice with exogenous CART ameliorated memory deficits; this effect was associated with improvements in synaptic ultrastructure and long-term potentiation, but not a reduction of the Aβ plaques. Exogenous CART treatment in APP/PS1 mice prevented depolarization of the mitochondrial membrane and stimulated mitochondrial complex I and II activities, resulting in an increase in ATP levels. CART treatment of APP/PS1 mice also reduced reactive oxygen species and 4-hydroxynonenal, and mitigated oxidative DNA damage. In summary, CART treatment reduced multiple neuropathological measures and improved memory in APP/PS1 mice, and may therefore be a promising and novel therapy for AD.
PMCID: PMC4426675  PMID: 25959573
25.  The lycopene β-cyclase plays a significant role in provitamin A biosynthesis in wheat endosperm 
BMC Plant Biology  2015;15:112.
Lycopene β-cyclase (LCYB) is a key enzyme catalyzing the biosynthesis of β-carotene, the main source of provitamin A. However, there is no documented research about this key cyclase gene’s function and relationship with β-carotene content in wheat. Therefore, the objectives of this study were to clone TaLCYB and characterize its function and relationship with β-carotene biosynthesis in wheat grains. We also aimed to obtain more information about the endogenous carotenoid biosynthetic pathway and thus provide experimental support for carotenoid metabolic engineering in wheat.
In the present study, a lycopene β-cyclase gene, designated TaLCYB, was cloned from the hexaploid wheat cultivar Chinese Spring. The cyclization activity of the encoded protein was demonstrated by heterologous complementation analysis. The TaLCYB gene was expressed differentially in different tissues of wheat. Although TaLCYB had a higher expression level in the later stages of grain development, the β-carotene content still showed a decreasing tendency. The expression of TaLCYB in leaves was dramatically induced by strong light and the β-carotene content variation corresponded with changes of TaLCYB expression. A post-transcriptional gene silencing strategy was used to down-regulate the expression of TaLCYB in transgenic wheat, resulting in a decrease in the content of β-carotene and lutein, accompanied by the accumulation of lycopene to partly compensate for the total carotenoid content. In addition, changes in TaLCYB expression also affected the expression of several endogenous carotenogenic genes to varying degrees.
Our results suggest that TaLCYB is a genuine lycopene cyclase gene and plays a crucial role in β-carotene biosynthesis in wheat. Our attempt to silence it not only contributes to elucidating the mechanism of carotenoid accumulation in wheat but may also help in breeding wheat varieties with high provitamin A content through RNA interference (RNAi) to block specific carotenogenic genes in the wheat endosperm.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0514-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4433027  PMID: 25943989
Lycopene; Lycopene β-cyclase; β-carotene; Provitamin A; RNA interference; Wheat

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