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1.  Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2 
OncoTargets and therapy  2015;8:2577-2587.
Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR) and human epidermal receptor (HER-2). SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2.
Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and downstream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1 on tumorigenicity and trastuzumab sensitivity were confirmed via in vivo xenograft model.
Trastuzumab-resistant SKBr-3 cells showed aberrant co-expression of EGFR and HER-2. Introduction of wild-type SHP-1 inhibited cell proliferation, clone formation, and promoted the apoptosis induced by trastuzumab. Meanwhile, SHP-1 overexpression reduced phosphorylation levels of EGFR and HER-2 both in parental and trastuzumab-resistant SKBr-3 cells. In vivo study showed an increased antitumor effect of trastuzumab in SHP-1 overexpressed xenografts. At last, we discovered that SHP-1 can make complexes with both EGFR and HER-2, and both phospho-EGFR and phosphor-HER-2 levels in wild-type SHP-1 immunoprecipitates were less than those in phosphatase-inactive SHP-1 (C453S) immunoprecipitates, indicating that EGFR and HER-2 are potential substrates of SHP-1.
Taken together, we have demonstrated that the SHP-1 is a negative regulatory factor of the tyrosine kinase activity of HER-2 and EGFR through inhibiting phosphorylation. Dual targeting of EGFR and HER-2, by combining trastuzumab with SHP-1 overexpression, may improve response in HER-2 overexpressing breast cancer cells that also express high levels of EGFR.
PMCID: PMC4576899  PMID: 26396531
breast cancer; trastuzumab; EGFR; HER-2; SHP-1; drug resistance
2.  Population-level expression variability of mitochondrial DNA-encoded genes in humans 
European Journal of Human Genetics  2014;22(9):1093-1099.
Human mitochondria contain multiple copies of a circular genome made up of double-stranded DNA (mtDNA) that encodes proteins involved in cellular respiration. Transcript abundance of mtDNA-encoded genes varies between human individuals, yet the level of variation in the general population has not been systematically assessed. In the present study, we revisited large-scale RNA sequencing data generated from lymphoblastoid cell lines of HapMap samples of European and African ancestry to estimate transcript abundance and quantify expression variation for mtDNA-encoded genes. In both populations, we detected up to over 100-fold difference in mtDNA gene expression between individuals. The marked variation was not due to differences in mtDNA copy number between individuals, but was shaped by the transcription of hundreds of nuclear genes. Many of these nuclear genes were co-expressed with one another, resulting in a module-enriched co-expression network. Significant correlations in expression between genes of the mtDNA and nuclear genomes were used to identify factors involved with the regulation of mitochondrial functions. In conclusion, we determined the baseline amount of variability in mtDNA gene expression in general human populations and cataloged a complete set of nuclear genes whose expression levels are correlated with those of mtDNA-encoded genes. Our findings will enable the integration of information from both mtDNA and nuclear genetic systems, and facilitate the discovery of novel regulatory pathways involving mitochondrial functions.
PMCID: PMC4135407  PMID: 24398800
mitochondrial DNA-encoded genes; nuclear genes; gene expression variability; human populations; mitochondrial DNA copy number
3.  Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients*  
Objective: Professional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs). Methods: We searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect. Results: Twelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3+ T-lymphocytes (MD=−11.65, P<0.05) and CD4+ T-lymphocytes (MD=−8.18, P<0.01) of the combination group were higher. Conclusions: Immunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.
PMCID: PMC4569682  PMID: 26365116
Solid carcinoma; Meta-analysis; Dendritic cells; Cytokine-induced killer cells; Immunotherapy
4.  Moesin and myosin phosphatase confine neutrophil orientation in a chemotactic gradient 
Jingsong Xu and colleagues investigate how neutrophils initiate polarized migration toward bacteria or chemoattractants. They find that attractant-induced activation of myosin phosphatase results in the deactivation of moesin at the prospective leading edge and its redistribution to the trailing edge, establishing polarity and directional pseudopod formation.
Neutrophils respond to invading bacteria by adopting a polarized morphology, migrating in the correct direction, and engulfing the bacteria. How neutrophils establish and precisely orient this polarity toward pathogens remains unclear. Here we report that in resting neutrophils, the ERM (ezrin, radixin, and moesin) protein moesin in its active form (phosphorylated and membrane bound) prevented cell polarization by inhibiting the small GTPases Rac, Rho, and Cdc42. Attractant-induced activation of myosin phosphatase deactivated moesin at the prospective leading edge to break symmetry and establish polarity. Subsequent translocation of moesin to the trailing edge confined the formation of a prominent pseudopod directed toward pathogens and prevented secondary pseudopod formation in other directions. Therefore, both moesin-mediated inhibition and its localized deactivation by myosin phosphatase are essential for neutrophil polarization and effective neutrophil tracking of pathogens.
PMCID: PMC4322047  PMID: 25601651
5.  Retrospective comparison of the effects of epidural anesthesia versus peripheral nerve block on postoperative outcomes in elderly Chinese patients with femoral neck fractures 
Clinical Interventions in Aging  2015;10:1223-1231.
Geriatric patients with femoral neck fracture (FNF) have unacceptably high rates of postoperative complications and mortality. The purpose of this study was to compare the effects of epidural anesthesia versus peripheral nerve block (PNB) on postoperative outcomes in elderly Chinese patients with FNF.
This retrospective study explored mortality and postoperative complications in geriatric patients with FNF who underwent epidural anesthesia or PNB at the Chinese People’s Liberation Army General Hospital from January 2008 to December 2012. The electronic database at the Chinese People’s Liberation Army General Hospital includes discharge records for all patients treated in the hospital. Information on patient demographics, preoperative comorbidity, postoperative complications, type of anesthesia used, and in-hospital, 30-day, and 1-year mortality after surgery was obtained from this database.
Two hundred and fifty-eight patients were identified for analysis. The mean patient age was 79.7 years, and 71.7% of the patients were women. In-hospital, 30-day, and 1-year postoperative mortality was 4.3%, 12.4%, and 22.9%, respectively, and no differences in mortality or cardiovascular complications were found between patients who received epidural anesthesia and those who received PNB. More patients with dementia or delirium were given PNB. No statistically significant differences were found between groups for other comorbidities or intraoperative parameters. The most common complications were acute cardiovascular events (23.6%), electrolyte disturbances (20.9%), and hypoxemia (18.2%). Patients who received PNB had more postoperative delirium (P=0.027). Postoperative acute respiratory events were more common (P=0.048) and postoperative stroke was less common (P=0.018) in the PNB group. There were fewer admissions to intensive care (P=0.024) in the epidural anesthesia group. Key factors with a negative influence on mortality were acute cardiovascular events, dementia, male sex, age, American Society of Anesthesiologists score, acute respiratory events, intensive care admission, and comorbidities.
PNB was not associated with lower mortality or lower cardiovascular complication rates when compared with epidural anesthesia in elderly patients with FNF.
PMCID: PMC4535552  PMID: 26300631
femoral neck fractures; elderly; epidural anesthesia; peripheral nerve block; postoperative outcomes
6.  Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes 
Flavonoids, the major polyphenol components in Cotinus coggygria (CC), have been found to show an anticancer effect in our previous study; however, the exact mechanisms of inducing human glioblastoma (GBM) cell death remain to be resolved. In this study, a novel polyvinylpyrrolidone K-30/sodium dodecyl sulfate and polyethyleneglycol-coated liposome loaded with CC flavonoids (CCFs) was developed to enhance solubility and the antibrain tumor effect, and the molecular mechanism regarding how CCF nanoliposomes (CCF-NLs) induce apoptotic cell death in vitro was investigated. DBTRG-05MG GBM cell lines treated with CCF-NLs showed potential antiproliferative effects. Regarding the underlying mechanisms of inducing apoptosis in DBTRG-05MG GBM cells, CCF-NLs were shown to downregulate the expression of antiapoptotic B-cell lymphoma/leukemia 2 (Bcl-2), an apoptosis-related protein family member, but the expression of proapoptotic Bcl-2-associated X protein was enhanced compared with that in controls. CCF-NLs also inhibited the activity of caspase-3 and -9, which is the initiator caspase of the extrinsic and intrinsic apoptotic pathways. Blockade of caspase activation consistently induced apoptosis and inhibited growth in CCF-NL-treated DBTRG-05MG cells. This study further investigated the role of the Akt pathway in the apoptotic cell death by CCF-NLs, showing that CCF-NLs deactivated Akt. Specifically, CCF-NLs downregulated the expression of p-Akt and SIRT1 as well as the level of phosphorylated p53. Together, these results indicated SIRT1/p53-mediated cell death was induced by CCF-NLs, but not by extracellular signal-regulated kinase, in DBTRG-05MG cells. Overall, this study suggested caspase-dependent activation of both the intrinsic and extrinsic signaling pathways, probably through blockade of the SIRT1/p53-mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells.
PMCID: PMC4531020  PMID: 26345416
Cotinus coggygria flavonoid nanoliposomes; cell death; SIRT1; mitochondrial; PI3K/Akt pathway
7.  Paclitaxel reduces formation of hypertrophic scars in the rabbit ear model 
Background and objective
The onset and progression of pathological scarring involves multiple cytokines and complex mechanisms. However, hyperplasia of fibroblasts and neovascularization plays important roles, which can be inhibited by paclitaxel. The aim of this study was to investigate the efficacy of paclitaxel in the treatment of hypertrophic scars on rabbit ears.
Rabbit ear models of hypertrophic scars were established to observe the therapeutic effects of paclitaxel at different concentrations (12 mg/L, 24 mg/L, 48 mg/L, 96 mg/L, 18 mg/L, 54 mg/L, 162 mg/L, 486 mg/L, 30 mg/L, 150 mg/L, 750 mg/L, 3,750 mg/L). The outcome measures included hypertrophic index (HI), density of fibroblasts, density of collagenous fibers, and microvessel density.
In comparison with the control group, the concentrations of 96 mg/L, 150 mg/L, and 162 mg/L significantly reduce the formation of hypertrophic scars in the rabbit ear models. However, local necrosis was found in the rabbit ear models treated with paclitaxel solution >400 mg/L.
Paclitaxel has strong inhibitory effects on the hyperplasia of fibroblasts, deposition of collagen, and microangiogenesis in hypertrophic scars on rabbit ears within the concentration range from 48 mg/L to 162 mg/L, without causing local necrosis.
PMCID: PMC4524470  PMID: 26251604
hypertrophic scar; paclitaxel; rabbit ear model
8.  Serum Uric Acid and Renal Transplantation Outcomes: At Least 3-Year Post-transplant Retrospective Multivariate Analysis 
PLoS ONE  2015;10(7):e0133834.
Since the association of serum uric acid and kidney transplant graft outcome remains disputable, we sought to evaluate the predictive value of uric acid level for graft survival/function and the factors could affect uric acid as time varies. A consecutive cohort of five hundred and seventy three recipients transplanted during January 2008 to December 2011 were recruited. Data and laboratory values of our interest were collected at 1, 3, 6, 12, 24 and 36 months post-transplant for analysis. Cox proportional hazard model, and multiple regression equation were built to adjust for the possible confounding variables and meet our goals as appropriate. The current cohort study lasts for 41.86 ± 15.49 months. Uric acid level is proven to be negatively associated with eGFR at different time point after adjustment for age, body mass index and male gender (standardized β ranges from -0.15 to -0.30 with all P<0.001).Males with low eGFR but high level of TG were on CSA, diuretics and RAS inhibitors and experienced at least one episode of acute rejection and diabetic issue were associated with a higher mean uric acid level. Hyperuricemia was significantly an independent predictor of pure graft failure (hazard ratio=4.01, 95% CI: 1.25-12.91, P=0.02) after adjustment. But it was no longer an independent risk factor for graft loss after adjustment. Interestingly, higher triglyceride level can make incidence of graft loss (hazard ratio=1.442, for each unit increase millimoles per liter 95% CI: 1.008-2.061, P=0.045) and death (hazard ratio=1.717, 95% CI: 1.105-2.665, P=0.016) more likely. The results of our study suggest that post-transplant elevated serum uric acid level is an independent predictor of long-term graft survival and graft function. Together with the high TG level impact on poor outcomes, further investigations for therapeutic effect are needed.
PMCID: PMC4514650  PMID: 26208103
9.  Flexural bending of southern Tibet in a retro foreland setting 
Scientific Reports  2015;5:12076.
The highest elevation of the Tibetan Plateau, lying 5,700 m above sea level, occurs within the part of the Lhasa block immediately north of the India-Tibet suture zone (Yarlung Zangbo suture zone, YZSZ), being 700 m higher than the maximum elevation of more northern parts of the plateau. Various mechanisms have been proposed to explain this differentially higher topography and the rock uplift that led to it, invoking crustal compression or extension. Here we present the results of structural investigations along the length of the high elevation belt and suture zone, which rather indicate flexural bending of the southern margin of the Lhasa block (Gangdese magmatic belt) and occurrence of an adjacent foreland basin (Kailas Basin), both elements resulting from supra-crustal loading of the Lhasa block by the Zangbo Complex (Indian plate rocks) via the Great Counter Thrust. Hence we interpret the differential elevation of the southern margin of the plateau as due originally to uplift of a forebulge in a retro foreland setting modified by subsequent processes. Identification of this flexural deformation has implications for early evolution of the India-Tibet continental collision zone, implying an initial (Late Oligocene) symmetrical architecture that subsequently transitioned into the present asymmetrical wedge architecture.
PMCID: PMC4502525  PMID: 26174578
10.  Reliability and validity of the Chinese version of the Short Musculoskeletal Function Assessment questionnaire in patients with skeletal muscle injury of the upper or lower extremities 
The Short Musculoskeletal Function Assessment (SMFA) questionnaire is one of the most commonly used scales to evaluate functional status and quality of life (QOL) of patients with a broad range of musculoskeletal disorders. However, a Chinese version of the SMFA questionnaire for the psychometric properties of skeletal muscle injury patients in China is still lacking. The current study translated the SMFA into Chinese and assessed its reliability and validity among Chinese patients with skeletal muscle injury of the upper or lower extremities.
The original SMFA was translated from English into Chinese and culturally adapted according to cross-cultural adaptation guidelines. A multicenter cross-sectional study was conducted, comprising 339 skeletal muscle injury patients (aged 20–75 years) from 4 hospitals. The SMFA, the health survey short form (SF-36) along with a region-specific questionnaire (including the disabilities of the arm, shoulder, and hand questionnaire (DASH), the hip disability and osteoarthritis outcome score (HOOS), the knee injury and osteoarthritis outcome score (KOOS), and the foot function index (FFI)) were completed according to the region of injury. Reliability was estimated from the internal consistency using Cronbach’s α and validity was assessed via convergent validity, known-groups comparison, and construct validity.
Cronbach’s α coefficient was over 0.75 for two subscales and four categories of the SMFA, suggesting that the internal consistency reliability of the SMFA was satisfactory. Known-groups comparison showed that the dysfunction index and the bother index of the SMFA discriminated well between patients who differed in age, gender, injury location, and operation status rather than in subgroups based on the body mass index (BMI). The convergent validity of the SMFA was good, as moderate to excellent correlations were found between the subscales of the SMFA and the four subscales of SF-36 (physical function, role-physical, bodily pain, and social functioning) and the region-specific questionnaires. The construct validity was proved by the presence of a six-factor structure that accounted for 66.85 % of the variance.
The Chinese version of the SMFA questionnaire is a reliable and valid instrument to measure patient-reported impact of musculoskeletal injuries in the upper or lower extremities.
PMCID: PMC4493803  PMID: 26148546
Musculoskeletal disorders; Chinese; Short Musculoskeletal Function Assessment; Exploratory factor analysis; Quality of life
11.  Enhancement of Apoptosis by Titanium Alloy Internal Fixations during Microwave Treatments for Fractures: An Animal Study 
PLoS ONE  2015;10(7):e0132046.
Microwaves are used in one method of physical therapy and can increase muscle tissue temperature which is useful for improving muscle, tendon and bone injuries. In the study, we sought to determine whether titanium alloy internal fixations influence apoptosis in tissues subjected to microwave treatments at 2,450 MHz and 40 W during the healing of fractures because this issue is not yet fully understood.
In this study, titanium alloy internal fixations were used to treat 3.0-mm transverse osteotomies in the middle of New Zealand rabbits’ femurs. After the operation, 30-day microwave treatments were applied to the 3.0 mm transverse osteotomies 3 days after the operation. The changes in the temperatures of the muscle tissues in front of the implants or the 3.0 mm transverse osteotomies were measured during the microwave treatments. To characterize the effects of titanium alloy internal fixations on apoptosis in the muscles after microwave treatment, we performed TUNEL assays, fluorescent real-time (quantitative) PCR, western blotting analyses, reactive oxygen species (ROS) detection and transmission electron microscopy examinations.
The temperatures were markedly increased in the animals with the titanium alloy implants. Apoptosis in the muscle cells of the implanted group was significantly more extensive than that in the non-implanted control group at different time points. Transmission electron microscopy examinations of the skeletal muscles of the implanted groups revealed muscular mitochondrial swelling, vacuolization. ROS, Bax and Hsp70 were up-regulated, and Bcl-2 was down-regulated in the implanted group.
Our results suggest that titanium alloy internal fixations caused greater muscular tissue cell apoptosis following 2,450 MHz, 40 W microwave treatments in this rabbit femur fracture models.
PMCID: PMC4488932  PMID: 26132082
12.  Relationships between Depressive Symptoms and Endothelial Function Among Outpatients of a General Hospital in China 
This study aimed to investigate the endothelial function by reactive hyperemia index (RHI) in patients with depression, subjects recovering from depression, and subjects without a history of depression.
Outpatients were recruited from a general hospital in China; 62 patients diagnosed with depression and the 17-item Hamilton Rating Scale for Depression (HAMD17) total scores ≥17 were enrolled as the depression group, 62 patients with a history of depression, discontinuation of antidepressants therapy at least 3 months ago, and HAMD17 ≤7 were recruited as remission group, and 62 subjects without a history of depression served as the control group (HAMD17 ≤7).
The mean RHI was 1.93, 2.34, and 2.19 in depression, control, and remission groups, respectively, showing a significant difference among the 3 groups (P=0.0004). In addition, a marked difference in RHI was found between depression and control groups (P=0.0003) and between depression and remission groups (P=0.0270). However, there was no significant difference between remission and control groups (P=0.3363).
There is a relationship between depression and endothelial dysfunction in outpatients from a general hospital in China. The improvement of depression is synchronous with the improvement of endothelial function.
PMCID: PMC4492485  PMID: 26101428
Cross-Sectional Studies; Depression; Endothelial Cells; Remission Induction
13.  Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents 
The unusual fused β-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase. In this study, a structure-based lead optimization of vibralactone resulted in three series of 104 analogs, among which compound C1 exhibited the most potent inhibition of pancreatic lipase, with an IC50 value of 14 nM. This activity is more than 3000-fold higher than that of vibralactone. The effect of compound C1 on obesity was investigated using high-fat diet (HFD)-induced C57BL/6 J obese mice. Treatment with compound C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity, primarily through the improvement of metabolic parameters, such as triglyceride levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0062-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4488150  PMID: 26085282
Natural products; Structure optimization; Antiobesity agents; Pancreatic lipase inhibitors; Vibralactone derivatives
14.  Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents 
The unusual fused β-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase. In this study, a structure-based lead optimization of vibralactone resulted in three series of 104 analogs, among which compound C1 exhibited the most potent inhibition of pancreatic lipase, with an IC50 value of 14 nM. This activity is more than 3000-fold higher than that of vibralactone. The effect of compound C1 on obesity was investigated using high-fat diet (HFD)-induced C57BL/6 J obese mice. Treatment with compound C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity, primarily through the improvement of metabolic parameters, such as triglyceride levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-015-0062-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4488150  PMID: 26085282
Natural products; Structure optimization; Antiobesity agents; Pancreatic lipase inhibitors; Vibralactone derivatives
15.  Relationship between insecticide resistance and kdr mutations in the dengue vector Aedes aegypti in Southern China 
Parasites & Vectors  2015;8:325.
Aedes aegypti is an important vector for dengue virus and thus has been targeted with pyrethroid insecticides in many areas of the world. As such, resistance has been detected to several of these insecticides, including in China, but the mechanisms of the resistance are not well understood in this country.
Using the World Health Organization larval mosquito bioassay, five field populations of Aedes aegypti from Southern China were characterized for their resistance to cypermethrin and cyhalothrin. RNA extraction with PCR amplification, cloning and sequencing of the sodium channel gene was followed by comparisons of susceptible and wild mosquito strains Additionally, genomic DNA was used for Allele-specific PCR (AS-PCR) genotyping of the sodium channel genes to detect S989P, V1016G and F1534C mutations and allow for correlation analysis of resistance expression for the different mutations.
All wild strains expressed resistance to cypermethrin and cyhalothrin and the resistance expression between the two insecticides was highly correlated suggesting cross-resistance between these two pyrethroids. The AS-PCR technique effectively distinguished individual genotypes for all three mutations. Among the five wild strains tested, two strains carried all three mutations. Although the S989P and V1016G mutations were positively correlated to resistance expression of both pyrethroids, the F1534C mutation was negatively correlated.
Our methodology proved highly reliable and will aid future detection of kdr mutations. The three sodium channel mutations were common in the Ae. aegypti strains sampled from Southern China. The V1016G mutation appears to be the most important kdr mutation in Ae. aegypti strains in Southern China.
PMCID: PMC4475621  PMID: 26068925
Aedes aegypti; kdr mutation; China
16.  Polymorphisms in NFKB1 and NFKBIA Genes Modulate the Risk of Developing Prostate Cancer among Han Chinese 
Nuclear factor kappa B (NF-κB) pathway proteins play an important role in modulating inflammation and other carcinogenic processes. Polymorphisms within NF-κB pathway genes may influence cancer risk. This study aimed to examine the association between NFKB19-4 ATTG ins→del, NFKBIA 3′ UTR A→G, -826CT and -881AG polymorphisms and prostate cancer risk among Chinese.
The polymorphisms were genotyped via PCR-RFLP technique on 936 prostate cancer patients and 936 population-based healthy controls. Logistic regression model was used to measure the risk association present.
With the exception of NFKBIA 3′ UTR polymorphism, the heterozygous and mutant genotypes of the other polymorphisms were significantly associated with prostate cancer risk. For NFKB1 polymorphism, a decreased risk was observed, with adjusted OR: 0.69; 95% CI: 0.44, 0.98; P=0.01 (heterozygous) and adjusted OR: 0.60; 95% CI: 0.37, 0.91; P=0.02 (mutant). NFKBIA -826CT and -881AG polymorphisms were in complete linkage disequilibrium and shared the same risk association, with adjusted OR: 1.34; 95% CI: 1.09, 1.62; P=0.02 (heterozygous) and adjusted OR: 2.83; 95% CI: 1.79, 4.50; P=0.01 (mutants). Interestingly, the impact of the NFKB1 polymorphism was not present in nonsmokers and younger (<60 years) subjects (P<0.05).
In conclusion, polymorphisms in NFKB1 and NFKBIA genes may modulate the risk of developing prostate cancer among Chinese.
PMCID: PMC4473804  PMID: 26068031
Asian Continental Ancestry Group; Association; Genetic Association Studies; Genotype; Polymorphism, Genetic
17.  Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Infection Induced Apoptosis and Autophagy in Thymi of Infected Piglets 
PLoS ONE  2015;10(6):e0128292.
Previously, we demonstrated that the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) HuN4 strain causes obvious thymic atrophy and thymocytes apoptosis in infected piglets after birth, which is more severe than that induced by classical PRRSV. In this study, we investigated apoptosis and autophagy in the thymus of piglets infected with the HP-PRRSV HuN4 strain, and found that both apoptosis and autophagy occurred in the thymus of piglets infected with HP-PRRSV. In addition to a few virus-infected cells, CD14+ cells, the main autophagic cells in the thymus were thymic epithelial cells. These findings demonstrated that HP-PRRSV induces apoptosis in bystander cells, and induces autophagy in both infected and bystander cells in the thymus of infected piglets. Herein, we first present new data on the thymic lesions induced by HP-PRRSV, and show that apoptosis and autophagy are key mechanisms involved in cell survival and determinants of the severity of thymic atrophy in infected piglets. Finally, future studies of the mechanism underlying immune responses are proposed based on our current understanding of PRRSV-host interactions.
PMCID: PMC4457848  PMID: 26046751
18.  Histone deacetylation of memory T lymphocytes by You-Gui-Wan alleviates allergen-induced eosinophilic airway inflammation in asthma 
Chinese Medicine  2015;10:9.
You-Gui pills (You-Gui-Wan; YGW) can promote T lymphocyte proliferation and differentiation, and restore Th1/Th2 balance in the treatment of asthma, but their mechanism of action is not fully known. This study aims to explore whether YGW can induce histone deacetylation or acetylation in memory T lymphocytes (Tm) for improvement of airway inflammation in asthma.
CD4+CD45RBlow cells, as Tm, were obtained by magnetic-activated cell sorting and flow cytometry from the spleens of BALB/c mice with ovalbumin (OVA)-induced asthma. Tm were cocultured with hydrocortisone (CORT; 1000 nM), serum containing low (0.225 g/kg), moderate (0.9 g/kg), or high (3.6 g/kg) doses of YGW, or medium only, and then adoptively transferred into naïve mice (n = 5 per group). Recipient mice were challenged with aerosolized OVA. The levels of IL-4, IL-5, IL-13, and IFN-γ in culture supernatants and bronchoalveolar lavage fluid (BALF) from the OVA-challenged mice were measured by ELISA. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities and protein expressions of T-bet, GATA-3, and HDAC1–11 in lung tissue were measured by western blotting analyses. The alveolar eosinophilic inflammation index (AEII) was evaluated in the lungs of adoptive transfer recipient mice.
YGW reduced inflammation and eosinophil infiltration into the lung tissues as evidenced by histology, with similar effects to those of CORT. High-, moderate-, and low-YGW increased HDAC (P < 0.0001, P = 0.0009 and P = 0.0253 respectively) and decreased HAT (P = 0.0001, P = 0.0000 and P = 0.0039, respectively) activities in dose-dependent manners in the lung tissues of adoptive transfer recipient mice. Increased histone deacetylation of Tm by YGW reduced the AEII by reducing GATA-3 (P = 0.014),IL-4 (P = 0.0004), IL-5 (P = 0.0067), and IL-13 (P = 0.0002), and inducing IFN-γ release (P = 0.0375). Moreover, YGW reduced inflammatory cytokines such as IL-4, IL-5, and IL-13 by upregulating the activities of HDAC7 (P = 0.003)/10 (P = 0.003), HDAC11 (P < 0.0001), and HDAC9–11 (P < 0.0001, P < 0.0001 and P < 0.0001, respectively), respectively, and increased IFN-γ release by increasing HDAC9 (P < 0.0001).
Histone deacetylation of Tm was observed during alleviation of allergen-induced eosinophilic airway inflammation in asthma by YGW.
PMCID: PMC4465301  PMID: 26075017
19.  Molecular Signatures of Major Depression 
Current Biology  2015;25(9):1146-1156.
Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.
•Amount of mtDNA is increased, and telomeric DNA is shortened in major depression•Both changes can be induced with stress but are contingent on the depressed state•Changes are tissue specific and in part due to glucocorticoid secretion•Changes are in part reversible and represent switches in metabolic strategy
Cai et al. found increases in mtDNA and a reduction in telomeric DNA in cases of major depression using whole-genome sequencing. Both changes are depression state dependent. Mice exposed to chronic stress or glucorticoids showed that these changes reflect switches in metabolic strategy and are tissue specific and partial reversible.
PMCID: PMC4425463  PMID: 25913401
20.  Magic electron affection in preparation process of silicon nanocrystal 
Scientific Reports  2015;5:9932.
It is very interesting that magic electron affection promotes growth of nanocrystals due to nanoscale characteristics of electronic de Broglie wave which produces resonance to transfer energy to atoms. In our experiment, it was observed that silicon nanocrystals rapidly grow with irradiation of electron beam on amorphous silicon film prepared by pulsed laser deposition (PLD), and silicon nanocrystals almost occur in sphere shape on smaller nanocrystals with less irradiation time of electron beam. In the process, it was investigated that condensed structures of silicon nanocrystals are changed with different impurity atoms in silicon film, in which localized states emission was observed. Through electron beam irradiation for 15min on amorphous Si film doped with oxygen impurity atoms by PLD process, enhanced photoluminescence emission peaks are observed in visible light. And electroluminescence emission is manipulated into the optical communication window on the bigger Si-Yb-Er nanocrystals after irradiation of electron beam for 30min.
PMCID: PMC4408977  PMID: 25909481
21.  The prevalence of Escherichia coli strains with extended spectrum beta-lactamases isolated in China 
The extended-spectrum-lactamases-producing Escherichia coli has rapidly spread worldwide. Escherichia coli has been becoming much more resistant to β-lactam antibiotics and other commonly available antimicrobials. We investigated the prevalence, resistance, and probable gene type of extended spectrum beta-lactamases (ESBLs) using minimum inhibitory concentrations (MICs) testing and polymerase chain reaction (PCR). We have collected 289 single-patient E. coli Isolates based on samples of China from July 2013 to August 2014. This article explored that the prevalence of ESBL-producing Isolates showed multi-resistant to antimicrobials such as fluoroquinolones, trimethoprim, tetracycline and aminoglycosides, and so on. The frequencies of resistance in Isolates were as follows: Ciprofloxacin, 74%, gentamicin, 69.5%, levofloxacin, 63%, tobramycin, 39%, and minocycline, 7.9%. According to our results, 197(68.2%) of the total 289 Isolates were ESBL-producing strains; further, 172 (87.3%) producers contained genes encoding CTX-M enzymes and 142(72.1%) producers contained genes encoding TEM enzymes. Most ESBL-producing Escherichia coli has produced more than one type of β-lactamase. Nucleotide sequence analysis has revealed the diversity of ESBLs types: CTX-M -15 is in the majority and TEM-135, CTX-M-3, CTX-M-98, CTX-M-14, CTX-M-142, CTX-M-65, CTX-M-55, CTX-M-27, and CTX-M-123 have been recovered. The results confirm that ESBL producers which are common in hospital strains of Escherichia coli are resistant to cephalosporins and other antibiotics in China. It is important to monitor such strains closely and provide scientific evidence of rational application of antibiotics to prevent their spread.
PMCID: PMC4404919  PMID: 25954262
extended-spectrum-lactamase; Escherichia coli; multi-drug resistant; PCR; TEM; CTX-M
22.  Serum and Synovial Fluid Nesfatin-1 Concentration is Associated with Radiographic Severity of Knee Osteoarthritis 
Nesfatin-1, a member of the adipokine family, has been detected in synovial fluid (SF) from OA patients. This study aimed to determine whether there is a marked correlation of nesfatin-1 levels in serum and SF of knee OA patients with the disease severity of OA.
This cross-sectional research enrolled 202 knee OA subjects. The Kellgren-Lawrence grading system was utilized to evaluate the severity of knee OA.
Elevated nesfatin-1 concentrations in serum were found in knee OA patients compared with the controls. Nesfatin-1 concentrations were markedly elevated with increased KL grades. Serum and SF nesfatin-1 concentrations were both significantly associated with the disease severity evaluated by KL grading criteria.
Our investigation indicates a marked association of serum and SF nesfatin-1 concentrations with OA disease severity.
PMCID: PMC4410725  PMID: 25872767
Adipokines; Osteoarthritis; Serum; Severity of Illness Index; Synovial Fluid
23.  SNCA Gene, but Not MAPT, Influences Onset Age of Parkinson's Disease in Chinese and Australians 
BioMed Research International  2015;2015:135674.
Background. α-Synuclein (SNCA) and microtubule-associated protein tau (MAPT) are the two major genes independently, but not jointly, associated with susceptibility for Parkinson's disease (PD). The SNCA gene has recently been identified as a major modifier of age of PD onset. Whether MAPT gene synergistically influences age of onset of PD is unknown. Objective. To investigate independent and joint effects of MAPT and SNCA on PD onset age. Methods. 412 patients with PD were recruited from the Australian PD Research Network (123) and the Neurology Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University, China (289). MAPT (rs17650901) tagging H1/H2 haplotype and SNCA (Rep1) were genotyped in the Australian cohort, and MAPT (rs242557, rs3744456) and SNCA (rs11931074, rs894278) were genotyped in the Chinese cohort. SPSS regression analysis was used to test genetic effects on age at onset of PD in each cohort. Results. SNCA polymorphisms associated with the onset age of PD in both populations. MAPT polymorphisms did not enhance such association in either entire cohort. Conclusion. This study suggests that, in both ethnic groups, SNCA gene variants influence the age at onset of PD and α-synuclein plays a key role in the disease course of PD.
PMCID: PMC4413514  PMID: 25960998
25.  GSK3β-Dzip1-Rab8 Cascade Regulates Ciliogenesis after Mitosis 
PLoS Biology  2015;13(4):e1002129.
The primary cilium, which disassembles before mitotic entry and reassembles after mitosis, organizes many signal transduction pathways that are crucial for cell life and individual development. However, how ciliogenesis is regulated during the cell cycle remains largely unknown. Here we show that GSK3β, Dzip1, and Rab8 co-regulate ciliogenesis by promoting the assembly of the ciliary membrane after mitosis. Immunofluorescence and super-resolution microscopy showed that Dzip1 was localized to the periciliary diffusion barrier and enriched at the mother centriole. Knockdown of Dzip1 by short hairpin RNAs led to failed ciliary localization of Rab8, and Rab8 accumulation at the basal body. Dzip1 preferentially bound to Rab8GDP and promoted its dissociation from its inhibitor GDI2 at the pericentriolar region, as demonstrated by sucrose gradient centrifugation of purified basal bodies, immunoprecipitation, and acceptor-bleaching fluorescence resonance energy transfer assays. By means of in vitro phosphorylation, in vivo gel shift, phospho-peptide identification by mass spectrometry, and GST pulldown assays, we demonstrated that Dzip1 was phosphorylated by GSK3β at S520 in G0 phase, which increased its binding to GDI2 to promote the release of Rab8GDP at the cilium base. Moreover, ciliogenesis was inhibited by overexpression of the GSK3β-nonphosphorylatable Dzip1 mutant or by disabling of GSK3β by specific inhibitors or knockout of GSK3β in cells. Collectively, our data reveal a unique cascade consisting of GSK3β, Dzip1, and Rab8 that regulates ciliogenesis after mitosis.
The asymmetric assembly of a new primary cilium in one of two daughter cells after mitosis is regulated by a cascade involving GSK3β, Dzip1, and Rab8.
Author Summary
The primary cilium is an antenna-like organelle that projects out from the surface of cells and is present in almost all vertebrate cells, playing crucial roles in many cellular processes, including chemical sensation, signal transduction, and control of cell growth. The primary cilium assembles via a dynamic process called ciliogenesis that is regulated during the cell cycle: it assembles after mitosis and disassembles again before entering the next mitotic cycle. Here we investigate the regulatory mechanisms underlying this process. We show that Dzip1—a protein known to promote ciliogenesis—is preferentially recruited to the centrosome of the daughter cell that contains the grandmother centriole. Once in the centrosome, Dzip1 promotes release of Rab8GDP—a small GTPase that regulates membrane vesicular trafficking to the cilium—from its inhibitor GDI2 at the pericentriolar region, thereby facilitating ciliogenesis. This process is further regulated by an enzyme, GSK3β, whose increased kinase activity during the M- to G0-phase transition of the cell cycle results in phosphorylation of Dzip1, promoting the ability of Dzip1 to release Rab8GDP. Our findings identify the molecular mechanism underlying the GSK3β-Dzip1-Rab8 signaling cascade, shedding light on how ciliogenesis is coordinated with mitotic exit. They also provide an understanding of why ciliogenesis always takes place earlier in one of the two daughter cells.
PMCID: PMC4393111  PMID: 25860027

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