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1.  Using Gelatin Nanoparticle Mediated Intranasal Delivery of Neuropeptide Substance P to Enhance Neuro-Recovery in Hemiparkinsonian Rats 
PLoS ONE  2016;11(2):e0148848.
Intranasal administration of phospholipid-based gelatin nanoparticles (GNP) was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP) on hemiparkinsonian rats.
The SP-loaded gelatin nanoparticles (SP-GNP) were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM). The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH), phosphorylated c-Jun protein (p-c-Jun) and Caspase-3 (Cas-3) expressed in substantia nigra (SN) region of hemiparkinsonian rats.
PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration.
With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis.
PMCID: PMC4760767  PMID: 26894626
2.  Association of Megsin Gene Variants With IgA Nephropathy in Northwest Chinese Population 
Medicine  2016;95(6):e2694.
Megsin is a mesangial cell-predominant gene that encodes a serpin family protein which is expressed in the renal mesangium. Overexpression of megsin has been observed in the glomeruli of patients with IgA nephropathy (IgAN). The aim of this study was to evaluate the association of megsin polymorphisms (rs1055901 and rs1055902) with IgAN in a Chinese population.
We examined 351 patients with histologically proven IgAN and compared them with 310 age, sex, and ethnicity-matched healthy subjects. Two single nucleotide polymorphisms (SNPs) in megsin were genotyped by Sequenom MassARRAY. SPSS 18.0 was used for statistical analyses, and SNP Stats to test for associations between these polymorphisms and IgAN risk. Odds ratios with 95% confidence intervals were used to assess the relationships.
We found that rs1055901 and rs1055902 SNPs were not correlated with susceptibility to IgAN in Northwest Chinese population. Analyses of the relationship between genotypes and clinical variables indicated that in patients with IgAN, rs1055901 was associated with 24-hour proteinuria, an increase in blood pressure, and Lee's grade (P = 0.04, 0.02, and 0.04, respectively), and rs1055902 was associated with 24-hour proteinuria and Lee's grade (P = 0.03 and 0.01, respectively). However, the results showed no association between these gene variants and sex of the patients.
These results indicate that megsin gene variants may play a role in the severity, development, and/or progression of IgAN in Northwest Chinese population.
PMCID: PMC4753896  PMID: 26871801
3.  Does Marriage Make Us Healthier? Inter-Country Comparative Evidence from China, Japan, and Korea 
PLoS ONE  2016;11(2):e0148990.
This study focuses on East Asian countries and investigates the difference in the marriage premium on the health-marriage protection effect (MPE) between younger and older generations and the intra-couple education concordance effect (ECE) on the health of married individuals. This study used inter-country comparative data from China, Japan, and Korea.
This study focused on individuals (n = 7,938) in China, Japan, and Korea who were sampled from the 2010 East Asian Social Survey. To investigate MPE and ECE, four health indicators were utilized: a physical and mental components summary (PCS and MCS), self-rated health status (Dself), and happiness level (Dhappy). Ordinary least squares regression was conducted by country- and gender-specific subsamples.
We found that the MPE on PCS, MCS, and Dself was more significant for the older generation than for the younger generation in both China and Japan, whereas the results were inconclusive in Korea. With regard to the ECE on happiness (Dhappy), for both men and women, couples tend to be happier when both the husband and the wife are well educated (“higher balanced marriage”) compared to couples with a lower level of educational achievement (“lower balanced marriage”). Significant benefits from a “higher balanced marriage” on MCS and Dself were observed for women only. In contrast, no statistically significant differences in health status were observed between “higher balanced marriage” couples and couples with different levels of educational achievements (“upward marriage” or “downward marriage”).
This study found that (1) the MPE was more significant for the older generation, and (2) the health gap, particularly the happiness gap, between higher- and lower-balanced married couples was significant. The inter-country comparative findings are useful to explain how the role of marriage (and therefore of family) on health has been diluted due to the progress of industrialization and modernization.
PMCID: PMC4749249  PMID: 26862896
4.  Clinical Severity in Lesch-Nyhan Disease: the Role of Residual Enzyme and Compensatory Pathways 
Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), cause Lesch-Nyhan disease (LND) and more mildly affected Lesch-Nyhan variants. Prior studies have suggested a strong correlation between residual hypoxanthine recycling activity and disease severity. However, the relevance of guanine recycling and compensatory changes in the de novo synthesis of purines have received little attention. In the current studies, fibroblast cultures were established for 21 healthy controls and 36 patients with a broad spectrum of disease severity related to HGprt deficiency. We assessed hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis. There was a strong correlation between disease severity and either hypoxanthine or guanine recycling. Intracellular purines were normal in the HGprt-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from the cells. The normal intracellular purines in the HGprt-deficient fibroblasts was likely due in part to a compensatory increase in purine synthesis, as demonstrated by a significant increase in purinosomes. However, the increase in purine synthesis did not appear to correlate with disease severity. These results refine our understanding of the potential sources of phenotypic heterogeneity in LND and its variants.
PMCID: PMC4277921  PMID: 25481104
Inherited metabolic disease; Genotype-phenotype correlation; Purine metabolism; Purinosome
5.  Extremely high proportions of male flowers and geographic variation in floral ratios within male figs of Ficus tikoua despite pollinators displaying active pollen collection 
Ecology and Evolution  2016;6(2):607-619.
Most plants are pollinated passively, but active pollination has evolved among insects that depend on ovule fertilization for larval development. Anther‐to‐ovule ratios (A/O ratios, a coarse indicator of pollen‐to‐ovule ratios) are strong indicators of pollination mode in fig trees and are consistent within most species. However, unusually high values and high variation of A/O ratios (0.096–10.0) were detected among male plants from 41 natural populations of Ficus tikoua in China. Higher proportions of male (staminate) flowers were associated with a change in their distribution within the figs, from circum‐ostiolar to scattered. Plants bearing figs with ostiolar or scattered male flowers were geographically separated, with scattered male flowers found mainly on the Yungui Plateau in the southwest of our sample area. The A/O ratios of most F. tikoua figs were indicative of passive pollination, but its Ceratosolen fig wasp pollinator actively loads pollen into its pollen pockets. Additional pollen was also carried on their body surface and pollinators emerging from scattered‐flower figs had more surface pollen. Large amounts of pollen grains on the insects' body surface are usually indicative of a passive pollinator. This is the first recorded case of an actively pollinated Ficus species producing large amounts of pollen. Overall high A/O ratios, particularly in some populations, in combination with actively pollinating pollinators, may reflect a response by the plant to insufficient quantities of pollen transported in the wasps’ pollen pockets, together with geographic variation in this pollen limitation. This suggests an unstable scenario that could lead to eventual loss of wasp active pollination behavior.
PMCID: PMC4729252  PMID: 26843943
Active pollination; anther‐to‐ovule ratios; Ceratosolen; fig wasp; inflorescence design; P/O ratios; pollen limitation
6.  Self-rated chronic conditions and 2-week prevalence in adults in Zhongshan, China: an epidemiological survey 
BMJ Open  2015;5(11):e008441.
To examine the association between behavioural factors and the risk of chronic conditions and 2-week prevalence.
This was a cross-sectional survey.
The study was conducted in Zhongshan, China.
A multistage clustering sampling method was used to select a representative sample of residents from the household registration system between July and September 2011. The overall sample replacement rate was 9.4%, and the final sample included 43 028 individuals.
Outcome measures
Chronic conditions and 2-week prevalence.
4979 (11.6%) of the participants reported having at least one chronic condition, 1067 (2.5%) had two or more concurrent chronic conditions, and 6830 (15.9%) reported having at least one disease in a 2-week recall period. The most common chronic condition was primary hypertension, which was reported by 6.8% of participants. Logistic regression models demonstrated that the main factors for having a chronic condition and 2-week prevalence were older age (≥65 years of age; OR 44.91, 95% CI 33.05 to 61.03; and OR 12.71, 95% CI 10.44 to 15.46, respectively), obesity (OR 3.00, 95% CI 2.63 to 3.42; and OR 2.50, 95% CI 2.22 to 2.82, respectively) and being a former smoker (OR 3.02, 95% CI 2.54 to 3.58; and OR 3.24, 95% CI 2.74 to 3.82, respectively).
This study suggests that older age, obesity and unhealthy behaviours are high-risk factors for poorer health status among the residents of Zhongshan, China. The present findings highlight the importance of recognising and managing harmful behaviours in order to improve health.
PMCID: PMC4654384  PMID: 26560055
7.  miR-21 expression predicts prognosis in diffuse large B-cell lymphoma 
Background: Expression patterns of microRNAs in serum are involved in potentially biomarkers for various diseases. The aim of the study was to investigate the expression level of miR-21 in diffuse large B cell lymphoma (DLBCL) and its prognostic value. Methods: Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure miR-21 levels in serum samples from 112 patients with DLBCL as well as in serum samples from 45 healthy controls. The associations between miR-21 expression and clinicopathologic parameters and overall survival of the patients, were analyzed by chi-square test and Kaplan-Meier method. The Cox proportional hazards regression analyses were performed to estimate the prognostic values for patient survival prediction. Results: We found that serum miR-21 expression was markedly upregulated in patients with DLBCL than healthy controls. Increased miR-21 expression was significantly correlated with B symptoms, IPI score, CHOP-like treatment and Rituximab (all Ps<0.05). Moreover, DLBCL patients with miR-21 higher expression have shown significantly worse overall survival than those with lower miR-21 expression. And miR-21 expression was an independent prognostic marker of overall survival in a multivariate analysis (P=0.001, HR: 4.404, 95% CI: 1.770-10.956). Conclusion: The results of the present study suggested miR-21 expression level could be a novel potential biomarker for DLBCL prognosis.
PMCID: PMC4713624  PMID: 26823838
MicroRNA-21; diffuse large B-cell lymphoma; prognosis
8.  Impacts of wind stilling on solar radiation variability in China 
Scientific Reports  2015;5:15135.
Solar dimming and wind stilling (slowdown) are two outstanding climate changes occurred in China over the last four decades. The wind stilling may have suppressed the dispersion of aerosols and amplified the impact of aerosol emission on solar dimming. However, there is a lack of long-term aerosol monitoring and associated study in China to confirm this hypothesis. Here, long-term meteorological data at weather stations combined with short-term aerosol data were used to assess this hypothesis. It was found that surface solar radiation (SSR) decreased considerably with wind stilling in heavily polluted regions at a daily scale, indicating that wind stilling can considerably amplify the aerosol extinction effect on SSR. A threshold value of 3.5 m/s for wind speed is required to effectively reduce aerosols concentration. From this SSR dependence on wind speed, we further derived proxies to quantify aerosol emission and wind stilling amplification effects on SSR variations at a decadal scale. The results show that aerosol emission accounted for approximately 20% of the typical solar dimming in China, which was amplified by approximately 20% by wind stilling.
PMCID: PMC4604519  PMID: 26463748
9.  Diffusion-weighted magnetic resonance imaging without bowel preparation for detection of ulcerative colitis 
AIM: To evaluate the accuracy of diffusion-weighted imaging (DWI) without bowel preparation, the optimal b value and the changes in apparent diffusion coefficient (ADC) in detecting ulcerative colitis (UC).
METHODS: A total of 20 patients who underwent 3T magnetic resonance imaging (MRI) without bowel preparation and colonoscopy within 24 h were recruited. Biochemical indexes, including C-reactive protein (CRP), erythrocyte sedimentation rate, hemoglobin, leucocytes, platelets, serum iron and albumin, were determined. Biochemical examinations were then performed within 24 h before or after MR colonography was conducted. DWI was performed at various b values (b = 0, 400, 600, 800, and 1000 s/mm2). Two radiologists independently and blindly reviewed conventional- and contrast-enhanced MR images, DWI and ADC maps; these radiologists also determined ADC in each intestinal segment (rectum, sigmoid, left colon, transverse colon, and right colon). Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic performance of DWI hyperintensity from various b factors, ADC values and different radiological signs to detect endoscopic inflammation in the corresponding bowel segment. Optimal ADC threshold was estimated by maximizing the combination of sensitivity and specificity. MR findings were correlated with endoscopic results and clinical markers; these findings were then estimated by ROC analysis.
RESULTS: A total of 100 segments (71 with endoscopic colonic inflammation; 29 normal) were included. The proposed total magnetic resonance score (MR-score-T) was correlated with the total modified Baron score (Baron-T; r = 0.875, P < 0.0001); the segmental MR score (MR-score-S) was correlated with the segmental modified Baron score (Baron-S; r = 0.761, P < 0.0001). MR-score-T was correlated with clinical and biological markers of disease activity (r = 0.445 to 0.831, P < 0.05). MR-score-S > 1 corresponded to endoscopic colonic inflammation with a sensitivity of 85.9%, a specificity of 82.8% and an area under the curve (AUC) of 0.929 (P < 0.0001). The accuracy of DWI hyperintensity was significantly greater at b = 800 than at b = 400, 600, or 1000 s/mm2 (P < 0.05) when endoscopic colonic inflammation was detected. DWI hyperintensity at b = 800 s/mm2 indicated endoscopic colonic inflammation with a sensitivity of 93.0%, a specificity of 79.3% and an AUC of 0.867 (P < 0.0001). Quantitative analysis results revealed that ADC values at b = 800 s/mm2 differed significantly between endoscopic inflamed segment and normal intestinal segment (1.56 ± 0.58 mm2/s vs 2.63 ± 0.46 mm2/s, P < 0.001). The AUC of ADC values was 0.932 (95% confidence interval: 0.881-0.983) when endoscopic inflammation was detected. The threshold ADC value of 2.18 × 10-3 mm2/s indicated that endoscopic inflammation differed from normal intestinal segment with a sensitivity of 89.7% and a specificity of 80.3%.
CONCLUSION: DWI combined with conventional MRI without bowel preparation provides a quantitative strategy to differentiate actively inflamed intestinal segments from the normal mucosa to detect UC.
PMCID: PMC4562963  PMID: 26361426
Diffusion-weighted imaging; Apparent diffusion coefficient; Quantitative; Ulcerative colitis; Without bowel preparation
10.  Down-regulation of TET2 in CD3+ and CD34+ cells of myelodysplastic syndromes and enhances CD34+ cells proliferation 
Aims and background: To investigate the expressions of TET2 mRNA in bone marrow CD3+ and CD34+ cells of the patients with myelodysplastic syndromes (MDS) and to study the effect of silencing TET2 by small interfering RNA (siRNA) on the biological characteristics of CD34+ cells. Methods: CD3+ and CD34+ cells were sorted by magnetic activated cell-sorting system from bone marrow of MDS patients and controls. The mRNA expressions of TET2 in bone marrow CD3+ and CD34+ cells of 28 MDS patients and 20 controls were detected by qPCR. The silencing effect of RNA interference (RNAi) on TET2 expression in CD34+ bone marrow cells of normal control was identified by qPCR and Western blot analysis. The cell cycle kinetics and cell apoptosis were then detected by flow cytometry. Results: The expression of TET2 mRNA in CD3+ and CD34+ cells was down-regulated in MDS compared with that in controls [(0.16±0.11) vs. (1.05±0.32) (P<0.001); (0.58±0.26) vs. (1.25±0.94) (P<0.005)]. The siRNA targeting TET2 suppressed the expression of TET2 in normal CD34+ cells. Meanwhile, the proliferation activity was significantly enhanced [G0/G1: (87.82±8.25)% vs. (92.65±7.06)% and (93.60±5.54)%, P<0.05; S: (11.50±8.31)% vs. (6.92±7.04)% and (5.95±5.53)%, P<0.05] and the apoptosis rate was declined [(21.28±9.73)% vs. (26.17±9.88)% and (26.20±9.78)%] in the cells which transfected with TET2 siRNA as compared to those in the cells transfected with scrambled siRNA and control cells. Conclusions: The TET2 expression of in CD3+ and CD34+ cells of MDS patients was decreased. Suppression of TET2 expression renders the CD34+ cells harboring more aggressive phenotype. This preliminary finding suggests that CD34+ cells lowering expression of TET2 may play an oncogenic role on myeloid tumor and CD3+ T cells of MDS patients may be derived from the malignant clone.
PMCID: PMC4637612  PMID: 26617797
Myelodysplastic syndromes; CD3+ T cells; CD34+ cells; TET2; siRNA; Biological effect
11.  Detection and Significance of CD4+CD25+CD127dim Regulatory T Cells in Individuals with Severe Aplastic Anemia 
Turkish Journal of Hematology  2015;32(3):220-227.
To investigate the relationship between CD4+CD25+CD127dim regulatory T cells (Tregs) and immune imbalance in acquired severe aplastic anemia (SAA).
Materials and Methods:
The quantity of CD4+CD25+CD127dim Tregs in 44 SAA patients and 23 normal controls was measured by flow cytometry. Correlations between Tregs and T cell subsets, dendritic cell (DC) subsets, granulocyte counts, and percentage of reticulocytes (RET%) were analyzed.
The percentage of CD4+CD25+CD127dim Tregs in peripheral blood lymphocytes (PBLs) of untreated patients was lower than in recovery patients and normal controls (0.83±0.44% vs. 2.91±1.24% and 2.18±0.55%, respectively, p<0.05). The percentage of CD4+CD25+CD127dim Tregs in CD4+ T lymphocytes of recovery patients was higher than that of untreated patients and normal controls (9.39±3.51% vs. 7.61±5.3% and 6.83±1.4%, respectively, p<0.05). The percentage of CD4+ T lymphocytes in PBLs of untreated patients was lower than in recovery patients and normal controls (13.55±7.37% vs. 31.82±8.43% and 32.12±5.88%, respectively, p<0.05). T cell subset (CD4+/CD8+ ratio) was 0.41±0.24 in untreated patients, which was lower than in recovery patients (1.2±0.4) and normal controls (1.11±0.23) (p<0.05). DC subset (myeloid DC/plasmacytoid DC ratio, DC1/DC2 ratio) was 3.08±0.72 in untreated patients, which was higher than in recovery patients (1.61±0.49) and normal controls (1.39±0.36) (p<0.05). The percentage of CD4+CD25+CD127dim Tregs in PBLs was positively associated with T cell subset (r=0.955, p<0.01) and negatively associated with DC subset (r=-0.765, p<0.01). There were significant positive correlations between CD4+CD25+CD127dim Tregs/PBL and granulocyte counts and RET% (r=0.739 and r=0.749, respectively, p<0.01).
The decrease of CD4+CD25+CD127dim Tregs in SAA patients may cause excessive functioning of T lymphocytes and thus lead to hematopoiesis failure in SAA.
PMCID: PMC4563197  PMID: 25912955
Severe aplastic anemia; Regulatory T cell; Bone marrow failure
12.  Genotypic and Phenotypic Spectrum in Attenuated Variants of Lesch-Nyhan Disease 
Molecular genetics and metabolism  2014;112(4):280-285.
Lesch-Nyhan disease and its attenuated variants are caused by deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). All patients exhibit excessive production of uric acid, which increases the risk for nephrolithiasis, renal failure, gouty arthritis and tophi. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe clinical phenotype includes prominent neurological abnormalities and the universal feature is self-injurious behavior. In between the mildest and most severe syndromes is a broad spectrum of phenotypes with varying degrees of neurological, neurocognitive and behavioral abnormalities. The effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management.
PMCID: PMC4122630  PMID: 24930028
Lesch-Nyhan disease; Lesch-Nyhan variant; genotype; phenotype
13.  Fish Oil Supplements Lower Serum Lipids and Glucose in Correlation with a Reduction in Plasma Fibroblast Growth Factor 21 and Prostaglandin E2 in Nonalcoholic Fatty Liver Disease Associated with Hyperlipidemia: A Randomized Clinical Trial 
PLoS ONE  2015;10(7):e0133496.
Fish oil has been used effectively in the treatment of cardiovascular disease via triglyceride reduction and inflammation modulation. This study aimed to assess the effects of fish oil on patients with nonalcoholic fatty liver disease (NAFLD) associated with hyperlipidemia. Eighty participants with NAFLD associated with hyperlipidemia were randomly assigned to consume fish oil (n=40, 4 g/d) or corn oil capsules (n=40, 4 g/d) for 3 months in a double-blind, randomized clinical trial. Blood levels of lipids, glucose and insulin, liver enzymes, kidney parameters and cytokines at baseline and the end of the study were measured. Seventy people finished the trial. Plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid significantly increased in the fish oil group after intervention. After adjustment for age, gender and BMI, fish oil significantly decreased fasting serum concentrations of total cholesterol, triglyceride, apolipoprotein B and glucose (by (mean±SD) 0.49±0.43 mmol/L, 0.58±0.89 mmol/L, 0.28±0.33 g/L and 0.76±0.56 mmol/L, respectively, P<0.05), as well as alanine aminotransferase and γ-glutamyl transpeptidase levels (by (median (interquartile)) 9.0(0.5, 21.5) and 7.0(2.2, 20.0) IU/L, respectively, P<0.05), significantly increased serum adiponectin levels (by 1.29±0.62 μg/mL, P<0.001), and reduced serum levels of tumor necrosis factor α, leukotrienes B4, fibroblast growth factor 21 (FGF21), cytokeratin 18 fragment M30 and prostaglandin E2 (by 1.70±1.18 pg/mL, 0.59±0.28 ng/mL, 121±31 pg/mL, 83±60 IU/L and 10.9±2.3 pg/mL, respectively, P<0.001). Corn oil had no effect except for increasing serum creatinine concentrations by 7.7±8.9 μmol/L (P=0.008). The effects of fish oil on lipids, glucose and γ-glutamyl transpeptidase were positively correlated with the reductions of serum FGF21 and prostaglandin E2 concentrations after adjustment for age, gender and BMI (r = 0.275 to 0.360 and 0.261 to 0.375, respectively, P<0.05). In conclusion, our findings suggest that fish oil can benefit metabolic abnormalities associated with NAFLD treatment.
Trial Registration
PMCID: PMC4520650  PMID: 26226139
14.  Broad autism phenotype features of Chinese parents with autistic children and their associations with severity of social impairment in probands 
BMC Psychiatry  2015;15:168.
Parents of children with autism have higher rates of broad autism phenotype (BAP) features than parents of typically developing children (TDC) in Western countries. This study was designed to examine the rate of BAP features in parents of children with autism and the relationship between parental BAP and the social impairment of their children in a Chinese sample.
A total of 299 families with autistic children and 274 families with TDC participated in this study. Parents were assessed using the Broad Autism Phenotype Questionnaire (BAPQ), which includes self-report, informant-report, and best-estimate versions. Children were assessed using the Chinese version of the Social Responsiveness Scale (SRS).
Parents of children with autism were significantly more likely to have BAP features than were parents of TDC; mothers and fathers in families with autistic children had various BAP features. The total scores of the informant and best-estimate BAPQ versions for fathers were significantly associated with their children’s SRS total scores in the autism group, whereas the total scores of the three BAPQ versions for mothers were significantly associated with their children’s SRS total scores in the TDC group. In the autism group, the total SRS scores of children with “BAP present” parents (informant and best-estimate) were higher than the total SRS scores of children with“BAP absent” parents. In the TDC group, the total SRS scores of children with “BAP present” parents were higher than the total SRS scores of children with“BAP absent” parents (best-estimate).
Parents of autistic children were found to have higher rates of BAP than parents of TDC in a sample of Chinese parents. The BAP features of parents are associated with their children’s social functioning in both autism families and TDC families, but the patterns of the associations are different.
PMCID: PMC4511534  PMID: 26202327
Broad autism phenotype; Parent; Autism; Social Adjustment; Chinese
15.  Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats 
Cellular and Molecular Immunology  2014;12(4):444-455.
Due to their hypoimmunogenicity and unique immunosuppressive properties, mesenchymal stem cells (MSCs) are considered one of the most promising adult stem cell types for cell therapy. Although many studies have shown that MSCs exert therapeutic effects on several acute and subacute conditions, their long-term effects are not confirmed in chronic diseases. Immunogenicity is a major limitation for cell replacement therapy, and it is not well understood in vivo. We evaluated the immunogenicity of allogeneic MSCs in vivo by transplanting MSCs into normal and diabetic rats via the tail vein or pancreas and found that MSCs exhibited low immunogenicity in normal recipients and even exerted some immunosuppressive effects in diabetic rats during the initial phase. However, during the later stage in the pancreas group, MSCs expressed insulin and MHC II, eliciting a strong immune response in the pancreas. Simultaneously, the peripheral blood mononuclear cells in the recipients in the pancreas group were activated, and alloantibodies developed in vivo. Conversely, in the tail vein group, MSCs remained immunoprivileged and displayed immunosuppressive effects in vivo. These data indicate that different transplanting routes and microenvironments can lead to divergent immunogenicity of MSCs.
PMCID: PMC4496541  PMID: 25242276
allogeneic mesenchymal stem cells; diabetes; immunogenicity; transplantation routes
16.  Hodgkin's lymphoma associated with myelofibrosis: A case report 
Oncology Letters  2015;10(3):1551-1554.
In the present study, the case of a patient with nodular sclerosing Hodgkin's lymphoma (NSHL) presenting with diffuse fibrosis of the bone marrow (BM) was reported. A 30-year-old male complained of fever for 1 year, as well as lumbago, lymph node swelling and night sweats for 3 months. A biopsy of the lymph nodes established a diagnosis of NSHL. Aspiration of BM was a dry tap, and the BM biopsy demonstrated marked myelofibrosis with increased proliferation of reticulin fiber. Multiple skeletal lesions were detected in the patient's vertebra, pelvis, sternum and bilateral femur by magnetic resonance imaging and computed tomography. Following numerous courses of chemotherapy and radiotherapy, remission of the lymphoma was achieved. Subsequently, the BM aspiration became possible, and BM biopsy demonstrated a reduction in fibrosis.
PMCID: PMC4533276  PMID: 26622707
Hodgkin's lymphoma; myelofibrosis
17.  Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy 
Oncology Letters  2015;10(1):379-383.
Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb, Artemisia annua L., and has the ability to inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to inhibit the growth of a variety of types of human cancer. However, the effect of DHA on human glioma cells remains unclear. The aim of the present study was to investigate the effect of DHA on the proliferation of glioma cells, and whether DHA was able to enhance temozolomide (TMZ) sensitivity in vitro and in vivo. In total, 10 human glioma cell lines were used to analyze the growth inhibition ability of DHA by MTT assay. The typical autophagic vacuoles were monitored by the application of the autofluorescent agent, monodansylcadaverine. Western blotting was used to detect markers of apoptosis and autophagy, namely Caspase-3, Beclin-1 and LC3-B. The combination efficiency of DHA and TMZ was assessed in vitro and in vivo. The half maximal inhibitory concentration (IC50) of DHA differed among the ten human glioma cell lines. The number of autophagic vacuoles was higher in DHA-treated SKMG-4 cells; this was highest of all cell lines analyzed. The expression of autophagy molecular markers, Beclin-1 and LC3-B, was increased following DHA treatment, while no significant alteration was detected in the expression of apoptotic marker Caspase-3. When combined with DHA, the IC50 of TMZ decreased significantly in the four glioma cell lines analyzed. Furthermore, DHA enhanced the tumor inhibition ability of TMZ in tumor-burdened mice. The results of the present study demonstrated that DHA inhibited the proliferation of glioma cells and enhanced the tumor inhibition efficacy of TMZ in vitro and in vivo through the induction of autophagy.
PMCID: PMC4487108  PMID: 26171034
dihydroartemisinin; temozolomide; glioma; autophagy
18.  Genotype–phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder 
Brain  2013;137(5):1282-1303.
Genotype-phenotype correlations for most monogenic neurological disorders are incompletely understood. Fu et al. draw upon data on 615 HPRT mutations, including 130 new cases, and their relationship to Lesch-Nyhan disease severity. The effect of mutations on hypoxanthine-guanine phosphoribosyltransferase activity accounts for much but not all of the phenotypic variability.
Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype–phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype–phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype–phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype–phenotype correlations for other disorders.
PMCID: PMC3999711  PMID: 23975452
Lesch-Nyhan disease; genotype–phenotype correlations; neurogenetics
19.  Risk factors for HIV and syphilis infection among male sex workers who have sex with men: a cross-sectional study in Hangzhou, China, 2011 
BMJ Open  2015;5(4):e006791.
To investigate the prevalence and risk factors of HIV and syphilis infection among men who have sex with men (MSM) in male sex workers (MSW).
Cross-sectional survey.
Hangzhou, China.
259 MSW in MSM were recruited by respondent-driven sampling from May 2011 to December 2011.The inclusion criteria were: (1) age ≥18 years; (2) engaging in sex with men in the previous year and (3) willing to cooperate in the implementation of the study.
Outcome measures
HIV-related knowledge, high-risk behaviour and condom use.
Among these MSW in MSM, 23.2% were infected with HIV and/or syphilis, 8.9% were infected only with HIV, 12.7% only with syphilis and 1.5% with HIV/syphilis co-infection; 96.6% sold sex to males, 8.9% bought sex from males and 15.4% sold sex to females; 49.0% had non-commercial sex behaviours with males and 24.3% with females. The rate of condom use while having commercial sex with clients was 86.9% and 53.3% (selling anal and oral sex to males, respectively), 95.5% (buying sex from males) and 77.5% (selling sex to females), respectively. Regarding their non-commercial sex behaviour, the rate of condom use was 77.2% (with males) and 49.2% (with females), respectively. Multivariate analysis showed that age >30 years (OR 1.055; 95% CIs 1.015 to 1.095) and having ≥10 non-commercial male sex partners (OR, 1.573; 95% CI 1.018 to 2.452) were significantly associated with HIV/syphilis infection, while heterosexuality (OR, 0.238; 95% CI 0.066 to 0.855) was significantly associated with a low HIV/syphilis infection rate.
The MSW in MSM population in Hangzhou has a high prevalence of HIV/syphilis infection, poor perceived risks of HIV and more engagement in unsafe sex with its clients and partners, in addition to a low rate of condom use. These risk factors may account for their relatively high infection rate of HIV/syphilis.
PMCID: PMC4420951  PMID: 25922096
20.  Gelatin nanoparticle-mediated intranasal delivery of substance P protects against 6-hydroxydopamine-induced apoptosis: an in vitro and in vivo study 
The aim of this study was to investigate the protective role of intranasally administered substance P-loaded gelatin nanoparticles (SP-GNPs) against 6-hydroxydopamine (6-OHDA)-induced apoptosis in vitro and in vivo, and to provide a new strategy for treating brain pathology, such as Parkinson’s disease.
SP-GNPs were prepared by a water-in-water emulsion method, and their stability, encapsulating efficiency, and loading capacity were evaluated. PC-12 cells were used to examine the enhancement of growth and inhibition of apoptosis by SP-GNPs in vitro using MTT assays. In the in vivo study, hemiparkinsonian rats were created by intracerebroventricular injection of 6-OHDA. The rats then received intranasal SP-GNPs daily for 2 weeks. Functional improvement was assessed by quantifying rotational behavior, and the degree of apoptosis was assessed by immunohistochemical staining for caspase-3 in the substantia nigra region.
PC-12 cells with 6-OHDA-induced disease treated with SP-GNPs showed higher cell viability than their untreated counterparts, and cell viability increased as the concentration of substance P (SP) increased, indicating that SP could enhance cell growth and inhibit the cell apoptosis induced by 6-OHDA. Rats with 6-OHDA-induced hemiparkinsonism treated with SP-GNPs made fewer rotations and showed less staining for caspase-3 than their counterparts not treated with SP, indicating that SP protects rats with 6-OHDA-induced hemiparkinsonism from apoptosis and therefore demonstrates their functional improvement.
Intranasal delivery of SP-GNPs protects against 6-OHDA-induced apoptosis both in vitro and in vivo.
PMCID: PMC4396575  PMID: 25897205
gelatin nanoparticles; intranasal delivery; substance P; 6-hydroxydopamine; apoptosis; Parkinson’s disease
21.  Abnormal immunomodulatory ability on memory T cells in humans with severe aplastic anemia 
Severe aplastic anemia (SAA) is a bone marrow failure disease induced by hyperfunctional autoimmunic Th1 lymphocytes. Memory T cells (TM) are a component of the adaptive immune system. They ensure the host of more aggressive and faster immune response to efficiently eliminate the specific antigens after re-exposure and thus play a key role in T-cell functions. In this study we investigate the quantities and functions of memory T cells in SAA patients before and after immunosuppressive therapy (IST) to further clarify the mechanism of SAA apoptosis of bone marrow hematopoietic cells. Results showed that the percentage of CD4+ effector T cells in peripheral blood and bone marrow lymphocytes was decreased in SAA patients. The ratio of CD4+ memory T lymphocytes to CD8+ memory T subsets (CD4+/CD8+TM) in SAA patients was also lower. The percentage of CD8+ effector T cells in peripheral blood and CD8+ central memory T cells in the bone marrow lymphocytes was significantly higher in newly diagnosed patients. Furthermore, the median expressions of perforin and granzyme B on memory T cells were higher in SAA patients compared to those in normal controls. After IST, the quantities and functions of memory T cells return to normal level. Therefore, we concluded that the abnormal immunomodulatory ability on memory T cells may contribute to the imbalance of Th1/Th2 subsets and thus lead to over-function of T lymphocytes and hematopoiesis failure in SAA.
PMCID: PMC4466934  PMID: 26097547
Severe aplastic anemia; memory T cells; perforin; ganzyme B
22.  Downregulation of Sprouty homolog 2 by microRNA-21 inhibits proliferation, metastasis and invasion, however promotes the apoptosis of multiple myeloma cells 
Molecular Medicine Reports  2015;12(2):1810-1816.
The aim of the present study was to assess the effects of sprouty homolog 2 (SPRY2) gene regulation by miR-21 on the occurrence, development and tumor metastasis in multiple myeloma (MM). The miR-21 expression lentiviral vector (LV)-anti-miR-21 and a liposome transfection method were used to screen MM cell lines with stable silent SPRY2. Real-time quantitative polymerase chain reaction (PCR) and western blot analyses were used to detect SPRY2 expression and miR-21 protein expression levels. An MTT assay was used to assess cell proliferation. Flow cytometry was used for analysis of cell cycle. A scratch test/wound healing assay was used to detect the cell migration ability. A Transwell assay was used to detect the cell invasion ability. Real-time quantitative PCR and western blot analysis showed that in the MM cell lines with high endogenous miR-21 expression (RPMI8226 and KM3), SPRY2 expression was significantly lower. Conversely, in the U266 cell line with low endogenous miR-21 expression, SPRY2 expression was significantly higher, and the gray values of miR-21 and SPRY2 protein in the respective cell lines showed statistically significant differences (P<0.01). Following transfection of U266 cells, the expression of miR-21 in the U266/LV-anti-miR21 lentiviral multiplicity of infection (MOI) 20 group and -MOI 40 group decreased significantly compared with that in the untransfected U266 group (P<0.05). SPRY2 protein expression in U266 cells transfected with miR-21 mimics was significantly reduced compared with that in the non-transfected (untreated) group and the negative control-transfected group (P<0.01). An MTT assay showed that compared with the non-transfected and negative control groups, the cell growth rate as well as the proliferation rate were significantly decreased in the transfection group 48, 72 and 96 h after transfection (P<0.01). Flow cytometric analysis showed that 48 and 72 h after transfection of U266 cells with miR-21 mimics, the apoptotic rates were (24.7±1.97 and 38.6±1.56%) in the U266 group, (27.3±1.72 and 37.3±1.59%) in the siRNA group and (12.7±1.27 and 22.1±1.63%) in the U266/miR-21 group. Compared with the two control groups, the apoptotic rate in the U266/miR-21 group was significantly decreased and the G0/G1 phase cell population was significantly reduced (P<0.05). Scratch experiments showed that the cell migration ability was significantly reduced in the transfection group 24 and 48 h after transfection (P<0.05). A Transwell invasion assay confirmed that the number of U266 cells which migrated through a Matrigel-covered polyphosphate membrane significantly decreased in the transfection group 24 and 48 h after transfection. The cell-penetrating ability was also significantly decreased (P<0.05). In conclusion, the downregulation of SPRY2 gene expression mediated by miR-21 promotes the proliferation and invasion of MM cells in vitro, suggesting that miR-21 may be a novel potential molecular therapeutic target in the treatment of MM.
PMCID: PMC4464399  PMID: 25825239
multiple myeloma; microRNA-21; sprouty homolog 2; proliferation; invasion
23.  Recombinant Human Thrombopoietin Treatment Promotes Hematopoiesis Recovery in Patients with Severe Aplastic Anemia Receiving Immunosuppressive Therapy 
BioMed Research International  2015;2015:597293.
Objective. To assess the effectiveness of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients receiving immunosuppressive therapy (IST). Methods. Eighty-eight SAA patients receiving IST from January 2007 to December 2012 were included in this retrospective analysis. Of these, 40 subjects received rhTPO treatment (15000 U, subcutaneously, three times a week). rhTPO treatment was discontinued when the platelet count returned to normal range. Hematologic response, bone marrow megakaryocyte recovery, and time to transfusion independence were compared. Results. Hematologic response was achieved in 42.5%, 62.5%, and 67.5% of patients receiving rhTPO and 22.9%, 41.6%, and 47.9% of patients not receiving rhTPO at 3, 6, and 9 months after treatment, respectively (P = 0.0665, P = 0.0579, and P = 0.0847, resp.). Subjects receiving rhTPO presented an elevated number of megakaryocytes at 3, 6, and 9 months when compared with those without treatment (P = 0.025, P = 0.021, and P = 0.011, resp.). The time to platelet and red blood cell transfusion independence was shorter in patients who received rhTPO than in those without rhTPO treatment. Overall survival rate presented no differences between the two groups. Conclusion. rhTPO could improve hematologic response and promote bone marrow recovery in SAA patients receiving IST.
PMCID: PMC4377357  PMID: 25861635
24.  Possible Involvement of µ Opioid Receptor in the Antidepressant-Like Effect of Shuyu Formula in Restraint Stress-Induced Depression-Like Rats 
Recently μ opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants.
PMCID: PMC4363683  PMID: 25821488
25.  Anti-TMV Activity of Malformin A1, a Cyclic Penta-Peptide Produced by an Endophytic Fungus Aspergillus tubingensis FJBJ11 
Plant-associated microorganisms are known to produce a variety of metabolites with novel structures and interesting biological activities. An endophytic fungus FJBJ11, isolated from the plant tissue of Brucea javanica (L.) Merr. (Simaroubaceae), was proven to be significantly effective in producing metabolites with anti-Tobacco mosaic virus (TMV) activities. The isolate was identified as Aspergillus tubingensis FJBJ11 based on morphological characteristics and ITS sequence. Bioassay-guided isolation led to the identification of a cycli penta-peptide, malformin A1, along with two cyclic dipeptides, cyclo (Gly-l-Pro) and cyclo (Ala-Leu). Malformin A1 showed potent inhibitory effect against the infection and replication of TMV with IC50 values of 19.7 and 45.4 μg·mL−1, as tested using local lesion assay and leaf-disc method, respectively. The results indicated the potential use of malformin A1 as a leading compound or a promising candidate of new viricide.
PMCID: PMC4394503  PMID: 25775156
malformin A1; cyclic peptide; Tobacco mosaic virus (TMV); Aspergillus; endophytic fungus; Brucea javanica

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