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1.  The Stratifying Value of Hangzhou Criteria in Liver Transplantation for Hepatocellular Carcinoma 
PLoS ONE  2014;9(3):e93128.
The selection criteria for patients with hepatocellular carcinoma (HCC) as candidates for deceased donor liver transplantation (DDLT) are well studied. In this era of limited deceased donor organs, the value of living donor liver transplantation (LDLT) for HCC remains controversial. The aim of the present study was to verify the stratification value of the Hangzhou criteria for LDLT.
The data of 47 LDLT recipients and 94 matched DDLT recipients at our center were evaluated. Overall survival and tumor-free survival were calculated. Prognostic factors influencing post-liver transplantation (LT) survival were identified. The stratification values of the Hangzhou criteria and Milan criteria were compared.
LDLT recipients spent much less time on the waiting list. The post-LT survival of recipients fulfilling the Milan criteria and recipients fulfilling the Hangzhou criteria were comparable (P>0.05). The overall and tumor-free survival did not differ statistically between the two groups. In both groups, more recipients not meeting the Milan criteria but with a satisfactory outcome were identified by the Hangzhou criteria. Among recipients who did not meet the Hangzhou criteria, tumor-free survival was better for the LDLT recipients than the DDLT recipients (P = 0.024).
The Hangzhou criteria are reliable for stratifying HCC patients in terms of prognosis. HCC patients fulfilling the Hangzhou criteria gain satisfactory survival from LT. Outcomes after LDLT are better than those after DDLT for HCC patients who do not meet the Hangzhou criteria.
PMCID: PMC3968059  PMID: 24676010
2.  Scaffolds for Tympanic Membrane Regeneration in Rats 
Tissue Engineering. Part A  2012;19(5-6):657-668.
Tympanic membrane (TM) perforations lead to significant hearing loss and result in possible infection of the middle ear. Myringoplasty is commonly performed to repair chronic perforations. Although various grafts and materials have been used to promote TM regeneration, all have associated limitations. The aim of this study was to evaluate the efficacy and feasibility of two graft materials, silk fibroin scaffold (SFS) and porcine-derived acellular collagen type I/III scaffold (ACS), compared with two commonly used graft materials (paper patch and Gelfoam) for the promotion of TM regeneration. These scaffolds were implanted using on-lay myringoplasty in an acute TM perforation rat model. Surface morphology of the scaffolds was observed with scanning electron microscopy. The morphology of the TM was assessed at various time points postimplantation using otoscopy, light and electron microscopy, and functional outcomes by auditory brainstem responses. We found that SFS and ACS significantly accelerated the TM perforation closure, obtained optimal TM thickness, and resulted in better trilaminar morphology with well-organized collagen fibers and early restoration of hearing. However, paper patch and Gelfoam lost their scaffold function in the early stages and showed an inflammatory response, which may have contributed to delayed healing. This study indicates that compared with paper patch and Gelfoam, SFS and ACS are more effective in promoting an early TM regeneration and an improved hearing, suggesting that these scaffolds may be potential substitutes for clinical use.
PMCID: PMC3566677  PMID: 23092139
3.  Long Non-Coding RNA HOTAIR Promotes Cell Migration and Invasion via Down-Regulation of RNA Binding Motif Protein 38 in Hepatocellular Carcinoma Cells 
Long non-coding RNA HOTAIR exerts regulatory functions in various biological processes in cancer cells, such as proliferation, apoptosis, mobility, and invasion. We previously found that HOX transcript antisense RNA (HOTAIR) is a negative prognostic factor and exhibits oncogenic activity in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the role and molecular mechanism of HOTAIR in promoting HCC cell migration and invasion. Firstly, we profiled its gene expression pattern by microarray analysis of HOTAIR loss in Bel-7402 HCC cell line. The results showed that 129 genes were significantly down-regulated, while 167 genes were significantly up-regulated (fold change >2, p < 0.05). Bioinformatics analysis indicated that RNA binding proteins were involved in this biological process. HOTAIR suppression using RNAi strategy with HepG2 and Bel-7402 cells increased the mRNA and protein expression levels of RNA binding motif protein 38 (RBM38). Moreover, the expression levels of RBM38 in HCC specimens were significantly lower than paired adjacent noncancerous tissues. In addition, knockdown of HOTAIR resulted in a decrease of cell migration and invasion, which could be specifically rescued by down-regulation of RBM38. Taken together, HOTAIR could promote migration and invasion of HCC cells by inhibiting RBM38, which indicated critical roles of HOTAIR and RBM38 in HCC progression.
PMCID: PMC3975384  PMID: 24663081
RNA binding motif protein 38; HOX transcript antisense RNA; hepatocellular carcinoma; long non-coding RNA
4.  Activation of Toll-Like Receptors Inhibits Herpes Simplex Virus-1 Infection of Human Neuronal Cells 
Journal of neuroscience research  2009;87(13):2916-2925.
Toll-like receptors (TLRs) play an essential role in initiating intracellular type I interferon (IFN)-mediated innate immunity against viral infections. We examined whether human neuronal cells (primary human neurons, NT2-N and CHP-212 cells) express TLRs and mount type I IFN-mediated innate immunity against herpes simplex virus-1 (HSV-1) infection. Human neuronal cells expressed TLR family members 1–10 and IFN-α/β. The activation of TLR3 or TLR8 by double-stranded RNA (poly-I:C) or single-stranded RNA (ssRNA) induced IFN-α/β expression. In addition, HSV-1 infection of human neuronal cells induced IFN-α expression. Investigation of the mechanisms showed that poly-I:C or ssRNA treatment enhanced the expression of several IFN regulatory factors. Importantly, the activation of TLR3 or TLR8 by poly-I:C or ssRNA prior to HSV-1 infection reduced the susceptibility of the neuronal cells to infection. These observations indicate that human neuronal cells possess intracellular TLR-mediated innate immune protection against HSV-1 infection.
PMCID: PMC3935181  PMID: 19437550
human neuronal cells; Toll-like receptor; poly-I:C; ssRNA; herpes simplex virus-1; type I interferons
5.  Impaired dopamine D1 receptor-mediated vasorelaxation of mesenteric arteries in obese Zucker rats 
Obesity plays an important role in the pathogenesis of hypertension. Renal dopamine D1-like receptor-mediated diuresis and natriuresis are impaired in the obese Zucker rat, an obesity-related hypertensive rat model. The role of arterial D1 receptors in the hypertension of obese Zucker rats is not clear.
Plasma glucose and insulin concentrations and blood pressure were measured. The vasodilatory response of isolated mesenteric arteries was evaluated using a small vessel myograph. The expression and phosphorylation of D1 receptors were quantified by co-immunoprecipitation and immunoblotting To determine the effect of hyperinsulinemia and hyperglycemia on the function of the arterial D1 receptor, we studied obese Zucker rats (six to eight-weeks old) fed (6 weeks) vehicle or rosiglitazone, an insulin sensitizer (10 mg/kg per day) and lean Zucker rats (eight to ten-weeks old), fed high-fat diet to induce hyperinsulinemia or injected intraperitoneally with streptomycin (STZ) to induce hyperglycemia.
In obese Zucker rats, the vasorelaxant effect of D1-like receptors was impaired that could be ascribed to decreased arterial D1 receptor expression and increased D1 receptor phosphorylation. In these obese rats, rosiglitazone normalized the arterial D1 receptor expression and phosphorylation and improved the D1-like receptor-mediated vasorelaxation. We also found that D1 receptor-dependent vasorelaxation was decreased in lean Zucker rats with hyperinsulinemia or hyperglycemia but the D1 receptor dysfunction was greater in the former than in the latter group. The ability of insulin and glucose to decrease D1 receptor expression and increase its phosphorylation were confirmed in studies of rat aortic smooth muscle cells.
Both hyperinsulinemia and hyperglycemia caused D1 receptor dysfunction by decreasing arterial D1 receptor expression and increasing D1 receptor phosphorylation. Impaired D1 receptor-mediated vasorelaxation is involved in the pathogenesis of obesity-related hypertension.
PMCID: PMC3938077  PMID: 24559270
Dopamine D1 receptor; Vasorelaxation; Hyperinsulinemia; Hyperglycemia; Obesity-related hypertension; Obese Zucker rats
6.  Mini-Flank Supra-12th Rib Incision for Open Partial Nephrectomy Compared with Laparoscopic Partial Nephrectomy and Traditional Open Partial Nephrectomy 
PLoS ONE  2014;9(2):e89155.
The purpose of this study was to report our approach of partial nephrectomy (PN) using a supra-12th rib mini-flank incision. We compared mini-incision open partial nephrectomy (MI-OPN) with open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN) to verify whether MI-OPN can be an alternative to OPN and LPN.
This was a retrospective single-center study including 194 patients who underwent partial nephrectomy (PN) between February 2005 and December 2010. Demographic, perioperative, and complication data were compared among the MI-OPN group, OPN group and LPN group.
No statistical differences were reported in either group for age, sex, BMI, tumour side (right or left kidney), RENAL nephrometry scores, PADUA score and preoperative eGFR. The operative time was longer in LPN group when compared with MI-OPN and OPN group (all P<0.001). The warm ischemia time of LPN group was longer than MI-OPN group (P = 0.032) and OPN group (P = 0.005). The length of stay of LPN group was shorter than OPN group (P = 0.018), but was similar to MI-OPN group (P = 0.094). The incidence of renal artery clamping was lower in OPN group when compared with MI-OPN and LPN group (all P<0.001). More estimated blood loss was found in OPN group when compared with MI-OPN group (p = 0.003) and LPN group (P = 0.014). The overall incidence of postoperative complications was similar.
The approach of MI-OPN can couple the benefits of both minimally invasive and open partial nephrectomy techniques with less estimated blood loss, shorter operative time, shorter length of stay, less postoperative complications, and a smaller incision. MI-OPN may be an effective alternative to laparoscopic or traditional open approaches, which maybe more suitable for the tumors with high RENAL nephrometry score or PADUA score.
PMCID: PMC3931681  PMID: 24586557
7.  Prevalence and Predictors of HIV among Chinese Tuberculosis Patients by Provider-Initiated HIV Testing and Counselling (PITC): A Multisite Study in South Central of China 
PLoS ONE  2014;9(2):e89723.
Tuberculosis (TB) and HIV are two worldwide public health concerns. Co-infection of these two diseases has been considered to be a major obstacle for the global efforts in reaching the goals for the prevention of HIV and TB.
A comprehensive cross-sectional study was conducted to recruit TB patients in three provinces (Guangxi, Henan and Sichuan) of China between April 1 and September 30, 2010.
A total of 1,032 consenting TB patients attended this survey during the study period. Among the participants, 3.30% were HIV positive; about one quarter had opportunistic infections. Nearly half of the participants were 50 years or older, the majority were male and about one third were from minority ethnic groups. After adjusting for site, gender and areas of residence (using the partial/selective Model 1), former commercial plasma donors (adjusted OR [aOR] = 33.71) and injecting drug users(aOR = 15.86) were found to have significantly higher risk of being HIV-positivity. In addition, having extramarital sexual relationship (aOR = 307.16), being engaged in commercial sex (aOR = 252.37), suffering from opportunistic infections in the past six months (aOR = 2.79), losing 10% or more of the body weight in the past six months (aOR = 5.90) and having abnormal chest X-ray findings (aOR = 20.40) were all significantly associated with HIV seropositivity (each p<0.05).
HIV prevalence among TB patients was high in the study areas of China. To control the dual epidemic, intervention strategies targeting socio-demographic and behavioral factors associated with higher risk of TB-HIV co-infection are urgently called for.
PMCID: PMC3931821  PMID: 24586987
8.  Atomic-scale Chemical Imaging and Quantification of Metallic Alloy Structures by Energy-Dispersive X-ray Spectroscopy 
Scientific Reports  2014;4:3945.
Determination of atomic-scale crystal structure for nanostructured intermetallic alloys, such as magnetic alloys containing Al, Ni, Co (alnico) and Fe, is crucial for understanding physical properties such as magnetism, but technically challenging due to the small interatomic distances and the similar atomic numbers. By applying energy-dispersive X-ray spectroscopy (EDS) mapping to the study of two intermetallic phases of an alnico alloy resulting from spinodal decomposition, we have determined atomic-scale chemical composition at individual lattice sites for the two phases: one is the B2 phase with Fe0.76Co0.24 -Fe0.40Co0.60 ordering and the other is the L21 phase with Ni0.48Co0.52 at A-sites, Al at BΙ-sites and Fe0.20Ti0.80 at BΙΙ-sites, respectively. The technique developed through this study represents a powerful real-space approach to investigate structure chemically at the atomic scale for a wide range of materials systems.
PMCID: PMC3912478  PMID: 24492747
9.  Cardiotoxic and Cardioprotective Features of Chronic β-adrenergic Signaling 
Circulation research  2012;112(3):498-509.
In the failing heart, persistent β-adrenergic receptor (βAR) activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II (CaMKII). β-Adrenergic signaling pathways are also capable of activating cardioprotective mechanisms.
This study used a novel PKA inhibitor peptide (PKI) to inhibit PKA activity to test the hypothesis that βAR signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways.
Methods and Results
In PKI transgenic mice, chronic isoproterenol (ISO) failed to induce cardiac hypertrophy, fibrosis, myocyte apoptosis and depressed cardiac function. In cultured adult feline ventricular myocytes (AFVMs), PKA inhibition protected myocytes from death induced by β1-AR agonists by preventing cytosolic and SR Ca2+ overload and CaMKII activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/EPAC /Rap1/Rac/ERK pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction (MI) that was superior to β-blocker therapy.
These results suggest that selective block of PKA could be a novel heart failure therapy.
PMCID: PMC3562387  PMID: 23104882
Apoptosis; Ca2+/dependent protein kinase II; ERK2; EPAC
10.  Perceptions of Heat Risk to Health: A Qualitative Study of Professional Bus Drivers and Their Managers in Jinan, China 
Summer extreme heat threatens the health of individuals, especially persons who are involved in outdoor activities. Ensuring the normal function of a city, bus drivers are among those who participate in outdoor physical activities and are exposed to excessive heat in hot summer weather. This qualitative study was performed to explore professional bus drivers’ in-depth views of extreme heat risks to their health, and ultimately develop targeted advice and policy interventions for city bus drivers. An interview-based study was performed among professional bus drivers in Jinan, China, including four focus groups with professional bus drivers (n = 37) and three interviews with their managers (n = 14). Five central themes or categories from the bus driver interviews were found: concerns about summer heat; health effects related to extreme heat; adaptive measures; barriers in implementing these adaptive measures; and suggested interventions. The beneficial role of cooling facilities (particularly air-conditioning) during extreme heat are addressed. The barriers not only impede the implementation of behavioral adaptive measures but also enhance the negative attitudes of bus drivers towards their effectiveness. The responsibilities of managers in promoting preventive actions are addressed.
PMCID: PMC3945551  PMID: 24477213
occupational driver; heat; risk perception; public health
11.  Comparative Study of Nanosecond Electric Fields In Vitro and In Vivo on Hepatocellular Carcinoma Indicate Macrophage Infiltration Contribute to Tumor Ablation In Vivo 
PLoS ONE  2014;9(1):e86421.
Background and Aim
Recurrence and metastasis are associated with poor prognosis in hepatocellular carcinoma even in the patients who have undergone radical resection. Therefore, effective treatment is urgently needed for improvement of patients' survival. Previously, we reported that nanosecond pulse electric fields (nsPEFs) can ablate melanoma by induction of apoptosis and inhibition of angiogenesis. This study aims to investigate the in vivo ablation strategy by comparing the dose effect of nanosecond electric fields in vitro and in vivo on hepatocellular carcinoma.
Materials and Methods
Four hepatocellular carcinoma cell lines HepG2, SMMC7721, Hep1-6, and HCCLM3 were pulsed to test the anti-proliferation and anti-migration ability of 100 ns nsPEFs in vitro. The animal model of human subdermal xenograft HCCLM3 cells into BALB/c nude mouse was used to test the anti-tumor growth and macrophage infiltration in vivo.
In vitro assays showed anti-tumor effect of nsPEFs is dose-dependant. But the in vivo study showed the strategy of low dose and multiple treatments is superior to high dose single treatment. The macrophages infiltration significantly increased in the tumors which were treated by multiple low dose nsPEFs.
The low dose multiple nsPEFs application is more efficient than high dose single treatment in inhibiting the tumor volume in vivo, which is quite different from the dose-effect relationship in vitro. Beside the electric field strength, the macrophage involvement must be considered to account for effect variability and toxicology in vivo.
PMCID: PMC3903538  PMID: 24475118
12.  Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR Genetic Polymorphisms on Tacrolimus Metabolism in Chinese Renal Transplant Recipients 
PLoS ONE  2014;9(1):e86206.
Tacrolimus is a widely used immunosuppressive drug for preventing the rejection of solid organ transplants. The efficacy of tacrolimus shows considerable variability, which might be related to genetic variation among recipients. We conducted a retrospective study of 240 Chinese renal transplant recipients receiving tacrolimus as immunosuppressive drug. The retrospective data of all patients were collected for 40 days after transplantation. Seventeen SNPs of CYP3A5, CYP3A4, COMT, IL-10 and POR were identified by the SNaPshot assay. Tacrolimus blood concentrations were obtained on days 1–3, days 6–8 and days 12–14 after transplantation, as well as during the period of the predefined therapeutic concentration range. Kruskal–Wallis test was used to examine the effect of genetic variation on the tacrolimus concentration/dose ratio (C0/D) at different time points. Chi-square test was used to compare the proportions of patients who achieved the target C0 range in the different genotypic groups at weeks 1, 2, 3 and 4 after transplantation. After correction for multiple testing, there was a significant association of C0/D with CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C at different time points after transplantation. The proportion of patients in the IL-10 rs1800871-TT group who achieved the target C0 range was greater (p = 0.004) compared to the IL-10 rs1800871-CT and IL-10 rs1800871-CC groups at week 3 after transplantation. CYP3A5*3, CYP3A4 *1G, CYP3A4 rs4646437 T>C and IL-10 rs1800871 C>T might be potential polymorphisms affecting the interindividual variability in tacrolimus metabolism among Chinese renal transplant recipients.
PMCID: PMC3897654  PMID: 24465960
13.  Single Nucleotide Polymorphisms in the Metastasis-associated in Colon Cancer-1 Gene Predict the Recurrence of Hepatocellular Carcinoma after Transplantation 
Background: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT). Methods: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients. Results: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls. Conclusions: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients.
PMCID: PMC3894398  PMID: 24465159
metastasis-associated in colon cancer-1; epithelial-to-mesenchymal transition
14.  Role of overexpression of MACC1 and/or FAK in predicting prognosis of hepatocellular carcinoma after liver transplantation 
Background: Metastasis-associated in colon cancer-1 (MACC1) acts as a promoter of tumor metastasis; however, the predictive value of MACC1 for hepatocellular carcinoma (HCC) after liver transplantation (LT) remains unclear.
Methods: We examined the expression of MACC1 and its target genes MET and FAK by quantitative PCR in 160 patients with HCC that was undergone LT.
Results: The patients with MACC1high or FAKhigh in HCCs showed a significantly shorter overall survival and higher cumulative recurrence rates after liver transplantation (LT), compared with MACC1low or FAKlow group. Multivariate analysis indicated that MACC1 alone or combination of MACC1/FAK was an independent prognostic factor for overall survival and cumulative recurrence.
Conclusions: MACC1 or combination of MACC1/FAK could serve as a novel biomarker in predicting the prognosis of HCC after LT.
PMCID: PMC3917116  PMID: 24516351
hepatocellular carcinoma; metastasis-associated in colon cancer-1; metastasis; prognosis; liver transplantation
15.  ZIP4, a Novel Determinant of Tumor Invasion in Hepatocellular Carcinoma, Contributes to Tumor Recurrence after Liver Transplantation 
Background and purpose: Recently, evidence that Zinc transporter ZRT/IRT-like protein 4 (ZIP4) is involved in invasiveness and apoptosis has emerged in pancreatic cancer and prostate cancer. Our aim was to assess the role of ZIP4 in invasiveness, migration and apoptosis of hepatocellular carcinoma (HCC). The prognostic value of ZIP4 in HCC after liver transplantation was evaluated.
Methods: The role of ZIP4 in HCC was investigated by overexpressing ZIP4 in BEL7402 and HepG2 cells and inhibiting ZIP4 in HuH-7 and HepG2 cells, using overexpression and shRNA plasmids in vitro studies. Immunohistochemical analysis was used to evaluate ZIP4 expression in HCC tissues from 60 patients undergoing liver transplantation, 36 cirrhotic tissue samples, and 6 normal tissue samples. Prognostic significance was assessed using the Kaplan-Meier method and the log-rank test.
Results: Specific suppression of ZIP4 reduced cell migration and invasiveness, whereas ZIP4 overexpression caused increases in cell migration and invasiveness. Furthermore, overexpression of ZIP4 resulted in increased expression of pro-metastatic genes (MMP-2, MMP-9) and decreased expression of pro-apoptotic genes (caspase-3, caspase-9, Bax). In contrast, suppression of ZIP4 resulted in an opposite effect. ZIP4 was more highly expressed in tumor tissues than non-tumor tissues (P < 0.0001). ZIP4 expression was significantly associated with tumor recurrence (P = 0.002), tumor node metastasis stage (P = 0.044), Child-Turcotte-Pugh score (P = 0.042), and tumor size (P = 0.022). Univariate analysis showed that ZIP4 expression was significantly associated with overall survival (P = 0.020) and tumor-free survival (P = 0.049). Multivariate analysis revealed that ZIP4 was an independent predictor of overall survival (P = 0.037) after liver transplantation.
Conclusions: ZIP4 could promote migration, invasiveness, and suppress apoptosis in hepatocellular carcinoma, and represent a novel predictor of poor prognosis and therapeutic target for patients with HCC who undergo liver transplantation.
PMCID: PMC3957080  PMID: 24643086
ZIP4; hepatocellular carcinoma; liver transplantation
16.  C-Terminal Domain of ICA69 Interacts with PICK1 and Acts on Trafficking of PICK1-PKCα Complex and Cerebellar Plasticity 
PLoS ONE  2013;8(12):e83862.
PICK1 (protein interacting with C-kinase 1) is a PKC (protein kinase C)-binding protein, which is essential for synaptic plasticity. The trafficking of PKCα-PICK1 complex to plasma membrane is critical for the internalization of GluR2 and induction of long-term depression. ICA69 (islet cell autoantigen 69 kDa) is identified as a major binding partner of PICK1. While heteromeric BAR domain complex is suggested to underlie the interaction between PICK1 and ICA69, the role of C-terminal domain of ICA69 (ICAC) in PICK1-ICA69 complex is unknown.
Methodology/Principal Findings
We found that ICAC interacted with PICK1 and regulated the trafficking of PICK1-PKCα complex. ICAC and ΔICAC (containing BAR domain) might function distinctly in the association of ICA69 with PICK1. While ΔICAC domain inclined to form clusters, the distribution of ICAC was diffuse. The trafficking of PICK1 to plasma membrane mediated by activated PKCα was inhibited by ICA69. This action might ascribe to ICAC, because overexpression of ICAC, but not ΔICAC, interrupted PKCα-mediated PICK1 trafficking. Notably, infusion of maltose binding protein (MBP) fusion protein, MBP-ICA69 or MBP-ICAC, in cerebellar Purkinje cells significantly inhibited the induction of long-term depression at parallel fiber- and climbing fiber-Purkinje cell synapses.
Our experiments showed that ICAC is an important domain for the ICA69-PICK1 interaction and plays essential roles in PICK1-mediated neuronal plasticity.
PMCID: PMC3865253  PMID: 24358315
17.  Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice1 
CD59 is a glycosylphosphatidylinositol (GPI)-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a−/−) mouse onto the MRL/lpr background and compared Cd59a+/+-MRL/lpr and Cd59a−/−-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both BM-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a−/−-MRL/lpr mice did not rescue the pro-autoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.
PMCID: PMC3507618  PMID: 23109726
18.  Evaluation of Anxiolytic-Like Effect of Aqueous Extract of Asparagus Stem in Mice 
There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
PMCID: PMC3853311  PMID: 24348707
19.  Safety and efficacy of radiation and chemoradiation in patients over 70 years old with inoperable esophageal squamous cell carcinoma 
Oncology Letters  2013;7(1):260-266.
The aim of the present study was to perform a retrospective analysis to investigate the outcome and toxicity of radiation (RT) and chemoradiation (CRT) in elderly, inoperable patients >70 years old. Between 2003 and 2012, 1,024 patients with squamous cell carcinoma (SCC) of the esophagus were treated at the Department of Thoracic Cancer, West China Hospital (Chengdu, China). Of these patients, 37 were >70 years old and had not undergone surgery, and were selected for analysis. Of these 37 patients, CRT had been administered to 20 (54%). Actuarial survival rates were determined by the Kaplan-Meier method. The one-year survival rate in the CRT group (n=20) was 85%, while 35% of patients in the RT group (n=17) survived for more than one year. The overall and progression-free survival in the CRT group versus the RT group were 17 months [95% confidence interval (CI), 11.861–22.139] versus eight months (95% CI, 6.674–9.326) (P=0.013) and 14 months (95% CI, 9.617–18.383) versus five months (95% CI, 2.311–7.689) (P=0.01), respectively. Patients irradiated with a dose of >50 Gy exhibited an improved survival rate compared with patients who received a dose of ≤50 Gy (18 vs. 14 months; P=0.049). Furthermore, patients with an Eastern Cooperative Oncology Group (ECOG) score of ≤1 had an improved prognosis compared with those with an ECOG score of 2 (14 vs. seven months; P=0.006). The two regimens were well-tolerated and there were no therapy-associated mortalities. The current retrospective study indicated that patients of >70 years old with inoperable esophageal SCC and a good ECOG score exhibit comparably better safety levels with CRT and improved survival rates compared with RT alone.
PMCID: PMC3861579  PMID: 24348860
esophageal squamous cancer; elderly; chemoradiation; radiation; toxicity
20.  LEPREL1 Expression in Human Hepatocellular Carcinoma and Its Suppressor Role on Cell Proliferation 
Background. Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide. It is characterized by its high invasive and metastatic potential. Leprecan-like 1 (LEPREL1) has been demonstrated to be downregulated in the HCC tissues in previous proteomics studies. The present study is aimed at a new understanding of LEPREL1 function in HCC. Methods. Quantitative RT-PCR, immunohistochemical analysis, and western blot analysis were used to evaluate the expression of LEPREL1 between the paired HCC tumor and nontumorous tissues. The biology function of LEPREL1 was investigated by Cell Counting Kit-8 (CCK8) assay and colony formation assay in HepG2 and Bel-7402 cells. Results. The levels of LEPREL1 mRNA and protein were significantly lower in the HCC tissues as compared to those of the nontumorous tissues. Reduced LEPREL1 expression was not associated with conventional clinical parameters of HCC. Overexpression of LEPREL1 in HepG2 and Bel-7402 cells inhibited cell proliferation (P < 0.01) and colony formation (P < 0.05). LEPREL1 suppressed tumor cell proliferation through regulation of the cell cycle by downregulation of cyclins. Conclusions. Clinical parameters analysis suggested that LEPREL1 was an independent factor in the development of HCC. The biology function experiments showed that LEPREL1 might serve as a potential tumor suppressor gene by inhibiting the HCC cell proliferation.
PMCID: PMC3844253  PMID: 24319452
21.  MicroRNA-155 Promotes Autophagy to Eliminate Intracellular Mycobacteria by Targeting Rheb 
PLoS Pathogens  2013;9(10):e1003697.
Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects one-third of the global population. It can live within macrophages owning to its ability to arrest phagolysosome biogenesis. Autophagy has recently been identified as an effective way to control the intracellular mycobacteria by enhancing phagosome maturation. In the present study, we demonstrate a novel role of miR-155 in regulating the autophagy-mediated anti-mycobacterial response. Both in vivo and in vitro studies showed that miR-155 expression was significantly enhanced after mycobacterial infection. Forced expression of miR-155 accelerated the autophagic response in macrophages, thus promoting the maturation of mycobacterial phagosomes and decreasing the survival rate of intracellular mycobacteria, while transfection with miR-155 inhibitor increased mycobacterial survival. However, macrophage-mediated mycobacterial phagocytosis was not affected after miR-155 overexpression or inhibition. Furthermore, blocking autophagy with specific inhibitor 3-methyladenine or silencing of autophagy related gene 7 (Atg7) reduced the ability of miR-155 to promote autophagy and mycobacterial elimination. More importantly, our study demonstrated that miR-155 bound to the 3′-untranslated region of Ras homologue enriched in brain (Rheb), a negative regulator of autophagy, accelerated the process of autophagy and sequential killing of intracellular mycobacteria by suppressing Rheb expression. Our results reveal a novel role of miR-155 in regulating autophagy-mediated mycobacterial elimination by targeting Rheb, and provide potential targets for clinical treatment.
Author Summary
microRNA-155 (miR-155) plays an essential role in regulating the host immune response by post-transcriptionally repressing the expression of target genes. However, little is known regarding its activity in modulating autophagy, an important host defense mechanism against intracellular bacterial infection. Mycobacterium tuberculosis is a hard-to-eradicate intracellular pathogen that infects approximately one-third of the global population, and causes 1.5 million deaths annually. The present study explores a novel role of miR-155 in the host response against mycobacterial infection. Our data demonstrates that mycobacterial infection triggers the expression of miR-155, and the induction of miR-155 in turn activates autophagy by targeting Rheb, a negative regulator of autophagy. miR-155-promoted autophagy accelerates the maturation of the mycobacterial phagosome, thus decreasing the survival of intracellular mycobacteria in macrophages. These findings contribute to a better understanding of the host defense mechanisms against mycobacterial infection, providing useful information for development of potential therapeutic interventions against tuberculosis.
PMCID: PMC3795043  PMID: 24130493
22.  Nanosecond Pulsed Electric Field Inhibits Cancer Growth Followed by Alteration in Expressions of NF-κB and Wnt/β-Catenin Signaling Molecules 
PLoS ONE  2013;8(9):e74322.
Cancer remains a leading cause of death worldwide and total number of cases globally is increasing. Novel treatment strategies are therefore desperately required for radical treatment of cancers and long survival of patients. A new technology using high pulsed electric field has emerged from military application into biology and medicine by applying nsPEF as a means to inhibit cancer. However, molecular mechanisms of nsPEF on tumors or cancers are still unclear. In this paper, we found that nsPEF had extensive biological effects in cancers, and clarified its possible molecular mechanisms in vitro and in vivo. It could not only induce cell apoptosis via dependent-mitochondria intrinsic apoptosis pathway that was triggered by imbalance of anti- or pro-apoptosis Bcl-2 family proteins, but also inhibit cell proliferation through repressing NF-κB signaling pathway to reduce expressions of cyclin proteins. Moreover, nsPEF could also inactivate metastasis and invasion in cancer cells by suppressing Wnt/β-Catenin signaling pathway to down-regulating expressions of VEGF and MMPs family proteins. More importantly, nsPEF could function safely and effectively as an anti-cancer therapy through inducing tumor cell apoptosis, destroying tumor microenvironment, and depressing angiogenesis in tumor tissue in vivo. These findings may provide a creative and effective therapeutic strategy for cancers.
PMCID: PMC3775773  PMID: 24069295
23.  Rapid warming in Tibet, China: public perception, response and coping resources in urban Lhasa 
Environmental Health  2013;12:71.
Tibet, average altitude more than 4,000 meters, is warming faster than anywhere else in China. The increase in temperatures may aggravate existing health problems and lead to the emergence of new risks. However, there are no actions being taken at present to protect population health due to limited understanding about the range and magnitude of health effects of climate change.
The study was a cross-sectional survey of 619 respondents from urban Lhasa, Tibet in August 2012 with the aim to investigate public perceptions of risk, heat experiences, and coping resources.
Respondents are aware of the warming that has occurred in Lhasa in recent years. Over 78% reported that rising temperature is either a “very” or “somewhat” serious threat to their own health, and nearly 40% reported they had experienced heat-related symptoms. Sex, age, education and income influenced perceived risks, health status, and heat experience. The vast majority of respondents reported that they had altered their behaviour on hot summer days. Bakuo, a sub-district at the city center, is considered especially vulnerable to heat because of sparse vegetation, high population density, poor dwelling conditions and a high proportion of low-income population. However, neighborhood social ties were stronger in Bakuo than other study locations.
The study suggests that actions are needed now to minimize downside effects of rapid warming in Tibet, because of increasing human exposure to high temperatures and uneven distribution of the resources needed to cope.
PMCID: PMC3765900  PMID: 24103412
Climate change; Global warming; Perceptions; Human health; Tibet; Vulnerability
24.  The Effect of Chinese Herbal Medicine on Albuminuria Levels in Patients with Diabetic Nephropathy: A Systematic Review and Meta-Analysis 
To evaluate the effect of Chinese herbal medicine (CHM) on albuminuria levels in patients with diabetic nephropathy (DN), we performed comprehensive searches on Medline database, Cochrane Library, CNKI database, CBM database, Wanfang database, and VIP database up to December 2012. A total of 29 trials including 2440 participants with DN met the selection criteria. CHM was tested to be more effective in reducing urinary albumin excretion rate (UAER) (MD −82.95 μg/min, [−138.64, −27.26]) and proteinuria (MD −565.99 mg/24 h, [−892.41, −239.57]) compared with placebo. CHM had a greater beneficial effect on reduction of UAER (MD −13.41 μg/min, [−20.63, −6.19]) and proteinuria (MD −87.48 mg/24 h, [−142.90, −32.06]) compared with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Combination therapy with CHM and ACEI/ARB showed significant improvement in UAER (MD −28.18 μg/min, [−44.4, −11.97]), urinary albumin-creatinine ratio (MD −347.00, [−410.61, −283.39]), protein-creatinine ratio (MD −2.49, [−4.02, −0.96]), and proteinuria (MD −26.60 mg/24 h, [−26.73, −26.47]) compared with ACEI/ARB alone. No serious adverse events were reported. CHM seems to be an effective and safe therapy option to treat proteinuric patients with DN, suggesting that further study of CHM in the treatment of DN is warranted in rigorously designed, multicentre, large-scale trials with higher quality worldwide.
PMCID: PMC3770054  PMID: 24062795
25.  MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma 
Increasing evidence indicates that deregulation of microRNAs (miRNAs) is involved in tumorigenesis. Downregulation of microRNA-503 has been observed in various types of diseases, including cancer. However, the biological function of miR-503 in hepatocellular carcinoma (HCC) is still largely unknown. In this study we aimed to elucidate the prognostic implications of miR-503 in HCC and its pathophysiologic role.
Quantitative reverse transcriptase polymerase chain reaction was used to evaluate miR-503 expression in HCC tissues and cell lines. Western blotting was performed to evaluate the expression of the miR-503 target genes. In vivo and in vitro assays were performed to evaluate the function of miR-503 in HCC. Luciferase reporter assay was employed to validate the miR-503 target genes.
miR-503 was frequently downregulated in HCC cell lines and tissues. Low expression levels of miR-503 were associated with enhanced malignant potential such as portal vein tumor thrombi, histologic grade, TNM stage, AFP level and poor prognosis. Multivariate analysis indicated that miR-503 downregulation was significantly associated with worse overall survival of HCC patients. Functional studies showed miR-503 suppressed the proliferation of HCC cells by induction of G1 phase arrest through Rb-E2F signaling pathways, and thus may function as a tumor suppressor. Further investigation characterized two cell cycle-related molecules, cyclin D3 and E2F3, as the direct miR-503 targets.
Our data highlight an important role for miR-503 in cell cycle regulation and in the molecular etiology of HCC, and implicate the potential application of miR-503 in prognosis prediction and miRNA-based HCC therapy.
PMCID: PMC3765277  PMID: 23967867
Hepatocellular carcinoma; microRNA-503; Cyclin D3; E2F3; Overall survival; G1/S transition

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