Search tips
Search criteria

Results 1-25 (64)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
author:("An, jisheng")
2.  Expanding Regulatory T Cells Alleviates Chikungunya Virus-Induced Pathology in Mice 
Journal of Virology  2015;89(15):7893-7904.
Chikungunya virus (CHIKV) infection is a reemerging pandemic human arboviral disease. CD4+ T cells were previously shown to contribute to joint inflammation in the course of CHIKV infection in mice. The JES6-1 anti-IL-2 antibody selectively expands mouse regulatory T cells (Tregs) by forming a complex with IL-2. In this study, we show that the IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology. It does so by inhibiting the infiltration of CD4+ T cells due to the induction of anergy in CHIKV-specific CD4+ effector T cells. These findings suggest that activation of Tregs could also become an alternative approach to control CHIKV-mediated disease.
IMPORTANCE Chikungunya virus (CHIKV) has reemerged as a pathogen of global significance. Patients infected with CHIKV suffer from incapacitating joint pain that severely affects their daily functioning. Despite the best efforts, treatment is still inadequate. While T cell-mediated immunopathology in CHIKV infections has been reported, the role of regulatory T cells (Tregs) has not been explored. The JES6-1 anti-interleukin 2 (IL-2) antibody has been demonstrated to selectively expand mouse Tregs by forming a complex with IL-2. We reveal here that IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology in mice by neutralizing virus-specific CD4+ effector T (Teff) cells. We show that this treatment abrogates the infiltration of pathogenic CD4+ T cells through induction of anergy in CHIKV-specific CD4+ Teff cells. This is the first evidence where the role of Tregs is demonstrated in CHIKV pathogenesis, and its expansion could control virus-mediated immunopathology.
PMCID: PMC4505607  PMID: 25995249
3.  Caribbean and La Réunion Chikungunya Virus Isolates Differ in Their Capacity To Induce Proinflammatory Th1 and NK Cell Responses and Acute Joint Pathology 
Journal of Virology  2015;89(15):7955-7969.
Chikungunya virus (CHIKV) is a mosquito-borne arthralgic alphavirus that has garnered international attention as an important emerging pathogen since 2005. More recently, it invaded the Caribbean islands and the Western Hemisphere. Intriguingly, the current CHIKV outbreak in the Caribbean is caused by the Asian CHIKV genotype, which differs from the La Réunion LR2006 OPY1 isolate belonging to the Indian Ocean lineage. Here, we adopted a systematic and comparative approach against LR2006 OPY1 to characterize the pathogenicity of the Caribbean CNR20235 isolate and consequential host immune responses in mice. Ex vivo infection using primary mouse tail fibroblasts revealed a weaker replication efficiency by CNR20235 isolate. In the CHIKV mouse model, CNR20235 infection induced an enervated joint pathology characterized by moderate edema and swelling, independent of mononuclear cell infiltration. Based on systemic cytokine analysis, localized immunophenotyping, and gene expression profiles in the popliteal lymph node and inflamed joints, two pathogenic phases were defined for CHIKV infection: early acute (2 to 3 days postinfection [dpi]) and late acute (6 to 8 dpi). Reduced joint pathology during early acute phase of CNR20235 infection was associated with a weaker proinflammatory Th1 response and natural killer (NK) cell activity. The pathological role of NK cells was further demonstrated as depletion of NK cells reduced joint pathology in LR2006 OPY1. Taken together, this study provides evidence that the Caribbean CNR20235 isolate has an enfeebled replication and induces a less pathogenic response in the mammalian host.
IMPORTANCE The introduction of CHIKV in the Americas has heightened the risk of large-scale outbreaks due to the close proximity between the United States and the Caribbean. The immunopathogenicity of the circulating Caribbean CHIKV isolate was explored, where it was demonstrated to exhibit reduced infectivity resulting in a weakened joint pathology. Analysis of serum cytokine levels, localized immunophenotyping, and gene expression profiles in the organs revealed that a limited Th1 response and reduced NK cells activity could underlie the reduced pathology in the host. Interestingly, higher asymptomatic infections were observed in the Caribbean compared to the La Réunion outbreaks in 2005 and 2006. This is the first study that showed an association between key proinflammatory factors and pathology-mediating leukocytes with a less severe pathological outcome in Caribbean CHIKV infection. Given the limited information regarding the sequela of Caribbean CHIKV infection, our study is timely and will aid the understanding of this increasingly important disease.
PMCID: PMC4505608  PMID: 25995257
4.  Timing and Spatial Distribution of Loess in Xinjiang, NW China 
PLoS ONE  2015;10(5):e0125492.
Central Asia is one of the most significant loess regions on Earth, with an important role in understanding Quaternary climate and environmental change. However, in contrast to the widely investigated loess deposits in the Chinese Loess Plateau, the Central Asian loess–paleosol sequences are still insufficiently known and poorly understood. Through field investigation and review of the previous literature, the authors have investigated the distribution, thickness and age of the Xinjiang loess, and analyzed factors that control these parameters in the Xinjiang in northwest China, Central Asia. The loess sediments cover river terraces, low uplands, the margins of deserts and the slopes of the Tianshan Mountains and Kunlun Mountains and are also present in the Ili Basin. The thickness of the Xinjiang loess deposits varies from several meters to 670 m. The variation trend of the sand fraction (>63 μm) grain-size contour can indicate the local major wind directions, so we conclude that the NW and NE winds are the main wind directions in the North and South Xinjiang, and the westerly wind mainly transport dust into the Ili basin. We consider persistent drying, adequate regional wind energy and well-developed river terraces to be the main factors controlling the distribution, thickness and formation age of the Xinjiang loess. The well-outcropped loess sections have mainly developed since the middle Pleistocene in Xinjiang, reflecting the appearance of the persistent drying and the present air circulation system. However, the oldest loess deposits are as old as the beginning of the Pliocene in the Tarim Basin, which suggests that earlier aridification occurred in the Tarim Basin rather than in the Ili Basin and the Junggar Basin.
PMCID: PMC4430276  PMID: 25970617
5.  Enhancing the Antitumor Activity of Berberine Hydrochloride by Solid Lipid Nanoparticle Encapsulation 
AAPS PharmSciTech  2014;15(4):834-844.
Berberine hydrochloride (BH) is an isoquinolin alkaloid with promising anticancer efficacies. Nevertheless, further development and application of this compound had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism in the body. In this study, a solid lipid nanoparticle (SLN)-based system was developed for efficient incorporation and persistent release of BH. The drug-loading SLNs (BH-loaded SLNs) were stable, with a mean particle size of 81.42 ± 8.48 nm and zeta potential of −28.67 ± 0.71 mV. BH-loaded SLNs showed desirable drug entrapment efficiency and drug-loaded, and the release of BH from SLNs was significantly slower than free BH. Importantly, our in vitro study indicated that BH-loaded SLNs more significantly inhibited cell proliferation on MCF-7, HepG 2, and A549 cancer cells. Meanwhile, clone formation, cellular uptake, cell cycle arrest, and cell apoptosis studies also demonstrated that BH-loaded SLNs enhanced the antitumor efficacies of BH on MCF-7 cancer cells. Taken together, our results suggest that this SLN formulation may serve as a novel, simple, and efficient system for the delivery of BH.
PMCID: PMC4113611  PMID: 24696391
antitumor evaluation; apoptosis; berberine hydrochloride; solid lipid nanoparticles
6.  A Online NIR Sensor for the Pilot-Scale Extraction Process in Fructus Aurantii Coupled with Single and Ensemble Methods 
Sensors (Basel, Switzerland)  2015;15(4):8749-8763.
Model performance of the partial least squares method (PLS) alone and bagging-PLS was investigated in online near-infrared (NIR) sensor monitoring of pilot-scale extraction process in Fructus aurantii. High-performance liquid chromatography (HPLC) was used as a reference method to identify the active pharmaceutical ingredients: naringin, hesperidin and neohesperidin. Several preprocessing methods and synergy interval partial least squares (SiPLS) and moving window partial least squares (MWPLS) variable selection methods were compared. Single quantification models (PLS) and ensemble methods combined with partial least squares (bagging-PLS) were developed for quantitative analysis of naringin, hesperidin and neohesperidin. SiPLS was compared to SiPLS combined with bagging-PLS. Final results showed the root mean square error of prediction (RMSEP) of bagging-PLS to be lower than that of PLS regression alone. For this reason, an ensemble method of online NIR sensor is here proposed as a means of monitoring the pilot-scale extraction process in Fructus aurantii, which may also constitute a suitable strategy for online NIR monitoring of CHM.
PMCID: PMC4431187  PMID: 25875194
online NIR sensor; PLS; bagging-PLS; Fructus aurantii; synergy interval partial least squares
7.  A Novel Clustering Algorithm Inspired by Membrane Computing 
The Scientific World Journal  2015;2015:929471.
P systems are a class of distributed parallel computing models; this paper presents a novel clustering algorithm, which is inspired from mechanism of a tissue-like P system with a loop structure of cells, called membrane clustering algorithm. The objects of the cells express the candidate centers of clusters and are evolved by the evolution rules. Based on the loop membrane structure, the communication rules realize a local neighborhood topology, which helps the coevolution of the objects and improves the diversity of objects in the system. The tissue-like P system can effectively search for the optimal partitioning with the help of its parallel computing advantage. The proposed clustering algorithm is evaluated on four artificial data sets and six real-life data sets. Experimental results show that the proposed clustering algorithm is superior or competitive to k-means algorithm and several evolutionary clustering algorithms recently reported in the literature.
PMCID: PMC4385684  PMID: 25874264
8.  Chaos Time Series Prediction Based on Membrane Optimization Algorithms 
The Scientific World Journal  2015;2015:589093.
This paper puts forward a prediction model based on membrane computing optimization algorithm for chaos time series; the model optimizes simultaneously the parameters of phase space reconstruction (τ, m) and least squares support vector machine (LS-SVM) (γ, σ) by using membrane computing optimization algorithm. It is an important basis for spectrum management to predict accurately the change trend of parameters in the electromagnetic environment, which can help decision makers to adopt an optimal action. Then, the model presented in this paper is used to forecast band occupancy rate of frequency modulation (FM) broadcasting band and interphone band. To show the applicability and superiority of the proposed model, this paper will compare the forecast model presented in it with conventional similar models. The experimental results show that whether single-step prediction or multistep prediction, the proposed model performs best based on three error measures, namely, normalized mean square error (NMSE), root mean square error (RMSE), and mean absolute percentage error (MAPE).
PMCID: PMC4385696  PMID: 25874249
9.  Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development 
Journal of cellular physiology  2012;227(4):1592-1603.
Posttranslational protein modification by ubiquitination, a signal for lysosomal or proteasomal proteolysis, can be regulated and reversed by deubiquitinating enzymes (DUBs). This study examined the roles of UCHL1 and UCHL3, two members of ubiquitin C-terminal hydrolase (UCH) family of DUBs, in murine fertilization and preimplantation development. Before fertilization, these proteins were associated with the oocyte cortex (UCHL1) and meiotic spindle (UCHL3). Intracytoplasmic injection of the general UCH-family inhibitor ubiquitin-aldehyde (UBAL) or antibodies against UCHL3 into mature metaphase II oocytes blocked fertilization by reducing sperm penetration of the zona pellucida and incorporation into the ooplasm, suggesting a role for cortical UCHL1 in sperm incorporation. Both UBAL and antibodies against UCHL1 injected at the onset of oocyte maturation (germinal vesicle stage) reduced the fertilizing ability of oocytes. The subfertile Uchl1gad−/− mutant mice showed an intriguing pattern of switched UCH localization, with UCHL3 replacing UCHL1 in the oocyte cortex. While fertilization defects were not observed, the embryos from homozygous Uchl1gad−/− mutant females failed to undergo morula compaction and did not form blastocysts in vivo, indicating a maternal effect related to UCHL1 deficiency. We conclude that the activity of oocyte UCHs contributes to fertilization and embryogenesis by regulating the physiology of the oocyte and blastomere cortex.
PMCID: PMC4351554  PMID: 21678411
oocyte; sperm; ubiquitin; proteasome; UCH
10.  Robust PLS Prediction Model for Saikosaponin A in Bupleurum chinense DC. Coupled with Granularity-Hybrid Calibration Set 
This study demonstrated particle size effect on the measurement of saikosaponin A in Bupleurum chinense DC. by near infrared reflectance (NIR) spectroscopy. Four types of granularity were prepared including powder samples passed through 40-mesh, 65-mesh, 80-mesh, and 100-mesh sieve. Effects of granularity on NIR spectra were investigated, which showed to be wavelength dependent. NIR intensity was proportional to particle size in the first combination-overtone and combination region. Local partial least squares model was constructed separately for every kind of samples, and data-preprocessing techniques were performed to optimize calibration model. The 65-mesh model exhibited the best prediction ability with root mean of square error of prediction (RMSEP) = 0.492 mg·g−1, correlation coefficient (RP) = 0.9221, and relative predictive determinant (RPD) = 2.58. Furthermore, a granularity-hybrid calibration model was developed by incorporating granularity variation. Granularity-hybrid model showed better performance than local model. The model performance with 65-mesh samples was still the most accurate with RMSEP = 0.481 mg·g−1, RP = 0.9279, and RPD = 2.64. All the results presented the guidance for construction of a robust model coupled with granularity-hybrid calibration set.
PMCID: PMC4363675  PMID: 25821634
11.  Oocyte spindle proteomics analysis leading to rescue of chromosome congression defects in cloned embryos 
Journal of proteome research  2010;9(11):6025-6032.
Embryos produced by somatic cell nuclear transfer (SCNT) display low term developmental potential. This is associated with deficiencies in spindle composition prior to activation and at early mitotic divisions, including failure to assemble certain proteins on the spindle. The protein-deficient spindles are accompanied by chromosome congression defects prior to activation and during the first mitotic divisions of the embryo. The molecular basis for these deficiencies and how they might be avoided are unknown. Proteomic analyses of spindles isolated from normal metaphase II (MII) stage oocytes and SCNT constructs, along with a systematic immunofluorescent survey of known spindle-associated proteins were undertaken. This was the first proteomics study of mammalian oocyte spindles. The study revealed four proteins as being deficient in spindles of SCNT embryos in addition to those previously identified; these were clathrin heavy chain (CLTC), aurora B kinase, dynactin 4, and casein kinase 1 alpha. Due to substantial reduction in CLTC abundance after spindle removal, we undertook functional studies to explore the importance of CLTC in oocyte spindle function and in chromosome congression defects of cloned embryos. Using siRNA knockdown we demonstrated an essential role for CLTC in chromosome congression during oocyte maturation. We also demonstrated rescue of chromosome congression defects in SCNT embryos at the first mitosis using CLTC mRNA injection. These studies are the first to employ proteomics analyses coupled to functional interventions to rescue a specific molecular defect in cloned embryos.
PMCID: PMC4316211  PMID: 20883044
somatic cell nuclear transfer; meiosis; oogenesis; gene expression; spindle assembly
12.  Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response 
EMBO Molecular Medicine  2014;7(1):24-41.
RNA-sensing toll-like receptors (TLRs) mediate innate immunity and regulate anti-viral response. We show here that TLR3 regulates host immunity and the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human and mouse fibroblasts with defective TLR3 signaling. Up to 100-fold increase in CHIKV load was observed in Tlr3−/− mice, alongside increased virus dissemination and pro-inflammatory myeloid cells infiltration. Infection in bone marrow chimeric mice showed that TLR3-expressing hematopoietic cells are required for effective CHIKV clearance. CHIKV-specific antibodies from Tlr3−/− mice exhibited significantly lower in vitro neutralization capacity, due to altered virus-neutralizing epitope specificity. Finally, SNP genotyping analysis of CHIKF patients on TLR3 identified SNP rs6552950 to be associated with disease severity and CHIKV-specific neutralizing antibody response. These results demonstrate a key role for TLR3-mediated antibody response to CHIKV infection, virus replication and pathology, providing a basis for future development of immunotherapeutics in vaccine development.
PMCID: PMC4309666  PMID: 25452586
Chikungunya virus; innate immunity; joint inflammation; neutralizing antibodies; TLR3
13.  High-density Lipoprotein Increases the Uptake of Oxidized Low Density Lipoprotein via PPARγ/CD36 Pathway in Inflammatory Adipocytes 
Aim: Previous studies have demonstrated that the dysregulated-secretion of adipokines by adipocytes may contribute to obesity-associated atherosclerosis (As) and high density lipoprotein (HDL) may protect against atherogenesis through multiple pathways. This study was to explore the effect of HDL on the oxLDL uptake in inflammatory adipocytes stimulated by endotoxin lipopolysaccharide (LPS) and the possible mechanism.
Methods and Results: 3T3-L1 adipocytes were cultured and induced to differentiation and maturation. Acute inflammation in adipocytes was induced by LPS (100 ng/ml) for 6 hours. The adipocytes were pretreated with HDL in various concentrations (10, 50, 100 μg/ml) for 16 hours or with specific PPARγ antagonist (GW9662, 10 μM) or agonist (Rosiglitazone, 10 μM) for 30 min before administration of LPS. The results showed that LPS significantly increased the release of inflammation-related adipokines, such as monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8 and IL-6, while decreasing the release of leptin and adiponectin. Meanwhile, LPS reduced the uptake and degradation of 125I-oxLDL, and down-regulated the expression of PPARγ and CD36. Pretreatment with HDL dose-dependently affected the release of IL-8 and IL-6 and the reduced uptake and degradation of oxLDL of adipocytes stimulated by LPS, accompanied with marked upregulation of PPARγ and CD36 expression. Pretreatment with GW9662 markedly inhibited the upregulation of CD36 expression mediated by HDL (100 μg/ml), while the effects of Rosiglitazone were opposite to GW9662.
Conclusions: HDL may increase oxLDL uptake of inflammatory adipocytes stimulated by LPS via upregulation of PPARγ/CD36 pathway, which may be a new mechanism of anti-atherosclerosis mediated by HDL.
PMCID: PMC4323365  PMID: 25678844
Lipoprotein; Atherosclerosis; Inflammation; Lipopolysaccharide
14.  Rapid Elemental Analysis and Provenance Study of Blumea balsamifera DC Using Laser-Induced Breakdown Spectroscopy 
Sensors (Basel, Switzerland)  2014;15(1):642-655.
Laser-induced breakdown spectroscopy (LIBS) was applied to perform a rapid elemental analysis and provenance study of Blumea balsamifera DC. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were implemented to exploit the multivariate nature of the LIBS data. Scores and loadings of computed principal components visually illustrated the differing spectral data. The PLS-DA algorithm showed good classification performance. The PLS-DA model using complete spectra as input variables had similar discrimination performance to using selected spectral lines as input variables. The down-selection of spectral lines was specifically focused on the major elements of B. balsamifera samples. Results indicated that LIBS could be used to rapidly analyze elements and to perform provenance study of B. balsamifera.
PMCID: PMC4327040  PMID: 25558999
LIBS; Blumea balsamifera DC; provenance study; PCA; PLS-DA
15.  Near-infrared for on-line determination of quality parameter of Sophora japonica L. (formula particles): From lab investigation to pilot-scale extraction process 
Pharmacognosy Magazine  2015;11(41):8-13.
Extraction process of dried flowers of formula particles should be investigated from lab investigation to pilot-scale because of good water absorbing capacity and obscure active pharmaceutical ingredients (API) dissolution.
Reliable analysis of on-line near-infrared (NIR) technique and novel application in fascinating modern, traditional Chinese medicine production (formula particles) was proved.
Materials and Methods:
The extraction process of Sophora japonica L. (formula particles) was used as an example, the rutin was regarded as API. On-line NIR technology was used to monitor the variation of rutin in the extraction process. High-performance liquid chromatography (HPLC) was used as a reference method to determine the content of rutin during the extraction process. The sample set was selected by Kennard-Stone (KS) algorithm. Different pretreatment methods were compared. The synergy interval partial least square (SiPLS) algorithm was applied. Chemometrics indicators and multivariate detection limits method were mutually used to assess the model.
According to both errors α (0.05) and β (0.05), rutin content could be detected by on-line NIR, which was more than 0.181 mg/mL.
This work demonstrated the feasibility of NIR for on-line determination of rutin in the pilot-scale extraction process of S. japonica. L. It provided technical support for the NIR application in the extraction process of formula particles.
PMCID: PMC4329637  PMID: 25709204
Formula particles; multivariate detection limits; near-infrared; on-line; Sophora japonica. L
16.  Biomass pyrolysis liquid to citric acid via 2-step bioconversion 
The use of fossil carbon sources for fuels and petrochemicals has serious impacts on our environment and is unable to meet the demand in the future. A promising and sustainable alternative is to substitute fossil carbon sources with microbial cell factories converting lignocellulosic biomass into desirable value added products. However, such bioprocesses require tolerance to inhibitory compounds generated during pretreatment of biomass. In this study, the process of sequential two-step bio-conversion of biomass pyrolysis liquid containing levoglucosan (LG) to citric acid without chemical detoxification has been explored, which can greatly improve the utilization efficiency of lignocellulosic biomass.
The sequential two-step bio-conversion of corn stover pyrolysis liquid to citric acid has been established. The first step conversion by Phanerochaete chrysosporium (P. chrysosporium) is desirable to decrease the content of other compounds except levoglucosan as a pretreatment for the second conversion. The remaining levoglucosan in solution was further converted into citric acid by Aspergillus niger (A. niger) CBX-209. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio-conversion technology. Under experimental conditions, levoglucosan yield is 12% based on the feedstock and the citric acid yield can reach 82.1% based on the levoglucosan content in the pyrolysis liquid (namely 82.1 g of citric acid per 100 g of levoglucosan).
The study shows that P. chrysosporium and A. niger have the potential to be used as production platforms for value-added products from pyrolyzed lignocellulosic biomass. Selected P. chrysosporium is able to decrease the content of other compounds except levoglucosan and levoglucosan can be further converted into citric acid in the residual liquids by A. niger. Thus the conversion of cellulose to citric acid is completed by both pyrolysis and bio-conversion technology.
PMCID: PMC4299680  PMID: 25551193
Lignocellulosic biomass; Pyrolysis; Levoglucosan; Bio-conversion; Citric acid
17.  Analysis of codon usage bias of mitochondrial genome in Bombyx mori and its relation to evolution 
Synonymous codon usage bias (SCUB) is an inevitable phenomenon in organismic taxa, generally referring to differences in the occurrence frequency of codons across different species or within the genome of the same species. SCUB happens in various degrees under pressure from nature selection, mutation bias and other factors in different ways. It also attaches great significance to gene expression and species evolution, however, a systematic investigation towards the codon usage in Bombyx mori (B. mori) has not been reported yet. Moreover, it is still indistinct about the reasons contributing to the bias or the relationship between the bias and the evolution of B. mori.
The comparison of the codon usage pattern between the genomic DNA (gDNA) and the mitochondrial DNA (mtDNA) from B. mori suggests that mtDNA has a higher level of codon bias. Furthermore, the correspondence analysis suggests that natural selection, such as gene length, gene function and translational selection, dominates the codon preference of mtDNA, while the composition constraints for mutation bias only plays a minor role. Additionally, the clustering results of the silkworm superfamily suggest a lack of explicitness in the relationship between the codon usage of mitogenome and species evolution.
Among the complicated influence factors leading to codon bias, natural selection is found to play a major role in shaping the high bias in the mtDNA of B. mori from our current data. Although the cluster analysis reveals that codon bias correlates little with the species evolution, furthermore, a detailed analysis of codon usage of mitogenome provides better insight into the evolutionary relationships in Lepidoptera. However, more new methods and data are needed to investigate the relationship between the mtDNA bias and evolution.
PMCID: PMC4276022  PMID: 25515024
Bombyx mori; Synonymous codon usage bias; Genomic DNA; Mitochondrial DNA; Evolution
18.  A Phase I Study of Vorinostat in Combination with Bortezomib in Patients with Advanced Malignancies 
Investigational new drugs  2013;31(6):1539-1546.
A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors.
Patients received vorinostat orally once daily on days 1–14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1.
Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1.
This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily x 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.
PMCID: PMC3901262  PMID: 24114121
SAHA; vorinostat; PS-341; bortezomib; phase I
19.  Doxorubicin-eluting beads versus conventional transarterialchemoembolization for the treatment of hepatocellular carcinoma: a meta-analysis 
Objective: We conducted a meta-analysis to evaluate the efficacy and toxicity of DEB-TACE in the treatment of patients with intermediate-stage HCC. Methods: Studies published in PubMed, Embase and Web of Science, were systematically reviewed to identify those that assessed the efficacy and toxicity of DEB-TACE in the treatment of patients with HCC. Hazard ratio, risk ratioand 95% confidence intervalswere calculated, using a fixed-effects model or a random-effects model. Results: Nine studies with a total of 830 patients met the inclusion criteria were included in this study. DEB-TACE significantly improved overall survivaland progression free survival, and also increased objective response rateand disease control rate. However, in subgroup analyses, pooled results showed that, the survival benefits of DEB-TACE were not found in the randomized controlled trials, but were observed in Non-RCTs. The incidence of most common adverse events, including nausea, pain, fever, and fatigue, was not significant difference between the DEB-TACE group and conventional TACEgroup. Conclusions: Despite DEB-TACE significantly prolonged the survival and response rate in the patients with HCC, the conclusion about the survival benefits should be interpreted with caution, since these findings were only found in retrospective Non-RCTs, and not in prospective RCTs.
PMCID: PMC4276155  PMID: 25550897
DEB-TACE; hepatocellular carcinoma; efficacy; toxicity; meta-analysis
20.  Potential Role of Cyr61 Induced Degeneration of Human Müller Cells in Diabetic Retinopathy 
PLoS ONE  2014;9(10):e109418.
The degeneration of Müller cells has been recognized to involve in the pathogenesis of diabetic retinopathy. However, the mechanism is not yet clear. This study is to explore the potential role of Cyr61, a secreted signaling protein in extracellular matrix, in inducing human Müller cell degeneration in diabetic retinopathy (DR). Twenty patients with proliferative diabetic retinopathy (PDR) and twelve non-diabetic patients were recruited for this study. Vitreous fluid was collected during vitrectomy surgery for Cyr61 ELISA. Human Müller cell line MIO-M1 were cultured to be subconfluent, and then treated with glucose (0–20 mM) or Cyr61 (0–300 ng/ml). Cyr61 expression induced by increasing concentrations of glucose was evaluated by RT-qPCR and Western blot. Effects of Cyr61 on Müller cells viability, migration and apoptosis were observed by MTT assay, Transwell assay, and TUNEL assay. Vitreous Cyr61 levels were observed to be 8-fold higher in patients with PDR (3576.92±1574.58 pg/mL), compared with non-diabetic controls (436.14±130.69 pg/mL). Interestingly, the active PDR group was significantly higher than the quiescent PDR group (P<0.01). In retinal Müller cells culture, high glucose significantly and dose-dependently elevated Cyr61 expression at both mRNA and protein levels. Cyr61 at high concentrations dose-dependently inhibited the viability and migration of Müller cells. TUNEL assay further revealed that high concentration of Cyr61 significantly promoted the cell apoptosis. In conclusion, these findings demonstrated for the first time that the expression of Cyr61 was elevated by high glucose in Müller cells, and Cyr61 inhibited cell viability and migration while induced apoptosis, suggesting the potential role of Cyr61 in Müller cell degeneration. The elevated Cyr61 levels in vitreous fluid of PDR patients further support its role in diabetic retinopathy (DR).
PMCID: PMC4199605  PMID: 25329584
21.  [125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease 
Neurochemistry international  2011;60(3):286-291.
The cannabinoid type-1 receptor (CB1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB1Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB1R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB1R radioligand to investigate regional variations in CB1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB1Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB1R autoradiography with [125I]SD-7015 as radioligand. Regional concentration of [125I]SD-7015, corresponding to, and thereby representing, regional CB1R densities, were expressed in fM/g_tissue. The results show that CB1R density inversely correlates with Braak tau pathology with the following tendency: controls
PMCID: PMC4180663  PMID: 22222721
Alzheimer's disease; Braak classification; Endocannabinoid system; Molecular imaging; Biomarker; Human brain autoradiography; CB1R; [125I]SD7015
Arthritis and rheumatism  2013;65(10):2724-2736.
Arthrogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) circulate worldwide. This virus class causes debilitating illnesses characterised by arthritis, arthralgia, and myalgia. We previously identified macrophage migration inhibitory factor (MIF) as a critical inflammatory factor in the pathogenesis of alphaviral disease. Here, we characterise the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides.
Mouse models of RRV and CHIKV infection were used to investigate the immunopathogenesis of arthritic alphavirus infection. The role of CD74 was assessed using histological analysis, real time PCR, flow cytometry and plaque assay.
In comparison to wild-type mice, CD74−/− mice developed only mild clinical features and had low levels of tissue damage. Leukocyte infiltration, characterised predominantly by inflammatory monocytes and natural killer cells, was substantially reduced in infected tissues of CD74−/− mice, but production of pro-inflammatory cytokines and chemokines were not decreased. CD74 deficiency was associated with increased monocyte apoptosis, but had no effect on monocyte migratory capacity. Consistent with these findings, alphaviral infection resulted in a dose-dependent up-regulation of CD74 expression in human peripheral blood mononuclear cells and serum MIF levels were significantly elevated in humans with RRV or CHIKV infections.
We propose that CD74 regulates immune responses to alphaviral infection through effects on cellular recruitment and survival. These findings suggest that both MIF and CD74 play a critical role in mediating alphaviral disease and blocking these factors with novel therapeutic agents can substantially ameliorate pathology.
PMCID: PMC3796577  PMID: 23896945
Brain research bulletin  2012;87(6):504-510.
Cannabinoid type-1 receptors (CB1Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB1Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB1R and dopamine receptor density in case of Parkinson’s disease (PD).
Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB1R and dopamine D2/D3 receptor autoradiography. [125I]SD7015, a novel selective CB1R inverse agonist, developed by a number of the present co-authors, and [3H]raclopride, a dopamine D2/D3 antagonist, were used as radioligands. Our results demonstrate unchanged CB1R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (l-DOPA). At the same time dopamine D2/D3 receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97 ± 10.00 fmol/g, PD: 3.73 ± 0.07 fmol/g (mean ± SEM), p < 0.05) and nucleus caudatus (control: 30.26 ± 2.48 fmol/g, PD: 12.84 ± 5.49 fmol/g, p < 0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected.
Our data suggest the presence of an unaltered CB1R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB1R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB1R population and a decreased dopamine D2/D3 receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size.
PMCID: PMC4180092  PMID: 22421165
Parkinson’s disease; Endocannabinoid CB1 receptor; Dopamine D2/D3 receptor; Molecular imaging biomarker; Human brain autoradiography; Striatum
Scientific Reports  2014;4:6381.
Precipitation variation on the Loess Plateau (LP) of China is not only important for rain-fed agriculture in this environmentally sensitive region, but also critical for the water and life securities over the whole Yellow River basin. Here we reconstruct high resolution precipitation variation on the western LP during the past 370 years by using two replicated, annually-laminated stalagmites. Spatial analysis suggests that the reconstruction can be also representative for the whole LP region. The precipitation variations show a significant quasi-50 year periodicity during the last 370 years, and have an important role in determining the runoff of the middle Yellow River. The main factor controlling the decadal scale variations and long-term trend in precipitation over this region is southerly water vapour transport associated with the Asian summer monsoon. The Pacific Decadal Oscillation is also an important influence on precipitation variation in this region, as it can affect the East Asian summer monsoon and the West Pacific Subtropical High.
PMCID: PMC4165273  PMID: 25223372
Objective: This study aimed to investigate the effect of Katanin p60 on the neurite growth and collateral formation in the hippocampus. Methods: Gene cloning was performed to construct the Katanin p60 eukaryotic vector. The microtubule cutting effect and protein expression of Katanin p60 were investigated in 293T cells. Then, these vectors were transfected into hippocampal neurons of rats, and the effects of Katanin p60 on the neurite growth and collateral formation were observed. Results: In the present study, we successfully constructed Katanin p60-GFP recombinant plasmids. After transfecting into 293T cells, the Katanin p60 was over-expressed in these cells, the mesh-like structure of microtubules was disrupted, the residual microtubules circled the nucleus, the expression microtubule proteins reduced, and the tapered protrusions disappeared. In hippocampal neurons with Katanin p60 over-expression, the neural neurite growth was obvious, and a lot of dendrites arose from cell bodies. In cells without Katanin p60 expression, the neurites were small, and the number and length of dendrites reduced significantly when compared with Katanin p60 over-expressing cells (P < 0.05). In addition, in Katanin p60 over-expressing cells, the number of collaterals from the neurites and dendrites increased markedly when compared with cells without Katanin p60 expression (P < 0.05). Conclusion: Katanin p60 can promote the neurite growth and collateral formation of hippocampal neurons.
PMCID: PMC4211748  PMID: 25356098
Katanin; neurite; collateral; microtubule; neuron; hippocampus

Results 1-25 (64)