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1.  A Computational Approach to Estimate Interorgan Metabolic Transport in a Mammal 
PLoS ONE  2014;9(6):e100963.
In multicellular organisms metabolism is distributed across different organs, each of which has specific requirements to perform its own specialized task. But different organs also have to support the metabolic homeostasis of the organism as a whole by interorgan metabolite transport. Recent studies have successfully reconstructed global metabolic networks in tissues and cell types and attempts have been made to connect organs with interorgan metabolite transport. Instead of these complicated approaches to reconstruct global metabolic networks, we proposed in this study a novel approach to study interorgan metabolite transport focusing on transport processes mediated by solute carrier (Slc) transporters and their couplings to cognate enzymatic reactions. We developed a computational approach to identify and score potential interorgan metabolite transports based on the integration of metabolism and transports in different organs in the adult mouse from quantitative gene expression data. This allowed us to computationally estimate the connectivity between 17 mouse organs via metabolite transport. Finally, by applying our method to circadian metabolism, we showed that our approach can shed new light on the current understanding of interorgan metabolite transport at a whole-body level in mammals.
PMCID: PMC4074118  PMID: 24971892
2.  A Minimalist NMR Approach for the Structural Revision of Mucoxin 
In an attempt to revise the structural assignment of mucoxin, and faced with 64 diastereomeric possibilities, we resorted to the synthesis of truncated structures that contained the core stereochemical sites. Twelve stereochemical analogues were synthesized, their 1H and 13C NMR spectra were analyzed and four recurring stereochemical trends were distilled from the data. Applying the observed trends to the diastereomeric population pared the possible choices for the correct structure of mucoxin from 64 to 4. Synthesis of these analogues led to the identification of the correct structure of mucoxin.
PMCID: PMC4064830  PMID: 21089037
acetogenins; mucoxin; natural products; NMR spectroscopy; structure elucidation
3.  Targeting of Antigens to B Lymphocytes via CD19 As A Means for Tumor Vaccine Development 
Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. Here, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single chain variable fragment miniAb. By using the tumor-associated Ag (TAA) her-2/neu extracellular domain (ECD), we showed that the co-engagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinomas models. Furthermore, four different ECDs of her-2/neu could be targeted to B cells to generate Abs against particular domains with different anti-tumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost which may be usable not only for cancer therapy but also for infectious agents.
PMCID: PMC3660458  PMID: 23630363
4.  Effects of yoga training in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis 
Journal of Thoracic Disease  2014;6(6):795-802.
Currently, several studies have assessed the effect of yoga training on the management of chronic obstructive pulmonary disease (COPD), but these studies involved a wide variation of sample and convey inconclusive results. Hence, the present study was performed a systematic review and meta-analysis to investigate the efficacy of yoga training in COPD patients.
PubMed, EMBASE, the Cochrane Library, Google Scholar, and databases were searched for relevant studies. The primary outcomes were forced expiratory volume in one second (FEV1), FEV1% predicted (% pred). Secondary outcomes included 6-min walking distance (6 MWD), arterial oxygen tension (PaO2), and arterial carbon dioxide tension (PaCO2). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed with the I2 test.
Five randomized controlled trials (RCTs) involving 233 patients fulfilled the inclusion criteria. Yoga training significantly improved FEV1 (WMD: 123.57 mL, 95% CI: 4.12-243, P=0.04), FEV1% pred (WMD: 3.90%, 95% CI: 2.27-5.54, P<0.00001), and 6 MWD (WMD: 38.84 m, 95% CI: 15.52-62.16, P=0.001). However, yoga training had no significant effects on PaO2 (WMD: 1.29 mmHg, 95% CI: –1.21-3.78, P=0.31) and PaCO2 (WMD: –0.76 mmHg, 95% CI: –2.06-0.53, P=0.25).
The current limited evidence suggested that yoga training has a positive effect on improving lung function and exercise capacity and could be used as an adjunct pulmonary rehabilitation program in COPD patients. However, further studies are needed to substantiate our preliminary findings and to investigate the long-term effects of yoga training.
PMCID: PMC4073384  PMID: 24977005
Chronic obstructive pulmonary disease (COPD); yoga; pulmonary function; meta-analysis
5.  Functional Analysis of KIF3A and KIF3B during Spermiogenesis of Chinese Mitten Crab Eriocheir sinensis 
PLoS ONE  2014;9(5):e97645.
Spermatogenesis represents the transformation process at the level of cellular development. KIF3A and KIF3B are believed to play some roles in the assembly and maintenance of flagella, intracellular transport of materials including organelles and proteins, and other unknown functions during this process. During spermatogenesis in Eriocheir sinensis, if the sperm shaping machinery is dependent on KIF3A and KIF3B remains unknown.
Methodology/Principal Findings
The cDNA of KIF3A and KIF3B were obtained by designing degenerate primers, 3′RACE, and 5′RACE. We detected the genetic presence of kif3a and kif3b in the heart, muscle, liver, gill, and testis of E. sinensis through RT-PCR. By western blot analysis, the protein presence of KIF3A and KIF3B in heart, muscle, gill, and testis reflected the content in protein level. Using in situ hybridization and immunofluorescence, we could track the dynamic location of KIF3A and KIF3B during different developmental phases of sperm. KIF3A and KIF3B were found surrounding the nucleus in early spermatids. In intermediate spermatids, these proteins expressed at high levels around the nucleus and extended to the final phase. During the nuclear shaping period, KIF3A and KIF3B reached their maximum in the late spermatids and were located around the nucleus and concentrated in the acrosome to some extent.
Our results revealed that KIF3A and KIF3B were involved in the nuclear and cellular morphogenesis at the levels of mRNA and protein. These proteins can potentially facilitate the intracellular transport of organelles, proteins, and other cargoes. The results represent the functions of KIF3A and KIF3B in the spermatogenesis of Crustacea and clarify phylogenetic relationships among the Decapoda.
PMCID: PMC4037190  PMID: 24870586
6.  Histological changes of gastric mucosa after Helicobacter pylori eradication: A systematic review and meta-analysis 
AIM: To systematically review pathological changes of gastric mucosa in gastric atrophy (GA) and intestinal metaplasia (IM) after Helicobacter pylori (H. pylori) eradication.
METHODS: A systematic search was made of PubMed, Web of Science, EMBASE,, OVID and the Cochran Library databases for articles published before March 2013 pertaining to H. pylori and gastric premalignant lesions. Relevant outcomes from articles included in the meta-analysis were combined using Review Manager 5.2 software. A Begg’s test was applied to test for publication bias using STATA 11 software. χ2 and I2 analyses were used to assess heterogeneity. Analysis of data with no heterogeneity (P > 0.1, I2 < 25%) was carried out with a fixed effects model, otherwise the causes of heterogeneity were first analyzed and then a random effects model was applied.
RESULTS: The results of the meta-analysis showed that the pooled weighted mean difference (WMD) with 95%CI was 0.23 (0.18-0.29) between eradication and non-eradication of H. pylori infection in antral IM with a significant overall effect (Z = 8.19; P <0.00001) and no significant heterogeneity (χ2 = 27.54, I2 = 16%). The pooled WMD with 95%CI was -0.01 (-0.04-0.02) for IM in the corpus with no overall effect (Z = 0.66) or heterogeneity (χ2 = 14.87, I2 =0%) (fixed effects model). In antral GA, the pooled WMD with 95% CI was 0.25 (0.15-0.35) with a significant overall effect (Z = 4.78; P < 0.00001) and significant heterogeneity (χ2 = 86.12, I2 = 71%; P < 0.00001). The pooled WMD with 95% CI for GA of the corpus was 0.14 (0.04-0.24) with a significant overall effect (Z = 2.67; P = 0.008) and significant heterogeneity (χ2 = 44.79, I2 = 62%; P = 0.0003) (random effects model).
CONCLUSION: H. pylori eradication strongly correlates with improvement in IM in the antrum and GA in the corpus and antrum of the stomach.
PMCID: PMC4024801  PMID: 24914352
Helicobacter pylori eradication; Gastric atrophy; Intestinal metaplasia; Pathological changes; Gastric mucosa; Meta-analysis
7.  Blockade of ICAM-1 Improves the Outcome of Polymicrobial Sepsis via Modulating Neutrophil Migration and Reversing Immunosuppression 
Mediators of Inflammation  2014;2014:195290.
Intercellular adhesion molecule-1 (ICAM-1) is a key adhesion molecule mediating neutrophil migration and infiltration during sepsis. But its role in the outcome of sepsis remains contradictory. The current study was performed to investigate the role of anti-ICAM-1 antibody in the outcome of polymicrobial sepsis and sepsis-induced immune disturbance. Effect of anti-ICAM-1 antibody on outcome of sepsis induced by cecal ligation and puncture (CLP) was evaluated by the survival analysis, bacterial clearance, and lung injury. Its influence on neutrophil migration and infiltration, as well as lymphocyte status, in thymus and spleen was also investigated. The results demonstrated that ICAM-1 mRNA was upregulated in lung, thymus, and spleen of CLP mice. Anti-ICAM-1 antibody improved survival and bacterial clearance in CLP mice and attenuated lung injury. Migration of neutrophils to peritoneal cavity was enhanced while their infiltration into lung, thymus, and spleen was hampered by ICAM-1 blockade. Anti-ICAM-1 antibody also prevented sepsis-induced apoptosis in thymus and spleen. Positive costimulatory molecules including CD28, CD80, and CD86 were upregulated, while negative costimulatory molecules including PD-1 and PD-L1 were downregulated following anti-ICAM-1 antibody administration. In conclusion, ICAM-1 blockade may improve outcome of sepsis. The rationale may include the modulated neutrophil migration and the reversed immunosuppression.
PMCID: PMC4033397  PMID: 24891762
8.  Ab initio molecular dynamics study of high-pressure melting of beryllium oxide 
Scientific Reports  2014;4:4707.
We investigate, through first-principles molecular dynamics simulations, the high-pressure melting of BeO in the range 0 ≤ p ≤ 100 GPa. The wurtzite (WZ), zinc blend (ZB), and rocksalt (RS) phases of BeO are considered. It is shown that below 40 GPa, the melting temperature for the WZ phase is higher than that for the ZB and RS phases. When the pressure is beyond 66 GPa, the melting temperature for the RS phase is the highest one, in consistent with the previously reported phase diagram calculated within the quasiharmonic approximation. We find that in the medium pressure range between 40 to 66 GPa, the ZB melting data are very close to those of RS, which results from the fact that the ZB structure first transforms to RS phase before melting. The ZB-RS-liquid phase transitions have been observed directly during the molecular dynamics runs and confirmed using the pair correlation functions analysis. In addition, we propose the melting curve of BeO in the form Tm = 2696.05 (1 + P/24.67)0.42, the zero-pressure value of 2696.05 K falling into the experimental data range of 2693 ~ 2853 K.
PMCID: PMC3998012  PMID: 24759594
9.  Enhanced circulating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed rats 
Berberine (BBR), a natural plant extract, has been shown to improve lipid metabolism. However, its effects on PCSK9, a key factor involving in the lipid metabolism, have not yet been evaluated in vivo. The aim of the present study was to investigate the effect of BBR on PCSK9 expression in high fat diet-fed (HFD) rats.
Thirty-two male Sprague Dawley (SD) rats were randomized into the four groups (n = 8): normal diet (Control), HFD, HFD + simvastatin (Sim, 2 mg/kg/d) and HDF + BBR (400 mg/kg/d) for 6 weeks. The following parameters were determined: 1) body weight; 2) serum lipid profile; 3) serum PCSK9 measured by enzyme-linked immuno sorbent assay (ELISA) ; 4) hepatic expressions of low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1 (HNF1) were examined by real time quantitative polymerase chain reaction (RT-PCR) and western blotting analysis.
Compared with HFD rats, Sim and BBR significantly reduced body weight gain and improved lipid profile (P < 0.05 respectively). In addition, either of drug treatment for 6 weeks could increase serum concentration of PCSK9 in HFD rats (P < 0.05). This enhanced PCSK9 expression was demonstrated to be associated with the up-regulation of hepatic expression of LDLR and SREBP-2 and the down-regulation of hepatic expression of HNF1 (P < 0.05 respectively).
The data provided the first line of the evidence that BBR, similar to the Sim, could increase the expression of PCSK9 levels in HFD rats through SREBP-2 activation, suggesting that impacts of BBR on lipid profile may also be linked to SREBP-2 pathway.
PMCID: PMC4000533  PMID: 24755036
Berberine; Simvastatin; Proprotein convertase subtilisin/kexin type 9; Low density lipoprotein receptor; High fat diet-fed rats
10.  Guided cobalamin biosynthesis supports Dehalococcoides mccartyi reductive dechlorination activity 
Dehalococcoides mccartyi strains are corrinoid-auxotrophic Bacteria and axenic cultures that require vitamin B12 (CN-Cbl) to conserve energy via organohalide respiration. Cultures of D. mccartyi strains BAV1, GT and FL2 grown with limiting amounts of 1 µg l−1 CN-Cbl quickly depleted CN-Cbl, and reductive dechlorination of polychlorinated ethenes was incomplete leading to vinyl chloride (VC) accumulation. In contrast, the same cultures amended with 25 µg l−1 CN-Cbl exhibited up to 2.3-fold higher dechlorination rates, 2.8–9.1-fold increased growth yields, and completely consumed growth-supporting chlorinated ethenes. To explore whether known cobamide-producing microbes supply Dehalococcoides with the required corrinoid cofactor, co-culture experiments were performed with the methanogen Methanosarcina barkeri strain Fusaro and two acetogens, Sporomusa ovata and Sporomusa sp. strain KB-1, as Dehalococcoides partner populations. During growth with H2/CO2, M. barkeri axenic cultures produced 4.2 ± 0.1 µg l−1 extracellular cobamide (factor III), whereas the Sporomusa cultures produced phenolyl- and p-cresolyl-cobamides. Neither factor III nor the phenolic cobamides supported Dehalococcoides reductive dechlorination activity suggesting that M. barkeri and the Sporomusa sp. cannot fulfil Dehalococcoides' nutritional requirements. Dehalococcoides dechlorination activity and growth occurred in M. barkeri and Sporomusa sp. co-cultures amended with 10 µM 5′,6′-dimethylbenzimidazole (DMB), indicating that a cobalamin is a preferred corrinoid cofactor of strains BAV1, GT and FL2 when grown with chlorinated ethenes as electron acceptors. Even though the methanogen and acetogen populations tested did not produce cobalamin, the addition of DMB enabled guided biosynthesis and generated a cobalamin that supported Dehalococcoides' activity and growth. Guided cobalamin biosynthesis may offer opportunities to sustain and enhance Dehalococcoides activity in contaminated subsurface environments.
PMCID: PMC3638461  PMID: 23479750
reductive dechlorination; organohalide respiration; vitamin B12; Dehalococcoides
11.  Association of MTHFR C677T polymorphism with schizophrenia and its effect on episodic memory and gray matter density in patients 
Behavioural brain research  2013;243:146-152.
Growing evidence suggests that the methylenetetrahydrofolate reductase (MTHFR) may play a role in the pathogenesis of schizophrenia. Recent studies suggested that the MTHFR 677T, as a risk allele, has an impact on brain activation and memory function in schizophrenia patients. To confirm further the association between this functional polymorphism and schizophrenia, we detected genotypes of MTHFR C677T polymorphism in 1,002 schizophrenic patients and 1,036 controls of Chinese Han population, by using direct DNA sequencing method. To explore further effects of MTHFR C677T polymorphism on memory and brain function in schizophrenia, 33 schizophrenia patients and 29 healthy participants were selected from above samples to be assessed with MRI scanning and episodic memory (EM) examination. The case - control association study results showed that the MTHFR C677T was associated with schizophrenia (χ2 = 14.11, P = 1.74 × 10−4, OR = 0.79; 95% CI = 0.70 – 0.89). We also found that the MTHFR 677T allele had a load-dependent effect on EM in schizophrenic patients, but not in healthy control participants. Further analysis on gray matter density (GMD) revealed significant diagnostic effects in bilateral frontal cortices, bilateral insula, left medial temporal cortex and bilateral occipital cortices, effects of MTHFR genotype in the right insula, right inferior frontal gyrus, right rolandic opercula, right parahippocampal gyrus and right medial temporal pole, and effects of genotype-diagnosis interaction in the right temporal gyrus. Our findings suggested that the MTHFR 677T allele might have effect on risk of schizophrenia, memory impairment and GMD changes in patients.
PMCID: PMC3755007  PMID: 23318463
schizophrenia; methylenetetrahydrofolate reductase (MTHFR); association study; gray matter density (GMD); episodic memory (EM)
12.  Microarray Meta-Analysis of RNA-Binding Protein Functions in Alternative Polyadenylation 
PLoS ONE  2014;9(3):e90774.
Alternative polyadenylation (APA) is a post-transcriptional mechanism to generate diverse mRNA transcripts with different 3′UTRs from the same gene. In this study, we systematically searched for the APA events with differential expression in public mouse microarray data. Hundreds of genes with over-represented differential APA events and the corresponding experiments were identified. We further revealed that global APA differential expression occurred prevalently in tissues such as brain comparing to peripheral tissues, and biological processes such as development, differentiation and immune responses. Interestingly, we also observed widespread differential APA events in RNA-binding protein (RBP) genes such as Rbm3, Eif4e2 and Elavl1. Given the fact that RBPs are considered as the main regulators of differential APA expression, we constructed a co-expression network between APAs and RBPs using the microarray data. Further incorporation of CLIP-seq data of selected RBPs showed that Nova2 represses and Mbnl1 promotes the polyadenylation of closest poly(A) sites respectively. Altogether, our study is the first microarray meta-analysis in a mammal on the regulation of APA by RBPs that integrated massive mRNA expression data under a wide-range of biological conditions. Finally, we present our results as a comprehensive resource in an online website for the research community.
PMCID: PMC3951239  PMID: 24622240
13.  Significance of red cell distribution width measurement for the patients with isolated coronary artery ectasia 
Red cell distribution width (RDW) has been recognized as a novel marker for several cardiovascular diseases. The aim of this study was to evaluate the association between RDW levels and the presence of isolated coronary artery ectasia (CAE).
We studied 414 subjects including 113 patients with isolated CAE (Group A), 144 patients with coronary artery disease (CAD, group B) and 157 angiographically normal controls (group C). Baseline clinical characteristics and laboratory findings including RDW were compared among three groups.
The levels of RDW were significantly higher in group A and B compared with that in group C (12.97 ± 1.4 and 12.88 ± 1.0 vs 12.34 ± 0.9, p = 0.020) while no difference was found between CAE and CAD (p = 0.17). Additionally, the levels of CRP were also higher in patients with CAE and CAD compared with normal controls (0.26 ± 0.14 mg/L, 0.31 ± 0.27 mg/L vs 0.20 ± 0.06 mg/L, p = 0.04). The multivariate analysis indicated that RDW and CRP were the independent variables most strongly associated with the presence of isolated CAE and CAD. There was a positive correlation between levels of RDW and CRP in patients with isolated CAE (γ=0.532, p = 0.001).
Our data suggested that RDW may be a useful marker and independent predictor for the presence of isolated CAE.
PMCID: PMC3975450  PMID: 24606910
Red cell distribution width; Coronary artery ectasia; Coronary artery disease; C-reactive protein
14.  Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor 
Berberine is an isoquinoline alkaloid mainly extracted from Rhizoma Coptidis and has been shown to possess a potent inhibitory activity against bacterial. However, the role of berberine in anti-bacterial action has not been extensively studied.
The animal model was established to investigate the effects of berberine on bacterial and LPS infection. Docking analysis, Molecular dynamics simulations and Real-time RT-PCR analysis was adopted to investigate the molecular mechanism.
Treatment with 40 mg/kg berberine significantly increased the survival rate of mice challenged with Salmonella typhimurium (LT2), but berberine show no effects in bacteriostasis. Further study indicated that treatment with 0.20 g/kg berberine markedly increased the survival rate of mice challenged with 2 EU/ml bacterial endotoxin (LPS) and postpone the death time of the dead mice. Moreover, pretreatment with 0.05 g/kg berberine significantly lower the increasing temperature of rabbits challenged with LPS. The studies of molecular mechanism demonstrated that Berberine was able to bind to the TLR4/MD-2 receptor, and presented higher affinity in comparison with LPS. Furthermore, berberine could significantly suppressed the increasing expression of NF-κB, IL-6, TNFα, and IFNβ in the RAW264.7 challenged with LPS.
Berberine can act as a LPS antagonist and block the LPS/TLR4 signaling from the sourse, resulting in the anti-bacterial action.
PMCID: PMC3946165  PMID: 24602493
15.  Synthesis, identification and in vivo studies of tumor-targeting agent peptide doxorubicin (PDOX) to treat peritoneal carcinomatosis of gastric cancer with similar efficacy but reduced toxicity 
Molecular Cancer  2014;13:44.
This work aimed to synthesize a cathepsin B (CTSB)-cleavable tumor-targeting prodrug peptide doxorubicin (PDOX) and study the in vivo efficacy and toxicities on an animal model of gastric peritoneal carcinomatosis (PC).
PDOX was synthesized using doxorubicin (DOX) attaching to a CTSB-cleavable dipeptide Ac-Phe-Lys and a para-amino-benzyloxycarbonyl (PABC) spacer. PC model was established by injecting VX2 tumor cells into the gastric sub-mucosa of 40 rabbits, which then were randomized into 4 groups: the Control (n = 10) without treatment, the HIPEC (n = 10) receiving cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the PDOX (n = 10) and the DOX (n = 10) receiving systemic chemotherapy with PDOX 50.0 mg/kg or DOX 5.0 mg/kg, respectively, after CRS + HIPEC.
The median overall survivals (OS) were 23.0 d (95% CI: 19.9 d - 26.1 d) in the Control, 41.0 d (36.9 d - 45.1 d) in the HIPEC, 65.0 d (44.1 d - 71.9 d) in the PDOX, and 58.0 d (39.6 d - 54.4 d) in the DOX. Compared with the Control, the OS was extended by 70% in the HIPEC (p < 0.001) and further extended by 40% in the DOX (p = 0.029) and by 58% in the PDOX (p = 0.021), and the PC severity was decreased in the HIPEC and further decreased in the PDOX and DOX. Animals receiving DOX treatment showed hematological toxicities with marked reduction of white blood cells and platelets, as well as cardiac toxicities with significant increases in creatine kinase mb isoenzyme, evident myocardium coagulation necrosis, significant nuclear degeneration, peri-nucleus mitochondria deletion, mitochondria-pyknosis, and abnormal intercalated discs. But these toxicities were not evident in the PDOX.
PDOX is a newly synthesized tumor-targeting prodrug of DOX. Compared with DOX, PDOX has similar efficacy but reduced hematological and cardiac toxicities in treating rabbit model of gastric PC.
PMCID: PMC3984748  PMID: 24588871
Peritoneal carcinomatosis; Gastric cancer; Peptide doxorubicin; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy
16.  Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp 
A new water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR), gas chromatography (GC) and nuclear magnetic resonance (NMR) analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of →4)-α-d-Glcp-(1→4)-α-d-GalpA-(1→4)-α-d-Glcp-(1→4)-β-d-Glcp-(1→ units with poly saccharide side chains composed of →2)-β-d-Fruf-(1→2)-l-sorbose-(1→ attached to the O-6 position of the α-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-γ (IFN-γ), increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity.
PMCID: PMC3975445  PMID: 24663085
structure; antitumor activity; immunomodulatory activity; polysaccharide; Dimocarpus longan pulp
17.  Silencing Alpha-Fetoprotein Inhibits VEGF and MMP-2/9 Production in Human Hepatocellular Carcinoma Cell 
PLoS ONE  2014;9(2):e90660.
Alpha-fetoprotein not only serves as a diagnostic marker for liver cancer, but also posses a variety of biological functions. However, the role of Alpha-fetoprotein on tumor angiogenesis and cell invasion remains incompletely understood. In this study, we aimed to evaluate if Alpha-fetoprotein can regulate the major angiogenic factors and matrix metalloproteinases in human liver cancer cells. Alpha-fetoprotein silencing was achieved by Stealth RNAi. Expression of Alpha-fetoprotein was examined by a full-automatic electrochemistry luminescence immunity analyzer. Expression of VEGF, VEGFR-2, MMP-9, and MMP-2 was examined by Western blot and immunocytochemistry. Apoptosis was detected by TUNEL assay. Angiogenesis was detected by in vitro angiogenesis assay kit. Silencing of Alpha-fetoprotein led to an increased apoptosis, which was associated with a decreased expression of vascular endothelial growth factor, vascular endothelial growth factor receptor 2, matrix metalloproteinases-2/9. These results suggest that Alpha-fetoprotein may play a regulatory role on angiogenesis and cell invasion during liver cancer development.
PMCID: PMC3938808  PMID: 24587407
18.  In Site Bioimaging of Hydrogen Sulfide Uncovers Its Pivotal Role in Regulating Nitric Oxide-Induced Lateral Root Formation 
PLoS ONE  2014;9(2):e90340.
Hydrogen sulfide (H2S) is an important gasotransmitter in mammals. Despite physiological changes induced by exogenous H2S donor NaHS to plants, whether and how H2S works as a true cellular signal in plants need to be examined. A self-developed specific fluorescent probe (WSP-1) was applied to track endogenous H2S in tomato (Solanum lycopersicum) roots in site. Bioimaging combined with pharmacological and biochemical approaches were used to investigate the cross-talk among H2S, nitric oxide (NO), and Ca2+ in regulating lateral root formation. Endogenous H2S accumulation was clearly associated with primordium initiation and lateral root emergence. NO donor SNP stimulated the generation of endogenous H2S and the expression of the gene coding for the enzyme responsible for endogenous H2S synthesis. Scavenging H2S or inhibiting H2S synthesis partially blocked SNP-induced lateral root formation and the expression of lateral root-related genes. The stimulatory effect of SNP on Ca2+ accumulation and CaM1 (calmodulin 1) expression could be abolished by inhibiting H2S synthesis. Ca2+ chelator or Ca2+ channel blocker attenuated NaHS-induced lateral root formation. Our study confirmed the role of H2S as a cellular signal in plants being a mediator between NO and Ca2+ in regulating lateral root formation.
PMCID: PMC3937356  PMID: 24587333
19.  Chemoenzymatic synthesis of mono- and di-fluorinated Thomsen-Friedenreich (T) antigens and their sialylated derivatives 
Organic & biomolecular chemistry  2012;11(5):842-848.
Fluorinated Thomsen-Friedenreich (T) antigens were synthesized efficient from chemically produced fluorinated monosaccharides using a highly efficient one-pot two-enzyme chemoenzymatic approach containing a galactokinase and a D-galactosyl-β1–3-N-acetyl-D-hexosamine phosphorylase. These fluorinated T-antigens were further sialylated to form fluorinated ST-antigens using a one-pot two-enzyme system containing a CMP-sialic acid synthetase and an α2–3-sialyltransferase.
PMCID: PMC3616747  PMID: 23241945
20.  VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma 
Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer.
Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan’s blue lymphangiography. Tumoral lymphatics were delineated with both Evan’s blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing.
Mice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls.
Our data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.
PMCID: PMC3929486  PMID: 24502459
Ovarian carcinoma; VEGF-D; Metastasis; Lymphangiogenesis; Xenograft
21.  Objective assessment of urban built environment related to physical activity — development, reliability and validity of the China Urban Built Environment Scan Tool (CUBEST) 
BMC Public Health  2014;14:109.
Some aspects of the neighborhood built environment may influence residents’ physical activity, which in turn, affects their health. This study aimed to develop an urban built environment evaluation tool and conduct necessary reliability and validity tests.
A 41-item urban built environment scan tool was developed to objectively assess the neighborhood built environment features related to physical activity. Six neighborhoods in Hangzhou were selected from three types of administrative planning units. A pair of auditors independently assessed all of the 205 street segments at the same time. Half of the segments (n = 104) were audited twice by the same auditor after a two-week time interval. Inter-rater reliability was assessed by comparing the audits of paired observers, while intra-rater reliability was evaluated by comparing an auditor’s repeated assessments of the same segments. The construct validity was tested using factor analysis.
The inter-rater reliability for most items was above 0.8. The intra-rater reliability for most items was above 0.4, and was lower than corresponding inter-rater reliability. Six factors were extracted by factor analysis and the factor loading matrix showed good construct validity.
The CUBEST is a reliable and valid instrument that can be used to assess the physical activity-related built environment in Hangzhou, and potentially other cities in China.
PMCID: PMC3916581  PMID: 24495676
Environmental scan; Physical activity; Reliability; Validity
22.  Identification of Differentially Expressed Proteins in Porcine Alveolar Macrophages Infected with Virulent/Attenuated Strains of Porcine Reproductive and Respiratory Syndrome Virus 
PLoS ONE  2014;9(1):e85767.
The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is still a serious threat to the swine industry. However, the pathogenic mechanism of HP-PRRSV remains unclear. We infected host porcine alveolar macrophages (PAMs) with the virulent HuN4 strain and the attenuated HuN4-F112 strain and then utilized fluorescent two-dimensional difference gel electrophoresis (2D-DIGE) to screen for intracellular proteins that were differentially expressed in host cells infected with the two strains. There were 153 proteins with significant different expression (P<0.01) observed, 42 of which were subjected to mass spectrometry, and 24 proteins were identified. PAM cells infected with the virulent strain showed upregulated expression of pyruvate kinase M2 (PKM2), heat shock protein beta-1 (HSPB1), and proteasome subunit alpha type 6 (PSMA6), which were downregulated in cells infected with the attenuated strain. The upregulation of PKM2 provides sufficient energy for viral replication, and the upregulation of HSPB1 inhibits host cell apoptosis and therefore facilitates mass replication of the virulent strain, while the upregulation of PSMA6 facilitates the evasion of immune surveillance by the virus. Studying on those molecules mentioned above may be able to help us to understand some unrevealed details of HP-PRRSV infection, and then help us to decrease its threat to the swine industry in the future.
PMCID: PMC3897507  PMID: 24465692
23.  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
24.  Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury 
Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection.
Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors.
These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.
PMCID: PMC3902418  PMID: 24397824
Colorectal cancer; Liver metastases; Ischemia-reperfusion; TNF-α; Enbrel
25.  A Critical Role for the TLR4/TRIF Pathway in Allogeneic Hematopoietic Cell Rejection by Innate Immune Cells 
Cell transplantation  2012;22(12):10.3727/096368912X658881.
We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMC as organ allografts are rejected mainly via MyD88 signaling. Using T or T/B cell-deficient mice, we found that BMC allorejection occurred early before T cell activation and was T and B cell-independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not MyD88 or TLR3. The restored cytotoxicity in TRIF deficient recipients transferred with wildtype F4/80+ or NK1.1+ cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T and B cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating rejection of allogeneic BMC. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation.
PMCID: PMC3720759  PMID: 23146386
TLR4; TRIF; bone marrow transplantation; innate immunity

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