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1.  4-[(Z)-(2-Fur­yl)(2-naphthyl­amino)methyl­ene)]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one. Corrigendum 
Corrigendum to Acta Cryst. (2009), E65, o1824.
The title of the paper by Li, Li, Li, Zhang & Li [Acta Cryst. (2009), E65, o1824] is corrected.
PMCID: PMC2979883  PMID: 21579582
2.  4-[(Z)-(2-Fur­yl)(2-naphthyl­amino)methyl­ene)]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 
The title compound, C25H19N3O2, crystallizes as discrete mol­ecules which are well ordered through one intra­molecular N—H⋯O hydrogen bond. Structural analysis indicates that the mol­ecules exist as the amine–one form.
PMCID: PMC2977223  PMID: 21583526
3.  The Disordered C-Terminal Domain of Human DNA Glycosylase NEIL1 Contributes to Its Stability via Intramolecular Interactions 
Journal of molecular biology  2013;425(13):2359-2371.
NEIL1 [Nei (endonuclease VIII)-like protein 1], one of the five mammalian DNA glycosylases that excise oxidized DNA base lesions in the human genome to initiate base excision repair, contains an intrinsically disordered C-terminal domain (CTD; ∼100 residues), not conserved in its Escherichia coli prototype Nei. Although dispensable for NEIL1's lesion excision and AP lyase activities, this segment is required for efficient in vivo enzymatic activity and may provide an interaction interface for many of NEIL1's interactions with other base excision repair proteins. Here, we show that the CTD interacts with the folded domain in native NEIL1 containing 389 residues. The CTD is poised for local folding in an ordered structure that is induced in the purified fragment by osmolytes. Furthermore, deletion of the disordered tail lacking both Tyr and Trp residues causes a red shift in NEIL1's intrinsic Trp-specific fluorescence, indicating a more solvent-exposed environment for the Trp residues in the truncated protein, which also exhibits reduced stability compared to the native enzyme. These observations are consistent with stabilization of the native NEIL1 structure via intramolecular, mostly electrostatic, interactions that were disrupted by mutating a positively charged (Lysrich) cluster of residues (amino acids 355–360) near the C-terminus. Small-angle X-ray scattering (SAXS) analysis confirms the flexibility and dynamic nature of NEIL1's CTD, a feature that may be critical to providing specificity for NEIL1's multiple, functional interactions.
PMCID: PMC3779128  PMID: 23542007
DNA repair; intrinsically unstructured region; electrostatic interactions; protein stability; oxidative DNA damage
4.  Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis 
Nature medicine  2011;17(8):952-960.
Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.
PMCID: PMC4089394  PMID: 21804539
5.  Integrative Approach Detected Association between Genetic Variants of microRNA Binding Sites of TLRs Pathway Genes and OSCC Susceptibility in Chinese Han Population 
PLoS ONE  2014;9(7):e101695.
Oral squamous cell carcinoma (OSCC) is a leading malignancy worldwide; the overall 5-year survival rate is approximately 50%. A variety of proteins in Toll-like receptors (TLRs) pathway have been related with the risk of OSCC. However, the influence of genetic variations in TLRs pathway genes on OSCC susceptibility is unclear. Previous studies mainly focused on the coding region of genes, while the UTR region remains unstudied. In the current study, a bioinformatics approach was performed to select candidate single nucleotide polymorphisms (SNPs) on microRNA binding sites of TLRs pathway genes related with OSCC. After screening 90 OSCC related TLRs pathway genes, 16 SNPs were selected for genotyping. We found that rs5030486, the polymorphisms on 3′ UTR of TRAF6, was significantly associated with OSCC risk. AG genotype of TRAF6 was strongly associated with a decreased risk of OSCC (OR = 0.252; 95% CI = 0.106, 0.598; p = 0.001). In addition, AG genotype was also related with a reduced risk of OSCC progression both in univariable analysis (HR = 0.303, 95% CI = 0.092, 0.995) and multivariable analysis (HR = 0.272, 95% CI = 0.082, 0.903). Furthermore, after detecting the mRNA expression level of TRAF6 in 24 OSCC patients, we found that TRAF6 expression level was significantly different between patients carrying different genotypes at locus rs5030486 (p = 0.013), indicating that rs5030486 of TRAF6 might contribute to OSCC risk by altering TRAF6 expression level. In general, these data indicated that SNP rs5030486 could be a potential bio-marker for OSCC risk and our results might provide new insights into the association of polymorphisms within the non-coding area of genes with cancers.
PMCID: PMC4085003  PMID: 24999832
6.  MicroRNA-122 Triggers Mesenchymal-Epithelial Transition and Suppresses Hepatocellular Carcinoma Cell Motility and Invasion by Targeting RhoA 
PLoS ONE  2014;9(7):e101330.
The loss of microRNA-122 (miR-122) expression is strongly associated with increased invasion and metastasis, and poor prognosis of hepatocellular carcinoma (HCC), however, the underlying mechanisms remain poorly understood. In the present study, we observed that miR-122 over-expression in HCC cell lines Sk-hep-1 and Bel-7402 triggered the mesenchymal-epithelial transition (MET), as demonstrated by epithelial-like morphological changes, up-regulated epithelial proteins (E-cadherin, ZO-1, α-catenin, occludin, BVES, and MST4), and down-regulated mesenchymal proteins (vimentin and fibronectin). The over-expression of miRNA-122 also caused cytoskeleton disruption, RhoA/Rock pathway inactivation, enhanced cell adhesion, and suppression of migration and invasion of Sk-hep-1 and Bel-7402 cells, whereas, these effects could be reversed through miR-122 inhibition. Additional studies demonstrated that the inhibition of wild-type RhoA function induced MET and inhibited cell migration and invasion, while RhoA over-expression reversed miR-122-induced MET and inhibition of migration and invasion of HCC cells, suggesting that miR-122 induced MET and suppressed the migration and invasion of HCC cells by targeting RhoA. Moreover, our results demonstrated that HNF4α up-regulated its target gene miR-122 that subsequently induced MET and inhibited cell migration and invasion, whereas miR-122 inhibition reversed these HNF4α-induced phenotypes. These results revealed functional and mechanistic links among the tumor suppressors HNF4α, miR-122, and RhoA in EMT and invasive and metastatic phenotypes of HCC. Taken together, our study provides the first evidence that the HNF4α/miR-122/RhoA axis negatively regulates EMT and the migration and invasion of HCC cells.
PMCID: PMC4081555  PMID: 24992599
7.  Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon 
Recent studies have shown two distinct non-CIMP methylation clusters in colorectal cancer, raising the possibility that DNA methylation, involving non-CIMP genes, may play a role in the conventional adenoma–carcinoma pathway. A total of 135 adenomas (65 left colon and 70 right colon) were profiled for epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip. A principal components analysis was performed to examine the association between variability in DNA methylation and adenoma location. Linear regression and linear mixed effects models were used to identify locus-specific differential DNA methylation in adenomas of right and left colon. A significant association was present between the first principal component and adenoma location (P = 0.007), even after adjustment for subject age and gender (P = 0.009). A total of 168 CpG sites were differentially methylated between right- and left-colon adenomas and these loci demonstrated enrichment of homeobox genes (P = 3.0 × 10−12). None of the 168 probes were associated with CIMP genes. Among CpG loci with the largest difference in methylation between right- and left-colon adenomas, probes associated with PRAC(prostate cancer susceptibility candidate) gene showed hypermethylation in right-colon adenomas whereas those associated with CDX2(caudal type homeobox transcription factor 2) showed hypermethylation in left-colon adenomas. A subgroup of left-colon adenomas enriched for current smokers (OR = 6.1, P = 0.004) exhibited a methylation profile similar to right-colon adenomas. In summary, our results indicate distinct patterns of DNA methylation, independent of CIMP genes, in adenomas of the right and left colon.
PMCID: PMC3880603  PMID: 23868178
colon polyps; colorectal cancer; CpG island methylator phenotype; epigenetics
8.  Comparative Virus Replication and Host Innate Responses in Human Cells Infected with Three Prevalent Clades (2.3.4, 2.3.2, and 7) of Highly Pathogenic Avian Influenza H5N1 Viruses 
Journal of Virology  2014;88(1):725-729.
Highly pathogenic avian influenza H5N1 virus clades 2.3.4, 2.3.2, and 7 are the dominant cocirculating H5N1 viruses in poultry in China. However, humans appear to be clinically susceptible mostly to the 2.3.4 virus clade. Here, we demonstrated that A549 cells and human macrophages infected with clade 2.3.4 viruses produced significantly more viruses than those infected with the other two clades. Likewise, clade 2.3.4-infected macrophages caused the most severe cellular damage and strongest proinflammatory response.
PMCID: PMC3911739  PMID: 24131718
9.  Platinum Electrodeposition on Unsupported Single Wall Carbon Nanotubes and Its Application as Methane Sensing Material 
This paper reports the decoration of single wall carbon nanotubes (SWCNTs) with platinum (Pt) nanoparticles using an electrochemical technique, rotating disk slurry electrode (RoDSE). Pt/SWCNTs were electrochemically characterized by cyclic voltammetry technique (CV) and physically characterized through the use of transmission electron microscopy (TEM), energy dispersive spectroscopy - X-ray florescence (EDS-XRF) and X-ray diffraction (XRD). After characterization it was found that electrodeposited nanoparticles had an average particle size of 4.1 ± 0.8 nm. Pt/SWCNTs were used as sensing material for methane (CH4) detection and showed improved sensing properties in a range of concentration from 50 ppm to 200 ppm parts per million (ppm) at room temperature, when compared to other Pt/CNTs-based sensors. The use of this technique for the preparation of Pt/SWCNTs opens a new possibility in the bulk preparation of samples using an electrochemical method and thus their potential use in a wide variety of applications in chemical sensing, fuel cell and others.
PMCID: PMC4074597  PMID: 24991061
10.  Ophthalmic Delivery of Brinzolamide by Liquid Crystalline Nanoparticles: In Vitro and In Vivo Evaluation 
AAPS PharmSciTech  2013;14(3):1063-1071.
Brinzolamide (BLZ) is a drug used to treat glaucoma; however, its use is restricted due to some unwanted adverse events. The goal of this study was to develop BLZ-loaded liquid crystalline nanoparticles (BLZ LCNPs) and to figure out the possibility of LCNPs as a new therapeutic system for glaucoma. BLZ LCNPs were produced by a modified emulsification method and their physicochemical aspects were estimated. In vitro release study revealed BLZ LCNPs displayed to some extent prolonged drug release behavior in contrast to that of BLZ commercial product (Azopt®). The ex vivo apparent permeability coefficient of BLZ LCNP systems demonstrated a 3.47-fold increase compared with that of Azopt®. The pharmacodynamics was checked over by calculating the percentage fall in intraocular pressure and the pharmacodynamic test showed that BLZ LCNPs had better therapeutic potential than Azopt®. Furthermore, the in vivo ophthalmic irritation was evaluated by Draize test. In conclusion, BLZ LCNPs would be a promising delivery system used for the treatment of glaucoma, with advantages such as lower doses but maintaining the effectiveness, better ocular bioavailability, and patient compliance compared with Azopt®.
PMCID: PMC3755158  PMID: 23813437
brinzolamide; liquid crystalline nanoparticles; ocular bioavailability; ocular irritation; ophthalmic delivery
11.  In Vitro Characterization of Human Adenovirus Type 55 in Comparison with Its Parental Adenoviruses, Types 11 and 14 
PLoS ONE  2014;9(6):e100665.
Human adenovirus type 55 (HAdV-B55) represents a re-emerging human pathogen, and this adenovirus has been reported to cause outbreaks of acute respiratory diseases among military trainees and in school populations around the world. HAdV-B55 has been revealed to have evolved from homologous recombination between human adenovirus type 14 (HAdV-B14) and type 11 (HAdV-B11), but it presents different clinical manifestations from parental virus HAdV-B11. In the present paper, we report the distinct biological features of HAdV-B55 in comparison with the parental viruses HAdV-B11 and HAdV-B14 in cell cultures. The results showed that HAdV-B55 replicated well in various cells, similar to HAdV-B11 and HAdV-B14, but that its processing had a slower and milder cytopathic effect in the early stages of infection. Viral fitness analysis showed that HAdV-B55 exhibited higher levels of replication in respiratory cells than did either of its parents. Cytotoxicity and apoptosis analyses in A549 cells indicated that HAdV-B55 was less cytotoxic than HAdV-B11 and HAdV-B14 were and induced milder apoptosis. Finally, thermal sensitivity analysis revealed that HAdV-B55 exhibited lower thermostability than did either HAdV-B11 or HAdV-B14, which may limit the transmission of HAdV-B55 in humans. Together, the findings described here expand current knowledge about this re-emerging recombinant HAdV, shedding light on the pathogenesis of HAdV-B55.
PMCID: PMC4067339  PMID: 24956280
12.  Epidermal Growth Factor-Like Domain-Containing Protein 7 (EGFL7) Enhances EGF Receptor−AKT Signaling, Epithelial−Mesenchymal Transition, and Metastasis of Gastric Cancer Cells 
PLoS ONE  2014;9(6):e99922.
Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial–mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR−AKT−Snail signaling pathway. Disruption of EGFL7−EGFR−AKT−Snail signaling may a promising therapeutic strategy for gastric cancer.
PMCID: PMC4063792  PMID: 24945379
13.  DDB2 Suppresses Epithelial to Mesenchymal Transition in Colon Cancer 
Cancer research  2013;73(12):3771-3782.
Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial to mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here we show that the xeroderma pigmentosum group E (XPE) gene product DDB2 is down-regulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.
PMCID: PMC3686976  PMID: 23610444
14.  Genetic diversity and differentiation of the rhesus macaque (Macaca mulatta) population in western Sichuan, China, based on the second exon of the major histocompatibility complex class II DQB (MhcMamu-DQB1) alleles 
Rhesus macaques living in western Sichuan, China, have been separated into several isolated populations due to habitat fragmentation. Previous studies based on the neutral or nearly neutral markers (mitochondrial DNA or microsatellites) showed high levels of genetic diversity and moderate genetic differentiation in the Sichuan rhesus macaques. Variation at the major histocompatibility complex (MHC) loci is widely accepted as being maintained by balancing selection, even with a low level of neutral variability in some species. However, in small and isolated or bottlenecked populations, balancing selection may be overwhelmed by genetic drift. To estimate microevolutionary forces acting on the isolated rhesus macaque populations, we examined genetic variation at Mhc-DQB1 loci in 119 wild rhesus macaques from five geographically isolated populations in western Sichuan, China, and compared the levels of MHC variation and differentiation among populations with that previously observed at neutral microsatellite markers.
23 Mamu-DQB1 alleles were identified in 119 rhesus macaques in western Sichuan, China. These macaques exhibited relatively high levels of genetic diversity at Mamu-DQB1. The Hanyuan population presented the highest genetic variation, whereas the Heishui population was the lowest. Analysis of molecular variance (AMOVA) and pairwise FST values showed moderate genetic differentiation occurring among the five populations at the Mhc-DQB1 locus. Non-synonymous substitutions occurred at a higher frequency than synonymous substitutions in the peptide binding region. Levels of MHC variation within rhesus macaque populations are concordant with microsatellite variation. On the phylogenetic tree for the rhesus and crab-eating macaques, extensive allele or allelic lineage sharing is observed betweenthe two species.
Phylogenetic analyses confirm the apparent trans-species model of evolution of the Mhc-DQB1 genes in these macaques. Balancing selection plays an important role in sharing allelic lineages between species, but genetic drift may share balancing selection dominance to maintain MHC diversity. Great divergence at neutral or adaptive markers showed that moderate genetic differentiation had occurred in rhesus macaque populations in western Sichuan, China, due to the habitat fragmentation caused by long-term geographic barriers and human activity. The Heishui population should be paid more attention for its lowest level of genetic diversity and relatively great divergence from others.
PMCID: PMC4070090  PMID: 24930092
Genetic diversity; Genetic differentiation; Macaca mulatta; Major histocompatibility complex; Trans-species evolution
15.  Genetic variations in IL1A and IL1RN are associated with the risk of preeclampsia in Chinese Han population 
Scientific Reports  2014;4:5250.
Preeclampsia (PE) is an excessive systemic inflammation response with dysfunction of endothelial. Our study was to investigate the association between genetic variations in IL-1 and the susceptibility to PE in Chinese Han population. 402 PE patients and 554 normal pregnant women of third trimester were enrolled. The polymorphisms of rs315952 in IL1RN and rs17561 in IL1A were genotyped by TaqMan allelic discrimination real-time PCR. Obviously statistic difference of the genotypic frequencies were found in both of IL1RN rs315952 and IL1A rs17561 between cases and controls (for rs315952, P = 0.001; for rs17561, P = 0.021.). For rs315952, the C allele was associated with development of PE (P = 0.003, OR = 1.319, 95%CI 1.099–1.583). Patients with CC or CT genotype were less likely to develop severe PE than patients carrying TT genotype(P < 0.001, OR = 0.24, 95%CI 0.15–0.40). For rs17561, the C allele was the risk factor for predisposition to PE (P = 0.012, OR = 1.496, 95%CI 1.089–2.055). Our results suggest IL1RN and IL1A may involve in the development of PE in Chinese Han population.
PMCID: PMC4052713  PMID: 24918527
16.  Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma 
PLoS ONE  2014;9(6):e98653.
Transcriptional regulatory network (TRN) is used to study conditional regulatory relationships between transcriptional factors and genes. However few studies have tried to integrate genomic variation information such as copy number variation (CNV) with TRN to find causal disturbances in a network. Intrahepatic cholangiocarcinoma (ICC) is the second most common hepatic carcinoma with high malignancy and poor prognosis. Research about ICC is relatively limited comparing to hepatocellular carcinoma, and there are no approved gene therapeutic targets yet.
We first constructed TRN of ICC (ICC-TRN) using forward-and-reverse combined engineering method, and then integrated copy number variation information with ICC-TRN to select CNV-related modules and constructed CNV-ICC-TRN. We also integrated CNV-ICC-TRN with KEGG signaling pathways to investigate how CNV genes disturb signaling pathways. At last, unsupervised clustering method was applied to classify samples into distinct classes.
We obtained CNV-ICC-TRN containing 33 modules which were enriched in ICC-related signaling pathways. Integrated analysis of the regulatory network and signaling pathways illustrated that CNV might interrupt signaling through locating on either genomic sites of nodes or regulators of nodes in a signaling pathway. In the end, expression profiles of nodes in CNV-ICC-TRN were used to cluster the ICC patients into two robust groups with distinct biological function features.
Our work represents a primary effort to construct TRN in ICC, also a primary effort to try to identify key transcriptional modules based on their involvement of genetic variations shown by gene copy number variations (CNV). This kind of approach may bring the traditional studies of TRN based only on expression data one step further to genetic disturbance. Such kind of approach can easily be extended to other disease samples with appropriate data.
PMCID: PMC4045758  PMID: 24897108
17.  Simultaneous structure-activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate 
Nature chemistry  2013;5(6):510-517.
To fully exploit the inherent and enduring potential of natural products for fundamental cell biology and drug lead discovery, synthetic methods for functionalizing unique sites are highly desirable. Here we describe a strategy for the derivatization of natural products at ‘unfunctionalized’ positions via Rh(II)-catalyzed amination enabling simultaneous structure-activity relationship (SAR) studies and arming (alkynylation) of natural products. Employing Du Bois C–H amination, allylic and benzylic C–H bonds underwent amination and olefins underwent aziridination. With tertiary amine-containing natural products, amidines were produced via C–H amination/oxidation and unusual N-aminations provided hydrazine sulfamate inner salts. The alkynylated derivatives are readied for subsequent conjugation to access cellular probes for mechanism of action studies. Both chemo- and site-selectivity was studied by application to a diverse set of natural products including the marine-derived anticancer diterpene, eupalmerin acetate (EPA). Quantitative proteome profiling with an alkynyl EPA derivative obtained by site-selective, allylic C–H amination led to identification of several protein targets in HL-60 cells, including several known to be associated with cancer proliferation, suggestive of a polypharmacological mode of action for EPA.
PMCID: PMC4041531  PMID: 23695633
18.  Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases 
Pharmacology & therapeutics  2013;138(3):441-451.
Autoimmune connective tissue diseases (ACTDs) are a family of consistent systemic autoimmune inflammatory disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and Sjögren’s syndrome (SS). Toll-like receptors (TLRs) are located on various cellular membranes and sense exogenous and endogenous danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), playing a critical role in innate immune responses. During the past decade, the investigation of TLRs in inflammation autoimmune diseases has been fruitful. In this report, we review the significant biochemical, physiological and pathological studies of the key functions of TLRs in ACTDs. Several proteins in the TLR signaling pathways (e.g., IKK-2 and MyD88) have been identified as potential therapeutic targets for the treatment of ACTDs. Antibodies, oligodeoxyribonucleotides (ODNs) and small molecular inhibitors (SMIs) have been tested to modulate TLR signaling. Some drug-like SMIs of TLR signaling, such as RDP58, ST2825, ML120B and PHA-408, have demonstrated remarkable potential, with promising safety and efficacy profiles, which should warrant further clinical investigation. Nonetheless, one should bear in mind that all TLRs exert both protective and pathogenic functions; the function of TLR4 in inflammatory bowel disease represents such an example. Therefore, an important aspect of TLR modulator development involves the identification of a balance between the suppression of disease-inducing inflammation, while retaining the beneficiary host immune response.
PMCID: PMC3686650  PMID: 23531543
Toll-like receptor; autoimmune diseases; inflammation; small molecule modulator; drug discovery
20.  Identification of Marine Neuroactive Molecules in Behaviour-Based Screens in the Larval Zebrafish 
Marine Drugs  2014;12(6):3307-3322.
High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1–36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37–42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.
PMCID: PMC4071578  PMID: 24886868
behavior-based screen; zebrafish; PTZ; c-fos
21.  In Vivo Kinematics of the Knee during Weight Bearing in High Flexion 
Journal of biomechanics  2013;46(9):1576-1582.
Achieving high flexion is an objective of contemporary total knee arthoplasty, however little is known on the knee biomechanics at high flexion under weight-bearing conditions. This study is to investigate the 6DOF kinematics and tibiofemoral cartilage contact biomechanics of the knee during weight-bearing flexion from full extension to maximal flexion. Eight knees from seven healthy subjects with no history of injuries or chronic pain were recruited. The knees were MRI scanned to create 3D models of the tibia and femur, including their articular cartilage surfaces. The subjects were then imaged using a dual fluoroscopic image system while performing a weight-bearing quasi-static single-legged lunge from full extension to maximal flexion. The 6DOF kinematics and the articular cartilage contact locations were measured along the flexion path of the knee. The result indicated that the internal tibial rotation increased sharply at low flexion angles (full extension to 30°), maintained a small variation in the middle range of flexion (30° to 120°), and then sharply increased again at high flexion angles (120° to maximal flexion). The contact point moved similarly in the medial and lateral compartments before 120° of flexion, but less on the medial compartment at high flexion angles. The results indicated that the knee motion couldn’t be described using one character in the entire range of flexion, especially in high flexion. The knee kinematic data in the entire range of flexion of the knee could be instrumental for designing new knee prostheses to achieve physical high flexion and improving rehabilitation protocols after knee injuries.
PMCID: PMC3660465  PMID: 23591448
In vivo knee kinematics; Cartilage contact; High flexion
22.  (3Z)-3-[(Z)-2-(2-Oxoindolin-3-yl­idene)hydrazin-1-yl­idene]indolin-2-one 0.17-hydrate 
In the title compound, C16H10N4O2·0.17H2O, prepared by the one-step condensation reaction of isatin with hydrazine hydrate under microwave irradiation, the complete organic mol­ecule is generated by crystallographic inversion symmetry and therefore exists in an S-trans conformation. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds, generating a three-dimensional framework with [001] channels, which are occupied by the disordered water mol­ecules.
PMCID: PMC4051016  PMID: 24940290
23.  Regulation of the cholesterol biosynthetic pathway and its integration with fatty acid biosynthesis in the oleaginous microalga Nannochloropsis oceanica 
Sterols are vital structural and regulatory components in eukaryotic cells; however, their biosynthetic pathways and functional roles in microalgae remain poorly understood.
In the oleaginous microalga Nannochloropsis oceanica, the sterol biosynthetic pathway produces phytosterols as minor products and cholesterol as the major product. The evidence together with their deduced biosynthetic pathways suggests that N. oceanica exhibits features of both higher plants and mammals. Temporal tracking of sterol profiles and sterol-biosynthetic transcripts in response to changes in light intensity and nitrogen supply reveal that sterols play roles in cell proliferation, chloroplast differentiation, and photosynthesis. Furthermore, the dynamics of fatty acid (FA) and FA-biosynthetic transcripts upon chemical inhibitor-induced sterol depletion reveal possible co-regulation of sterol production and FA synthesis, in that the squalene epoxidase inhibitor terbinafine reduces sterol content yet significantly elevates free FA production. Thus, a feedback regulation of sterol and FA homeostasis is proposed, with the 1-deoxy-D-xylulose 5-phosphate synthase (DXS, the committed enzyme in isoprenoid and sterol biosynthesis) gene potentially subject to feedback regulation by sterols.
These findings reveal features of sterol function and biosynthesis in microalgae and suggest new genetic engineering or chemical biology approaches for enhanced oil production in microalgae.
PMCID: PMC4052811  PMID: 24920959
Cholesterol biosynthetic pathway; Fatty acid biosynthesis; Feedback regulation; Nannochloropsis
24.  Differential expression patterns and clinical significance of estrogen receptor-α and β in papillary thyroid carcinoma 
BMC Cancer  2014;14:383.
The incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.
Immunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n = 89) and nodular thyroid goiter (NTG; n = 30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.
The positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18–45 years old; n = 50) than age-matched female NTG patients (n = 30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n = 39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.
The differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.
PMCID: PMC4049482  PMID: 24884830
ERα; ERβ1; Papillary thyroid cancer; Ki-67; Mutant P53; VEGF
25.  The effect of cigarette prices on brand-switching in China: a longitudinal analysis of data from the ITC China Survey 
Tobacco control  2013;23(0 1):i54-i60.
Recent studies have found that Chinese smokers are relatively unresponsive to cigarette prices. As the Chinese government contemplates higher tobacco taxes, it is important to understand the reasons for this low response. One possible explanation is that smokers buffer themselves from rising cigarette prices by switching to cheaper cigarette brands.
This study examines how cigarette prices influence consumers’ choices of cigarette brands in China.
This study uses panel data from the first three waves of the International Tobacco Control China Survey, drawn from six large cities in China and collected between 2006 and 2009. The study sample includes 3477 smokers who are present in at least two waves (8552 person-years). Cigarette brands are sorted by price into four tiers, using excise tax categories to determine the cut-off for each tier. The analysis relies on a conditional logit model to identify the relationship between price and brand choice.
Overall, 38% of smokers switched price tiers from one wave to the next. A ¥1 change in the price of cigarettes alters the tier choice of 4–7% of smokers. Restricting the sample to those who chose each given tier at baseline, a ¥1 increase in price in a given tier would decrease the share choosing that tier by 4% for Tier 1 and 1–2% for Tiers 2 and 3.
China's large price spread across cigarette brands appears to alter the brand selection of some consumers, especially smokers of cheaper brands. Tobacco pricing and tax policy can influence consumers’ incentives to switch brands. In particular, whereas ad valorem taxes in a tiered pricing system like China's encourage trading down, specific excise taxes discourage the practice.
PMCID: PMC4035484  PMID: 23697645

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