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1.  Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer 
AIM: To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC).
METHODS: Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated.
RESULTS: The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P < 0.01), and the VEGF level was significantly correlated with primary tumor size, lymph node metastasis, histopathologic type, and clinical stage (P < 0.01). Of 83 evaluable cases, VEGF level was significantly decreased after radiotherapy in 32 patients in the drug group (P < 0.05), with an effective rate of 71.88%. The incidence of dizziness and/or burnout in the drug group and non-drug group was 62.50% and 15.69%, respectively (P = 0.000), and the incidence of somnolence was 12.50% and 0%, respectively (P = 0.019). No significant differences were observed.
CONCLUSION: Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients.
doi:10.3748/wjg.v20.i17.5098
PMCID: PMC4009547  PMID: 24803825
Thalidomide; Radiotherapy; Esophageal cancer; Vascular endothelial growth factor
2.  Emerging role of Interleukin-22 in autoimmune diseases 
Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren’s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
doi:10.1016/j.cytogfr.2012.07.002
PMCID: PMC4003867  PMID: 22906768
IL-22; Th17; Th22; autoimmune; therapeutic
3.  Two cases of multiple ossifying fibromas in the jaws 
Diagnostic Pathology  2014;9:75.
Background
The clinicopathologic characteristics of multiple ossifying fibroma (OF) are unclear due to the condition’s rarity, making diagnosis challenging. Sporadic multiple OFs must be distinguished from hyperparathyroidism-jaw tumour syndrome (HPT-JT) related OF and other fibro-osseous lesions.
Methods
Multiple OF cases were identified from ossifying fibroma cases. Clinical data including age, sex, anatomic site, radiographic features, clinical impression, treatment and available follow-up data as well as serum calcium, phosphorus, and parathyroid hormone (PTH) were recorded. GNAS and HRPT2 genetic mutations were examined in the two present cases. Case reports of sporadic multiple ossifying fibroma and HPT-JT-related OF were also reviewed.
Results
The two present cases were confirmed as sporadic multiple OF, with no genetic GNAS and HRPT2 mutations found. The incidence of sporadic multiple ossifying fibroma was 2.0% (2/102). The total 18 sporadic multiform OF cases were characterized as followed: 13 (72.2%) female; 5 (27.8%) male; mean age 28.6 years; 2/16 (11.1%) cases only in the mandible; 4/18 (22.2%) cases only in the maxilla; and 12/18 (66.7%) cases in both the maxilla and mandible. Radiographically, the lesions were radiolucent in 5/18 (27.8%) cases and mixed density in 13/18 (72.2%) cases. Along with 24 cases of HPT-JT related OF were reviewed, sixteen (66.7%) patients were diagnosed with a single lesion, and 8 patients (33.3%) were diagnosed with multiple jaw lesions.
Conclusions
Sporadic multiple OFs are very rare, but must be distinguished from HPT-JT related OF. We strongly recommend that patients diagnosed with multiple ossifying fibromas receive serum PTH testing and mutation screening of HRPT2.
Virtual slides
http://www.diagnosticpathology.diagnomx.eu/vs/1194507146115753
doi:10.1186/1746-1596-9-75
PMCID: PMC3974450  PMID: 24678936
Multiple ossifying fibroma; HPT-JT; Fibrous dysplasia; GNAS gene; HRPT2 gene; Osseous dysplasia
4.  Discrepancy between the effects of morronside on apoptosis in human embryonic lung fibroblast cells and lung cancer A549 cells 
Oncology Letters  2014;7(4):927-932.
Morroniside is a water-soluble compound extracted from the fruit of Cornus officinalis and is used to protect lung activity against aging. In the present study, the manner in which morroniside regulates normal lung and cancer cells was examined. The human embryonic lung fibroblast (HELF) cell line and lung cancer A549 cell line, and their responses to morroniside treatment, were examined. Results showed that morroniside reverses the apoptotic effect of H2O2 on HELF cell growth, protecting cell proliferation and normal cell morphology and inhibiting apoptosis. However, these effects were not present in A549 cells. Western blotting showed that morroniside also markedly downregulated retinoblastoma protein in HELF cells. These results suggest that morroniside treatment exhibits different effects on apoptosis in HELF and A549 cells, making it a viable compound for decreasing the side effects of anticancer medicines in normal cells.
doi:10.3892/ol.2014.1850
PMCID: PMC3961276  PMID: 24944645
human embryonic lung fibroblasts cells; apoptosis; morroniside; retinoblastoma protein
5.  Identification of Human Disease Genes from Interactome Network Using Graphlet Interaction 
PLoS ONE  2014;9(1):e86142.
Identifying genes related to human diseases, such as cancer and cardiovascular disease, etc., is an important task in biomedical research because of its applications in disease diagnosis and treatment. Interactome networks, especially protein-protein interaction networks, had been used to disease genes identification based on the hypothesis that strong candidate genes tend to closely relate to each other in some kinds of measure on the network. We proposed a new measure to analyze the relationship between network nodes which was called graphlet interaction. The graphlet interaction contained 28 different isomers. The results showed that the numbers of the graphlet interaction isomers between disease genes in interactome networks were significantly larger than random picked genes, while graphlet signatures were not. Then, we designed a new type of score, based on the network properties, to identify disease genes using graphlet interaction. The genes with higher scores were more likely to be disease genes, and all candidate genes were ranked according to their scores. Then the approach was evaluated by leave-one-out cross-validation. The precision of the current approach achieved 90% at about 10% recall, which was apparently higher than the previous three predominant algorithms, random walk, Endeavour and neighborhood based method. Finally, the approach was applied to predict new disease genes related to 4 common diseases, most of which were identified by other independent experimental researches. In conclusion, we demonstrate that the graphlet interaction is an effective tool to analyze the network properties of disease genes, and the scores calculated by graphlet interaction is more precise in identifying disease genes.
doi:10.1371/journal.pone.0086142
PMCID: PMC3899204  PMID: 24465923
6.  Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs 
Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1−/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5x in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments were significantly increased. Additionally, new PG synthesis was reduced 2-3x in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1−/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.
doi:10.1016/j.mad.2012.11.002
PMCID: PMC3558562  PMID: 23262094
Intervertebral disc; aging; DNA damage; genotoxic stress; matrix proteoglycan
7.  Baseline Prognostic Factors and Statistic Model to Predict Early Virological Response in Telbivudine-Treated Patients With Chronic Hepatitis B 
Hepatitis Monthly  2013;13(12):e15573.
Background:
Hepatitis B virus (HBV) infection is still a worldwide disease, which may cause liver cirrhosis or even hepatocellular carcinoma. Telbivudine is a potent nucleoside analogue used in the treatment of chronic hepatitis B (CHB); however, drug resistance has remained a challenge. As early virological response can predict long-term efficacy of nucleotide analogue treatment, numerous studies have been conducted in this area.
Objectives:
The aim of this study was to establish baseline prognostic factors and a statistical model to predict early virological response in telbivudine-treated CHB patients.
Patients and Methods:
One hundred and eight CHB patients without any experience of nucleotide analogue therapy were assigned to receive telbivudine (600 mg, once daily) for at least 24 weeks, and then were followed up every two weeks. Cox proportional hazard regression model analyses were employed to evaluate baseline variables, and further developing a statistical model to predict early virological response.
Results:
Negative family history of HBV infection (P = 0.000235), baseline higher serum TBIL (P = 0.038714) and AST (P = 0.020684) concentrations, and lower level of HBV-DNA (P = 0.0034784) were identified to be associated with higher possibility of early virological response. A model was established based on these variables to calculate the risk scores (R) for CHB patients. R > -0.38 suggested early virological response to telbivudine. The model was validated among an independent set of 20 patients.
Conclusions:
Family history as well as baseline bilirubin, AST and HBV DNA levels can predict early virological response. The model provides a better tool for response prediction based on the four prognostic factors.
doi:10.5812/hepatmon.15573
PMCID: PMC3877653  PMID: 24403918
Hepatitis B, Chronic; Telbivudine; Proportional Hazards Models; Virology
8.  Randomized Clinical Trial: The Clinical Effects of Herb-Partitioned Moxibustion in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome 
Objective. To explore the efficacy of Herb-partitioned moxibustion in treating IBS-D patients. Method. 210 IBS-D patients were randomly assigned on a 3 : 3 : 2 basis to group HM, group FM, or group PB for 4-week treatment. The change of GSRS total score at weeks 4 and 8, the changes of GSRS specific scores, and adverse events were evaluated. Results. Patients in group HM and group FM had lower GSRS total score at week 4 (1.98 ± 0.303, 2.93 ± 0.302 versus 3.73 ± 0.449) and at week 8 (2.75 ± 0.306, 3.56 ± 0.329 versus 4.39 ± 2.48) as compared with patients' score in group PB. However, there was no significant difference of GSRS total score between group HM and group FM. The effect of HM was significantly greater than that of orally taking PB in ameliorating the symptoms of rugitus (0.38 versus 0.59, P < 0.05), abdominal pain (0.28 versus 0.57, P < 0.01), abdominal distension (0.4 versus 0.7, P < 0.01), and increased passage of stools (0.06 versus 0.25, P < 0.01) at the end of treatment period. In the follow-up period, patients' therapeutic effect in group HM remained greater than that in group FM (in abdominal pain, abdominal distension, and increased passage of stools) and that in group PB (in loose stools). Conclusions. HM appears to be a promising, efficacious, and well-tolerated treatment for patients with IBS-D.
doi:10.1155/2013/605460
PMCID: PMC3880695  PMID: 24454500
9.  Autophagy contributes to apoptosis in A20 and EL4 lymphoma cells treated with fluvastatin 
Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. However, the relationship between apoptosis and autophagy in lymphoma cells exposed to statins remains unclear. The objective of this study was to elucidate the potential involvement of autophagy in fluvastatin-induced cell death of lymphoma cells. We found that fluvastatin treatment enhanced the activation of pro-apoptotic members such as caspase-3 and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells. The process was accompanied by increases in numbers of annexin V alone or annexin V/PI double positive cells. Furthermore, both autophagosomes and increases in levels of LC3-II were also observed in fluvastatin-treated lymphoma cells. However, apoptosis in fluvastatin-treated lymphoma cells could be blocked by the addition of 3-methyladenine (3-MA), the specific inhibitor of autophagy. Fluvastatin-induced activation of caspase-3, DNA fragmentation, and activation of LC3-II were blocked by metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggest that autophagy contributes to fluvastatin-induced apoptosis in lymphoma cells, and that these regulating processes require inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.
doi:10.1186/1475-2867-13-111
PMCID: PMC3832223  PMID: 24209962
Fluvastatin; Lymphoma cells; Apoptosis; Autophagy; Mevalonate pathway
10.  Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy 
Arthritis Research & Therapy  2013;15(5):R146.
Introduction
Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy.
Methods
A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA).
Results
A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation.
Conclusions
Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.
doi:10.1186/ar4329
PMCID: PMC3978604  PMID: 24286216
11.  ISSLS PRIZE WINNER: INHIBITION OF NF-κB ACTIVITY AMELIORATES AGE-ASSOCIATED DISC DEGENERATION IN A MOUSE MODEL OF ACCELERATED AGING 
Spine  2012;37(21):1819-1825.
Study Design
NF-κB activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes.
Objective
To study the mediatory role of NF-κB signaling pathway in age-dependent intervertebral disc degeneration.
Summary of Background Data
Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-κB is a family of transcription factors which play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-κB activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-κB inhibition on IDD using a DNA repair-deficient mouse model of accelerated aging (Ercc1-/Δ mice) previously been reported to exhibit age-related IDD.
Methods
Systemic inhibition of NF-κB activation was achieved either genetically by deletion of one allele of the NF-κB subunit p65 (Ercc1-/Δp65+/- mice) or pharmacologically by chronic intra-peritoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-κB, IκB Inducible Kinase (IKK), in Ercc1-/Δ mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice and untreated controls were assessed.
Results
Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-κB activity were observed in discs of progeroid Ercc1-/Δ mice and naturally aged wild-type compared to young WT mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1-/Δ mice increased disc proteoglycan synthesis and ameriolated loss disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1-/Δp65+/- mice.
Conclusion
These findings demonstrate that the IKK/NF-κB signaling pathway is a key mediator of age-dependent IDD and represents a therapeutic target for mitigating disc degenerative diseases associated with aging.
doi:10.1097/BRS.0b013e31824ee8f7
PMCID: PMC3395770  PMID: 22343279
NF-kB;aging; proteoglycan; disc degeneration; DNA damage repair; ERCC1-deficient mice
12.  Association of FAS gene polymorphisms with systemic lupus erythematosus: A case-control study and meta-analysis 
The association of functional polymorphisms in the promoter of the apoptosis gene FAS with systemic lupus erythematosus (SLE) susceptibility has been a controversial subject. We conducted a case-control study to investigate this association in a Chinese population and performed a meta-analysis in different populations. The single nucleotide polymorphisms (SNPs) rs2234767 (−1377G>A) and rs1800682 (−670A>G) were genotyped by TaqMan allelic discrimination assays in 552 Chinese SLE patients and 718 healthy controls. In our case-control study, we observed allelic association between the promoter SNP rs2234767 [P=0.033, odds ratio (OR)=0.836, 95% confidence interval (CI), 0.709–0.986] and SLE but not the SNP rs1800682. Haplotype analysis revealed that one haplotype of GA was significantly associated with the disease (P=0.039, OR=1.184, 95% CI, 1.009–1.391). In the meta-analysis available studies, including our data, were combined using the STATA software package v.7.0. The meta-analysis revealed a significant association between FAS polymorphisms and SLE (rs2234767 A vs. G allele; P=0.004, OR=0.819, 95% CI, 0.715–0.938, rs1800682 G vs. A allele: P=0.034, OR=0.791, 95% CI, 0.637–0.983). In conclusion, FAS gene polymorphisms may contribute to SLE susceptibility in the Chinese population, and the meta-analysis shows that FAS polymorphisms may be associated with SLE susceptibility in different populations.
doi:10.3892/etm.2012.625
PMCID: PMC3503889  PMID: 23181125
systemic lupus erythematosus; FAS; single-nucleotide polymorphisms; meta-analysis
13.  Production of ACAT1 56-kDa isoform in human cells via trans-splicing involving the ampicillin resistance gene 
Cell Research  2013;23(8):1007-1024.
Trans-splicing, a process involving the cleavage and joining of two separate transcripts, can expand the transcriptome and proteome in eukaryotes. Chimeric RNAs generated by trans-splicing are increasingly described in literatures. The widespread presence of antibiotic resistance genes in natural environments and human intestines is becoming an important challenge for public health. Certain antibiotic resistance genes, such as ampicillin resistance gene (Ampr), are frequently used in recombinant plasmids. Until now, trans-splicing involving recombinant plasmid-derived exogenous transcripts and endogenous cellular RNAs has not been reported. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key enzyme involved in cellular cholesterol homeostasis. The 4.3-kb human ACAT1 chimeric mRNA can produce 50-kDa and 56-kDa isoforms with different enzymatic activities. Here, we show that human ACAT1 56-kDa isoform is produced from an mRNA species generated through the trans-splicing of an exogenous transcript encoded by the antisense strand of Ampr (asAmp) present in common Ampr-plasmids and the 4.3-kb endogenous ACAT1 chimeric mRNA, which is presumably processed through a prior event of interchromosomal trans-splicing. Strikingly, DNA fragments containing the asAmp with an upstream recombined cryptic promoter and the corresponding exogenous asAmp transcripts have been detected in human cells. Our findings shed lights on the mechanism of human ACAT1 56-kDa isoform production, reveal an exogenous-endogenous trans-splicing system, in which recombinant plasmid-derived exogenous transcripts are linked with endogenous cellular RNAs in human cells, and suggest that exogenous DNA might affect human gene expression at both DNA and RNA levels.
doi:10.1038/cr.2013.86
PMCID: PMC3731566  PMID: 23835473
trans-splicing; chimeric RNA; ampicillin resistance gene; recombinant plasmid; ACAT1
14.  On Weak Exponential Expansiveness of Evolution Families in Banach Spaces 
The Scientific World Journal  2013;2013:284630.
The aim of this paper is to give several characterizations for the property of weak exponential expansiveness for evolution families in Banach spaces. Variants for weak exponential expansiveness of some well-known results in stability theory (Datko (1973), Rolewicz (1986), Ichikawa (1984), and Megan et al. (2003)) are obtained.
doi:10.1155/2013/284630
PMCID: PMC3745963  PMID: 23983627
15.  Association of c-Jun Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Chinese Population 
DNA and Cell Biology  2012;31(7):1274-1278.
C-Jun has been proved as playing an important role in the pathogenesis of tumors, as a main component of Activator protein 1 and c-Jun gene polymorphisms are associated with colorectal cancer. However, the relationship between the c-Jun gene polymorphism and the susceptibility to systemic lupus erythematosus (SLE) has not been known. Our purpose is to evaluate whether the c-Jun gene polymorphism (SNP rs3748814) is associated with susceptibility to SLE in a Chinese population. In this study, we enrolled 502 SLE patients and 652 healthy controls. The c-Jun polymorphism (rs3748814) was specified from genomic DNA using the TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of the A/G genotype in SLE patients was lower than in healthy controls, whereas the frequency of the G/G genotype was significantly higher in SLE patients than in healthy controls (A/G vs. G/G p=8.670e-08, odds ratio [OR]=0.290, 95% confidence interval [CI]=0.184–0.456). In addition, the frequency of allele A in the patients group was significantly lower than in the control group (A vs. G p=5.221e-09, OR=0.308, 95% CI=0.212–0.466). The distribution of genotype and allele frequency in SLE patients with lupus nephritis (LN) compared with SLE patients without LN was not statistically significant (A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785; A vs. G p=0.748, OR=1.152, 95% CI=0.486–2.734; A/A+A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785). Furthermore, we did not find any significant association between other clinical features and genotypes. Our findings suggest that the c-Jun polymorphism (rs3748814) may be significantly associated with the susceptibility to SLE in a Chinese population.
doi:10.1089/dna.2011.1536
PMCID: PMC3391490  PMID: 22489574
16.  TRIF and IRF-3 Binding to the TNF Promoter Results in Macrophage TNF Dysregulation and Steatosis Induced by Chronic Ethanol1 
Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF-α production by macrophages and Kupffer cells and signaling via the p55 TNF receptor have been shown to be critical for these effects of chronic EtOH; however, the molecular mechanisms leading to augmented TNF-α production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF-α transcription, which is independent of NF-κB. Using reporter assays and chromatin immunoprecipitation we found that this increased transcription is due to increased IRF-3 binding to and transactivation of the TNF promoter. As IRF-3 is downstream from the TLR4 adaptor TIR-domain-containing adapter-inducing IFN-β (Trif), we demonstrate that macrophages from Trif−/− mice are resistant to this dysregulation of TNF-α transcription by EtOH in vitro as well as EtOH-induced steatosis and TNF dysregulation in vivo. These data demonstrate that the Trif/IRF-3 pathway is a target to ameliorate liver dysfunction associated with chronic EtOH.
PMCID: PMC3690475  PMID: 18713975
17.  8β-Eth­oxy­eremophil-3,7(11)-diene-8α,12;6α,15-diolide 
The title compound, C17H20O5, an eremophilane sesquiternoid, was isolated from the roots of Ligularia lapathifolia. The mol­ecule contains four fused rings of which the six-membered ring A adopts a half-chair conformation, the six-membered ring B adopts a chair conformation, the five-membered ring C is almost planar (r.m.s. deviation = 0.015 Å) and the five-membered ring D adopts an envelope conformation with the quaternary C atom as the flap. The methyl and the eth­oxy groups adopt a syn conformation and the A/B ring junction is cis-fused. No directional inter­molecular inter­actions could be identified in the crystal.
doi:10.1107/S1600536813015729
PMCID: PMC3770365  PMID: 24046650
18.  Exploring the Ligand-Protein Networks in Traditional Chinese Medicine: Current Databases, Methods, and Applications 
The traditional Chinese medicine (TCM), which has thousands of years of clinical application among China and other Asian countries, is the pioneer of the “multicomponent-multitarget” and network pharmacology. Although there is no doubt of the efficacy, it is difficult to elucidate convincing underlying mechanism of TCM due to its complex composition and unclear pharmacology. The use of ligand-protein networks has been gaining significant value in the history of drug discovery while its application in TCM is still in its early stage. This paper firstly surveys TCM databases for virtual screening that have been greatly expanded in size and data diversity in recent years. On that basis, different screening methods and strategies for identifying active ingredients and targets of TCM are outlined based on the amount of network information available, both on sides of ligand bioactivity and the protein structures. Furthermore, applications of successful in silico target identification attempts are discussed in detail along with experiments in exploring the ligand-protein networks of TCM. Finally, it will be concluded that the prospective application of ligand-protein networks can be used not only to predict protein targets of a small molecule, but also to explore the mode of action of TCM.
doi:10.1155/2013/806072
PMCID: PMC3684027  PMID: 23818932
19.  Antitumor activity of bacterial exopolysaccharides from the endophyte Bacillus amyloliquefaciens sp. isolated from Ophiopogon japonicus 
Oncology Letters  2013;5(6):1787-1792.
The endophytic bacterium, MD-b1, was isolated from the medicinal plant Ophiopogon japonicas and identified as the Bacillus amyloliquefaciens sp. with 99% similarity based on the partial sequence analysis of 16S rDNA. Exopolysaccharides were extracted from the endophyte for the evaluation of its antitumor activity against gastric carcinoma cell lines (MC-4 and SGC-7901). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and microscopy were performed to estimate the cell viability and morphological changes of the MC-4 and SGC-7901 cells following treatment with the exopolysaccharides at 14, 22 and 30 μg/μl. The results revealed that the exopolysaccharides displayed concentration-dependent inhibitory effects against the MC-4 and SGC-7901 cells, with an IC50 of 19.7 and 26.8 μg/μl, respectively. The exopolysaccharides also induced morphological abnormalities in the cells. These effects indicated the the exopolysaccharides had an antitumoral mechanism of action associated with the mitochondrial dysfunction of the treated cells. This is the first study to investigate the endophytic microorganism isolated from O. japonicas and also the first discovery of such antitumoral exopolysaccharides derived from the genus Bacillus. This provides a promising and reproducible natural product source with high therapeutic value for anticancer treatment, thereby facilitating the development of new anticancer agents.
doi:10.3892/ol.2013.1284
PMCID: PMC3700801  PMID: 23833642
Ophiopogon japonicas; Bacillus amyloliquefaciens; exopolysaccharides; endophytic bacteria; antitumor
20.  Improvement in visual function and quality of life following a blindness prevention surgery program in a rural area of Eastern China 
The aim of this study was to assess the changes in visual function (VF) and quality of life (QOL) among patients following blindness prevention surgery in a rural area of Eastern China. The prospective study selected cataract patients via mobile eye screening camps. VF and QOL questionnaires originally developed by Fletcher et al were completed prior to and 6 months after surgery. Small-incision cataract surgery (SICS) with posterior chamber intraocular lens (IOL) implantation was performed on patients by a blindness prevention surgery group. The VF and QOL scores of 178 cataract patients preoperatively were 48.58±31.18 and 65.97±26.77, respectively. The scores decreased in proportion to decreasing vision status. The VF and QOL scale scores were significantly correlated with the vision grade of the patient (rVF=−17.2093, t=−10.87, P<0.001, rQOL=−13.1399, t=−8.87, P<0.001) and age (rVF=−0.6505, t=−3.87, P<0.001, rQOL=− 0.3309, t=−2.10, P=0.037). A total of 131 patients responded to the second survey, VF and QOL scores increased significantly over a six-month postoperative period (VF=83.21±16.40, P<0.001; QOL=86.53±16.33, P<0.001). The VF scale scores were correlated with the grade of vision and residence area, the QOL scale scores were correlated with the grade of vision and gender. The VF and QOL of patients were significantly improved by performing SICS with posterior chamber IOL implantation collectively in a short period in rural areas of Eastern China. It is important to follow-up cataract patients postoperatively as untreated complications of the surgery may affect the stability of VF and QOL postoperatively.
doi:10.3892/etm.2013.1037
PMCID: PMC3702720  PMID: 23837062
prevent blindness; quality of life; visual function; cataract; surgery
21.  Cortactin is a sensitive biomarker relative to the poor prognosis of human hepatocellular carcinoma 
Background
Cortactin is an important regulator involved in invasion and migration of hepatocellular carcinoma (HCC). The aim of this study was to elucidate the forecasting role of cortactin in resectable HCCs.
Methods
We compared the invasiveness and motility among liver epithelial cell line and HCC cell lines by using Transwell assay and wound healing assay. We further investigated the CTTN mRNA expression by real-time PCR. Next, 91 HCC and 20 normal liver tissue samples were detected by IHC and real-time PCR. Finally, we analyzed the clinicopathologic features and survival time of the HCC cases.
Results
We identified that HepG2, LM3, and SK-Hep-1 had more invasiveness and motility (P <0.05). Compared with liver epithelial cell line, CTTN expression was higher in LM3, HepG2, and MHCC97-L (P <0.01) and lower in SK-Hep-1 (P <0.05). IHC examination showed cortactin expression was closely relative to TNM stage (AJCC/UICC), cancer embolus, and metastasis (P <0.01). Cortactin overexpression indicated a longer survival time of 52 ± 8.62 months and low expression of a shorter survival time of 20 ± 4.95 months (P <0.01). Cortactin examination has more predictive power in patients with Child-Pugh grade A and BCLC stage 0-B.
Conclusions
Overexpression of cortactin is closely associated with poor human HCCs prognosis that caused by cancer embolus and metastasis. Cortactin and CTTN should be used for differentiating varieties of survival for patients after HCC resection.
doi:10.1186/1477-7819-11-74
PMCID: PMC3620941  PMID: 23518204
Hepatocellular carcinoma; Cortactin; Neoplasm invasiveness; Prognosis
22.  A Novel Moderate Constitutive Promoter Derived from Poplar (Populus tomentosa Carrière) 
A novel sequence that functions as a promoter element for moderate constitutive expression of transgenes, designated as the PtMCP promoter, was isolated from the woody perennial Populus tomentosa. The PtMCP promoter was fused to the GUS reporter gene to characterize its expression pattern in different species. In stable Arabidopsis transformants, transcripts of the GUS reporter gene could be detected by RT-PCR in the root, stem, leaf, flower and silique. Further histochemical and fluorometric GUS activity assays demonstrated that the promoter could direct transgene expression in all tissues and organs, including roots, stems, rosette leaves, cauline leaves and flowers of seedlings and maturing plants. Its constitutive expression pattern was similar to that of the CaMV35S promoter, but the level of GUS activity was significantly lower than in CaMV35S promoter::GUS plants. We also characterized the promoter through transient expression in transgenic tobacco and observed similar expression patterns. Histochemical GUS staining and quantitative analysis detected GUS activity in all tissues and organs of tobacco, including roots, stems, leaves, flower buds and flowers, but GUS activity in PtMCP promoter::GUS plants was significantly lower than in CaMV35S promoter::GUS plants. Our results suggested that the PtMCP promoter from poplar is a constitutive promoter with moderate activity and that its function is presumably conserved in different species. Therefore, the PtMCP promoter may provide a practical choice to direct moderate level constitutive expression of transgenes and could be a valuable new tool in plant genetic engineering.
doi:10.3390/ijms14036187
PMCID: PMC3634493  PMID: 23507754
constitutive promoter; moderate expression; RT-PCR; GUS; transgenic plants
23.  Gene–Gene and Gene-Sex Epistatic Interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in Systemic Lupus Erythematosus 
PLoS ONE  2012;7(12):e51090.
Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene–gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48–3.44 [P = 1.21×104]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene–gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE.
doi:10.1371/journal.pone.0051090
PMCID: PMC3517573  PMID: 23236436
24.  Fluorescence in situ hybridization as adjunct to cytology improves the diagnosis and directs estimation of prognosis of malignant pleural effusions 
Background
The identification of malignant cells in effusions by conventional cytology is hampered by its limited sensitivity and specificity. The aim of this study was to investigate the value of fluorescence in situ hybridization (FISH) as adjuncts to conventional cytologic examination in patients with malignant pleural effusions.
Methods
We conducted a retrospective cohort study of 93 inpatients with pleural effusions (72 malignant pleural effusions metastatic from 11 different organs and 21 benign) over 23 months. All the patients came from Chinese northeast areas. Aspirated pleural fluid underwent cytologic examination and fluorescence in situ hybridization (FISH) for aneuploidy. We used FISH in single-colour or if appropriate in dual-colour evaluation to detect chromosomal aberrations (chromosomes 7, 11, and 17) in effusion cells as markers of malignancy, to raise the diagnostic yield and identified the efficiency by diagnostic biopsy. Predominant cytogenetic anomalies and patterns of intratumor cytogenetic heterogeneity were brought in relation to overall survival rate.
Results
Cytology alone confirmed malignant pleural effusions in 45 of 72 patients (sensitivity 63%), whereas FISH alone positively identified 48 of 72 patients (sensitivity 67%). Both tests had high specificity in predicting benign effusions. If cytology and FISH were considered together, they exhibited 88% sensitivity and 94.5% specificity in discriminating benign and malignant effusions. Combined, the two assays were more sensitive than either test alone. Although the positive predictive value of each test was 94.5%, the negative predictive value of cytology and FISH combined was 78%, better than 47% and 44% for FISH and cytology alone, respectively. There was a significantly prolonged survival rate for patients with aneuploidy for chromosome 17.
Conclusions
FISH in combination with conventional cytology is a highly sensitive and specific diagnostic tool for detecting malignant cells in pleural effusions . The high sensitivity and specificity may be associated with geographic area and race. Simple numeric FISH anomalies may be prognostic.
doi:10.1186/1749-8090-7-121
PMCID: PMC3514305  PMID: 23148562
Malignant pleural effusions; FISH; Prognosis; Sensitivity; Specificity
25.  Somatosensory evoked potential from S1 nerve root stimulation 
European Spine Journal  2011;20(10):1613-1619.
The objective of this study was to detect cerebral potentials elicited by proximal stimulation of the first sacral (S1) nerve root at the S1 dorsal foramen and to investigate latency and amplitude of the first cerebral potential. Tibial nerve SEP and S1 nerve root SEP were obtained from 20 healthy subjects and 5 patients with unilateral sciatic nerve or tibial nerve injury. Stimulation of the S1 nerve root was performed by a needle electrode via the S1 dorsal foramen. Cerebral potentials were recorded twice to document reproducibility. Latencies and amplitudes of the first cerebral potentials were recorded. Reproducible cerebral evoked potentials were recorded and P20s were identified in 36 of 40 limbs in the healthy subjects. The mean latency of P20 was 19.8 ± 1.6 ms. The mean amplitude of P20–N30 was 1.2 ± 0.9 μV. In the five patients, P40 of tibial nerve SEP was absent, while well-defined cerebral potentials of S1 nerve root SEP were recorded and P20 was identified from the involved side. This method may be useful in detecting S1 nerve root lesion and other disorders affecting the proximal portions of somatosensory pathway. Combined with tibial nerve SEP, it may provide useful information for diagnosis of lesions affecting the peripheral nerve versus the central portion of somatosensory pathway.
doi:10.1007/s00586-011-1768-8
PMCID: PMC3175881  PMID: 21556731
Somatosensory evoked potentials; Intra-operative monitoring; S1 nerve root; Nerve root stimulation

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