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1.  Patients with Old Age or Proximal Tumors Benefit from Metabolic Syndrome in Early Stage Gastric Cancer 
PLoS ONE  2014;9(3):e89965.
Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated.
Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed.
Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis).
Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.
PMCID: PMC3943843  PMID: 24599168
2.  SepD/SepL-Dependent Secretion Signals of the Type III Secretion System Translocator Proteins in Enteropathogenic Escherichia coli 
Journal of Bacteriology  2015;197(7):1263-1275.
The type III protein secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE) is essential for the pathogenesis of attaching/effacing bacterial pathogens, including enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and Citrobacter rodentium. These pathogens use the T3SS to sequentially secrete three categories of proteins: the T3SS needle and inner rod protein components; the EspA, EspB, and EspD translocators; and many LEE- and non-LEE-encoded effectors. SepD and SepL are essential for translocator secretion, and mutations in either lead to hypersecretion of effectors. However, how SepD and SepL control translocator secretion and secretion hierarchy between translocators and effectors is poorly understood. In this report, we show that the secreted T3SS components, the translocators, and both LEE- and non-LEE-encoded effectors all carry N-terminal type III secretion and translocation signals. These signals all behave like those of the effectors and are sufficient for mediating type III secretion and translocation by wild-type EPEC and hypersecretion by the sepD and sepL mutants. Our results extended previous observations and suggest that the secretion hierarchy of the different substrates is determined by a signal other than the N-terminal secretion signal. We identified a domain located immediately downstream of the N-terminal secretion signal in the translocator EspB that is required for SepD/SepL-dependent secretion. We further demonstrated that this EspB domain confers SepD/SepL- and CesAB-dependent secretion on the secretion signal of effector EspZ. Our results thus suggest that SepD and SepL control and regulate secretion hierarchy between translocators and effectors by recognizing translocator-specific export signals.
IMPORTANCE Many bacterial pathogens use a syringe-like protein secretion apparatus, termed the type III protein secretion system (T3SS), to secrete and inject numerous proteins directly into the host cells to cause disease. The secreted proteins perform different functions at various stages during infection and are classified into three substrate categories (T3SS components, translocators, and effectors). They all contain secretion signals at their N termini, but how their secretion hierarchy is determined is poorly understood. Here, we show that the N-terminal secretion signals from different substrate categories all behave the same and do not confer substrate specificity. We further characterize the secretion signals of the translocators and identify a translocator-specific signal, demonstrating that substrate-specific secretion signals are required in regulating T3SS substrate hierarchy.
PMCID: PMC4352668  PMID: 25645555
3.  MiR-9a-5p regulates proliferation and migration of hepatic stellate cells under pressure through inhibition of Sirt1 
AIM: To reveal the functions of microRNAs (miRNAs) with respect to hepatic stellate cells (HSCs) in response to portal hypertension.
METHODS: Primary rat HSCs were exposed to static water pressure (10 mmHg, 1 h) and the pressure-induced miRNA expression profile was detected by next-generation sequencing. Quantitative real-time polymerase chain reaction was used to verify the expression of miRNAs. A potential target of MiR-9a-5p was measured by a luciferase reporter assay and Western blot. CCK-8 assay and Transwell assay were used to detect the proliferation and migration of HSCs under pressure.
RESULTS: According to the profile, the expression of miR-9a-5p was further confirmed to be significantly increased after pressure overload in HSCs (3.70 ± 0.61 vs 0.97 ± 0.15, P = 0.0226), which resulted in the proliferation, migration and activation of HSCs. In vivo, the up-regulation of miR-9a-5p (2.09 ± 0.91 vs 4.27 ± 1.74, P = 0.0025) and the down-regulation of Sirt1 (2.41 ± 0.51 vs 1.13 ± 0.11, P = 0.0006) were observed in rat fibrotic liver with portal hypertension. Sirt1 was a potential target gene of miR-9a-5p. Through restoring the expression of Sirt1 in miR-9a-5p transfected HSCs on pressure overload, we found that overexpression of Sirt1 could partially abrogate the miR-9a-5p mediated suppression of the proliferation, migration and activation of HSCs.
CONCLUSION: Our results suggest that during liver fibrosis, portal hypertension may induce the proliferation, migration and activation of HSCs through the up-regulation of miR-9a-5p, which targets Sirt1.
PMCID: PMC4566383  PMID: 26379395
MicroRNA; miR-9a-5p; Sirt1; Pressure; Hepatic stellate cells
4.  Cornichon-2 Modulates AMPA Receptor–Transmembrane AMPA Receptor Regulatory Protein Assembly to Dictate Gating and Pharmacology 
Neuronal AMPA receptor complexes comprise a tetramer of GluA pore-forming subunits as well as accessory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon-2/3 (CNIH-2/3). The mechanisms that control AMPA receptor complex assembly remain unclear. AMPA receptor responses in neurons differ from those in cell lines transfected with GluA plus TARPs γ-8 or γ-7, which show unusual resensitization kinetics and non-native AMPA receptor pharmacologies. Using tandem GluA/TARP constructs to constrain stoichiometry, we show here that these peculiar kinetic and pharmacological signatures occur in channels with four TARP subunits per complex. Reducing the number of TARPs per complex produces AMPA receptors with neuron-like kinetics and pharmacologies, suggesting a neuronal mechanism controls GluA/TARP assembly. Importantly, we find that coexpression of CNIH-2 with GluA/TARP complexes reduces TARP stoichiometry within AMPA receptors. In both rat and mouse hippocampal neurons, CNIH-2 also associates with AMPA receptors on the neuronal surface in a γ-8-dependent manner to dictate receptor pharmacology. In the cerebellum, however, CNIH-2 expressed in Purkinje neurons does not reach the neuronal surface. In concordance, stargazer Purkinje neurons, which express CNIH-2 and γ-7, display AMPA receptor kinetics/pharmacologies that can only be recapitulated recombinantly by a low γ-7/GluA stoichiometry. Together, these data suggest that CNIH-2 modulates neuronal AMPA receptor auxiliary subunit assembly by regulating the number of TARPs within an AMPA receptor complex to modulate receptor gating and pharmacology.
PMCID: PMC4562416  PMID: 21543622
5.  Adiponectin Gene Polymorphisms are Associated with Increased Risk of Colorectal Cancer 
This meta-analysis investigates the associations of adiponectin (ADIPOQ) genetic polymorphisms with the susceptibility to colorectal cancer (CRC).
2 reviewers independently searched 6 databases – PubMed, Cochrane Library, Ovid, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases – to identify published studies relevant to adiponectin gene polymorphisms and CRC. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria. Full texts of the selected studies were accessed and related data was extracted using a standardized data extraction form. Comprehensive Meta-analysis 2.0 software was used for statistical analyses.
A total of 188 studies were initially retrieved from database search, and 6 studies were eventually selected, through a rigorous screening process, for inclusion in this meta-analysis. The 6 studies contained a total of 1897 patients (Asians: 1190; white: 707) with CRC in case group and 2475 healthy controls (Asians: 1325; white: 1150) in the control group. Results of the current meta-analysis revealed that the rs2241766 T>G single-nucleotide polymorphisms (SNP) increase the risk of CRC; rs1501299 G>T under dominant model was associated with increased risk of CRC; and rs266729 C>G SNP under allele model conferred an increased risk of CRC.
Our meta-analysis strongly suggests that the ADIPOQ rs2241766 T>G, rs1501299 G>T, and rs266729 C>G SNPs correlate with an increased risk of CRC.
PMCID: PMC4562615  PMID: 26329379
Adiponectin; Colorectal Neoplasms; Polymorphism, Genetic
6.  Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer 
Cancer Biology & Therapy  2014;15(9):1268-1279.
The high morbidity and mortality of colorectal cancer pose a significant public health problem worldwide. Here we assessed the pro-cancer efficacy and mechanism of action of CCNB1 in different colorectal cancer cells. We provided evidence that CCNB1 mRNA and protein level were upregulated in a subset of human colorectal tumors, and positively correlated with Chk1 expression. Repression of Chk1 caused a significant decrease in cell proliferation and CCNB1 protein expression in colorectal cancer cells. Furthermore, downregulation of CCNB1 impaired colorectal cancer proliferation in vitro and tumor growth in vivo. Specifically, suppression of CCNB1 caused a strong G2/M phase arrest in both HCT116 and SW480 cells, interfering with the expression of cdc25c and CDK1. Additionally, CCNB1 inhibition induced apoptotic death in certain colorectal cancer cells. Together, these results suggest that CCNB1 is activated by Chk1, exerts its oncogenic role in colorectal cancer cells, and may play a key role in the development of a novel therapeutic approach against colorectal cancer.
PMCID: PMC4128869  PMID: 24971465
CCNB1; colorectal cancer; Chk1; cell growth; cell cycle; apoptosis
7.  Cesarean scar pregnancy treated by curettage and aspiration guided by laparoscopy 
Pregnancy in a cesarean scar is the rarest form of an ectopic pregnancy. The treatment for cesarean scar pregnancy mainly includes systemic methotrexate and uterine artery embolization. Here, we reported a case of cesarean scar pregnancy treated by curettage and aspiration guided by laparoscopy. The treatment plan included two phases. Three days after a combination of methotrexate and mifepristone was administered, the gestational sac was removed under laparoscopy, which enabled a successful treatment for the unruptured ectopic pregnancy in a previous cesarean scar and made it possible to preserve the reproductive capability of the patient.
PMCID: PMC4529265  PMID: 26345396
cesarean scar pregnancy; laparoscopy; curettage and aspiration
8.  Simvastatin Inhibits Lipopolysaccharide-Induced Osteoclastogenesis and Reduces Alveolar Bone Loss in Experimental Periodontal Disease 
Journal of periodontal research  2013;49(4):518-526.
Background and Objective
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and have anti-inflammatory effects independent of cholesterol lowering. Recent clinical studies have indicated that statin intake has beneficial effect on periodontal disease. However, the underlying mechanisms have not been well understood. In the current study, we employed a rat model with lipopolysaccharide (LPS)-induced periodontal disease and determined the effect of simvastatin, a commonly prescribed statin, on osteoclastogenesis, gingival inflammation and alveolar bone loss.
Material and Methods
Sprague-Dawley rats were injected with A. actinomycetemcomitans LPS in periodontal tissue 3 times per week for 8 weeks and part of the rats with LPS injection were also given simvastatin via gavage. After the treatments, the rat maxillae were scanned by microcomputed tomography and the images were analyzed to determine alveolar bone loss. To explore the underlying mechanisms, the effect of simvastatin on osteoclastogenesis and gingival expression of pro-inflammatory cytokines were also determined by tartate-resistant acid phosphatase staining and real-time polymerase chain reaction assays, respectively.
Results showed that LPS treatment markedly increased bone loss, but administration of simvastatin significantly alleviated the bone loss. Results also showed that LPS treatment stimulated osteoclastogenesis and the expression of inflammatory cytokines, but simvastatin significantly modulate the stimulatory effect of LPS on osteoclastogenesis and cytokine expression.
This study demonstrated that simvastatin treatment inhibits LPS-induced osteoclastogenesis and gingival inflammation and reduces alveolar bone loss, indicating that the intake of simvastatin may hinder the progression of periodontal disease.
PMCID: PMC3979522  PMID: 24117880
Simvastatin; periodontal disease; lipopolysaccharide; inflammation; alveolar bone
9.  Fast Transmethylation of Total Lipids in Dried Blood by Microwave Irradiation and its Application to a Population Study 
Lipids  2014;49(8):839-851.
A methodology combining finger-pricked blood sampling, microwave accelerated fatty acid assay, fast gas chromatography data acquisition, and automated data processing was developed, evaluated and applied to a population study. Finger-pricked blood was collected on filter paper previously impregnated with 0.05 mg of the antioxidant butylated hydroxytoluene and air-dried at room temperature. Transmethylation was accelerated by microwave irradiation in an explosion-proof multimode microwave reaction system. The chemical procedure was based on a one-step direct transmethylation procedure catalyzed by acetyl chloride. The short-term stability of PUFA in blood dried on filter paper and stored overnight at room temperature was examined using venous blood. The recoveries ranged from 97–101 % for the categorized fatty acids as well as the ratios of n-6 to n-3 PUFA and the n-3% highly unsaturated fatty acid. Specifically, recoveries were 99, 98, 97, and 97 % for linoleic acid (18:2n-6), arachidonic acid (ARA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), respectively. The mol% (mean ± SD, 95% confidence interval) of fatty acid composition in subjects from the population study was determined as 36.2±3.8 (35.8, 36.7), 23.2±3.0 (22.8, 23.5), 36.8±3.5 (36.4, 37.2) and 3.79±1.0 (3.68, 3.91) for the saturated, monounsaturated, n-6 and n-3 PUFA, respectively. Individually, the mean mol% (95% CI) was 22.6 (22.3, 22.9) for 18:2n-6, 9.5 (9.3, 9.7) for ARA, 0.51 (0.49, 0.53) for ALA, 0.42 (0.38, 0.47) for eicosapentaenoic acid (EPA), and 1.67 (1.61, 1.73) for DHA. This methodology provides an accelerated yet high-efficiency, chemically safe, and temperature-controlled transmethylation, with diverse laboratory applications including population studies.
PMCID: PMC4138836  PMID: 24986160
Finger pricked blood; Filter paper; Dried blood spot; Microwave reaction system; PUFA; omega-3; omega-6
10.  Untethering the TIR1 auxin receptor from the SCF complex increases its stability and inhibits auxin response 
Nature plants  2015;1(3):14030.
Plant genomes encode large numbers of F-box proteins (FBPs), the substrate recognition subunit of SKP1–CULLIN–F-box (SCF) ubiquitin ligases. There are ~700 FBPs in Arabidopsis, most of which are uncharacterized. TIR1 is among the best-studied plant FBPs and functions as a receptor for the plant hormone auxin. Here we use a yeast two-hybrid system to identify novel TIR1 mutants with altered properties. The analysis of these mutants reveals that TIR1 associates with the CULLIN1 (CUL1) subunit of the SCF through the N-terminal H1 helix of the F-box domain. Mutations that untether TIR1 from CUL1 stabilize the FBP and cause auxin resistance and associated growth defects, probably by protecting TIR1 substrates from degradation. Based on these results we propose that TIR1 is subject to autocatalytic degradation when assembled into an SCF. Further, our results suggest a general method for determining the physiological function of uncharacterized FBPs. Finally, we show that a key amino acid variation in the F-box domain of auxin signalling F-box (AFB1), a closely related FBP, reduces its ability to form an SCF, resulting in an increase in AFB1 levels.
PMCID: PMC4520256
11.  Andrographolide sodium bisulphite-induced inactivation of urease: inhibitory potency, kinetics and mechanism 
The inhibitory effect of andrographolide sodium bisulphite (ASB) on jack bean urease (JBU) and Helicobacter pylori urease (HPU) was performed to elucidate the inhibitory potency, kinetics and mechanism of inhibition in 20 mM phosphate buffer, pH 7.0, 2 mM EDTA, 25 °C.
The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of ASB was characterized with IC50 values. Lineweaver-Burk and Dixon plots for JBU inhibition of ASB was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni2+ binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode.
The IC50 of ASB against JBU and HPU was 3.28 ± 0.13 mM and 3.17 ± 0.34 mM, respectively. The inhibition proved to be competitive and concentration- dependent in a slow-binding progress. The rapid formation of initial ASB-JBU complex with an inhibition constant of Ki = 2.86 × 10−3 mM was followed by a slow isomerization into the final complex with an overall inhibition constant of Ki* = 1.33 × 10−4 mM. The protective experiment proved that the urease active site is involved in the binding of ASB. Thiol reagents (L-cysteine and dithiothreithol) strongly protect the enzyme from the loss of enzymatic activity, while boric acid and fluoride show weaker protection, indicating that the active-site sulfhydryl group of JBU was potentially involved in the blocking process. Moreover, inhibition of ASB proved to be reversible since ASB-inactivated JBU could be reactivated by dithiothreitol application. Molecular docking assay suggested that ASB made contacts with the important sulfhydryl group Cys-592 residue and restricted the mobility of the active-site flap.
ASB was a competitive inhibitor targeting thiol groups of urease in a slow-binding manner both reversibly and concentration-dependently, serving as a promising urease inhibitor for the treatment of urease-related diseases.
PMCID: PMC4504079  PMID: 26179287
Andrographolide sodium bisulphite; Urease; Inhibition; Slow-binding; Sulfhydryl group; Molecular docking
12.  FTY720 inhibited proinflammatory cytokine release and osteoclastogenesis induced by Aggregatibacter actinomycetemcomitans 
Periodontitis is a bacteria-driven inflammatory bone loss disease. Previous studies showed that the oral pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) stimulated the generation of sphingosine 1 phosphate (S1P). In addition, S1P signaling regulated the migration of osteoclast precursors and affected osteoclastogenesis. Furthermore, treatment with FTY720 (also called fingolimod, a modulator of multiple S1P receptors) alleviated osteoporosis and suppressed arthritis in animals. This study determined the effect of FTY720 on proinflammatory cytokine production and osteoclastogenesis in murine bone marrow cells with or without A. actinomycetemcomitans stimulation.
Murine bone marrow-derived monocytes and macrophages (BMMs) were treated with vehicle ethanol or FTY720, and were either unstimulated or stimulated for 0.5 to 6 h with A. actinomycetemcomitans. The protein levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the media of BMMs were quantified by enzyme-linked immunosorbent assay (ELISA). Protein expressions, including phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, p-extracellular signal-regulated kinase (p-ERK), PI3K, Akt, and ERK were evaluated by Western blot. In addition, murine bone marrow-derived pre-osteoclasts were treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) for three days. Then the cells were treated with either vehicle or FTY720 and were either unstimulated or stimulated with A. actinomycetemcomitans for 4 to 24 h. Control cells were treated with M-CSF alone with or without bacterial stimulation. Osteoclasts were stained by tartrate-resistant acid phosphatase (TRAP) staining. The mRNA levels of osteoclastogenic factors, including nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 1 (Nfatc1), cathepsin K (Ctsk), acid phosphatase 5 (Acp5), osteoclast-associated receptor (Oscar), and RANKL were quantified by quantitative real-time polymerase chain reaction (PCR).
FTY720 dose-dependently inhibited IL-1β, IL-6, and TNF-α protein levels induced by A. actinomycetemcomitans in BMMs compared with controls. Additionally, FTY720 attenuated p-PI3K, p-Akt, and p-ERK expressions induced by A. actinomycetemcomitans. Furthermore, FTY720 suppressed osteoclastogenesis in bone marrow-derived pre-osteoclasts with or without bacterial stimulation and reduced the mRNA levels of Nfatc1, Ctsk, Acp5, and Oscar, but not RANKL in bone marrow-derived pre-osteoclasts.
FTY720 inhibited proinflammatory cytokine production and suppressed osteoclastogenesis, supporting FTY720 as a potential therapy for inflammatory bone loss diseases.
PMCID: PMC4492085  PMID: 26138336
FTY720; Sphingosine-1-phosphate; Periodontitis; Cytokine; Osteoclastogenesis; Aggregatibacter actinomycetemcomitans
13.  A novel recombinant lineage’s contribution to the outbreak of coxsackievirus A6-associated hand, foot and mouth disease in Shanghai, China, 2012-2013 
Scientific Reports  2015;5:11700.
Since late 2012, coxsackievirus A6 (CVA6) has gradually become the predominant pathogen responsible for hand-foot-mouth disease (HFMD) in several provinces of China. A total of 626 patients diagnosed with HFMD in Shanghai, China from January 2012 to September 2013 were enrolled in this study. Of these, 292 CVA6 infected cases were subjected to clinical analyses. Whole-genome sequencing, recombination and phylogenetic analyses were also performed. A recombinant CVA6 monophyletic lineage was found during an outbreak of CVA6-associated HFMDs in Shanghai, China in November 2012, and accounted for 21.9% (64/292) of the CVA6 strains during the study period. Recombination analyses showed that the 2C gene of the novel CVA6 virus was probably derived from a coxsackievirus A4 (CVA4) strain circulating in the population. Clinical observation showed that this recombinant CVA6 virus led to a more generalized rash than did the non-recombinant CVA6 virus. This newly emerged CVA6 lineage was associated with a considerable proportion of HFMD cases from 2012 to 2013 in Shanghai, and poses a potential threat to public health.
PMCID: PMC4485158  PMID: 26121916
14.  MicroRNA-143/-145 in Cardiovascular Diseases 
BioMed Research International  2015;2015:531740.
MicroRNAs (miRNAs) play an essential role in the onset and development of many cardiovascular diseases. Increasing evidence shows that miRNAs can be used as potential diagnostic biomarkers for cardiovascular diseases, and miRNA-based therapy may be a promising therapy for the treatment of cardiovascular diseases. The microRNA-143/-145 (miR-143/-145) cluster is essential for differentiation of vascular smooth muscle cells (VSMCs) and determines VSMC phenotypic switching. In this review, we summarize the recent progress in knowledge concerning the function of miR-143/-145 in the cardiovascular system and their role in cardiovascular diseases. We discuss the potential role of miR-143/-145 as valuable biomarkers for cardiovascular diseases and explore the potential strategy of targeting miR-143 and miR-145.
PMCID: PMC4499377  PMID: 26221598
15.  How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones 
The origin of selectivity in the α-fluorination of cyclic ketones catalyzed by cinchona alkaloid-derived primary amines is determined with density functional calculations. The chair preference of a seven-membered ring at the fluorine transfer transition state is key in determining the sense and level of enantiofacial selectivity.
PMCID: PMC4105079  PMID: 24967514
16.  Inhibition of MiR-155 suppresses cell migration in nasopharyngeal carcinoma through targeting ZDHHC2 
Overexpression of miR-155 in nasopharygeal carcinoma (NPC) is partly driven by Epstein-Bar virus infection. However the role of miR-155 in NPC oncogenesis is unclear. This study showed that miR-155 inhibitor could inhibit the cell migration in NPC cell lines. ZDHHC2 was identified as a direct target of miR-155 and downregulation of ZDHHC2 prompted cell migration in NPC. Furthermore, reduced ZDHHC2 expression was associated significantly with metastasis and poor survival of NPC patients. Collectively, inhibition of miR-155 suppresses cell migration in NPC through targeting ZDHHC2. The potential of miR-155 and ZDHHC2 as therapeutic targets in NPC should be further investigated.
PMCID: PMC4538107  PMID: 26309499
Nasopharyngeal carcinoma; miR-155; ZDHHC2; cell migration
17.  Hypercaloric enteral nutrition in Amyotrophic Lateral Sclerosis: a randomized double-blind placebo-controlled trial 
Lancet  2014;383(9934):2065-2072.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in ALS patients and calorie-dense diets increase survival in an ALS mouse model. We therefore hypothesized that hypercaloric diets might lead to weight gain and slow ALS disease progression.
In this double-blind, placebo-controlled, multi-center clinical trial, we enrolled adults with ALS without a history of diabetes, significant liver or cardiovascular disease, who were already receiving percutaneous enteral nutrition. We randomly assigned participants to one of three dietary interventions: replacement calories using an isocaloric diet (controls) vs. a high-carbohydrate hypercaloric diet (HC/HC), vs. a high-fat hypercaloric diet (HF/HC). Participants received the intervention diets for four months and were followed for five months. The primary outcomes were safety and tolerability. Secondary outcomes included measures of disease progression, survival, and metabolism. This trial is registered with, number NCT00983983.
A total of 24 participants were enrolled of whom 20 initiated study diet (six control, eight HC/HC, six HF/HC). Baseline demographics were similar among the three study arms. The HC/HC diet was better tolerated with fewer serious adverse events than the control diet (zero vs. nine, p<0·001) and fewer dose discontinuations due to adverse events (0% vs. 50%). There were no deaths in the HC/HC arm vs. three deaths (43%) in the control arm (logrank p = 0·03). The HF/HC arm was not statistically different from the controls in adverse events, tolerability, deaths or disease progression.
Our results suggest that hypercaloric enteral nutrition is safe and tolerable in ALS and support the study of nutritional interventions at earlier stages of the disease.
The Muscular Dystrophy Association with additional support from the National Center for Research Resources, the National Institutes of Health, and the Harvard NeuroDiscovery Center.
PMCID: PMC4176708  PMID: 24582471
18.  Distinct Characteristics of Indole-3-Acetic Acid and Phenylacetic Acid, Two Common Auxins in Plants 
Plant and Cell Physiology  2015;56(8):1641-1654.
The phytohormone auxin plays a central role in many aspects of plant growth and development. IAA is the most studied natural auxin that possesses the property of polar transport in plants. Phenylacetic acid (PAA) has also been recognized as a natural auxin for >40 years, but its role in plant growth and development remains unclear. In this study, we show that IAA and PAA have overlapping regulatory roles but distinct transport characteristics as auxins in plants. PAA is widely distributed in vascular and non-vascular plants. Although the biological activities of PAA are lower than those of IAA, the endogenous levels of PAA are much higher than those of IAA in various plant tissues in Arabidopsis. PAA and IAA can regulate the same set of auxin-responsive genes through the TIR1/AFB pathway in Arabidopsis. IAA actively forms concentration gradients in maize coleoptiles in response to gravitropic stimulation, whereas PAA does not, indicating that PAA is not actively transported in a polar manner. The induction of the YUCCA (YUC) genes increases PAA metabolite levels in Arabidopsis, indicating that YUC flavin-containing monooxygenases may play a role in PAA biosynthesis. Our results provide new insights into the regulation of plant growth and development by different types of auxins.
PMCID: PMC4523386  PMID: 26076971
Auxin transport; Indole-3-acetic acid; Metabolism; Phenylacetic acid; Signal transduction
19.  Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis 
AIM: To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection.
METHODS: Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach.
RESULTS: We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P < 0.05). These results led us to hypothesize that BIFICO treatment would diminish the H. pylori-induced inflammatory response in gastric mucosal epithelial cells in vitro via the NF-κB and MAPK signaling pathways. Indeed, we observed a decrease in the expression of the NF-κB subunit p65 and in the phosphorylation of IκB-α, ERK and p38. Moreover, there was a significant decrease in the production of IL-8, TNF-α, G-CSF and GM-CSF (P < 0.05), and the increased expression of TLR2, TLR4 and MyD88 induced by H. pylori in the stomach was also significantly reduced following BIFICO treatment (P < 0.05).
CONCLUSION: Our results suggest that the probiotic cocktail BIFICO can ameliorate H. pylori-induced gastritis by inhibiting the inflammatory response in gastric epithelial cells.
PMCID: PMC4458766  PMID: 26074694
BIFICO; Gastritis; Helicobacter pylori; Nuclear factor-κB; Inflammation; Toll-like receptors; Bifidobacterium longum; MAPK
20.  LHON Gene Therapy Vector Prevents Visual Loss and Optic Neuropathy Induced by G11778A Mutant Mitochondrial DNA: Biodistribution and Toxicology Profile 
To demonstrate safety and efficacy of allotopic human ND4 for treatment of a Leber's hereditary optic neuropathy (LHON) mouse model harboring the G11778A mitochondrial mutation.
We induced LHON in mice by intravitreal injection of mutant (G11778A) human ND4 DNA, responsible for most cases of LHON, that was directed to mitochondria using an AAV2 vector to which we appended a mitochondrial targeting sequence to the VP2 capsid. We then attempted rescue of visual loss using our test article (ScAAV2-P1ND4v2) containing a synthetic nuclear encoded G11778G ND4 gene that was allotopically expressed. Control mice either were uninjected or received AAV2-GFP or AAV2-mCherry. We performed RT-PCR and confocal microscopy at 2 weeks post injection. Pattern electroretinograms (PERGs), spectral-domain optical coherence tomography (SD-OCT), histology, and transmission electron microscopy (TEM) were performed. For toxicology and biodistribution studies, the test article was administered intravitreally to rats and rhesus macaques at different doses.
Mutant and wild-type ND4 were efficiently expressed in the mitochondria of retinal ganglion cells (RGCs). Visual function assessed by serial PERGs and retinal structure by serial SD-OCT showed a significant rescue by the test article. Histology and ultrastructural analysis confirmed that loss of RGCs and demise of axons was prevented by ScAAV2-P1ND4v2. Rat and nonhuman primate biodistribution studies showed that vector spread outside the injected eye into spleen and lymph nodes was minimal. Histopathology of tissues and organs including the eyes was comparable to that of uninfected and saline-injected eyes.
Allotopically expressed wild-type ND4 prevents the phenotype induced by G11778A mitochondrial DNA with a toxicology profile acceptable for testing in a phase I clinical trial.
Allotopic expression of the LHON gene therapy test article suppressed visual loss, demise of RGCs, and optic nerve axons induced by mutant ND4 delivered to mouse retinal mitochondria. Rodent and primate toxicology studies suggest an acceptable profile of the test article for human trials.
PMCID: PMC4249950  PMID: 25342621
LHON; mitochondria; gene therapy
21.  Clinical and pathological analysis of 116 cases of adult adrenal cortical adenoma and literature review 
OncoTargets and therapy  2015;8:1251-1257.
The aim of this study is to investigate origin, gross features, microscopic features, immunohistochemical properties, and differential diagnosis of adrenal cortical adenoma (ACA) in patients ≥20 years old.
The clinicopathological features of 116 cases of ACA and the immunohistochemical features of 50 cases of ACA were evaluated, and the relevant literature was reviewed.
In our cohort, 76.72% (89/116) of the cases were functional, and 27 cases had non-functional, benign adrenal adenomas. ACA presented as an island tumor with an envelope, and the mean tumor size was 3.6 cm (range 1–5 cm), with a mean tumor weight of 9.28 g (range 5–113 g). The shape of the tumor cells was consistent, and mitosis was rarely observed. Forty of the 46 patients with cortisol-secreting ACA had tumors containing granule cells. Primary aldosteronism was observed in 43 cases. Thirty-eight cases had endoscopically visible tumors, with clear cells and lipid-rich cytoplasm arranged in irregular patches or strips. Cortisol-producing ACAs were associated with atrophy of the non-tumorous cortex. Adrenocortical adenomas displayed positive immunohistochemical staining for MELAN-A, Syn (46 of 50 cases of ACA), NSE (44 of 50 cases of ACA), Vim (42 of 50 cases of ACA) and Ki-67 <5% (24 of 50 cases of ACA; the remaining 26 cases were negative for Ki-67).
Prediction of endocrine syndrome in functional ACA was possible based on its structure and morphologic features, which could prevent an unanticipated postoperative crisis. However, a clinical study is needed to validate these findings.
PMCID: PMC4455871  PMID: 26064059
adrenal cortical adenoma; pathological features; immunohistochemical staining; pathological analysis
22.  The Relationship between Gentle Tactile Stimulation on the Fetus and Its Temperament 3 Months after Birth 
Behavioural Neurology  2015;2015:371906.
Objective. The aim of this study was to evaluate the effect of gentle tactile stimulation on the fetus in its temperament 3 months after birth. Method. A total of 302 mother-3-month-infant dyads enrolled the retrospective cohort study. 76 mothers had regular gentle tactile stimulation on the fetus in their pregnancy; 62 mothers had irregular tactile stimulation on the fetus, and the rest of 164 mothers who had no tactile stimulation served as nonexposure group. Temperament was assessed using the EITS (a nine-dimensional scale of temperament). Results. Significant difference in temperament type was found among infants in 3 groups at 3 months of age. In the regular practice group, the babies with easy type temperament accounted for 73.7%, which was higher than that in irregular practice group (53.2%, P = 0.012) and that in the control group (42.1%, P < 0.001). Compared to infants in no practice group, the infants who had received regular gentle tactile stimulation before birth were lower in negative mood (P = 0.047) while higher in adaptability (P < 0.001), approach (P = 0.001), and persistence (P = 0.001), respectively. Conclusion. Regular gentle tactile stimulation on fetus may promote the formation of easy type infant temperament.
PMCID: PMC4477442  PMID: 26180374
23.  Uric acid levels predict survival in men with amyotrophic lateral sclerosis 
Journal of neurology  2012;259(9):1923-1928.
Elevated uric acid levels have recently been found to be associated with slower disease progression in Parkinson’s disease, Huntington’s disease, multiple system atrophy, and mild cognitive impairment. The aim of this study is to determine whether serum uric acid levels predict survival in amyotrophic lateral sclerosis (ALS). A total of 251 people with ALS enrolled in two multicenter clinical trials were included in our analysis. The main outcome measure was survival time, which was calculated as time to death, tracheostomy, or permanent assistive ventilation, with any event considered a survival endpoint. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching a survival endpoint according to baseline uric acid levels after adjusting for markers of disease severity (FVC, total ALSFRS-R score, time since symptom onset, diagnostic delay, BMI, bulbar vs. spinal onset, age, and riluzole use). There was a dose-dependent survival advantage in men, but not women, with higher baseline uric acid levels (logrank test: p = 0.018 for men, p = 0.81 for women). There was a 39% reduction in risk of death during the study for men with each 1 mg/dl increase in uric acid levels (adjusted HR: 0.61, 95% CI 0.39–0.96, p = 0.03). This is the first study to demonstrate that serum uric acid is associated with prolonged survival in ALS, after adjusting for markers of disease severity. Similar to previous reports in Parkinson’s disease, this association was seen in male subjects only.
PMCID: PMC4441749  PMID: 22323210
Uric acid; Urate; Amyotrophic lateral sclerosis; Predictor; Survival
24.  Expression profile of microRNAs in gastrointestinal stromal tumors revealed by high throughput quantitative RT-PCR microarray 
AIM: To investigate the microRNA (miRNA) expression profile in gastrointestinal stromal tumor (GIST) tissues that could serve as a novel diagnostic biomarker for GIST detection.
METHODS: We performed a quantitative real-time quantitative reverse transcriptase polymerase chain reaction assay to analyze the expression of 1888 miRNAs in a sample set that included 54 GIST tissue samples.
RESULTS: We found that dysregulation of several miRNAs may be related to the malignant potential of GISTs. Six of these miRNAs, hsa-let-7c, miR-218, miR-488#, miR-4683, miR-34c-5p and miR-4773, were selected as the final list of biomarkers to separate the malignant GISTs (M group) from the benign GISTs (B group). In addition, MiR-29b-2#, hsa-let-7c, miR-891b, miR-218, miR-204, miR-204-3p, miR-628-5p, miR-744, miR-29c#, miR-625 and miR-196a were used to distinguish between the borderline (BO group) and M groups. There were 11 common miRNAs selected to separate the benign and borderline (BB) group from the M group, including hsa-let-7c, miR-218, miR-628-5p, miR-204-3p, miR-204, miR-891b, miR-488#, miR-145, miR-891a, miR-34c-5p and miR-196a.
CONCLUSION: The identified miRNAs appear to be novel biomarkers to distinguish malignant from benign GISTs, which may be helpful to understand the mechanisms of GIST oncogenesis and progression, and to further elucidate the characteristics of GIST subtypes.
PMCID: PMC4438018  PMID: 26019448
Gastrointestinal stromal tumors; MicroRNAs; Microarray analysis; Real-time polymerase chain reaction; Diagnosis
25.  Association of IL-17 polymorphisms with gastric cancer risk in Asian populations 
AIM: To investigate associations between the IL-17 rs2275913 G>A and rs763780 T>C polymorphisms and susceptibility to gastric cancer in Asian populations.
METHODS: We reviewed studies published up to 2014 on IL-17 polymorphisms with gastric cancer susceptibility systematically. Relevant articles were identified in the MEDLINE, Science Citation Index, Cochrane Library, PubMed, EMBASE, CINAHL and Current Contents Index databases. We used version 12.0 STATA statistical software to evaluate the statistical data. Two reviewers abstracted the data independently. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated.
RESULTS: Seven independent, case-control studies were chosen for the meta-analysis, which included 3210 gastric cancer patients and 3889 healthy controls. The overall estimation showed a positive association between the IL-17 rs2275913 G>A polymorphism and the occurrence of gastric cancer for five genetic models (all P < 0.05) and similar results were observed for the IL-17 rs763780 T>C variation with four genetic models (all P < 0.05), but not for the dominant model (P > 0.05). Subgroup analysis by country revealed that the rs2275913 G>A and rs763780 T>C polymorphisms may be the main risk factor for gastric cancer in Chinese and Japanese populations.
CONCLUSION: The IL-17 gene may be significantly correlated with gastric cancer risk in Asian populations, especially those carrying the rs2275913 G>A and rs763780 T>C polymorphisms.
PMCID: PMC4427697  PMID: 25987798
IL-17; Genetic polymorphism; Gastric cancer; Asian populations; Meta-analysis

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