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1.  Risk of Premotor Symptoms in Patients with Newly Diagnosed PD: A Nationwide, Population-Based, Case-Control Study in Taiwan 
PLoS ONE  2015;10(6):e0130282.
To evaluate the risk of premotor symptoms, namely rapid eye movement behavior disorder (RBD), constipation, and depression among patients with newly diagnosed Parkinson disease (PD).
A total of 705 PD patients and 2,820 control subjects were selected from the Taiwan National Health Insurance Research Database. Patients were traced back for a maximum of 14 years to determine the diagnoses of RBD, depression, and constipation. Logistic regression analysis was used to identify risk of premotor symptoms for PD. Moreover, subgroup analyses were performed by dividing the patients into a middle-age onset group (≤ 64 years) and an old-age onset group (≥ 65 years). The associations between these premotor symptoms and age of PD onset were further examined.
An association was found between a history of premotor symptoms and newly diagnosed PD in which a high occurrence of premotor symptoms was identified in PD patients as compared to selected controls (4.3% vs. 1.2% for RBD, 40.4% vs. 24.0% for constipation, and 13.0% vs. 5.1% for depression). The strength of this association remained statistically significant after adjustment for potential confounders (3.69 fold risk for RBD, 2.36 for constipation, and 2.82 for depression, all p < 0.0001). The average interval between premotor symptoms and PD ranged from 4.5 to 6.2 years. RBD and depression carried higher risks for PD in the middle-age onset group than in the old-age onset group (7.20- vs. 2.24-fold risk for RBD, 6.06 vs. 1.40 for depression).
The prevalence of premotor symptoms was higher among the PD patients than in the controls. Premotor symptoms appeared to be associated with a higher risk for PD in subjects with an earlier age of onset.
PMCID: PMC4479561  PMID: 26107935
2.  Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells 
British Journal of Pharmacology  2013;171(1):237-252.
This study aimed to evaluate the anti-hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action.
Using HCV replicon and HCVcc infectious systems, we identified anti-HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti-HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication.
In HCV replicon and HCVcc infectious systems, andrographolide time- and dose-dependently suppressed HCV replication. When combined with IFN-α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI-7977), andrographolide exhibited a significant synergistic effect. Andrographolide up-regulated the expression of haeme oxygenase-1 (HO-1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO-1-specific inhibitor or HO-1 gene knockdown, indicating that HO-1 contributed to the anti-HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)–mediated HO-1 expression, and this was found to be associated with its anti-HCV activity.
Our results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2–HO-1 signalling pathway might be a promising strategy for drug development.
PMCID: PMC3874710  PMID: 24117426
HCV; andrographolide; heme oxygenase-1; p38 MAPK; nuclear factor erythroid 2-related factor 2
3.  Rotating night shifts too quickly may cause anxiety and decreased attentional performance, and impact prolactin levels during the subsequent day: a case control study 
BMC Psychiatry  2014;14:218.
We investigated circadian changes and effects on mood, sleep-related hormones and cognitive performance when nurses worked consecutive night shifts in a rapidly rotating shift system. Daytime cognitive function, sleep propensity and sleep-related hormones (growth hormone, cortisol, prolactin, thyrotropin) were compared after participants worked two and four consecutive night shifts.
Twenty-three off-duty nurses, 20 nurses working two consecutive night shifts and 16 nurses working four consecutive night shifts were enrolled. All participants completed the Maintenance of Wakefulness Test, State-Trait Anxiety Inventory, Stanford Sleepiness Scale, visual attention tasks (VAT), Wisconsin Card Sorting Test, and modified Multiple Sleep Latency Test. Hormone levels were also measured four times throughout the day, at 2-h intervals.
During the day, the participants in the night shift groups were less able to maintain wakefulness, had poor performance on VAT, and higher thyrotropin levels than did those in the off-duty group. Participants who worked two night shifts were better able to maintain wakefulness, had higher anxiety scale scores, poorer initial performance and lack of learning effect on VAT, and higher prolactin levels compared with those who worked four night shifts. There were no differences in cortisol levels between the two- and four- shift groups.
Rotating night shifts too quickly may cause anxiety and decreased attentional performance, and may impact daytime prolactin levels after night shifts. It is possible that the two-shift group had a higher cortisol level than did the four-shift group, which would be consistent with the group’s higher state anxiety scores. The negative findings may be due to the small sample size. Further studies on the effects of consecutive night shifts on mood and cortisol levels during the daytime after sleep restriction would be valuable.
PMCID: PMC4141954  PMID: 25091387
Anxiety; Cognitive function; Nurse; Night shift; Sleep-related hormone; Circadian; Shift work
4.  Aqueous Extract of Gracilaria tenuistipitata Suppresses LPS-Induced NF-κB and MAPK Activation in RAW 264.7 and Rat Peritoneal Macrophages and Exerts Hepatoprotective Effects on Carbon Tetrachloride-Treated Rat 
PLoS ONE  2014;9(1):e86557.
In addition to the previous investigations of bioactivity of aqueous extract of the edible Gracilaria tenuistipitata (AEGT) against H2O2-induced DNA damage and hepatitis C virus replication, the purpose of this study is to evaluate the potential therapeutic properties of AEGT against inflammation and hepatotoxicity using lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 cells, primary rat peritoneal macrophages and carbon tetrachloride (CCl4)-induced acute hepatitis model in rats. AEGT concentration-dependently inhibited the elevated RNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2, thereby reducing nitric oxide and prostaglandin E2 levels, respectively. Moreover, AEGT significantly suppressed the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. These inhibitory effects were associated with the suppression of nuclear factor-kappa B activation and mitogen-activated protein kinase phosphorylation by AEGT in LPS-stimulated cells. In addition, we highlighted the hepatoprotective and curative effects of AEGT in a rat model of CCl4-intoxicated acute liver injury, which was evident from reduction in the elevated serum aspartate aminotransferase and alanine aminotransferase levels as well as amelioration of histological damage by pre-treatment or post-treatment of AEGT. In conclusion, the results demonstrate that AEGT may serve as a potential supplement in the prevention or amelioration of inflammatory diseases.
PMCID: PMC3903563  PMID: 24475143
5.  Green Tea Phenolic Epicatechins Inhibit Hepatitis C Virus Replication via Cycloxygenase-2 and Attenuate Virus-Induced Inflammation 
PLoS ONE  2013;8(1):e54466.
Chronic hepatitis C virus (HCV) infection is the leading risk factor for hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Green tea, in addition to being consumed as a healthy beverage, contains phenolic catechins that have been used as medicinal substances. In the present study, we illustrated that the epicatechin isomers (+)-epicatechin and (−)-epicatechin concentration-dependently inhibited HCV replication at nontoxic concentrations by using in vitro cell-based HCV replicon and JFH-1 infectious systems. In addition to significantly suppressing virus-induced cyclooxygenase-2 (COX-2) expression, our results revealed that the anti-HCV activity of the epicatechin isomers occurred through the down-regulation of COX-2. Furthermore, both the epicatechin isomers additively inhibited HCV replication in combination with either interferon-α or viral enzyme inhibitors [2′-C-methylcytidine (NM-107) or telaprevir]. They also had prominent anti-inflammatory effects by inhibiting the gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitrite oxide synthase as well as the COX-2 in viral protein-expressing hepatoma Huh-7 cells. Collectively, (+)-epicatechin and (−)-epicatechin may serve as therapeutic supplements for treating HCV-related diseases.
PMCID: PMC3554764  PMID: 23365670
6.  Differentially regulated splice variants and systems biology analysis of Kaposi's sarcoma-associated herpesvirus-infected lymphatic endothelial cells 
Nucleic Acids Research  2011;39(16):6970-6985.
Alternative RNA splicing greatly increases proteome diversity, and the possibility of studying genome-wide alternative splicing (AS) events becomes available with the advent of high-throughput genomics tools devoted to this issue. Kaposi's sarcoma associated herpesvirus (KSHV) is the etiological agent of KS, a tumor of lymphatic endothelial cell (LEC) lineage, but little is known about the AS variations induced by KSHV. We analyzed KSHV-controlled AS using high-density microarrays capable of detecting all exons in the human genome. Splicing variants and altered exon–intron usage in infected LEC were found, and these correlated with protein domain modification. The different 3′-UTR used in new transcripts also help isoforms to escape microRNA-mediated surveillance. Exome-level analysis further revealed information that cannot be disclosed using classical gene-level profiling: a significant exon usage difference existed between LEC and CD34+ precursor cells, and KSHV infection resulted in LEC-to-precursor, dedifferentiation-like exon level reprogramming. Our results demonstrate the application of exon arrays in systems biology research, and suggest the regulatory effects of AS in endothelial cells are far more complex than previously observed. This extra layer of molecular diversity helps to account for various aspects of endothelial biology, KSHV life cycle and disease pathogenesis that until now have been unexplored.
PMCID: PMC3167639  PMID: 21646333
7.  Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations 
BMC Genomics  2010;11:132.
Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.
We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.
Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.
PMCID: PMC2837036  PMID: 20178649
8.  Electroporating Fields Target Oxidatively Damaged Areas in the Cell Membrane 
PLoS ONE  2009;4(11):e7966.
Reversible electropermeabilization (electroporation) is widely used to facilitate the introduction of genetic material and pharmaceutical agents into living cells. Although considerable knowledge has been gained from the study of real and simulated model membranes in electric fields, efforts to optimize electroporation protocols are limited by a lack of detailed understanding of the molecular basis for the electropermeabilization of the complex biomolecular assembly that forms the plasma membrane. We show here, with results from both molecular dynamics simulations and experiments with living cells, that the oxidation of membrane components enhances the susceptibility of the membrane to electropermeabilization. Manipulation of the level of oxidative stress in cell suspensions and in tissues may lead to more efficient permeabilization procedures in the laboratory and in clinical applications such as electrochemotherapy and electrotransfection-mediated gene therapy.
PMCID: PMC2779261  PMID: 19956595
9.  Two-dimensional nanosecond electric field mapping based on cell electropermeabilization 
PMC Biophysics  2009;2:9.
Nanosecond, megavolt-per-meter electric pulses cause permeabilization of cells to small molecules, programmed cell death (apoptosis) in tumor cells, and are under evaluation as a treatment for skin cancer. We use nanoelectroporation and fluorescence imaging to construct two-dimensional maps of the electric field associated with delivery of 15 ns, 10 kV pulses to monolayers of the human prostate cancer cell line PC3 from three different electrode configurations: single-needle, five-needle, and flat-cut coaxial cable. Influx of the normally impermeant fluorescent dye YO-PRO-1 serves as a sensitive indicator of membrane permeabilization. The level of fluorescence emission after pulse exposure is proportional to the applied electric field strength. Spatial electric field distributions were compared in a plane normal to the center axis and 15-20 μm from the tip of the center electrode. Measurement results agree well with models for the three electrode arrangements evaluated in this study. This live-cell method for measuring a nanosecond pulsed electric field distribution provides an operationally meaningful calibration of electrode designs for biological applications and permits visualization of the relative sensitivities of different cell types to nanoelectropulse stimulation. PACS Codes: 87.85.M-
PMCID: PMC2779789  PMID: 19903362
10.  The M Type K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus Regulates MicroRNA Expression via Its SH2-Binding Motif To Induce Cell Migration and Invasion▿  
Journal of Virology  2008;83(2):622-632.
Kaposi's sarcoma (KS) associated herpesvirus (KSHV) is the etiological agent of KS. In vivo, KS is a tumor capable of spreading throughout the body, and pulmonary metastasis is observed clinically. In vitro, KSHV induces the invasiveness of endothelial cells. The KSHV open reading frame K15 is a KSHV-specific gene encoding a transmembrane protein. Two highly divergent forms of K15, the predominant (P) and minor (M) forms (K15P and K15M, respectively), have been identified in different KSHV strains. The two K15 alleles resemble the latent membrane protein 2A (LMP2A) gene of Epstein-Barr virus (EBV) in their genomic locations and protein topology. Also, both K15 proteins have motifs similar to those found in the EBV LMP1 protein. K15 therefore appears to be a hybrid of a distant evolutionary relative of EBV LMP1 and LMP2A. Since both LMP1 and LMP2A proteins are capable of inducing cell motility, we sought to determine whether K15 has similar abilities. In this study, we show that K15M is latently expressed in KSHV-positive PEL cells and knockdown of K15M in PEL cells reduces cell motility. K15M localizes to lysosomal membranes and induces cell migration, invasion, and NF-κB (but not AP-1) activity via its conserved SH2-binding motif. K15M also induces the expression of microRNAs miR-21 and miR-31 via this conserved motif, and knocking down both these microRNAs eliminates K15M-induced cell motility. Therefore, K15M may contribute to KSHV-mediated tumor metastasis and angiogenesis via regulation of miR-21 and miR-31, which we show here for the first time to be a specific regulator of cell migration. In light of these findings, the targeting of K15 or the downstream microRNAs regulated by it may represent novel therapies for treatment of KSHV-associated neoplasia.
PMCID: PMC2612383  PMID: 18971265

Results 1-10 (10)