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1.  Betel Chewing and Arecoline Affects Eotaxin-1, Asthma and Lung Function 
PLoS ONE  2014;9(3):e91889.
Background
Betel nut is commonly used in many countries. Despite evidence suggesting an association with asthma, few studies have investigated the connection between betel nut use and asthma; thus, the underlying mechanism for the association with asthma is also unclear. The aim of this study was to investigate the association between betel chewing and asthma as well as the associations of plasma arecoline (a biomarker for exposure) and eotaxin-1 (a potential mediator) with asthma and lung function.
Methods
We recruited 600 hospital-based asthmatic patients and 1200 age- and gender-matched community controls in southern Taiwan. To clarify the mechanism of action for eotaxin-1 in the association between betel chewing and asthma, we also designed an in vitro experiment to study the functional associations between arecoline exposure and eotaxin-1 levels.
Results
A significant association was found between asthma and current betel chewing (adjusted odds ratio 2.05, 95% CI = 1.12–3.76), which was independent of potential confounders but was attenuated following adjustment for eotaxin-1. Arecoline and eotaxin-1 levels were positively correlated (Spearman r = 0.303, p = 0.02), while arecoline and arecaidine were negatively correlated with lung function. Functionally, arecoline alone does not induce eotaxin-1 release in vitro from dermal and gingival fibroblasts. However, in the presence of IL-4 and TNF-alpha, arecoline at 100 μg/ml induced more eotaxin-1 release than arecoline at 0 μg/ml (2700±98 pg/ml vs 1850±142 pg/ml, p = 0.01 in dermal fibroblast cells, and 1489±78 pg/ml vs 1044±95 pg/ml, p = 0.03 in gingival fibroblast cells, respectively).
Conclusion
Betel chewing is associated with asthma in this population, with arecoline induction of eotaxin-1 supported as a plausible causal pathway.
doi:10.1371/journal.pone.0091889
PMCID: PMC3962362  PMID: 24658613
2.  Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection 
PLoS ONE  2014;9(3):e91167.
Background/Objective
Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved.
Methodology/Principal Findings
In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo.
Conclusion/Significance
The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.
doi:10.1371/journal.pone.0091167
PMCID: PMC3951295  PMID: 24621589
3.  Female Gender and Acne Disease Are Jointly and Independently Associated with the Risk of Major Depression and Suicide: A National Population-Based Study 
BioMed Research International  2014;2014:504279.
Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. Using a database from the National Health Insurance, which included 98% of the population of Taiwan in 2006, we identified patients of acne, major depression, and suicide based on ICD-9-CM codes. Totally 47111 patients with acne were identified (16568 males and 30543 females) from 1 million subjects. The youths of 7–12 years had the highest prevalence of acne (14.39%). Major depression was more common in those with acne (0.77%) than controls (0.56% , P < 0.0001) regardless of gender. Multiple logistic regression showed an increased risk of major depression in women without acne (OR = 1.85, 95% CI 1.75–1.96). The risk is additive in women with acne (OR = 2.78, 95% CI 2.43–3.17). Similar additive risk of suicide was noticed in women with acne. In conclusion, acne and gender, independently and jointly, are associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide.
doi:10.1155/2014/504279
PMCID: PMC3942337  PMID: 24678508
4.  Increased Tea Consumption Is Associated with Decreased Arterial Stiffness in a Chinese Population 
PLoS ONE  2014;9(1):e86022.
Background
Tea has attracted considerable attention for its potential cardioprotective effects. The primary chemical components of tea are thought to have a beneficial effect by reducing arterial stiffness. The objective of this study was to assess the association between tea consumption and brachial–ankle pulse wave velocity (baPWV) in a relatively healthy Chinese population.
Methods
We enrolled 3,135 apparently healthy subjects from October 2006 to August 2009. Subjects taking medication for diabetes, hypertension, or hyperlipidemia, or with a history of cardiovascular disease, were excluded from the study. The subjects were categorized into three groups according to their tea-drinking habits: (1) none to low (n = 1615), defined as non-habitual tea drinkers, or drinking for <1 year, or drinking ≤150 mL per day for ≥1 year ; (2) moderate tea consumption, defined as drinking for ≥1 year and consumption between 151 and 450 mL per day; and (3) heavy tea consumption, defined as a drinking for ≥1 year and consumption >450 mL per day. Multiple logistic regression was used to determine whether different levels of consumption were independently associated with the highest quartile of baPWV values, defined as ≥1428.5 cm/s.
Results
Of the 3,135 subjects, 48.5% had drunk >150 mL of tea per day for at least 1 year. In multivariate regression analysis with adjustment for co-variables, including, age, sex, current smoking, alcohol use, habitual exercise, total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio >5, obesity, newly diagnosed hypertension and diabetes, subjects with high tea consumption had a decreased risk of highest quartile of baPWV by 22% (odds ratio = 0.78, 95% confidence interval = 0.62–0.98, p = 0.032), while subjects with moderate tea consumption did not (p = 0.742), as compared subjects with none to low tea consumption.
Conclusions
High, but not moderate, habitual tea consumption may decrease arterial stiffness.
doi:10.1371/journal.pone.0086022
PMCID: PMC3899106  PMID: 24465848
5.  Host metabolism regulates intracellular growth of Trypanosoma cruzi 
Cell host & microbe  2013;13(1):108-117.
SUMMARY
Metabolic coupling of intracellular pathogens with host cells is essential for successful colonization of the host. Establishment of intracellular infection by the protozoan Trypanosoma cruzi leads to the development of human Chagas disease, yet the functional contributions of the host cell toward the infection process remain poorly characterized. Here, a genome-scale functional screen identified interconnected metabolic networks centered around host energy production, nucleotide metabolism, pteridine biosynthesis, and fatty acid oxidation as key processes that fuel intracellular T. cruzi growth. Additionally, the host kinase Akt, which plays essential roles in various cellular processes, was critical for parasite replication. Targeted perturbations in these host metabolic pathways or Akt-dependent signaling pathways modulated the parasite’s replicative capacity, highlighting the adaptability of this intracellular pathogen to changing conditions in the host. These findings identify key cellular process regulating intracellular T. cruzi growth and illuminate the potential to leverage host pathways to limit T. cruzi infection.
doi:10.1016/j.chom.2012.11.011
PMCID: PMC3560928  PMID: 23332160
6.  Acute kidney injury due to anti-tuberculosis drugs: a five-year experience in an aging population 
Background
Patients on anti-tuberculosis treatment may develop acute kidney injury (AKI), but little is known about the renal outcome and prognostic factors, especially in an aging population. This study aimed to calculate the incidence of AKI due to anti-TB drugs and analyze the outcomes and predictors of renal recovery.
Methods
From 2006 to 2010, patients on anti-TB treatment were identified and their medical records reviewed. Acute kidney injury was defined according to the criteria established by the AKI Network, while renal recovery was defined as a return of serum creatinine to baseline. Predictors of renal recovery were identified by Cox regression analysis.
Results
Ninety-nine out of 1394 (7.1%) patients on anti-TB treatment had AKI. Their median age was 68 years and there was male predominance. Sixty (61%) developed AKI within two months of anti-TB treatment, including 11 (11%) with a prior history of rifampin exposure. Thirty (30%) had co-morbid chronic kidney disease or end-stage renal disease. The median time of renal recovery was 39.6 days (range, 1–180 days). Factors predicting renal recovery were the presence of fever, rash, and gastro-intestinal disturbance at the onset of AKI. Sixty-two of the 71 (87%) patients who recovered from AKI had successful re-introduction or continuation of rifampin.
Conclusions
Renal function impairment is not a rare complication during anti-TB treatment in an elderly population. The presence of fever and rash may be associated with renal recovery. Rifampin can still be used in most patients who recover from AKI.
doi:10.1186/1471-2334-14-23
PMCID: PMC3898246  PMID: 24410958
Acute kidney injury; Anti-tuberculosis drug; Fever; Rash; Rifampin
7.  Meiotic Crossover Control by Concerted Action of Rad51-Dmc1 in Homolog Template Bias and Robust Homeostatic Regulation 
PLoS Genetics  2013;9(12):e1003978.
During meiosis, repair of programmed DNA double-strand breaks (DSBs) by recombination promotes pairing of homologous chromosomes and their connection by crossovers. Two DNA strand-exchange proteins, Rad51 and Dmc1, are required for meiotic recombination in many organisms. Studies in budding yeast imply that Rad51 acts to regulate Dmc1's strand exchange activity, while its own exchange activity is inhibited. However, in a dmc1 mutant, elimination of inhibitory factor, Hed1, activates Rad51's strand exchange activity and results in high levels of recombination without participation of Dmc1. Here we show that Rad51-mediated meiotic recombination is not subject to regulatory processes associated with high-fidelity chromosome segregation. These include homolog bias, a process that directs strand exchange between homologs rather than sister chromatids. Furthermore, activation of Rad51 does not effectively substitute for Dmc1's chromosome pairing activity, nor does it ensure formation of the obligate crossovers required for accurate homolog segregation. We further show that Dmc1's dominance in promoting strand exchange between homologs involves repression of Rad51's strand-exchange activity. This function of Dmc1 is independent of Hed1, but requires the meiotic kinase, Mek1. Hed1 makes a relatively minor contribution to homolog bias, but nonetheless this is important for normal morphogenesis of synaptonemal complexes and efficient crossing-over especially when DSB numbers are decreased. Super-resolution microscopy shows that Dmc1 also acts to organize discrete complexes of a Mek1 partner protein, Red1, into clusters along lateral elements of synaptonemal complexes; this activity may also contribute to homolog bias. Finally, we show that when interhomolog bias is defective, recombination is buffered by two feedback processes, one that increases the fraction of events that yields crossovers, and a second that we propose involves additional DSB formation in response to defective homolog interactions. Thus, robust crossover homeostasis is conferred by integrated regulation at initiation, strand-exchange and maturation steps of meiotic recombination.
Author Summary
Meiosis is the specialized cell division that produces gametes by precisely reducing the chromosome copy number from two to one. Accurate segregation of homologous chromosome pairs requires they be connected by crossing-over, the precise breakage and exchange of chromosome arms that is carried out by a process called recombination. Recombination is regulated so each pair of homologous chromosomes becomes connected by at least one crossover. We studied the roles of two recombination proteins, Rad51 and Dmc1, which can act directly to join homologous DNA molecules. Our evidence supports the idea that Dmc1 is the dominant joining activity, while Rad51 acts indirectly with other proteins to support and regulate Dmc1. Furthermore, Hed1, an inhibitor of Rad51's DNA joining activity, is also shown to enhance the efficiency of crossing-over. Cells in which Rad51 is activated to promote DNA joining in place of Dmc1 have unregulated and inefficient crossing-over that often leaves chromosome pairs without the requisite crossover. Despite these defects, most cells that use Rad51 in place of Dmc1 complete meiosis and produce high levels of crossovers. Our results indicate that compensatory processes ensure that meiotic cells accumulate high levels of crossover intermediates before progressing to the first round of chromosome segregation.
doi:10.1371/journal.pgen.1003978
PMCID: PMC3868528  PMID: 24367271
8.  Phenotypes and Genotypes of Patients with Pantothenate Kinase-Associated Neurodegeneration in Asian and Caucasian Populations: 2 Cases and Literature Review 
The Scientific World Journal  2013;2013:860539.
Objectives. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. Methods. Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. Results. We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations—lower prevalence of pyramidal signs, mental impairment, and parkinsonism—than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. Conclusions. Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.
doi:10.1155/2013/860539
PMCID: PMC3854131  PMID: 24348190
9.  Effects of Combined Phase III and Phase II Cardiac Exercise Therapy for Middle-aged Male Patients with Acute Myocardial Infarction 
Journal of Physical Therapy Science  2013;25(11):1415-1420.
[Purpose] To investigate the effects of cardiac exercise therapy (CET) on exercise capacity and coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Methods] Patients who participated in an 8-week supervised, hospital-based phase II and 6-month home-based phase III CET with monthly telephone and/or home visits were defined as the exercise group (EG) (n=20), while those who did not receive phase II or phase III CET were defined as the no-exercise group (NEG) (n=10). CRFs were evaluated pre- and post-phase II and eight months after discharge. One and two-way repeated measures ANOVA were used to perform intra- and inter-group comparisons. [Results] Thirty men with AMI aged 49.3 ± 8.3 years were studied. EG increased their exercise capacity (METs) (6.8 ± 1.6 vs.10.0 ± 1.9) after phase II CET and was able to maintain it at 8-month follow-up. Both groups had significantly fewer persons who kept on smoking compared to the first examination. High density lipoprotein cholesterol (HDL-C) increased from 38.1 ± 11.0 to 43.7 ± 8.7 mg/dl at follow-up in EG while no significant difference was noted in NEG. [Conclusion] After phase III CET subjects had maintained the therapeutic effects of smoking cessation, and increasing exercise capacity obtained in phase II CET. HDL-C in EG continued to improve during phase III CET.
doi:10.1589/jpts.25.1415
PMCID: PMC3881468  PMID: 24396201
Acute myocardial infarction; Cardiac exercise therapy; Coronary risk factors
10.  Analysis for Distinctive Activation Patterns of Pain and Itchy in the Human Brain Cortex Measured Using Near Infrared Spectroscopy (NIRS) 
PLoS ONE  2013;8(10):e75360.
Pain and itch are closely related sensations, yet qualitatively quite distinct. Despite recent advances in brain imaging techniques, identifying the differences between pain and itch signals in the brain cortex is difficult due to continuous temporal and spatial changes in the signals. The high spatial resolution of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has substantially advanced research of pain and itch, but these are uncomfortable because of expensiveness, importability and the limited operation in the shielded room. Here, we used near infrared spectroscopy (NIRS), which has more conventional usability. NIRS can be used to visualize dynamic changes in oxygenated hemoglobin and deoxyhemoglobin concentrations in the capillary networks near activated neural circuits in real-time as well as fMRI. We observed distinct activation patterns in the frontal cortex for acute pain and histamine-induced itch. The prefrontal cortex exhibited a pain-related and itch-related activation pattern of blood flow in each subject. Although it looked as though that activation pattern for pain and itching was different in each subject, further cross correlation analysis of NIRS signals between each channels showed an overall agreement with regard to prefrontal area involvement. As a result, pain-related and itch-related blood flow responses (delayed responses in prefrontal area) were found to be clearly different between pain (τ = +18.7 sec) and itch (τ = +0.63 sec) stimulation. This is the first pilot study to demonstrate the temporal and spatial separation of a pain-induced blood flow and an itch-induced blood flow in human cortex during information processing.
doi:10.1371/journal.pone.0075360
PMCID: PMC3789686  PMID: 24098378
11.  Multiscale Cross-Approximate Entropy Analysis as a Measurement of Complexity between ECG R-R Interval and PPG Pulse Amplitude Series among the Normal and Diabetic Subjects 
Physiological signals often show complex fluctuation (CF) under the dual influence of temporal and spatial scales, and CF can be used to assess the health of physiologic systems in the human body. This study applied multiscale cross-approximate entropy (MC-ApEn) to quantify the complex fluctuation between R-R intervals series and photoplethysmography amplitude series. All subjects were then divided into the following two groups: healthy upper middle-aged subjects (Group 1, age range: 41–80 years, n = 27) and upper middle-aged subjects with type 2 diabetes (Group 2, age range: 41–80 years, n = 24). There are significant differences of heart rate variability, LHR, between Groups 1 and 2 (1.94 ± 1.21 versus 1.32 ± 1.00, P = 0.031). Results demonstrated differences in sum of large scale MC-ApEn (MC-ApEnLS) (5.32 ± 0.50 versus 4.74 ± 0.78, P = 0.003). This parameter has a good agreement with pulse-pulse interval and pulse amplitude ratio (PAR), a simplified assessment for baroreflex activity. In conclusion, this study employed the MC-ApEn method, integrating multiple temporal and spatial scales, to quantify the complex interaction between the two physical signals. The MC-ApEnLS parameter could accurately reflect disease process in diabetics and might be another way for assessing the autonomic nerve function.
doi:10.1155/2013/231762
PMCID: PMC3794634  PMID: 24174987
12.  Functional Ginger Extracts from Supercritical Fluid Carbon Dioxide Extraction via In Vitro and In Vivo Assays: Antioxidation, Antimicroorganism, and Mice Xenografts Models 
The Scientific World Journal  2013;2013:210845.
Supercritical fluid carbon dioxide extraction technology was developed to gain the active components from a Taiwan native plant, Zingiber officinale (ginger). We studied the biological effects of ginger extracts via multiple assays and demonstrated the biofunctions in each platform. Investigations of ginger extracts indicated antioxidative properties in dose-dependant manners on radical scavenging activities, reducing powers and metal chelating powers. We found that ginger extracts processed moderate scavenging values, middle metal chelating levels, and slight ferric reducing powers. The antibacterial susceptibility of ginger extracts on Staphylococcus aureus, Streptococcus sobrinus, S. mutans, and Escherichia coli was determined with the broth microdilution method technique. The ginger extracts had operative antimicroorganism potentials against both Gram-positive and Gram-negative bacteria. We further discovered the strong inhibitions of ginger extracts on lethal carcinogenic melanoma through in vivo xenograft model. To sum up, the data confirmed the possible applications as medical cosmetology agents, pharmaceutical antibiotics, and food supplements.
doi:10.1155/2013/210845
PMCID: PMC3745960  PMID: 23983624
13.  Risk Factors of Fecal Toxigenic or Non-Toxigenic Clostridium difficile Colonization: Impact of Toll-Like Receptor Polymorphisms and Prior Antibiotic Exposure 
PLoS ONE  2013;8(7):e69577.
Background
This study is to investigate the significance and risk factors of fecal toxigenic (tCdC) or non-toxigenic Clostridium difficile colonization (ntCdC) among hospitalized patients.
Methods
Adults admitted to medical wards in a district hospital between January 2011 and June 2012 were enrolled, and those with a history of colectomy, C. difficile fecal colonization or infection or receipt of either metronidazole or oral vancomycin within 3 months, were excluded. Stools collected within 48 hours after admission and every week during hospitalization were cultured for C. difficile.
Findings
Among the 441 enrolled patients, 84 (20.0%) had CdC at initial screening, including 58 (13.2%) with tCdC and 26 (6.8%) with ntCdC. Among patients with initial negative fecal screening for CdC, it took an average of 70.6 days or 66.5 days to develop tCdC or ntCdC during the study period. Finally 78 (17.7%) had tCdC and 34 (7.7%) had ntCdC. During the follow-up period, the patients with tCdC had a higher risk of CDAD (11/79, 14.1%) than those without CdC (3/328, 0.9%) and those with ntCdC (0/34, 0%) (P<0.001). In multivariate analysis, the TLR4 rs1927914 polymorphism (GG genotype) (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.6–11.8, P = 0.003) and recent cefepime therapy (OR 5.3, 95% CI 2.1–13.2, P<0.001) were independently associated with tCdC, whereas recent cefuroxime (OR 11.7, 95% CI 2.3–60.2, P = 0.003) and glycopeptide therapy (OR 10.9, CI: 2.1–57.2, P = 0.005) associated with ntCdC.
Conclusion
The incidence of CDAD is highest in patients with tCdC and lowest in patients with ntCdC, and the TLR4 rs1927914 polymorphism GG genotype and recent cefepime therapy were independently associated with tCdC.
doi:10.1371/journal.pone.0069577
PMCID: PMC3723847  PMID: 23936050
14.  Increased Risk of Active Tuberculosis following Acute Kidney Injury: A Nationwide, Population-Based Study 
PLoS ONE  2013;8(7):e69556.
Background
Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited.
Methods
This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999–2008 and validated using the NSARF data. Time-dependent Cox proportional hazards model to adjust for the ongoing effect of end-stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization.
Results
Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; p<0.001) and did not (HR, 6.39; p<0.001) recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup (HR = 4.37; p = 0.049) had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis (HR, 1.34; p = 0.032).
Conclusions
AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB.
doi:10.1371/journal.pone.0069556
PMCID: PMC3723893  PMID: 23936044
15.  Standardization of Malaysian Adult Female Nasal Cavity 
This research focuses on creating a standardized nasal cavity model of adult Malaysian females. The methodology implemented in this research is a new approach compared to other methods used by previous researchers. This study involves 26 females who represent the test subjects for this preliminary study. Computational fluid dynamic (CFD) analysis was carried out to better understand the characteristics of the standardized model and to compare it to the available standardized Caucasian model. This comparison includes cross-sectional areas for both half-models as well as velocity contours along the nasal cavities. The Malaysian female standardized model is larger in cross-sectional area compared to the standardized Caucasian model thus leading to lower average velocity magnitudes. The standardized model was further evaluated with four more Malaysian female test subjects based on its cross-sectional areas and average velocity magnitudes along the nasal cavities. This evaluation shows that the generated model represents an averaged and standardized model of adult Malaysian females.
doi:10.1155/2013/519071
PMCID: PMC3697144  PMID: 23840279
17.  Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways 
Cell metabolism  2011;14(1):21-32.
Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
doi:10.1016/j.cmet.2011.06.002
PMCID: PMC3652544  PMID: 21723501
18.  Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways 
Nature medicine  2012;18(11):1665-1672.
Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling metabolic dysfunction associated with chronic inflammation remains unexplored. We demonstrate here that administration of Lacto-N-fucopentaose III (LNFPIII), a LewisX containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased Il-10 production by LNFPIII activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment up-regulates nuclear receptor Fxr-α (or Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-Ap1 pathway appears to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide novel therapeutic approaches to treat metabolic diseases.
doi:10.1038/nm.2962
PMCID: PMC3493877  PMID: 23104131
19.  Risk factors for pulmonary tuberculosis in patients with chronic obstructive airway disease in Taiwan: a nationwide cohort study 
BMC Infectious Diseases  2013;13:194.
Background
An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use. Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear.
Methods
We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB.
Results
Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected. Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205–2.762]) were independent risk factors for TB. Among the COPD cases, those who developed TB received more oral corticosteroids and oral β-agonists. Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral β-agonist dose, but not ICS dose, were independent risk factors for TB. The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios.
Conclusion
Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications. Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice.
doi:10.1186/1471-2334-13-194
PMCID: PMC3652752  PMID: 23631563
Chronic obstructive pulmonary disease; Tuberculosis; Inhaled corticosteroid; Oral corticosteroid; Time-dependent cox regression
20.  LASAGNA: A novel algorithm for transcription factor binding site alignment 
BMC Bioinformatics  2013;14:108.
Background
Scientists routinely scan DNA sequences for transcription factor (TF) binding sites (TFBSs). Most of the available tools rely on position-specific scoring matrices (PSSMs) constructed from aligned binding sites. Because of the resolutions of assays used to obtain TFBSs, databases such as TRANSFAC, ORegAnno and PAZAR store unaligned variable-length DNA segments containing binding sites of a TF. These DNA segments need to be aligned to build a PSSM. While the TRANSFAC database provides scoring matrices for TFs, nearly 78% of the TFs in the public release do not have matrices available. As work on TFBS alignment algorithms has been limited, it is highly desirable to have an alignment algorithm tailored to TFBSs.
Results
We designed a novel algorithm named LASAGNA, which is aware of the lengths of input TFBSs and utilizes position dependence. Results on 189 TFs of 5 species in the TRANSFAC database showed that our method significantly outperformed ClustalW2 and MEME. We further compared a PSSM method dependent on LASAGNA to an alignment-free TFBS search method. Results on 89 TFs whose binding sites can be located in genomes showed that our method is significantly more precise at fixed recall rates. Finally, we described LASAGNA-ChIP, a more sophisticated version for ChIP (Chromatin immunoprecipitation) experiments. Under the one-per-sequence model, it showed comparable performance with MEME in discovering motifs in ChIP-seq peak sequences.
Conclusions
We conclude that the LASAGNA algorithm is simple and effective in aligning variable-length binding sites. It has been integrated into a user-friendly webtool for TFBS search and visualization called LASAGNA-Search. The tool currently stores precomputed PSSM models for 189 TFs and 133 TFs built from TFBSs in the TRANSFAC Public database (release 7.0) and the ORegAnno database (08Nov10 dump), respectively. The webtool is available at http://biogrid.engr.uconn.edu/lasagna_search/.
doi:10.1186/1471-2105-14-108
PMCID: PMC3747862  PMID: 23522376
21.  Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy 
The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.
doi:10.3390/ijms14036414
PMCID: PMC3634415  PMID: 23519108
UVR; apoptosis; oxidative stress; keratinocyte; langerhans cells; immunosuppression; phototherapy
22.  A PML-PPARδ pathway for fatty acid oxidation regulates haematopoietic stem cell maintenance 
Nature medicine  2012;18(9):1350-1358.
Stem cell function is an exquisitely regulated process. To date, however, the contribution of metabolic cues to stem cell function is poorly understood. Here we identify a novel PML - Peroxisome-proliferator activated receptor delta (PPARδ) - fatty acid oxidation (FAO) pathway for haematopoietic stem cell (HSC) maintenance. We have found that loss of Ppard profoundly affects the maintenance of HSCs. Moreover, treatment with PPARδ agonists improves these HSC functions, whereas, conversely, inhibition of mitochondrial FAO induces loss of the HSC compartment. Importantly, we demonstrate that PML exerts its essential role in HSC maintenance through regulation of PPAR signalling and FAO. Mechanistically, the PML-PPARδ-FAO pathway controls HSC asymmetric division. Depletion of Ppard or Pml, as well as FAO inhibition, results in symmetric commitment of HSC daughter cells while, conversely, PPARδ activation increases asymmetric division. Thus, our findings identify a new metabolic switch for the control of HSC cell fate with important therapeutic implications.
doi:10.1038/nm.2882
PMCID: PMC3566224  PMID: 22902876
23.  Direct control of hepatic glucose production by interleukin-13 in mice 
Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13–/–) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13–/– mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.
doi:10.1172/JCI64941
PMCID: PMC3533296  PMID: 23257358
24.  Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA bindingand degradation 
Molecular Biology of the Cell  2012;23(18):3764-3774.
The prolyl hydroxylase Ofd1 enables yeast cells to adapt to hypoxia by regulating the DNA binding and degradation of the hypoxic transcription factor Sre1N. These two regulatory functions are inseparable in vivo. A mathematical model of the Ofd1 system is used to show that both functions are necessary for Ofd1 to work as observed.
Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element–binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen-dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved.
doi:10.1091/mbc.E12-06-0451
PMCID: PMC3442422  PMID: 22833559
25.  AhR activation underlies the CYP1A autoinduction by A-998679 in rats 
Frontiers in Genetics  2012;3:213.
Xenobiotic-mediated induction of cytochrome P450 (CYP) drug metabolizing enzymes (DMEs) is frequently encountered in drug discovery and can influence disposition, pharmacokinetic, and toxicity profiles. The CYP1A subfamily of DMEs plays a central role in the biotransformation of several drugs and environmental chemicals. Autoinduction of drugs through CYP3A enzymes is a common mechanism for their enhanced clearance. However, autoinduction via CYP1A is encountered less frequently. In this report, an experimental compound, A-998679 [3-(5-pyridin-3-yl-1,2,4-oxadiazol-3-yl) benzonitrile], was shown to enhance its own clearance via induction of Cyp1a1 and Cyp1a2. Rats were dosed for 5 days with 30, 100, and 200 mg/kg/day A-998679. During the dosing period, the compound's plasma AUC decreased at 30 mg/kg (95%) and 100 mg/kg (80%). Gene expression analysis and immunohistochemistry of the livers showed a large increase in the mRNA and protein levels of Cyp1a, which was involved in the biotransformation of A-998679. Induction of CYP1A was confirmed in primary rat, human, and dog hepatocytes. The compound also weakly inhibited CYP1A2 in human liver microsomes. A-998679 activated the aryl hydrocarbon receptor (AhR) in a luciferase gene reporter assay in HepG2 cells, upregulated expression of genes associated with AhR activation in rat liver and enhanced nuclear migration of AhR in HepG2 cells. Collectively these results demonstrate that A-998679 is an AhR activator that induces Cyp1a1 and Cyp1a2 expression, resulting in an autoinduction phenomenon. The unique properties of A-998679, along with its novel structure distinct from classical polycyclic aromatic hydrocarbons (PAHs), may warrant its further evaluation as a tool compound for use in studies involving AhR biology and CYP1A-related mechanisms of drug metabolism and toxicity.
doi:10.3389/fgene.2012.00213
PMCID: PMC3481155  PMID: 23112805
aryl hydrocarbon receptor; cytochrome P450; autoinduction

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