Tumor invasion and metastasis are the major causes of treatment failure and mortality in lung cancer patients. In this study, we identified a group of genes with differential expression in in situ ...and invasive lung adenocarcinoma tissues by expression profiling; among these genes we further characterized the association of the upregulation of PRNP, the gene encoding cellular Prion protein (PrPc), with lung adenocarcinoma invasiveness. Immunohistochemistry on clinical specimens showed an association of PrPc expression with invasive but not in situ lung adenocarcinoma. Consistently, the expression of PrPc was higher in the highly invasive than in the lowly invasive lung adenocarcinoma cell lines. Knockdown of PrPc expression in cultured lung adenocarcinoma cells decreased their lamellipodium formation, in vitro migration and invasion, and in vivo experimental lung metastasis. Phosphorylation of JNKs was found to correlate with PrPc expression and the inhibition of JNKs suppressed the PrPc-induced up-regulation of lamellipodium formation, cell migration, and invasion. Moreover, we identified the nuclear factor, interleukin 3 regulated (NFIL3) protein as a transcriptional activator of the PRNP promoter. Accordingly, NFIL3 promoted lung cancer cell migration and invasion in a PrPc-dependent manner. High NFIL3 expression in clinical specimens of lung adenocarcinoma was also associated with tumor invasiveness. Overall, our observations suggest that the NFIL3/PrPc axis, through regulating lamellipodium formation and cell mobility via JNK signaling, plays a critical role in lung cancer invasiveness and metastasis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming. Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal ...and umbilical cord leukocytes. Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure. Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 µg/L (range: < 1-230 µg/L). Methylation in LINE-1 increased by 1.36% 95% confidence interval (CI): 0.52, 2.21% and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation. Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
•Plasma selenium level was significantly positively associated with eGFR in a dose-dependent manner.•High plasma selenium and low red blood cell cadmium or lead levels significantly interacted to ...decrease the OR for CKD.•High plasma selenium and low red blood cell lead levels significantly interacted to increase the eGFR.
This study aimed to determine the interaction of red blood cell cadmium and lead, total urinary arsenic, and plasma selenium in chronic kidney disease (CKD). We recruited 220 CKD patients as well as 438 gender- and age-matched controls, and we defined CKD as <60 mL/min/1.73 m2 estimated glomerular filtration rate (eGFR) for three or more consecutive months. Plasma selenium and red blood cell cadmium and lead concentrations were measured by ICP-MS. Urinary arsenic species were determined via HPLC-HG-AAS and were summed to determine the total urinary arsenic concentration. Plasma selenium was positively correlated to eGFR, and subjects with high plasma selenium levels (>243.90 μg/L) had a significantly lower odds ratio (OR) and 95% confidence interval (CI) (0.23, 0.13–0.42) for CKD compared to those with low plasma selenium levels (≤ 196.70 μg/L). High plasma selenium and low red blood cell cadmium or lead concentrations interacted to decrease the OR and 95% CI for CKD (0.12, 0.06–0.26; 0.09, 0.04–0.19). High plasma selenium and low red blood cell lead levels also interacted to increase the eGFR (20.70, 15.56–26.01 mL/min/1.73 m2). This study is the first to suggest that selenium modifies the eGFR and OR in CKD induced by environmental toxicants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. ...The adiponectin gene
is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with diabetes and diabetic nephropathy. The purpose of this study was to investigate the association between
polymorphism and CKD. In addition; the combined effects of
polymorphism and diabetes and levels of total urinary arsenic and blood cadmium on CKD were also explored. This study included 215 CKD patients and 423 age-sex matched controls. The
polymorphisms were determined using the Agena Bioscience Mass ARRAY System. The levels of blood cadmium and urinary arsenic species were measured. The
rs182052 GA/AA genotype had a marginally lower odds ratio (OR) for CKD than the GG genotype. The OR (95% confidence interval; CI) was 16.33 (5.72-46.66) of CKD in subjects carrying the
rs182052 GG genotype and diabetes compared to non-diabetes subjects carrying the
rs182052 GA/AA genotype; the interaction term had
= 0.015; and the synergy index was 6.64 (1.81-24.36) after multivariate adjustment. A significant interaction of diabetes and
rs1501299 risk genotype increased the OR of CKD after multivariate adjustment with a synergy index of 0.31 (0.11-0.86) and a multiplicative interaction with
= 0.001. These results suggest that
rs182052 and rs1501299 risk genotypes may significantly modify the association between diabetes and CKD but not the association between total urinary arsenic and blood cadmium and CKD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Our study showed that total urinary arsenic concentrations were positively correlated with renal cell carcinoma (RCC). Chronic inflammation is a key player in the development of RCC. This study ...explored the association between nucleotide-binding domain-like receptor protein 3 (NLRP3) genotypes and the development of RCC. We also investigated whether any of the NLRP3 genotypes modified the risk between arsenic and RCC. We recruited 350 RCC patients and 700 age-sex matched controls. RCC was confirmed by pathological assessment following surgical resection or image-guided biopsy of a renal tumor. Fifteen sites of NLRP3 gene polymorphisms were identified using the Agena Bioscience MassARRAY platform. The concentrations of the urinary arsenic species were determined by HPLC-HG-AAS. There was a significant dose-dependent association between arsenic and RCC. In addition, six of thirteen NLRP3 alleles, including rs12239046 C, rs10925025 G, rs1539019 C, rs10925026 A, rs10157379 T, and rs12143966 A, had increased odds ratios (ORs) for RCC than other NLRP3 alleles. Among these sites, we found the novel haplotype of five tag-SNPs (C-A-A-A-A) was significantly related to RCC, the OR and 95% confidence interval was 1.44 (1.08-1.92). Furthermore, participants with high total urinary arsenic levels and the NLRP3 rs1539019 C allele had significantly multiplicative and additive interactions for the risk of RCC (p
= 0.012). This study is the first to identify the modified effects of NLRP3 risk alleles involved in the association between arsenic and RCC risk in a population with low arsenic exposure.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The emergence of carbapenemase-producing Klebsiella pneumoniae (CPKP) has become a great concern worldwide. In this study, 994 non-duplicate, carbapenem non-susceptible Klebsiella pneumonia isolates ...were collected in Taiwan from 2011 to 2013 for detection of the carbapenemase genes, assessment of antimicrobial susceptibility and molecular epidemiology studies. Of these 994 isolates, 183 (18.4%) had carbapenemase genes: 157 (15.8%) KPC (145 KPC-2 and 12 KPC-17), 16 (1.6%) IMP-8, 9 (0.9%) VIM-1, and 1 (0.1%) NDM-1. KPC had the highest prevalence rate among the carbapenemases and represented a major epidemic clone circulating in Taiwan. The ST512 and ST258 KPC-2 KPs were first identified in Taiwan and were grouped into a small cluster in the PFGE profile. In addition, the genetic structure encompassing the blaKPC gene of the ST512 and ST258 isolates showed a different pattern from that of other KPC isolates. ST11 may be a major sequence type circulating in Taiwan, although a specific minor clone has begun to be observed. This is the first report of ST258 and ST512 KPC-2 KP isolates in Taiwan, whether ST258 and ST512 will become the next endemic problems in Taiwan should be closely monitored.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Single nucleotide polymorphisms (SNPs) may influence arsenic methylation efficiency, affecting arsenic metabolism. Whether gene-environment interactions affect arsenic metabolism during pregnancy ...remains unclear, which may have implications for pregnancy outcomes.
We aimed to investigate main effects as well as potential SNP-arsenic interactions on arsenic methylation efficiency in pregnant women.
We recruited 1613 pregnant women in Bangladesh, and collected two urine samples from each participant, one at 4–16 weeks, and the second at 21–37 weeks of pregnancy. We determined the proportions of each arsenic metabolite inorganic As (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA)% from the total urinary arsenic level of each sample. A panel of 63 candidate SNPs was selected for genotyping based on their reported associations with arsenic metabolism (including in As3MT, N6AMT1, and GSTO2 genes). We used linear regression models to assess the association between each SNP and DMA% with an additive allelic assumption, as well as SNP-arsenic interaction on DMA%. These analyses were performed separately for two urine collection time-points to capture differences in susceptibility to arsenic toxicity.
Intron variants for As3MT were associated with DMA%. rs9527 (β = −2.98%, PFDR = 0.008) and rs1046778 (β = 1.64%, PFDR = 0.008) were associated with this measure in the early gestational period; rs3740393 (β = 2.54%, PFDR = 0.002) and rs1046778 (β = 1.97%, PFDR = 0.003) in the mid-to-late gestational period. Further, As3MT, GSTO2, and N6AMT1 polymorphisms showed different effect sizes on DMA% conditional on arsenic exposure levels. However, SNP-arsenic interactions were not statistically significant after adjusting for false discovery rate (FDR). rs1048546 in N6AMT1 had the highest significance level in the SNP-arsenic interaction test during mid-to-late gestation (β = −1.8% vs. 1.4%, PGxE_FDR = 0.075). Finally, As3MT and As3MT/CNNM2 haplotypes were associated with DMA% at both time points.
We found that not all genetic associations reported in arsenic methylation efficiency replicate in pregnant women. Arsenic exposure level has a limited effect in modifying the association between genetic variation and arsenic methylation efficiency.
•As3MT polymorphisms affect arsenic methylation efficiency throughout pregnancy.•The SNP-arsenic interaction effect on DMA% is not significant after adjusting for FDR.•N6AMT1 SNPs may interact with arsenic level affecting DMA% in the mid-to-late gestational period.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Spreading depolarization (SD) represents a neurological process characterized by a massive, self-sustaining wave of brain cell depolarization. Understanding its mechanism is important for treating ...ischemic or hemorrhagic stroke and migraine with aura. Many believed that ion fluxes through NMDA receptors (NMDARs) are responsible for neuronal transmembrane currents of SD. However, the explicit role of NMDARs remains ambiguous. This is in part due to the limitation of traditional pharmacological approaches in resolving the contribution of NMDARs in different intercellular and intracellular processes of SD. Here, we applied single-cell blockade and genetic deletion methods to remove functional NMDARs from individual hippocampal CA1 neurons in order to examine the role of NMDARs in the depolarization mechanism without affecting the propagation of SD. We analyzed neuronal membrane potential changes to demonstrate that NMDARs are not required for initiating the depolarization. Consistently, neuronal input resistance (RN) revealed a sharp decline at the start of SD, which was unaffected by blocking NMDARs. Instead, the recovery of both membrane potential and RN during the late phase of SD was facilitated by inhibition of NMDARs, indicating that NMDARs are responsible for sustaining the depolarization. Our results strongly indicate that NMDAR activation is not a determinant of the initiation of depolarization but is important for sustaining transmembrane ion fluxes during SD.
•Neuronal depolarization during SD consists of early phase and late sustained phase.•Single-cell dialysis of MK-801 inhibits NMDAR responses and the late phase of SD.•Knockout of functional NMDARs affects the late but not early depolarization phase.•Blocking NMDARs does not prevent rapid reduction in Rin but facilitates its recovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purity of chlorophylls plays one of the key role for the production of chlorophyllides. We have designed a facile method for chlorophyll purification by twice solvent extraction. Twice extraction ...causes the loss of chlorophylls, but the purity of total chlorophylls can be enhanced 182%. Then, the purified chlorophylls can be converted to relatively pure chlorophyllides facilely. The results show that higher purity of chlorophyllides could be obtained when purified chlorophylls (ethanol-hexane extract) was used as starting materials than that of crude chlorophylls (ethanol-only extract). In biocompatibility test, the results showed that the prepared chlorophyllides can be applied as biomaterials. When the prepared chlorophyllides were applied to anticancer tests, they were active both in MCF7 and MDA-MB-231 (multidrug resistant breast cancer cells) cell lines. In addition, the results suggested that the prepared chlorophyllides could be a potential candidate of combination therapy with doxorubicin to breast cancers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A batch sorption system using tree fern as biosorbent was investigated to remove Basic Red 13 from aqueous solutions. The system variables studied include sorbent particle size and temperature and ...results revealed the potential of tree fern, an agriculture product, as a low-cost sorbent. The Langmuir isotherm was found to represent the measured sorption data well. The dye sorption capacity of tree fern increased as the sorbent particle size decreased. Maximum saturated monolayer sorption capacity of tree fern for Basic Red 13 was 408
mg/g. Various thermodynamic parameters such as Δ
G°, Δ
H° and Δ
S° were calculated indicating that this system was a spontaneous and endothermic process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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