Factors Associated with Evidence-Based Practice Competencies among Taiwanese Nurses: A Cross-Sectional Study.

Evidence-based practice (EBP) is an essential component of healthcare practice that ensures the delivery of high-quality care by integrating the best available evidence. This study aimed to explore factors influencing EBP among nursing professionals in Taiwan. A cross-sectional survey study was conducted with 752 registered nurses and nurse practitioners recruited from a regional teaching hospital in southern Taiwan. EBP competency was evaluated using the Taipei Evidence-Based Practice Questionnaire (TEBPQ). The results showed that participation in evidence-based courses or training within the past year had the strongest association with EBP competencies (Std. B = 0.157, p < 0.001). Holding a graduate degree (Std. B = 0.151, p < 0.001), working in gynecology or pediatrics (Std. B = 0.126, p < 0.001), searching the literature in electronic databases (Std. B = 0.072, p = 0.039), and able to read academic articles in English (Std. B = 0.088, p = 0.005) were significantly associated with higher TEBPQ scores. Younger age (Std. B = -0.105, p = 0.005) and male gender (Std. B = 0.089, p = 0.010) were also identified as factors contributing to higher EBP competencies. The study highlights the importance of ongoing professional development, including EBP training and language proficiency, in enhancing EBP competencies among nursing professionals in Taiwan.

ERα-dependent estrogen-TNFα signaling crosstalk increases cisplatin tolerance and migration of lung adenocarcinoma cells.

Lung adenocarcinoma is the most common type of lung cancer in women. Our previous studies demonstrated that 17ß-estradiol (E2) promoted lung adenocarcinoma cell proliferation and tumor growth through estrogen receptor ERα. Transcriptomic analysis suggested that E2 potentiated TNFα-NFκB signaling in ERα-expressing lung adenocarcinoma cells. This study further demonstrated that E2 increased TNFα receptor expression and TNFα-triggered NFκB activity in ERα-expressing cells. E2-activated ERα had no physical association with NFκB p65/p50 heterodimer but facilitated TNFα-initiated IκBα degradation, NFκB nuclear translocation, and S468/S536 phosphorylation of p65 essential for NFκB activity. While knockdown of ERα prevented E2 from boosting NFκB activity, antiestrogen ICI 182,780 stimulated NFκB activity like E2. Inhibition of GSK3ß hampered E2:ERα-promoted NFκB activity and abolished S468 phosphorylation of p65, suggesting that GSK3ß played a role in the E2-TNFα signaling crosstalk. In ERα-expressing cells, E2 and TNFα synergistically regulated many genes that were not typically responsive to either E2 or TNFα. Functional analysis of microarray data inferred that E2/TNFα-induced transcriptomic changes improved cell survival and movement. Viability and colony formation assays validated that E2 and TNFα together increased cisplatin tolerance of ERα-expressing cells. Wound healing assays also confirmed that E2/TNFα cotreatment increased cell migration in an ERα-dependent manner. E2/TNFα-induced dysregulation of genes such as cell survival and movement-associated genes, proto-oncogenes, metallothioneins and histone core genes was correlated with poor overall survival in patients. In summary, E2 and TNFα engaged in an ERα-dependent positive crosstalk in lung adenocarcinoma cells, consequently increasing NFκB activation, cisplatin tolerance and cell migration and worsening prognosis.

Health risk of metal exposure via inhalation of cigarette sidestream smoke particulate matter.

Cigarette sidestream smoke particulate matter (CSSP) is a major source of airborne metals in the indoor environment. However, the health impacts of inhalation of CSSP-bound metals are rarely studied. In this study, we quantify the amount of 37 metals discharged through CSSP from a leading Taiwan brand of cigarette, Long Life. We also estimate cancer and non-cancer risks due to inhalation of these metals and investigate possible modes of toxic action. Long Life CSSP exhibits a distinctive carcinogenic metal profile compared with Western brands. When released to a 60-m3 poorly ventilated room, Long Life CSSP metals increase the risk for cancer by a 9.26 or 20.90 in a million chance and the hazard quotient for non-cancer toxicity by 0.496 or 0.286 per cigarette depending on risk estimation system. Cd accounts for more than 90% and 80% of cancer and non-cancer risk, respectively. Long Life CSSP also contains considerable amounts of Al, Ba, and Fe. Metals are not responsible for CSSP-induced cytotoxicity, oxidative stress, and transactivation activity of AhR, Nrf2, and ERα. However, they diminish resveratrol-activated Nrf2 activity and downstream antioxidant gene expression in low-AhR-expressing lung cells. Our results suggest that chronic exposure to Long Life CSSP elevates Cd-associated cancer and non-cancer risks. Furthermore, exposure to Long Life CSSP metals may impair Nrf2-mediated antioxidant protection.

Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells.

Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17ß-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3ß activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.

Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation.

Inhibition of 17α-hydroxylase/17,20-lyase (CYP17), which dictates the proceeding of androgen biosynthesis, is recommended as an effective treatment for androgen-dependent diseases. However, androgen depletion by selective CYP17 inhibition is accompanied with corticosteroid elevation, which increases risk of cardiovascular diseases. In this study, we evaluated the likelihood of polyphenols as a CYP17 inhibitor without cardiovascular complications. All examined polyphenols significantly inhibited CYP17 in human adrenocortical H295R cells, but their effects on androgen and cortisol biosynthesis were diverse. Resveratrol was the most potent CYP17 inhibitor with an approximate IC50 of 4 µM, and the inhibition might weigh on the 17α-hydroxylase activity more than the 17,20-lyase activity. Resveratrol also inhibited 21α-hydroxylase (CYP21) essential for corticosteroid biosynthesis but to a lesser extent, thus preventing the occurrence of cortisol elevation following CYP17 blockade. Although transcriptional down-regulation was important for α-naphthoflavone-mediated CYP17 inhibition, resveratrol inhibited CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein also inhibited CYP17 and CYP21 although less potent than resveratrol. Daidzein was the only polyphenol showing inhibition of 3ß-hydroxysteroid dehydrogenase type II (3ßHSD2). The exceptional 3ßHSD2 inhibition led to dehydroepiandrosterone accumulation alongside daidzein-caused androgen biosynthetic impairment. In contrast, androgen and cortisol secretion was increased or remained normal under α-naphthoflavone and ß-naphthoflavone treatments, suggesting that CYP17 inhibition was counteracted by increased substrate generation. α-naphthoflavone and ß-naphthoflavone also enhanced the formation of cortisol from 17-hydroxyprogesterone and testosterone from androstenedione. Our findings suggest a potential application of resveratrol in androgen deprivation therapy.

Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor α phenotypes.

Evidence suggests that estrogen affects the pulmonary response to carcinogenic pollutants, such as dioxins. In this study, we examined dioxin and estrogen signaling cross-talk in lung adenocarcinoma cell lines that were engineered to exhibit different aryl hydrocarbon receptor (AhR)/estrogen receptor (ER) α phenotypes. Data showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) weakly antagonized estrogen-activated ERα activity in cells expressing abundant ERα, but little AhR. Increase of AhR expression or presence of a dioxin-responsive element in proximity silenced the antiestrogenic effect of TCDD. AhR was bound to dioxin-responsive element and transcriptionally active in both TCDD-untreated and -treated lung adenocarcinoma cells. 17ß-estradiol (E2) reduced basal and TCDD-induced AhR activity only in ERα-positive cells. AhR and ERα exhibited a protein-protein interaction in the presence of E2. Cotreatment with TCDD moderated this protein interaction. Colocalization of ERα and AhR at the estrogen-responsive site under E2 and TCDD/E2 treatments implied that E2 ∣ ERα might hijack AhR away from the dioxin-responsive site. Increasing the relative expression of AhR to ERα counteracted inhibition of AhR activity by E2 ∣ ERα. When AhR and ERα were both highly expressed, TCDD and E2 up-regulated expression of dual-responsive genes cytochrome P450 (CYP) 1A1 and CYP1B1 in a cumulative manner, increasing the danger of metabolic activation of carcinogens. Whereas TCDD ∣ AhR and E2 ∣ ERα appeared to regulate CYP1B1 separately through their binding sites, E2 ∣ ERα increased the TCDD responsiveness and mRNA expression of CYP1A1 in a noncanonical way. In conclusion, AhR/ERα expression pattern, estrogen level, and promoter context determine the genomic action of dioxin in lung adenocarcinoma cells.

Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation.

Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3ß, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation.

Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress.

Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53-p21-Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity.

Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis.

CYP11B1 catalyzes the final step of cortisol biosynthesis. The effects of flavonoids on transcriptional expression and enzyme activity of CYP11B1 were investigated using the human adrenocortical H295R cell model. All tested nonhydroxylated flavones including 3',4'-dimethoxyflavone, α-naphthoflavone, and ß-naphthoflavone upregulated CYP11B1 expression and cortisol production, whereas apigenin and quercetin exhibited potent cytotoxicity and CYP11B1 repression at high concentrations. Nonhydroxylated flavones stimulated CYP11B1-catalyzed cortisol formation at transcriptional level. Resveratrol increased endogenous and substrate-supported cortisol production like nonhydroxylated flavones tested, but it had no effect on CYP11B1 gene expression and enzyme activity. Resveratrol appeared to alter cortisol biosynthesis at an earlier step. The Ad5 element situated in the -121/-106 region was required for basal and flavone-induced CYP11B1 expression. Overexpression of COUP-TFI did not improve the responsiveness of Ad5 to nonhydroxylated flavones. Although COUP-TFI overexpression increased CYP11B1 and CYP11B2 promoter activation, its effect was not mediated through the common Ad5 element. Treating cells with PD98059 (a flavone-type MEK1 inhibitor) increased CYP11B1 promoter activity, but not involving ERK signaling because phosphorylation of ERK1/2 remained unvarying throughout the course of treatment. Likewise, AhR was not responsible for the CYP11B1-modulating effects of flavonoids because inconsistency with their effects on AhR activation. 3',4'-dimethoxyflavone and 8-Br-cAMP additively activated CYP11B1 promoter activity. H-89 reduced 3',4'-dimethoxyflavone-induced CYP11B1 promoter activation but to a lesser extent as compared to its inhibition on cAMP-induced transactivation. Our data suggest that constant exposure to nonhydroxylated flavones raises a potential risk of high basal and cAMP-induced cortisol synthesis in consequence of increased CYP11B1 expression.

Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements.

CYP11B1 and CYP11B2 responsible for the final steps of cortisol and aldosterone synthesis, respectively, are believed to be duplicate genes with distinctive promoters. Our sequence analysis uncovers that these two genes share great homology in the proximal upstream regions, but insertion of Alu and L1 elements drives promoters divergent. Each CYP11B promoter contains two Alu elements embedded in a truncated L1 element, breaking L1 into three disconnected fragments. Alu functions as an enhancer in both genes regardless of orientation and copy number. Insertion of Alu upstream of a SV40 promoter also elevates promoter activity. However, the effect of Alu on CYP11B1 is blocked by a second L1 element (CYP11B1-L1.2) inserted between the first one and the conserved proximal upstream region. Although CYP11B1-L1.2 is 5'-truncated and lacks a functional ORF, replacing it with a fluorescent gene demonstrates that the element can be transcribed from the CYP11B1 core promoter in an opposite direction and a smaller magnitude compared to CYP11B1. Deletion of CYP11B1-L1.2 greatly increases CYP11B1 promoter activity and restores the enhancing effect of Alu. The Ad5 and SF-1 binding elements conserved in the proximal core promoter play a role in basal expression of both genes. Mutation of the Ad5 site reduces promoter activity to the minimal level. ERRα is the transcription factor interacting with Ad5 during basal expression. The core promoters of both genes are also conserved in mouse and rat despite the fact that the sites corresponding to cre, Ad5, and SF-1 in rodent Cyp11b1 promoters deviate from consensus.

Hybrid polymeric iodoplumbates constructed from morpholine and its derivatives: structures and properties.

Three hybrid polymeric iodoplumbates constructed from morpholine and its derivatives, {(Pb(4)I(15))[(Mph·H)(3)(Mph·1.5H)(2)]}(n)(1), {(edm-H(2))(Pb(3)I(8))]·2DMF}(n)(2), {(edm-H(2))[(dmp)(Pb(4)I(12))]˙2DMF}(n) (3) (Mph = morpholine, edm = ethylenedimorpholine, dmp(2+) = N,N'- dispiromorpholinopiperazonium) have been synthesized and structurally determined. In these compounds, morpholine and its derivatives weakly interact with or covalently bond to polymeric iodoplumbates. In 1, hydrogen bonds between (Pb(4)I(15))(7-) clusters and protonized Mph contribute to the formation of a 1-D hybrid chain. In 2, the 1-D [(Pb(3)I(8))](n)(2n-) chain is extended to be a 2-D layer via the edm(2+) ligand by means of Pb-O covalent bonds. Interestingly, the 2-D [(Pb(4)I(12))](n)(4n-) inorganic layer in 3 is concertedly templated by two kinds of organic cations. The above compounds exhibit a semiconductor nature, and third-order nonlinear optical (NLO) activities can be detected in 1 and 3.

Three silver iodides with zero and one-dimensional hybrid structures directed by conjugated organic templates: synthesis and theoretical study.

Under the direction of large conjugated organic cationic SDAs (structure-directing agents), three silver(I) iodides, (ipq)4(Ag2I6 x 2I2) (1), {[pql][Ag2I3]}n (2), [(npql)2(Ag4I6)]n (3) (ipq+ = N-(isopentyl)-quinolinium, pql+ = N-propyl-quinolinium, npql+ = N-(n-pentyl)-quinolinium) have been synthesized. 1 presents a zero-dimensional structure constituting of ipq+ cations, [Ag2I6]4- anions and molecular iodine. But 2 and 3 consist of one-dimensional coordination polymers that could be described as edge-sharing AgI4 tetrahedra. Electrostatic interactions between organic counter cations and inorganic moieties are present and contribute to the crystal packing. The structural differences between 1, 2 and 3 illustrate the influences of substituents of SDAs on the linkage modes of AgI4 tetrahedra. DFT calculations were carried out to reveal their electronic structures.

Glutathione regulation in arsenic-induced porcine aortic endothelial cells.

The objective was to investigate the regulation of glutathione (GSH) turnover in porcine aortic endothelial cells (PAECs) treated with sodium arsenite (NaAsO(2)), arsenic trioxide (As(2)O(3)) or sodium arsenate (Na(2)HAsO(4)) up to 72 hr at 0, 1, 5, and 10 microM, respectively. Intracellular GSH and glutathione disulfide (GSSG) contents, as well as the activities and mRNA levels of glutamate-cysteine lyase (GCL; gamma-glutamylcysteine synthetase) and gamma-glutamyl transpeptidase (GGT), were examined. The trivalent arsenic compounds increased GSH and GSSG contents in PAECs. An increase in GCL activity was observed at 24hr whereas an increase in GCL mRNA level was observed at 72 hr. The increase in GGT activity was only observed at 72 hr. In addition, a tendency of increase in GGT mRNA level was observed. Na(2)HAsO(4) treatment did not affect GSH content and the turnover-related enzymes. A differential GSH modulation in PAECs by trivalent arsenic compounds was found. The regulatory mechanism responsible for the As(2)O(3)-induced GSH increase is related to the GSH-turnover enzymes, GCL and GGT, while that for the NaAsO(2)-induced GSH increase may not be related to expression of GSH-turnover enzymes.

Oxidative DNA damage estimated by plasma 8-hydroxydeoxyguanosine (8-OHdG): influence of 4, 4'-methylenebis (2-chloroaniline) exposure and smoking.

Oxidative DNA damage may play an important role in the human carcinogenic process. Recently, we reported a case of bladder cancer among 4, 4'-methylenebis (2-chloroaniline) (MBOCA)-exposed workers. By measuring the plasma level of 8-hydroxydeoxyguanosine (8-OHdG), we investigated the association between oxidative DNA damage and MBOCA exposure. In addition, we examined the effects of different confounders on the plasma level of 8-OHdG. We undertook a cross-sectional survey at four MBOCA-producing factories in Taiwan (158 subjects). Plasma 8-OHdG levels and urinary MBOCA concentrations were measured by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). Personal characteristics were collected by questionnaire. The workers were classified according to their job titles as exposed (n=57) or unexposed (n=101) groups as well as classified according to urinary MBOCA levels as high urinary MBOCA (>20 microg/g creatinine) (n=45) or low urinary MBOCA (n=108) groups. Neither the MBOCA-exposed workers nor the high urinary MBOCA workers had a significant increase in the mean plasma 8-OHdG level, even after adjustment for potential confounders. Age and gender were significantly positively correlated with plasma 8-OHdG levels. Smokers among high urinary MBOCA workers also had significantly higher 8-OHdG levels than non-smokers among high urinary MBOCA workers. Our study provides evidence that smoking rather than MBOCA exposure induces elevation of plasma 8-OHdG levels among workers exposed to MBOCA, indicating that oxidative DNA damage does not play an important role in the carcinogenic processes of MBOCA.

4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells.

Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17beta-estradiol (E(2)) resulted from an interaction between TCDD and E(2) could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE(2)), especially 4-MeOE(2), accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E(2). In the present study, we demonstrate unique accumulation of 4-MeOE(2), as a result of TCDD/E(2) interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE(2)-treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE(2)-treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE(2) were unaffected by NAC. We concluded that 4-MeOE(2) accumulation resulting from TCDD and E(2) interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.

Modulation of the arsenic effects on cytotoxicity, viability, and cell cycle in porcine endothelial cells by selenium.

The differential effects of arsenic compounds and the effect of selenium on arsenic-induced changes in cytotoxicity, viability, and cell cycle of porcine aorta endothelial cells (PAECs) were investigated. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay indicated that arsenic trioxide (As(2)O(3)) and sodium arsenite (NaAsO(2)) showed similar cytotoxicity, whereas sodium arsenate (Na(2)HAsO(4)) did not show cytotoxicity in PAECs. As(2)O(3) and NaAsO(2) at 20 microM decreased PAEC viability, decreased G0/G1 phase, and increased apoptosis. An increased G2/M phase was observed in NaAsO(2)-treated PAECs, whereas an increase in secondary necrosis (late apoptosis) was observed in As(2)O(3)-treated PAECs. As(2)O(3)-induced apoptosis was associated with upregulation of p53 and caspase 3, whereas NaAsO(2)-induced apoptosis was associated with p53 upregulation. Sodium selenite (Na(2)SeO(3)) at 1 nM reduced 20 microM As(2)O(3)-induced cytotoxicity, but not apoptosis, at 24 h. Increased glutathione peroxidase (GPX) activity by Na(2)SeO(3) pretreatment in 20 microM As(2)O(3)-treated PAECs suggests that Na(2)SeO(3) modulates As(2)O(3)-induced cytoxicity by GPX modulation.