Microplastics (MPs) are now widely distributed across the aerial, terrestrial, and aquatic environments. Thus, exposure to MPs via the oral, inhalation, or dermal routes is inevitable. ...Polytetrafluoroethylene (PTFE)-MPs is mainly used for manufacturing nonstick cookware, semiconductors, and medical devices; however, their toxicity has been rarely studied. In the present study, six different human cell lines, which are representative of tissues and cells that directly or indirectly come into contact with MPs, were exposed to two different sizes of irregular shape PTFE-MPs (with an average diameter of 6.0 or 31.7 μm). PTFE-MPs-mediated cytotoxicity, oxidative stress, and changes in proinflammatory cytokine production were then evaluated. We found that the PTFE-MPs did not induce cytotoxicity under any of the experimental conditions. However, PTFE-MPs (especially average diameter of 6.0 μm) induced nitric oxide and reactive oxygen species production in all the cell lines tested. Moreover, both sizes of PTFE-MPs increased the secretion of tumor necrosis factor alpha and interleukin-6 from the U937 macrophage cell line and the A549 lung epithelial cell line, respectively. In addition, PTFE-MPs activated the MAPK signaling pathways, especially the ERK pathway, in A549 and U937 cells, and in the THP-1 dendritic cell line. We also found that the expression of the NLRP3 inflammasome was reduced in the U937 and THP-1 cell lines following treatment with the PTFE-MPs sized 31.7 μm average diameter. Furthermore, expression of the apoptosis regulator, BCL2, was markedly increased in the A549 and U937 cell lines. Thus, although PTFE-MPs exert different effects on different cell types, our findings suggest that PTFE-MPs-associated toxicity may be specifically linked to the activation of the ERK pathway, which ultimately induces oxidative stress and inflammation.
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•Polytetrafluorethylene microplastics enhanced production of nitric oxide and reactive oxygen species in human cell lines.•Polytetrafluorethylene microplastics enhanced inflammatory cytokine secretion at lung epithelial and macrophage cell lines.•Polytetrafluorethylene microplastics activated signaling pathway in lung epithelial, macrophage, and dendritic cell lines.
Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our ...group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents (I
Na
) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I
Na
in both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I
Na
, suggesting no involvement of TRPV1. Two types of I
Na
, tetrodotoxin (TTX)-resistant and TTX-sensitive I
Na
, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I
Na
in a TRPV1-independent manner. We suggest that I
Na
inhibition by eugenol contributes to its analgesic effect.
Methicillin-resistant
Staphylococcus aureus
bacteremia (MRSAB) often persists despite appropriate antibiotic therapy. It is unclear what microbiological factors contribute to poor clinical outcomes ...in persistent MRSAB (pMRSAB). We aimed to identify clinical and microbiological risk factors for in-hospital mortality in pMRSAB. We analysed MRSAB cases prospectively collected between 2009 and 2016 at 11 hospitals in Korea, defining cases of pMRSAB as MRSAB lasting ≥5 days despite administration of effective antibiotics. The first blood isolates from the pMRSAB cases were tested for staphylococcal cassette chromosome
mec
type, staphylococcal protein A type,
accessary gene regulator
(
agr
) type, genes for Panton-Valentine leukocidin and phenol-soluble modulin-
mec
, vancomycin minimum inhibitory concentration, vancomycin heteroresistance, and
agr
functionality. We also collected clinical information for each case. Of 960 MRSAB cases, 152 pMRSAB were finally eligible. Univariable analysis revealed that in-hospital mortality was significantly associated with Charlson’s comorbidity-weighted index (CCWI) score, Pitt bacteremia score, sequential organ failure assessment score, presentation with septic shock, pneumonia,
agr
dysfunction, and vancomycin heteroresistance. Bone and joint infections were negatively associated with in-hospital mortality. Multivariable analysis revealed the following independent risk factors for in-hospital mortality: CCWI score adjusted odds ratio (aOR), per one point, 1.25; 95% confidence interval (CI), 1.08–1.44;
P
= 0.003), Pitt bacteremia score (aOR, per one point, 1.33; 95% CI, 1.09–1.62;
P =
0.005), non-eradicated foci of infection (aOR, 3.12; 95% CI, 1.18–8.27;
P
= 0.022), and
agr
dysfunction (aOR, 2.48; 95% CI, 1.12–5.47;
P =
0.025).
agr
dysfunction is an independent risk factor for in-hospital mortality in pMRSAB.
Context:
Cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production have been shown to play key roles in the regulation of ovulation. The TGF-β superfamily members are important ...molecules that regulate many ovarian functions under normal physiological and pathological conditions. TGF-β1 and its receptors are expressed in human granulosa cells. However, to date, whether TGF-β1 can regulate COX-2 expression and PGE2 production, which in turn contribute to the process of ovulation, remains unknown.
Objective:
The objective of the study was to investigate the effects of TGF-β1 on COX-2 expression and PGE2 production in human granulosa cells.
Design:
SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with Simian virus 40 large T antigen. SVOG cells were used to investigate the effect of TGF-β1 on COX-2 expression and PGE2 production.
Setting:
The study was conducted at an academic research center.
Main Outcome Measures:
mRNA and protein levels were examined by RT-quantitative real-time PCR and Western blotting, respectively. The concentrations of PGE2 in the culture medium were measured by an ELISA.
Results:
TGF-β1 treatment induced COX-2 expression and PGE2 production. The inductive effects of TGF-β1 on COX-2 and PGE2 were abolished by the inhibition of TGF-β type I receptor (TβRI). In addition, treatment with TGF-β1 activated phosphorylated mothers against decapentaplegic (Smad)-2 and Smad3 signaling pathways. Inhibition of the Smad signaling pathways by small interfering RNA-mediated approaches attenuated the TGF-β1-induced COX-2 expression and PGE2 production.
Conclusion:
TGF-β1 induced PGE2 production by inducing the COX-2 expression through a Smad-dependent signaling pathway in human granulosa cells.
The incense sticks and cigarettes burning are key sources of particulate matter with a diameter of ≤ 2.5 μm (PM
2.5
) in indoor and outdoor air. While lead (Pb) isotope ratios provide valuable ...insights into the origin of particle pollution, their applicability for investigating these source remains unclear. The Pb isotope ratios in the PM
2.5
emitted from these two sources were analyzed, and effects of brands or nicotine contents on the ratios were assessed. In addition, As, Cr, and Pb were analyzed to investigate whether Pb isotope ratios can serve as an indicator for the source investigation of these metals. We found that average ratios of
206
Pb/
204
Pb,
206
Pb/
207
Pb, and
208
Pb/
207
Pb in cigarettes were heavier than those in incense sticks. Scatter plots of Pb isotope ratios indicated an overlap of values for incense sticks or cigarettes linked to different brands, in that ratios for cigarettes with high nicotine content were heavier than for those with low nicotine content. Scatter plots of As, Cr, or Pb concentration against Pb isotope ratios clearly distinguished the effects of cigarette burning versus incense sticks with respect to PM
2.5
of these metals. Results indicate that brand differences did not affect the determination of PM
2.5
in these two sources. We suggest that Pb isotope ratios can be a useful tool in investigating the influence of incense sticks and of cigarettes (with high or low nicotine content) burning to PM
2.5
and associated metals.
Human trophoblast cells express transforming growth factor-β (TGF-β) and TGF-β receptors. It has been shown that TGF-β1 treatment decreases the invasiveness of trophoblast cells. However, the ...molecular mechanisms underlying TGF-β1-decreased trophoblast invasion are still not fully understood. In the current study, we demonstrated that treatment of HTR-8/SVneo human trophoblast cells with TGF-β1 decreased cell invasion and down-regulated the expression of vascular endothelial cadherin (VE-cadherin). In addition, the inhibitory effect of TGF-β1 on VE-cadherin was confirmed in primary cultures of human trophoblast cells. Moreover, knockdown of VE-cadherin using siRNA decreased the invasiveness of HTR-8/SVneo cells and primary cultures of trophoblast cells. Treatment with TGF-β1 induced the activation of Smad-dependent signaling pathways and the expression of Snail and Slug. Knockdown of Smads attenuated TGF-β1-induced up-regulation of Snail and Slug and down-regulation of VE-cadherin. Interestingly, depletion of Snail, but not Slug, attenuated TGF-β1-induced down-regulation of VE-cadherin. Furthermore, overexpression of Snail suppressed VE-cadherin expression. Chromatin immunoprecipitation analyses showed the direct binding of Snail to the VE-cadherin promoter. These results provide evidence that Snail mediates TGF-β1-induced down-regulation of VE-cadherin, which subsequently contributed to TGF-β1-decreased trophoblast cell invasion.
Background: Transforming growth factor (TGF)-β1 treatment decreases human trophoblast invasion.
Results: Smad-dependent up-regulation of Snail mediates TGF-β1-induced down-regulation of VE-cadherin.
Conclusion: TGF-β1 decreases human trophoblast invasion by down-regulating VE-cadherin.
Significance: Our results provide important insights into the molecular mechanisms mediating TGF-β1-induced down-regulation of VE-cadherin and decreased cell invasion in human trophoblast cells.
Previous studies have used various definitions to classify chronic obstructive pulmonary disease (COPD) patients into chronic bronchitis (CB) and non-CB patients. This study was performed to identify ...differences among three definitions of CB based on the classical method, St. George's Respiratory Questionnaire (SGRQ), and the CAT (COPD Assessment Test) score.
We extracted data from the multicenter Korea COPD Subgroup Study (KOCOSS) cohort, for which patients recruited from among 47 medical centers in South Korea beginning in April 2012. Patients were classified according to three different definitions of CB: 1) classical definition; 2) SGRQ (using questions regarding cough and sputum); and 3) CAT score (comprising cough CAT1 and sputum CAT2 subscale scores).
A total of 2694 patients were enrolled in this study. The proportions of CB were 10.8%, 35.8%, and 24.0% according to the classical, SGRQ, and CAT definitions, respectively. The three definitions yielded consistently significant differences between CB and non-CB patients in modified Medical Research Council dyspnea scale CAT score, SGRQ score, number of moderate-to-severe exacerbations per year and forced expiratory volume in 1 second. By three definitions, CB consistently predicted future risk of exacerbation. The kappa coefficient of agreement between the classical definition and SGRQ definition was 0.29, that of the classical definition and CAT definition was 0.32, and that of the SGRQ definition and CAT definition was 0.44.
Patients with CB according to the new definitions based on SGRQ or CAT score showed similar clinical characteristics to those defined according to the classical definition. The new CB definitions may be used as alternatives to the classical definition.
Context:
Aberrant regulation of ovulation is one of the major causes of infertility. In animal models, 3 epidermal growth factor (EGF)-like growth factors, amphiregulin (AREG), betacellulin (BTC), ...and epiregulin (EREG), have been shown to be involved in ovulation by regulating cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. However, whether the same is true in humans remains largely unknown.
Objective:
Our objective was to investigate the effects of AREG, BTC, and EREG on COX-2 expression and PGE2 production in human granulosa cells.
Design and Setting:
SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with SV40 large T antigen. SVOG cells were used to investigate the effect of AREG, BTC, and EREG on ovulation-related functions at an academic research center.
Main Outcome Measures:
Levels of mRNA and protein were examined by quantitative RT-PCR and Western blotting, respectively. The protein levels of PGE2 were measured by ELISA.
Results:
LH treatment upregulated AREG, BTC, EREG, and COX-2. Knockdown of EGF receptor (EGFR) attenuated LH-induced COX-2 expression and PGE2 production. Treatment with AREG, BTC, and EREG upregulated COX-2 expression and PGE2 production. The stimulatory effects of AREG, BTC, and EREG on COX-2 expression and PGE2 production were blocked by inhibition of EGFR activity and expression. AREG-, BTC-, and EREG-activated ERK1/2 signaling, but not Akt signaling, was required for AREG-, BTC-, and EREG-induced COX-2 expression and PGE2 production.
Conclusion:
AREG, BTC, and EREG induced PGE2 production by upregulating COX-2 expression through ERK1/2 signaling in human granulosa cells.
Neuropeptide FF (NPFF) belongs to the RFamide peptide family. NPFF regulates a variety of physiological functions by binding to a G protein-coupled receptor (GPCR), NPFFR2. Epithelial ovarian cancer ...(EOC) is a leading cause of death among gynecological malignancies. The pathogenesis of EOC can be regulated by many local factors, including neuropeptides, through an autocrine/paracrine manner. However, to date, the expression and/or function of NPFF/NPFFR2 in EOC is undetermined. In this study, we show that the upregulation of NPFFR2 mRNA was associated with poor overall survival in EOC. The TaqMan probe-based RT-qPCR showed that NPFF and NPFFR2 were expressed in three human EOC cells, CaOV3, OVCAR3, and SKOV3. In comparison, NPFF and NPFFR2 expression levels were higher in SKOV3 cells than in CaOV3 or OVCAR3 cells. Treatment of SKOV3 cells with NPFF did not affect cell viability and proliferation but stimulated cell invasion. NPFF treatment upregulates matrix metalloproteinase-9 (MMP-9) expression. Using the siRNA-mediated knockdown approach, we showed that the stimulatory effect of NPFF on MMP-9 expression was mediated by the NPFFR2. Our results also showed that ERK1/2 signaling was activated in SKOV3 cells in response to the NPFF treatment. In addition, blocking the activation of ERK1/2 signaling abolished the NPFF-induced MMP-9 expression and cell invasion. This study provides evidence that NPFF stimulates EOC cell invasion by upregulating MMP-9 expression through the NPFFR2-mediated ERK1/2 signaling pathway.
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•NPFF and NPFFR2 are expressed in human EOC cells.•Upregulation of NPFFR2 is associated with poor survival.•NPFF stimulates EOC cell invasion.•ERK1/2 signaling mediates NPFF-induced EOC cell invasion and MMP-9 expression.
The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort.
The study ...comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell's concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan-Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis.
The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan-Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis.
The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.
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