32 research outputs found
Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma
Fenretinide induces apoptosis in neuroblastoma by induction of reactive oxygen species (ROS). In this study, we investigated the role of mitochondria in fenretinide-induced cytotoxicity and ROS production in six neuroblastoma cell lines. ROS induction by fenretinide was of mitochondrial origin, demonstrated by detection of superoxide with MitoSOX, the scavenging effect of the mitochondrial antioxidant MitoQ and reduced ROS production in cells without a functional mitochondrial respiratory chain (Rho zero cells). In digitonin-permeabilized cells, a fenretinide concentration-dependent decrease in ATP synthesis and substrate oxidation was observed, reflecting inhibition of the mitochondrial respiratory chain. However, inhibition of the mitochondrial respiratory chain was not required for ROS production. Co-incubation of fenretinide with inhibitors of different complexes of the respiratory chain suggested that fenretinide-induced ROS production occurred via complex II. The cytotoxicity of fenretinide was exerted through the generation of mitochondrial ROS and, at higher concentrations, also through inhibition of the mitochondrial respiratory chain
Cumulative maternal and neonatal effects of combined exposure to a mixture of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) during pregnancy in the Sprague-Dawley rat
Globally, biomonitoring data demonstrate virtually all humans carry residues of multiple per- and polyfluoroalkyl substances (PFAS). Despite pervasive co-exposure, limited mixtures-based in vivo PFAS toxicity research has been conducted. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are commonly detected PFAS in human and environmental samples and both produce adverse effects in laboratory animal studies, including maternal and offspring effects when orally administered during pregnancy and lactation. To evaluate the effects of combined exposure to PFOA and PFOS, we orally exposed pregnant Sprague-Dawley rats from gestation day 8 (GD8) to postnatal day 2 (PND2) to PFOA (10â250Â mg/kg/d) or PFOS (0.1â5Â mg/kg/d) individually to characterize effects and dose response curve parameters, followed by a variable-ratio mixture experiment with a constant dose of PFOS (2Â mg/kg/d) mixed with increasing doses of PFOA (3â80Â mg/kg/d). The mixture study design was intended to: 1) shift the PFOA dose response curves for endpoints shared with PFOS, 2) allow comparison of dose addition (DA) and response addition (RA) model predictions, 3) conduct relative potency factor (RPF) analysis for multiple endpoints, and 4) avoid overt maternal toxicity. Maternal serum and liver concentrations of PFOA and PFOS were consistent between the individual chemical and mixture experiments. Combined exposure with PFOS significantly shifted the PFOA dose response curves towards effects at lower doses compared to PFOA-only exposure for multiple endpoints and these effects were well predicted by dose addition. For endpoints amenable to mixture model analyses, DA produced equivalent or better estimates of observed data than RA. All endpoints evaluated were accurately predicted by RPF and DA approaches except for maternal gestational weight gain, which produced less-than-additive results in the mixture. Data support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and dose additive approaches for predictive estimates of mixture effects
Outcomes in ED patients with nonâspecific ECG findings and low highâsensitivity troponin
Abstract Background Although some emergency department risk stratification tools consider nonâspecific ECG findings as an aid in disposition decisions, their clinical value in patients with an initially low highâsensitivity cardiac troponin I (hsTnI) is unclear. Objective Our purpose was to determine if nonâspecific ECG (nsâECG) findings are associated with 30âday major adverse cardiac events (MACE) in ED patients presenting with suspected acute coronary syndromes (ACS) who have a low initial hsTnI. Methods Using the prospective Siemens Atellica hsTnI Food and Drug Administration submission observational database, we conducted a retrospective cohort study of the association between nsâECG findings (defined as left bundle branch block [LBBB], ST depression [STD], or Tâwave inversions [TWI]) and 30âday MACE (death, myocardial infarction, heart failure hospitalization, or coronary revascularization). Eligible patients presented with suspected ACS to one of 29 US EDs from April 2015 to April 2016, had stable vital signs, a blood sample for hsTnI (Siemen's Atellica, Siemens Healthineers, Inc, Malvern, PA) obtained at 1, 3, and 6 hours after ED presentation, and were followed for 30 days. The relationship between 30âday outcome, initial hsTnI, and nsâECG was evaluated using chiâsquare testing. Results Of 2676 enrolled, 1313 patients met the inclusion criteria and are included in the analysis. Median (interquartile range) age was 62 years (54, 72), 54% were male, with 56% white, and 39% African American. Median (interquartile range) times from symptom onset to presentation and presentation to specimen collection were 92 (0, 216) and 146 (117, 177) minutes, respectively. The most common presenting symptoms were chest pain (84%), followed by dyspnea (9%). ECG findings were categorized as Tâwave inversion or nonâspecific T wave changes (42%), ST depression nsâECG ST changes (16%), or LBBB (2%). Thirtyâday MACE occurred in 72 (5.5%) patients, with coronary revascularization (35 patients, 2.7%) and heart failure (25 patients, 1.9%) being the most frequent outcomes. In patients with an initial hsTnI below the limit of quantitation (LOQ) of 2.5 ng/L (n = 449), there was no association between nsâECG changes and 30âday MACE (P = 0.42). If the hsTnI was â„LOQ (2.5 ng/L), there were increased rates of 30âday MACE and nsâECG findings (P = 0.01). Conclusion In ED suspected ACS patients without unstable vital signs, and an initial hsTnI less than the LOQ (2.5 ng/L), nsâECG findings are not associated with 30âday major adverse cardiac events. The use of nsâECG findings in ACS disposition should be considered in the context of hsTnI levels