scholarly journals Bisphenol a Induces Autophagy Defects and AIF-Dependent Apoptosis via HO-1 and AMPK to Degenerate N2a Neurons

2021 ◽  
Vol 22 (20) ◽  
pp. 10948
Author(s):  
Ching-Tien Lee ◽  
Cheng-Fang Hsieh ◽  
Jiz-Yuh Wang
Keyword(s):  
Bisphenol A ◽  
Nuclear Translocation ◽  
Neuronal Degeneration ◽  
Epidemiological Studies ◽  
Oxygen Free Radical ◽  
Neuronal Viability ◽  
Brain Degeneration ◽  
Ros Scavenger ◽  
Apoptosis Inducing Factor ◽  
Amp Activated Protein Kinase

Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting in neurodegeneration remain unclear. Herein, cultured N2a neurons were subjected to BPA treatment, and neurotoxicity was assessed using neuronal viability and differentiation assays. Signaling cascades related to cellular self-degradation were also evaluated. BPA decreased cell viability and axon outgrowth (e.g., by down-regulating MAP2 and GAP43), thus confirming its role as a neurotoxicant. BPA induced neurotoxicity by down-regulating Bcl-2 and initiating apoptosis and autophagy flux inhibition (featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation). Both heme oxygenase (HO)-1 and AMP-activated protein kinase (AMPK) up-regulated/activated by BPA mediated the molecular signalings involved in apoptosis and autophagy. HO-1 inhibition or AIF silencing effectively reduced BPA-induced neuronal death. Although BPA elicited intracellular oxygen free radical production, ROS scavenger NAC exerted no effect against BPA insults. These results suggest that BPA induces N2a neurotoxicity characterized by AIF-dependent apoptosis and p62-related autophagy defects via HO-1 up-regulation and AMPK activation, thereby resulting in neuronal degeneration.

scholarly journals Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 776
Author(s):  
Katarina Letkovska ◽  
Pavel Babal ◽  
Zuzana Cierna ◽  
Silvia Schmidtova ◽  
Veronika Liskova ◽  
...  
Keyword(s):  
Germ Cell ◽  
Nuclear Translocation ◽  
Malignant Tumors ◽  
Expression Patterns ◽  
Germ Cell Tumors ◽  
Testicular Tissue ◽  
Testicular Germ Cell ◽  
Visceral Metastases ◽  
Apoptosis Inducing Factor ◽  
Clinicopathological Variables

Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p < 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11–0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs.

scholarly journals Nuclear Translocation of Apoptosis-Inducing Factor after Focal Cerebral Ischemia

2004 ◽  
Vol 24 (4) ◽  
pp. 458-466 ◽  
Author(s):  
Nikolaus Plesnila ◽  
Changlian Zhu ◽  
Carsten Culmsee ◽  
Moritz Gröger ◽  
Michael A. Moskowitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Cytochrome C ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Mitochondrial Protein ◽  
Neuronal Cell ◽  
Experimental Stroke ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.

scholarly journals Urinary bisphenol A and serum lipids: a meta-analysis of six NHANES examination cycles (2003–2014)

2019 ◽  
Vol 73 (11) ◽  
pp. 1012-1019 ◽  
Author(s):  
Linda Dunder ◽  
Margareta H Lejonklou ◽  
P Monica Lind ◽  
Lars Lind
Keyword(s):  
Bisphenol A ◽  
Meta Analysis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Epidemiological Studies ◽  
Lipoprotein Cholesterol ◽  
Linear Regression Models ◽  
Cross Sectional ◽  
Study Results

BackgroundMounting evidence from both experimental and epidemiological studies suggest that exposure to the endocrine disruptor bisphenol A (BPA) has a role in metabolic disorders. The aim of the present study was to assess whether urinary BPA concentrations were associated with dyslipidaemia in children (≤17 years old) and adults (≥18 years old) by performing a meta-analysis of data from six cycles (2003–2014) in the National Health and Nutrition Examination Survey (NHANES).MethodsWe conducted a meta-analysis of data from 4604 children and 10 989 adult participants who were part of a substudy of urinary BPA measurements from six NHANES cycles from 2003 to 2014. Linear regression models conducted in each cycle were used to perform a meta-analysis to investigate associations between urinary BPA and serum levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB).ResultsThe meta-analysis did not disclose any significant associations between urinary BPA concentrations and LDL-C, HDL-C, TC, TG and ApoB in children. In adults, the meta-analysis revealed negative regression coefficients for all five lipid variables. However, no associations were significant following Bonferroni correction for multiple tests.ConclusionsIn the present meta-analysis of cross-sectional data from NHANES, no associations were found between urinary BPA and the five different lipid variables when investigated in both children and adults. However, considering the cross-sectional nature of the present study, results should be clarified in carefully designed longitudinal cohort studies with repeated BPA measurements.

scholarly journals Autophagy is Activated In Vivo during Trimethyltin-Induced Apoptotic Neurodegeneration: A Study in the Rat Hippocampus

2019 ◽  
Vol 21 (1) ◽  
pp. 175 ◽  
Author(s):  
Sabrina Ceccariglia ◽  
Alessandra Alvino ◽  
Aurora Del Fà ◽  
Ornella Parolini ◽  
Fabrizio Michetti ◽  
...  
Keyword(s):  
Western Blotting ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Organotin Compound ◽  
Nuclear Antigen ◽  
Apoptotic Pathway

Trimethyltin (TMT) is an organotin compound known to produce significant and selective neuronal degeneration and reactive astrogliosis in the rodent central nervous system. Autophagy is the main cellular mechanism for degrading and recycling protein aggregates and damaged organelles, which in different stress conditions, such as starvation, generally improves cell survival. Autophagy is documented in several pathologic conditions, including neurodegenerative diseases. This study aimed to investigate the autophagy and apoptosis signaling pathways in hippocampal neurons of TMT-treated (Wistar) rats to explore molecular mechanisms involved in toxicant-induced neuronal injury. The microtubule-associated protein light chain (LC3, autophagosome marker) and sequestosome1 (SQSTM1/p62) (substrate of autophagy-mediated degradation) expressions were examined by Western blotting at different time points after intoxication. The results demonstrate that the LC3 II/I ratio significantly increased at 3 and 5 days, and that p62 levels significantly decreased at 7 and 14 days. Immunofluorescence images of LC3/neuronal nuclear antigen (NeuN) showed numerous strongly positive LC3 neurons throughout the hippocampus at 3 and 5 days. The terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay indicated an increase in apoptotic cells starting from 5 days after treatment. In order to clarify apoptotic pathway, immunofluorescence images of apoptosis-inducing factor (AIF)/NeuN did not show nuclear translocation of AIF in neurons. Increased expression of cleaved Caspase-3 was revealed at 5–14 days in all hippocampal regions by Western blotting and immunohistochemistry analyses. These data clearly demonstrate that TMT intoxication induces a marked increase in both autophagy and caspase-dependent apoptosis, and that autophagy occurring just before apoptosis could have a potential role in neuronal loss in this experimental model of neurodegeneration.

scholarly journals Endocrine-Disrupting Chemicals and Insulin Resistance in Children

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 137 ◽  
Author(s):  
Eleonora Rotondo ◽  
Francesco Chiarelli
Keyword(s):  
Insulin Resistance ◽  
Bisphenol A ◽  
Prospective Studies ◽  
Endocrine Disrupting Chemicals ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Cross Sectional ◽  
Obesity And Diabetes ◽  
Endocrine Disrupting ◽  
Background Exposure

The purpose of this article is to review the evidence linking background exposure to endocrine-disrupting chemicals (EDCs) with insulin resistance in children. Although evidence in children is scarce since very few prospective studies exist even in adults, evidence that EDCs might be involved in the development of insulin resistance and related diseases such as obesity and diabetes is accumulating. We reviewed the literature on both cross-sectional and prospective studies in humans and experimental studies. Epidemiological studies show a statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, aromatic polycyclic hydrocarbides, or dioxins and insulin resistance.

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