Silica nanoparticles induce autophagosome accumulation via activation of the EIF2AK3 and ATF6 UPR pathways in hepatocytes

Ji, Wang; Li, Yang; Duan, Junchao; Yang, Man; Yu, Yang; Lin, Feng; Yang, Xiaozhe; Zhou, Xianqing; Zhao, Zhendong; Sun, Zhiwei

doi:10.1080/15548627.2018.1458174

Cited by 66 publications

(51 citation statements)

References 56 publications

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“…The latter study was also the first to show that silica nanoparticles accumulate within the smooth endoplasmic reticulum (ER) and, by this, seem to induce ER-autophagy. This finding was recently confirmed by electron microscopy for hepatocytes [71], in which autophagosome accumulation involved the activation of the EIF2AK3 and ATF6 UPR pathways. Together these studies suggest that SAS nanomaterials have a similar mode of action on different cell types via the lysosomal pathway.…”

Section: Resultssupporting

confidence: 55%

Effects of Ultrasonic Dispersion Energy on the Preparation of Amorphous SiO2 Nanomaterials for In Vitro Toxicity Testing

Wiemann¹,

Vennemann²,

Stintz

et al. 2018

Nanomaterials

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Synthetic amorphous silica (SAS) constitute a large group of industrial nanomaterials (NM). Based on their different production processes, SAS can be distinguished as precipitated, fumed, gel and colloidal. The biological activity of SAS, e.g., cytotoxicity or inflammatory potential in the lungs is low but has been shown to depend on the particle size, at least for colloidal silica. Therefore, the preparation of suspensions from highly aggregated or agglomerated SAS powder materials is critical. Here we analyzed the influence of ultrasonic dispersion energy on the biologic activity of SAS using NR8383 alveolar macrophage (AM) assay. Fully characterized SAS (7 precipitated, 3 fumed, 3 gel, and 1 colloidal) were dispersed in H2O by stirring and filtering through a 5 µm filter. Aqueous suspensions were sonicated with low or high ultrasonic dispersion (USD) energy of 18 or 270 kJ/mL, respectively. A dose range of 11.25–90 µg/mL was administered to the AM under protein-free conditions to detect particle-cell interactions without the attenuating effect of proteins that typically occur in vivo. The release of lactate dehydrogenase (LDH), glucuronidase (GLU), and tumor necrosis factor α (TNF) were measured after 16 h. Hydrogen peroxide (H2O2) production was assayed after 90 min. The overall pattern of the in vitro response to SAS (12/14) was clearly dose-dependent, except for two SAS which showed very low bioactivity. High USD energy gradually decreased the particle size of precipitated, fumed, and gel SAS whereas the low adverse effect concentrations (LOECs) remained unchanged. Nevertheless, the comparison of dose-response curves revealed slight, but uniform shifts in EC50 values (LDH, and partially GLU) for precipitated SAS (6/7), gel SAS (2/3), and fumed SAS (3/3). Release of TNF changed inconsistently with higher ultrasonic dispersion (USD) energy whereas the induction of H2O2 was diminished in all cases. Electron microscopy and energy dispersive X-ray analysis showed an uptake of SAS into endosomes, lysosomes, endoplasmic reticulum, and different types of phagosomes. The possible effects of different uptake routes are discussed. The study shows that the effect of increased USD energy on the in vitro bioactivity of SAS is surprisingly small. As the in vitro response of AM to different SAS is highly uniform, the production process per se is of minor relevance for toxicity.

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Section: Resultssupporting

confidence: 55%

Effects of Ultrasonic Dispersion Energy on the Preparation of Amorphous SiO2 Nanomaterials for In Vitro Toxicity Testing

Wiemann¹,

Vennemann²,

Stintz

et al. 2018

Nanomaterials

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“…The increased expression of enzymes with antioxidant potential, also provide evidence for the activation of protective mechanisms induced by an abnormal amount of ROS generated within the cells. Activation of gene expression associated with the formation of autophagosomes (LAMP1, RAB24, GUSB) is also consistent with this phenomenon 24 . It should be noted however, that patients despite the increased formation of autophagosomes in T1D, the process of removing damaged proteins through autophagy is inefficient due to the inhibition of lysosomal hydrolysis 25 .…”

Section: Discussionsupporting

confidence: 57%

Specific gene expression in type 1 diabetic patients with and without cardiac autonomic neuropathy

Gastoł

Polus

Biela

et al. 2020

Sci Rep

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transduction 11. The induction of gp130 family of cytokines parallel axonal injury, in the experimentally induced diabetic mice, significantly decreased axonal regeneration 12. This study's goal is to follow, by microarray, the possible alteration of blood cell molecular pathways which may be altered to initiate the process of nervous tissue destruction in the course of T1D. Material and Methods Patients were selected from those attending the diabetic clinic at JUMC Department of Metabolic Disorders. The study group consisted of 60 patients with T1D, confirmed with a positive anti-GAD test result. These patients were treated with a standard therapeutic regimen: multiple daily injections (MDI) or continuous subcutaneous insulin infusions (CSII). The patients were randomized into two subgroups depending on the presence or absence of symptoms of autonomic neuropathy. The control group (n = 20) consisted of healthy non-obese volunteers recruited in accordance to age, gender and body weight. The exclusion criteria for all participants were: age under 20 and above 65 years; metabolic syndrome, cardiovascular diseases, cancer, chronic inflammation; severe liver or kidney failure, iron deficiency anaemia; pregnancy, breast feeding, hormone replacement therapy; anticoagulant treatment; usage of anti-inflammatory drugs and lack of the patient's written consent to participate in the study. The study protocol was approved by the Jagiellonian University Bioethical Committee and was in accordance with the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. Evaluation of autonomic neuropathy (CAN). The presence of CAN was based on the outcome of the reference method using the ProSciCard apparatus (Ewing test) 13. The severity of the cardiovascular neuropathy in the investigated group was determined by the number of abnormal results (from 3 up to 5) of Ewing test and pathological blood pressure variability [the guidelines for 2018 year of Polish Society of Diabetes] 13. Fasting venous blood was sampled from each participant for further tests. Part of the sample was sent for a routine laboratory diagnostic test, and another part was immediately centrifuged for serum isolation, and then transferred into sterile eppendorfs and stored at −20 °C. Whole blood samples were collected for mRNA isolation using PAXgene Blood RNA Tubes (Becton Dickinson) for material stabilization and transport. Each study participant underwent laboratory tests assessing the level of metabolic control, including: HbA1c level, lipidogram, renal markers, liver function tests and TSH levels. Biochemical tests were performed at the main Laboratory Diagnostics Department in the University Hospital, in accordance with standard procedures. RNA isolation. Purification of total RNA from human whole blood was performed using the PAXgene Blood RNA Kit, following producer protocol. The RNA quality was analysed using the Tapestation 2200 instrument (Agilent, USA) and quantified by spectrophotometry on the NanoDrop

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“…Similarly, SFN-Cys did not aggravate the upregulation of LC3II/LC3I in the present of chloroquine, suggesting SFN-Cys might inhibit either the fusion of autophagosomes to lysosomes or lysosomal degradation capacity. Whereas both immunofluorescence staining and co-immunoprecipitation results supported that SFN-Cys enhanced the fusion of autophagosome to lysosome in GBM 38 . Luckily, we identified that SFN-Cys downregulated both the lysosomal cysteine proteases Cathepsin D and TPP1 in the whole cell and Cathepsin 1 L in mitochondria by HPLC–MS/MS analysis.…”

Section: Discussionmentioning

confidence: 69%

Sulforaphane-cysteine inhibited migration and invasion via enhancing mitophagosome fusion to lysosome in human glioblastoma cells

Zhou

Wang

et al. 2020

Cell Death Dis

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Here we uncovered the involved subcellular mechanisms that sulforaphane-cysteine (SFN-Cys) inhibited invasion in human glioblastoma (GBM). SFN-Cys significantly upregulated 45 and downregulated 14 microtubule-, mitophagy-, and invasion-associated proteins in GBM cells via HPLC–MS/MS and GEO ontology analysis; SFN-Cys disrupted microtubule by ERK1/2 phosphorylation-mediated downregulation of α-tubulin and Stathmin-1 leading to the inhibition of cell migration and invasion; SFN-Cys downregulated invasion-associated Claudin-5 and S100A4, and decreased the interaction of α-tubulin to Claudin-5. Knockdown of Claudin-5 and S100A4 significantly reduced the migration and invasion. Besides, SFN-Cys lowered the expressions of α-tubulin-mediated mitophagy-associated proteins Bnip3 and Nix. Transmission electron microscopy showed more membrane-deficient mitochondria and accumulated mitophagosomes in GBM cells, and mitochondria fusion might be downregulated because that SFN-Cys downregulated mitochondrial fusion protein OPA1. SFN-Cys increased the colocalization and interplay of LC3 to lysosomal membrane-associated protein LAMP1, aggravating the fusion of mitophagosome to lysosome. Nevertheless, SFN-Cys inhibited the lysosomal proteolytic capacity causing LC3II/LC3I elevation but autophagy substrate SQSTM1/p62 was not changed, mitophagosome accumulation, and the inhibition of migration and invasion in GBM cells. These results will help us develop high-efficiency and low-toxicity anticancer drugs to inhibit migration and invasion in GBM.

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Silica nanoparticles induce autophagosome accumulation via activation of the EIF2AK3 and ATF6 UPR pathways in hepatocytes

Cited by 66 publications

References 56 publications

Effects of Ultrasonic Dispersion Energy on the Preparation of Amorphous SiO2 Nanomaterials for In Vitro Toxicity Testing

Effects of Ultrasonic Dispersion Energy on the Preparation of Amorphous SiO2 Nanomaterials for In Vitro Toxicity Testing

Specific gene expression in type 1 diabetic patients with and without cardiac autonomic neuropathy

Sulforaphane-cysteine inhibited migration and invasion via enhancing mitophagosome fusion to lysosome in human glioblastoma cells

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