14 research outputs found
Next-Generation Sequencing Reveals Low-Dose Effects of Cationic Dendrimers in Primary Human Bronchial Epithelial Cells
Gene expression profiling has developed rapidly in recent years with the advent of deep sequencing technologies such as RNA sequencing (RNA Seq) and could be harnessed to predict and define mechanisms of toxicity of chemicals and nanomaterials. However, the full potential of these technologies in (nano)toxicology is yet to be realized. Here, we show that systems biology approaches can uncover mechanisms underlying cellular responses to nanomaterials. Using RNA Seq and computational approaches, we found that cationic poly(amidoamine) dendrimers (PAMAM-NH<sub>2</sub>) are capable of triggering down-regulation of cell-cycle-related genes in primary human bronchial epithelial cells at doses that do not elicit acute cytotoxicity, as demonstrated using conventional cell viability assays, while gene transcription was not affected by neutral PAMAM-OH dendrimers. The PAMAMs were internalized in an active manner by lung cells and localized mainly in lysosomes; amine-terminated dendrimers were internalized more efficiently when compared to the hydroxyl-terminated dendrimers. Upstream regulator analysis implicated NF-κB as a putative transcriptional regulator, and subsequent cell-based assays confirmed that PAMAM-NH<sub>2</sub> caused NF-κB-dependent cell cycle arrest. However, PAMAM-NH<sub>2</sub> did not affect cell cycle progression in the human A549 adenocarcinoma cell line. These results demonstrate the feasibility of applying systems biology approaches to predict cellular responses to nanomaterials and highlight the importance of using relevant (primary) cell models
Effect of Thyroxine Therapy on Serum Lipoproteins in Patients with Mild Thyroid Failure: A Quantitative Review of the Literature*
Evidence for Age-Dependent <i>in Vivo</i> Conformational Rearrangement within Aβ Amyloid Deposits
Deposition
of aggregated Aβ peptide in the brain is one of the major hallmarks
of Alzheimer’s disease. Using a combination of two structurally
different, but related, hypersensitive fluorescent amyloid markers,
LCOs, reporting on separate ultrastructural elements, we show that
conformational rearrangement occurs within Aβ plaques of transgenic
mouse models as the animals age. This important mechanistic insight
should aid the design and evaluation of experiments currently using
plaque load as readout
Evidence for Age-Dependent <i>in Vivo</i> Conformational Rearrangement within Aβ Amyloid Deposits
Deposition
of aggregated Aβ peptide in the brain is one of the major hallmarks
of Alzheimer’s disease. Using a combination of two structurally
different, but related, hypersensitive fluorescent amyloid markers,
LCOs, reporting on separate ultrastructural elements, we show that
conformational rearrangement occurs within Aβ plaques of transgenic
mouse models as the animals age. This important mechanistic insight
should aid the design and evaluation of experiments currently using
plaque load as readout