Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage.

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable. Mitochondrial volume was increased with concentration and time, whereas the mitochondrial membrane potential and produced ATP amounts were significantly reduced. Autophagosome-like vacuoles and contraction of the mitochondrial inner membrane were observed in PFOA-treated cells. The expression of acetyl CoA carboxylase (ACC) and p-ACC proteins rapidly decreased, and that of mitochondrial dynamics-related proteins increased. The expression of solute carrier family 7 genes, ChaC glutathione-specific gamma-glutamylcyclotransferase 1, and 5S ribosomal RNA gene was up-regulated the most in cells exposed to PFOA for 24 h, and the KEGG pathway analysis revealed that PFOA the most affected metabolic pathways and olfactory transduction. More importantly, PPAR alpha, fatty acid binding protein 1, and CYP450 family 1 subfamily A member 1 were identified as the target proteins for binding between PFOA and cells. Taken together, we suggest that disruption of mitochondrial integrity and function may contribute closely to PFOA-induced cell proliferation inhibition.

Uptake and toxicity of cerium dioxide nanoparticles with different aspect ratio.

Cerium dioxide nanoparticles (CeONPs) have been extensively applied in research for future energy development due to two common oxidation states on their surface. Considering that shape (aspect ratio) is a key determinant of NPs-induced toxicity, we compared the toxicity of hexagonal (H)- and rod-shaped (R)-CeONPs in mice. At 24 h after pharyngeal aspiration, both types of CeONPs recruited surrounding immune cells (monocytes and neutrophils) into the lung, and R-CeONPs induced a more severe pulmonary inflammatory response compared with H-CeONPs. To identify an indicator to predict pulmonary inflammatory responses at the cellular level, we also investigated their responses in alveolar macrophage cells. At 24 h after treatment, both types of CeONPs were mainly located within the vacuoles (partially, in the lysosome) in the cytoplasm. Mitochondrial damage, intracellular calcium accumulation, and increased NO production were observed in cells exposed to both types of CeONPs, ultimately resulting in a decrease in cell viability. More interestingly, both types of CeONPs formed multinucleated giant cells. Meanwhile, contrary to when suspended in deionized water, R-CeONPs were strongly aggregated with a negative charge in cell culture media, whereas H-CeONPs were relatively well-dispersed with a positive charge. R-CeONPs-induced lysosomal extension was also recovered by premix with negatively charged DNA, and even NPs suspended in cell culture media without cells were detected under the FACS system, suggesting interference by protein corona. Therefore, we suggest that shape (aspect ratio) is an important factor determining inhaled NPs-induced pathology and that the effect of the surface charge and protein corona should be carefully considered in interpreting results derived from in vitro tests. Furthermore, we propose that the relationship between the formation of multinucleated giant cells and the inflammatory response of inhaled CeONPs should be further studied.

Comparison of toxicity and cellular responses following pulmonary exposure to different types of nanofibers.

Pulmonary effects of inhaled microfibers are an emerging public health concern. In this study, we investigated toxicity following pulmonary exposure to synthetic polyethylene oxide fibroin (PEONF) and silk fibroin (SFNF) nanofibers and the cellular responses. When instilled intratracheally weekly for four weeks, body weight gain was significantly reduced in female mice exposed to the higher dose of SFNF when compared with the control group. The total number of cells in the lungs was more significant in all treated groups than in the control, whereas the relative portion of neutrophils and eosinophils increased significantly only in female mice exposed to SFNF. Both types of nanofibers induced notable pathological changes and increased pulmonary expression of MCP-1α, CXCL1, and TGF-ß. More importantly, blood calcium, creatinine kinase, sodium, and chloride concentration were affected significantly, showing sex- and material-dependent differences. The relative portion of eosinophils increased only in SFNF-treated mice. In addition, both types of nanofibers induced necrotic and late apoptotic cell death in alveolar macrophages after 24 h of exposure, with accompanying oxidative stress, increased NO production, cell membrane rupture, intracellular organelle damage, and intracellular calcium accumulation. Additionally, multinucleated giant cells were formed in cells exposed to PEONF or SFNF. Taken together, the findings indicate that inhaled PEONF and SFNF may cause systemic adverse health effects with lung tissue damage, showing differences by sex- and material. Furthermore, PEONF- and SFNF-induced inflammatory response may be partly due to the low clearance of dead (or damaged) pulmonary cells and the excellent durability of PEONF and SFNF.

Novel peptides derived from neuropeptide Y prevent chemotherapy-induced bone marrow damage by regulating hematopoietic stem cell microenvironment.

Chemotherapy-induced bone marrow damage is accompanied by acute nerve injury in the bone marrow (BM), resulting in sensory and autonomic neuropathy. Cisplatin, a popular chemotherapy drugs, induces the impairment of hematopoietic stem cells (HSCs) and bone marrow regeneration, leading to chronic bone marrow abnormalities. Previously, we reported the protective roles of neuropeptide Y (NPY) against cisplatin-induced bone marrow impairment. In this study, we identified novel peptides, generated from full-length NPY that rescued cisplatin-induced sensory neuropathy and HSC suppression by regulating cell survival in the BM microenvironment. One of these peptides, especially, showed a better protective property against these impairments compared to that seen in full-length NPY. Therefore, we suggest the NPY sequences most effective against the chemotherapy-induced bone marrow dysfunction that could be potentially useful as therapeutic agents for patients receiving chemotherapy.

Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.

Although many reports have revealed the importance of defective microglia-mediated amyloid ß phagocytosis in Alzheimer's disease (AD), the underlying mechanism remains to be explored. Here we demonstrate that neurons in the brains of patients with AD and AD mice show reduction of sphingosine kinase1 (SphK1), leading to defective microglial phagocytosis and dysfunction of inflammation resolution due to decreased secretion of specialized proresolving mediators (SPMs). Elevation of SphK1 increased SPMs secretion, especially 15-R-Lipoxin A4, by promoting acetylation of serine residue 565 (S565) of cyclooxygenase2 (COX2) using acetyl-CoA, resulting in improvement of AD-like pathology in APP/PS1 mice. In contrast, conditional SphK1 deficiency in neurons reduced SPMs secretion and abnormal phagocytosis similar to AD. Together, these results uncover a novel mechanism of SphK1 pathogenesis in AD, in which impaired SPMs secretion leads to defective microglial phagocytosis, and suggests that SphK1 in neurons has acetyl-CoA-dependent cytoplasmic acetyltransferase activity towards COX2.