Cobalt nanoparticles induce mitochondrial damage and ß-amyloid toxicity via the generation of reactive oxygen species.

Exposure to cobalt nanoparticles (CoNPs) has been associated with neurodegenerative disorders, while the mitochondrial-associated mechanisms that mediate their neurotoxicity have yet to be fully characterized. In this study, we reported that CoNPs exposure reduced the survival and lifespan in the nematodes, Caenorhabditis elegans (C. elegans). Moreover, exposure to CoNPs aggravated the induction of paralysis and the aggregation of ß-amyloid (Aß). These effects were accompanied by reactive oxygen species (ROS) overproduction, ATP reduction as well as mitochondrial fragmentation. Dynamin-related protein 1 (drp-1) activation and ensuing mitochondrial fragmentation have been shown to be associated with CoNPs-reduced survival. In order to address the role of mitochondrial damage and ROS production in CoNPs-induced Aß toxicity, the mitochondrial reactive oxygen species scavenger mitoquinone (Mito Q) was used. Our results showed that Mito Q pretreatment alleviated CoNPs-induced ROS generation, rescuing mitochondrial dysfunction, thereby lessening the CoNPs-induced Aß toxicity. Taken together, we show for the first time, that increasing of ROS and the upregulation of drp-1 lead to CoNPs-induced Aß toxicity. Our novel findings provide in vivo evidence for the mechanisms of environmental toxicant-induced Aß toxicity, and can afford new modalities for the prevention and treatment of CoNPs-induced neurodegeneration.

JNK­IN­8 treatment alleviates lipopolysaccharide­induced acute lung injury via suppression of inflammation and oxidative stress regulated by JNK/NF­κB signaling.

JNK serves critical roles in numerous types of inflammation­ and oxidative stress­induced disease, including acute lung injury (ALI). JNK­IN­8 is the first irreversible JNK inhibitor that has been described. However, whether JNK­IN­8 can prevent lipopolysaccharide (LPS)­induced ALI by inhibiting JNK activation and its downstream signaling is poorly understood. The objective of the present study was to investigate the specific therapeutic effects of JNK­IN­8 on LPS­induced ALI and the molecular mechanisms involved. JNK­IN­8 attenuated myeloperoxidase activity, malondialdehyde and superoxide dismutase content and the lung wet/dry ratio, and improved the survival rate following lethal injection of LPS. Additionally, JNK­IN­8 decreased bronchoalveolar lavage fluid protein levels, lactate dehydrogenase activity, neutrophil infiltration and the number of macrophages (as demonstrated by flow cytometry), as well as the production of TNF­α, IL­6 and IL­1ß (as evaluated via ELISA). In addition, reverse transcription­quantitative PCR and ELISA showed that JNK­IN­8 attenuated LPS­induced inflammatory cytokine production and oxidative stress in primary murine peritoneal macrophages and RAW264.7 cells in vitro. Furthermore, the present study demonstrated that the JNK/NF­κB signaling pathway was involved in the therapeutic effect of JNK­IN­8 against LPS­induced injury both in vivo and in vitro. In conclusion, these findings indicated that JNK­IN­8 had a therapeutic effect on LPS­induced ALI in mice. The mechanism may be associated with inhibition of the JNK/NF­κB signaling pathway. JNK­IN­8 may be a potential therapeutic agent for the treatment of ALI.

Pretreatment with AM1241 Enhances the Analgesic Effect of Intrathecally Administrated Mesenchymal Stem Cells.

Mesenchymal stem cells have cannabinoid (CB) receptors type 1 and type 2 and can alleviate a variety of neuropathic pains, including chronic constriction injury (CCI). A selective CB2 receptor agonist is AM1241. In the present study, it was found that mice with CCI displayed a longer duration of mechanical and thermal analgesia when intrathecally (i.t.) injected with AM1241-treated mesenchymal stem cells, compared to those injected with untreated mesenchymal stem cells or AM1241 alone. Moreover, CCI-induced upregulation of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (p-ERK1/2) was inhibited following i.t. injection of AM1241-treated mesenchymal stem cells and this inhibition was noticeably higher compared to injection with untreated mesenchymal stem cells. The expression of transforming growth factor-ß1 (TGF-ß1) was also analyzed in the dorsal root ganglion (DRGs) and spinal cord of CCI mice. In untreated CCI mice, expression of TGF-ß1 was increased, whereas pretreatment with AM1241-treated mesenchymal stem cells regulated the expression of TGF-ß1 on 10 days and 19 days after surgery. In addition, i.t. injection of exogenous TGF-ß1 slightly alleviated neuropathic pain whilst neutralization of TGF-ß1 potently blocked the effect of AM1241-treated mesenchymal stem cells on thermal hyperalgesia and mechanical allodynia of CCI mice. In an in vitro experiment, AM1241 could enhance the release of TGF-ß1 in the supernatant of BMSCs after lipopolysaccharide (LPS) simulation. Taken together, the findings of the current study show that i.t. administration of AM1241-treated mesenchymal stem cells has a positive effect on analgesia and that TGF-ß1 and p-ERK1/2 may be the molecular signaling pathway involved in this process.