RESUMO
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.
Assuntos
Peptídeos beta-Amiloides , Nanopartículas , Animais , Espécies Reativas de Oxigênio/metabolismo , Peptídeos beta-Amiloides/toxicidade , Cobalto/toxicidade , Caenorhabditis elegans/metabolismo , Nanopartículas/toxicidadeRESUMO
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.
Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos/toxicidade , MAP Quinase Quinase 4 , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , CamundongosRESUMO
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.