Growing evidence suggests that the increased neuronal apoptosis is involved in n-hexane-induced neuropathy. We have recently reported that bone marrow-mesenchymal stem cells-derived conditioned medium (BMSC-CM) attenuated 2,5-hexanedione (HD, the active metabolite of n-hexane)-induced apoptosis in PC12 cells. Here, we explored the anti-apoptotic efficacy of BMSC in vivo. HD-treated rats received BMSC by tail vein injection 5 weeks after HD intoxication. We found that in grafted rats, BMSC significantly attenuated HD-induced neuronal apoptosis in the spinal cord, which was associated with elevation of nerve growth factor (NGF). Neutralization of NGF in BMSC-CM blocked the protection against HD-induced apoptosis in VSC4.1 cells, suggesting that NGF is essential for BMSC-afforded anti-apoptosis. Mechanistically, we found that the decreased activation of Akt induced by HD was significantly recovered in the spinal cord by BMSC and in VSC4.1 cells by BMSC-CM in a TrkA-dependent manner, leading to dissociation of Bad/Bcl-xL complex in mitochondria and release of anti-apoptotic Bcl-xL. The importance of Akt was further corroborated by showing the reduced anti-apoptotic potency of BMSC in HD-intoxicated VSC4.1 cells in the presence of Akt inhibitor, MK-2206. Thus, our findings show that BMSC attenuated HD-induced neuronal apoptosis in vivo through a NGF/Akt-dependent manner, providing a novel solution against n-hexane-induced neurotoxicity.
Osteoporosis is a skeletal disorder characterized by a systemic impairment of bone mineral density (BMD). Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for osteoporosis and BMD. However, the vast majority of susceptibility loci are located in non-coding regions of the genome and provide limited information about the genetic mechanisms of osteoporosis. Herein we performed a comprehensive functional analysis to investigate the genetic and epigenetic mechanisms of osteoporosis and BMD. BMD and osteoporosis are found to share many common susceptibility loci, and the corresponding susceptibility genes are significantly enriched in bone-related biological pathways. The regulatory element enrichment analysis indicated that BMD and osteoporosis susceptibility loci are significantly enriched in 5 UTR and DNase I hypersensitive sites (DHSs) of peripheral blood immune cells. By integrating GWAS and expression Quantitative Trait Locus (eQTL) data, we found that 15 protein-coding genes are regulated by the osteoporosis and BMD susceptibility loci. Our analysis provides new clues for a better understanding of the pathogenic mechanisms and offers potential therapeutic targets for osteoporosis.
Cobalt–chromium (Co-Cr) alloys have been widely used as dental-restoration materials for many years. This study sought to investigate whether selective laser melting (SLM) is a more appropriate process than traditional casting (CAST) for fabricating dental Co-Cr alloys. Metallurgical microscopy, X-ray photoelectron spectroscopy (XPS), Vickers hardness and nanoindentation tests, and friction and wear tests were used to evaluate the microstructure, surface compositions, mechanical properties, and wear resistance, respectively. Additionally, the biocompatibilities and cell adhesion of the alloys were evaluated with L-929 fibroblasts via CCK-8 assay, Live/Dead staining, flow cytometric analysis, scanning electron microscopy (SEM) observation and real-time PCR (RT-PCR) assay. The XPS results showed that the two alloys were all mainly comprised of Co, Cr, and O. The hardness in the CAST group equaled 7.15 ± 0.48 GPa, while in the SLM group, it equaled 9.06 ± 0.49 GPa. The friction coefficient of SLM alloys remained at approximately 0.46, but the CAST specimens fluctuated significantly. SLM alloys exhibited shallower wear scars and less wear debris compared with CAST alloys, simultaneously. Additionally, there were higher survival and expression of cell-adhesion-related genes on SLM alloys of L-929 cells, which meant that the deleterious effect on L-929 cells was significantly reduced compared with that for the CAST alloys. Overall, the wear resistances and biocompatibilities of the Co-Cr dental alloys were dramatically affected by the fabrication technique. The SLM technique is advantageous over the CAST technique for fabricating Co-Cr dental alloys.
Chronic exposure to n-hexane, a widely used organic solvent in industry, induces central-peripheral neuropathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). We recently reported that transplantation of bone marrow-mesenchymal stem cells (BMSC) significantly ameliorated HD-induced neuronal damage and motor deficits in rats. However, the mechanisms remain unclear. Here, we reported that inhibition of HD-induced autophagy contributed to BMSC-afforded protection. BMSC transplantation significantly reduced the levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the degradation of sequestosome-1 (p62) in the spinal cord and sciatic nerve of HD-intoxicated rats. Downregulation of autophagy by BMSC was also confirmed in VSC4.1 cells exposed to HD. Moreover, inhibition of autophagy by PIK III mitigated the neurotoxic effects of HD and, meanwhile, abolished BMSC-afforded neuroprotection. Furthermore, we found that BMSC failed to interfere with Beclin 1, but promoted activation of mammalian target of rapamycin (mTOR). Unc-like kinse 1 (ULK1) was further recognized as the downstream target of mTOR responsible for BMSC-mediated inhibition of autophagy. Altogether, BMSC transplantation potently ameliorated HD-induced autophagy through beclin 1-independent activation of mTOR pathway, providing a novel insight for the therapeutic effects of BMSC against n-hexane and other environmental toxicants-induced neurotoxicity.
Background N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.
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