Chronic exposure to 1-bromopropane (1-BP), an alternative to ozone-depleting solvents, produces potential neurotoxicity in occupational populations. However, no therapeutic strategy is available currently. Accumulating evidence suggests that cytochrome P4502E1 (CYP2E1) is critical for the active metabolism of 1-BP. The purpose of this study is aimed to test whether inhibition of CYP2E1 by allyl sulfide, a specific inhibitor of CYP2E1, could be able to protect against 1-BP-induced neurotoxicity. Male Wistar rats were intoxicated with 1-BP for 9 continuous weeks with or without allyl sulfide pretreatment. Results clearly demonstrated that 1-BP exposure induced decrease in NeuN+ cells and increase in cleaved caspase-3 expression and TUNEL+ cells in motor cortex of rats, which was significantly ameliorated by allyl sulfide. Allyl sulfide treatment also recovered the motor performance of rats treated with 1-BP. Mechanistically, allyl sulfide-inhibited 1-BP-induced expression of CYP2E1 in microglia, which was associated with suppression of microglial activation and M1 polarization in motor cortex of rats. Reduced oxidative stress was also observed in rats treated with combined allyl sulfide and 1-BP compared with 1-BP alone group. Furthermore, we found that allyl sulfide abrogated 1-BP-induced activation of Nuclear factor(NF)-κB and GSH/Thioredoxin/ASK1 pathways, the key factor for the maintenance of M1 microglial inflammatory response and oxidative stress-related neuronal apoptosis, respectively. Thus, our results showed that allyl sulfide exerted neuroprotective effects in combating 1-BP-induced neurotoxicity through inhibition of neuroinflammation and oxidative stress. Blocking CYP2E1 activity by allyl sulfide might be a promising avenue for the treatment of neurotoxicity elicited by 1-BP and other related neurotoxicants.
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.
Microglia-mediated chronic neuroinflammation has been associated with cognitive decline induced by rotenone, a well-known neurotoxic pesticide used in agriculture. However, the mechanisms remain unclear. This work aimed to elucidate the role of complement receptor 3 (CR3), a highly expressed receptor in microglia, in cognitive deficits induced by rotenone. Rotenone up-regulated the expression of CR3 in the hippocampus and cortex area of mice. CR3 deficiency markedly ameliorated rotenone-induced cognitive impairments, neurodegeneration and phosphorylation (Ser129) of α-synuclein in mice. CR3 deficiency also attenuated rotenone-stimulated microglial M1 activation. In microglial cells, siRNA-mediated knockdown of CR3 impeded, while CR3 activation induced by LL-37 exacerbated, rotenone-induced microglial M1 activation. Mechanistically, CR3 deficiency blocked rotenone-induced activation of nuclear factor κB (NF-κB), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathways. Pharmacological inhibition of NF-κB or STAT3 but not STAT1 was confirmed to suppress microglial M1 activation elicited by rotenone. Further study revealed that CR3 deficiency or knockdown also reduced rotenone-induced expression of C3, an A1 astrocyte marker, and production of microglial C1q, TNFα and IL-1α, a cocktail for activated microglia to induce neurotoxic A1 astrocytes, via NF-κB and STAT3 pathways. Finally, a small molecule modulator of CR3 efficiently mitigated rotenone-elicited cognitive deficits in mice even administered after the establishment of cognitive dysfunction. Taken together, our findings demonstrated that CR3 is a key factor in mediating neurotoxic glial activation and subsequent cognitive impairments in rotenone-treated mice, giving novel insights into the immunopathogenesis of cognitive impairments in pesticide-related Parkinsonism.
The Mw 6.3 Jinghe earthquake struck Xingjiang Province, China, on 8 August 2017 (05:15:04 UTC); the epicenter was near the Kusongmuxieke Piedmont Fault (KPF) of the northern Tian Shan Mountains. We used multi-source and multi-track satellite Synthetic Aperture Radar (SAR) imagery and Interferometric SAR (InSAR) techniques to reconstruct the coseismic displacement field from different line-of-sight geometries. To reduce the phase artifacts, we employed multi-temporal scenes acquired by Sentinel-1, and reconstructed the coseismic deformation through a temporal averaging strategy. Together with a single interferometric pair obtained using the Phased Array type L-band Synthetic Aperture Radar 2 (PALSAR2) sensor aboard the Advanced Land Observing Satellite 2 (ALOS2), we obtained five displacement maps with slightly different viewing geometries; all of which were used to constrain a geodetic inversion to retrieve the fault geometry parameters and slip distribution. Based on the focal mechanism and regional geology, we constructed multiple fault models that differ in dip direction (south and north dipping), and various striking angles. Both models fit the InSAR displacement maps, but have slip distributions of different depths. The slip depth of the south dipping model, with a dip of ~42°, is the most consistent with the relocated earthquake sequence and regional geological structure. Through the geodetic inversion, the maximum slip (0.25 m) occurred at 14.05 km and the associated rake was 89.56°. The result implies that the seismogenic fault is a blind thrust fault north of KPF (towards the foreland). Considering the relative locations of the suggested blind fault, the KPF, and the continuing north to south (N–S) shortening of the Tian Shan Mountains, this fault could be formed by the northward propagation of the regional fold-thrust belt.
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