Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss through activating microglial NADPH oxidase.

BACKGROUND: Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. METHODS: Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPH oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. RESULTS: In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100µg/cm2 induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10µg/cm2) and rotenone (2nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91phox, p47phox and p40phox); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47phox and p67phox translocation assembling active NADPH oxidase. CONCLUSION: ufCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD.

Polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets for chemo-photothermal synergetic therapy.

Multifunctional nanocarriers have been widely accepted and utilized for biomedical applications, because of their structural regularity, convenient post-modification and controllable structure and morphology. Herein, we reported polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets (rGO@PVMSNs) nanocomposites by a facile oil-water biphase stratification method. The synthesized rGO@PVMSNs nanocomposites performed excellent biocompatibility and photothermal performance. They could be employed as photoacoustic imaging contrast in vivo. Furthermore, the rGO@PVMSNs nanocarriers were used for loading the antitumor drug doxorubicin (DOX), the rGO@PVMSNs@DOX nanocomposites were also demonstrated to be with high inhibition of HepG2 cancer cells, especially with the help of near-infrared irradiation, which were more efficient than single chemotherapy or photothermal therapy. The rGO@PVMSNs@DOX nanocomposites of this work could be used as photoacoustic imaging and chemo-photothermal synergetic therapy agents, which show a new perspective for clinical tumor diagnosis and therapy.