Cu-II(atsm) Attenuates Neuroinflammation

Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex Cu-II(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of Cu-II(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). Cu-II(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of Cu-II(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.Peer reviewe

TAK1 Is Required for Survival of Mouse Fibroblasts Treated with TRAIL, and Does So by NF-κB Dependent Induction of cFLIPL

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a “death ligand”—a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-κB and JNK signalling pathways. To determine the role of TGF-β-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1−/− MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-κB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-κB, protected TAK1−/− MEFs against TRAIL killing, suggesting that TAK1 activation of NF-κB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-κB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK1−/− MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1–NF-κB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance

Effect of structural modifications to Glyoxal-bis(thiosemicarbazonato)copper(II) complexes on cellular copper uptake, copper-mediated ATP7A trafficking, and P-Glycoprotein mediated efflux

A 1-month field campaign of ozone (O3) flux measurements along a five-level vertical profile above, inside and below the canopy was run in a mature broadleaf forest of the Po Valley, northern Italy. The study aimed to characterize O3 flux dynamics and their interactions with nitrogen oxides (NOx) fluxes from the forest soil and the atmosphere above the canopy. Ozone fluxes measured at the levels above the canopy were in good agreement, thus confirming the validity of the constant flux hypothesis, while below-canopy O3 fluxes were lower than above. However, at the upper canopy edge O3 fluxes were surprisingly higher than above during the morning hours. This was attributed to a chemical O3 sink due to a reaction with the nitric oxide (NO) emitted from soil and deposited from the atmosphere, thus converging at the top of the canopy. Moreover, this mechanism was favored by the morning coupling between the forest and the atmosphere, while in the afternoon the fluxes at the upper canopy edge became similar to those of the levels above as a consequence of the in-canopy stratification. Nearly 80 % of the O3 deposited to the forest ecosystem was removed by the canopy by stomatal deposition, dry deposition on physical surfaces and by ambient chemistry reactions (33.3 % by the upper canopy layer and 46.3 % by the lower canopy layer). Only a minor part of O3 was removed by the understorey vegetation and the soil surface (2 %), while the remaining 18.2 % was consumed by chemical reaction with NO emitted from soil. The collected data could be used to improve the O3 risk assessment for forests and to test the predicting capability of O3 deposition models. Moreover, these data could help multilayer canopy models to separate the influence of ambient chemistry vs. O3 dry deposition on the observed fluxes