Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-jB (NF-jB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of a-synucleinpositive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN + /Nrf-2 + cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-jB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.

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ABSTRACT:The inflammasome NLRP3 is a molecular pathway activated by a wide range of cellular insults to elicit innate immune defenses through the activation of caspase-1 and the maturation of proinflammatory cytokines, such as IL-1b and IL-18. The expression of NRLP3 is abnormally elevated in numerous human inflammatory diseases, including pulmonary diseases. An injection of carrageenan (CAR) into the pleural cavity triggered an acute inflammatory response, leading to tissue damage, inflammatory exudates, leukocyte infiltration, and increased myeloperoxidase activity. The aim of this study was to assess the effect of the inflammasome blocking agents BAY 11-7082 (30 mg/kg, i.p.) and Brilliant Blue G (BBG) (45.5 mg/kg, i.p.) in a mouse model of CAR-induced pleurisy. Treatment with BAY 11-7082 or BBG 1 h after CAR injection attenuated pulmonary membrane thickening and polymorphonuclear leukocyte infiltration, reduced NF-kB translocation in the nucleus, and inhibited the assembly of the NRLP3/ASC/caspase-1 complex. Treatment with BAY 11-7082 or BBG also down-regulated iNOS, nitrotyrosine, and poly-ADP-ribosyl polymerase expression and inhibited CAR-induced apoptosis. Our results demonstrate that treatment with inflammasome-blocking agents can significantly reduce the development of acute CAR-induced lung injury.-Fusco, R. Gugliandolo, E., Biundo, F., Campolo, M., Di Paola, R., Cuzzocrea, S. Inhibition of inflammasome activation improves lung acute injury induced by carrageenan in a mouse model of pleurisy. FASEB J. 31, 3497-3511 (2017). www.fasebj.org

BackgroundIn vertebrates, there is an intimate relationship between copper and iron homeostasis. Copper deficiency, which leads to a defect in ceruloplasmin enzymatic activity, has a strong effect on iron homeostasis resulting in cellular iron retention. Much is known about the mechanisms underlying cellular iron retention under “normal” conditions, however, less is known about the effect of copper deficiency during inflammation.ResultsWe show that copper deficiency and the inflammatory cytokine interleukin-6 have different effects on the expression of proteins involved in iron and copper metabolism such as the soluble and glycosylphosphtidylinositol anchored forms of ceruloplasmin, hepcidin, ferroportin1, transferrin receptor1, divalent metal transporter1 and H-ferritin subunit. We demonstrate, using the human HepG2 cell line, that in addition to ceruloplasmin isoforms, copper deficiency affects other proteins, some posttranslationally and some at the transcriptional level. The addition of interleukin-6, moreover, has different effects on expression of ferroportin1 and ceruloplasmin, in which ferroportin1 is decreased while ceruloplasmin is increased. These effects are stronger when a copper chelating agent and IL-6 are used simultaneously.ConclusionsThese results suggest that copper chelation has effects not only on ceruloplasmin but also on other proteins involved in iron metabolism, sometimes at the mRNA level and, in inflammatory conditions, the functions of ferroportin and ceruloplasmin may be independent.

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