Growing evidence indicates that viral replication is regulated by the redox state of the host cell. We demonstrate that cells of different origins display differential permissivity for influenza A virus replication, depending on their intracellular redox power as reflected by Bcl-2 expression and glutathione (GSH) content. Bcl-2 expressing cells were found to have higher intracellular levels of GSH and to produce lower amounts of virus than Bcl-2 negative cells. Two different steps in the virus life-cycle were involved in Bcl-2/GSH mediated viral inhibition: 1) expression of late viral proteins (in particular hemagglutinin and matrix); and 2) nuclear-cytoplasmic translocation of viral ribonucleoproteins (vRNPs). Buthionine-sulfoximine-induced inhibition of GSH synthesis in Bcl-2 expressing cells caused an increase in the expression of late viral proteins but did not restore vRNP export to the cytoplasm. Collectively, our findings show that both Bcl-2 expression and GSH content contribute to the host cell's ability to down-regulate influenza virus replication, although their effects are exerted at different stages of the viral life-cycle. In certain cell populations, this form of down-regulation might conceivably favor the establishment of persistent viral infection.

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Fasting promotes longevity by reprogramming metabolic and stress resistance pathways. However, although the impact on adipose tissue physiology through hormonal inputs is well established, the direct role of fasting on adipose cells is poorly understood. Herein we show that white and beige adipocytes, as well as mouse epididymal and subcutaneous adipose depots, respond to nutrient scarcity by acquiring a brown-like phenotype. Indeed, they improve oxidative metabolism through modulating the expression of mitochondrial-and nuclear-encoded oxidative phosphorylation genes as well as mitochondrial stress defensive proteins (UCP1, SOD2). Such adaptation is placed in a canonical mitohormetic response that proceeds via mitochondrial reactive oxygen species (mtROS) production and redistribution of FoxO1 transcription factor into nucleus. Nuclear FoxO1 (nFoxO1) mediates retrograde communication by inducing the expression of mitochondrial oxidative and stress defensive genes. Collectively, our findings describe an unusual white/beige fat cell response to nutrient availability highlighting another health-promoting mechanism of fasting.

GSH is mostly considered a non-enzymatic antioxidant that serves for modulating the redox status of protein thiols, detoxification and direct scavenging activity of oxyradicals. Within the cells, GSH has also the role to buffer the flux of nitric oxide (NO), which in the nervous system is physiologically produced being an important neuromodulator and neurotransmitter. However, this role of GSH in modulating NO toxicity is often considered of secondary importance. Recently, we confuted such assumption as we demonstrated that GSH depletion triggers a severe NO imbalance, which is the primary cause of neuronal death. Here we report that even a slight and non-toxic decrease of GSH in brain mice causes protein nitration that is reversed by inhibiting NO production. This evidence indicates that NO imbalance and the associated nitrosative hallmarks observed in neurodegenerative diseases as well as in health ageing are likely the consequence of the progressive decline of GSH.