In light of the emerging interplay between redox and metabolic signaling pathways we investigated the potential cross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase (AMPK), central regulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as an activator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influence on Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation and pharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNA level. XN leads to AMPK activation via interference with mitochondrial function and activation of liver kinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1 response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogen synthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmic reticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response. Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPK and the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as an additional player and suggesting tight cooperation between signaling pathways controlling cellular redox, energy, or protein homeostasis.

In a human pilot intervention study (healthy + ileostomy probands), the questions were addressed whether in vivo consumption of an anthocyanin-rich bilberry (Vaccinium myrtillius L.) pomace extract (BE) affects (i) the transcription of Nrf2-dependent genes in peripheral blood mononuclear cells (PBMC), indicative for systemic effects, and (ii) the level of oxidative DNA damage in these cells. In healthy test subjects transcripts of NAD(P)H quinone oxidoreductase 1 (NQO1) were significantly elevated throughout the observation period (1-8 h), whereas transcription of heme oxygenase 1 (HO-1) and Nrf2 was significantly decreased. NQO1 and HO-1 transcription remained unchanged in the ileostomy probands, whereas Nrf2-transcription was suppressed in both groups. Decrease in oxidative DNA damage was observed 2 h after BE consumption again only in healthy subjects. In vitro studies using a reporter gene approach (CHO) and qPCR (HT29) indicate that not the intact anthocyanins/anthocyanidins are the activating constituents but the intestinal degradation product phloroglucinol aldehyde (PGA). Taken together, consumption of anthocyanin-rich BE was found to modulate Nrf2-dependent gene expression in PBMCs indicative for systemic activity. Limitation of the effect to healthy test subjects suggests a role of colonic processes for bioactivity, supported by the results on Nrf2-activating properties of the intestinal anthocyanin degradation product PGA.

Activation of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) is one of the major cellular defense lines against oxidative and xenobiotic stress, but also influences genes involved in lipid and glucose metabolism. It is unresolved whether the cytoprotective and metabolic responses mediated by Nrf2 are connected or separable events in non-malignant cells. In this study we show that activation of Nrf2, either by the small molecule sulforaphane or knockout of the Nrf2 inhibitor Keap1, leads to increased cellular glucose uptake and increased glucose addiction in fibroblasts. Upon Nrf2 activation glucose is preferentially metabolized through the pentose phosphate pathway with increased production of NADPH. Interference with the supply of glucose or the pentose phosphate pathway and NADPH generation not only hampers Nrf2-mediated detoxification of reactive oxygen species on the enzyme level but also Nrf2-initiated expression of antioxidant defense proteins, such as glutathione reductase and heme-oxygenase1. We conclude that the Nrf2-dependent protection against oxidative stress relies on an intact pentose phosphate pathway and that there is crosstalk between metabolism and detoxification already at the level of gene expression in mammalian cells.

One finding in recent motor control and learning research is that an external focus (i.e., attending to environmental aspects) improves performance, whereas an internal focus (i.e., controlling bodily movements) impedes it. Despite being replicated in behavioral studies, the neurophysiological basis of this phenomenon remains largely unknown. The present authors separate global attention to actions into an external and an internal focus. Using a between-participants design, participants were either trained to attend to moving their fingers (internal focus) or to the keys to be hit (external focus) during learning a finger sequence. Subsequently, they applied functional magnetic resonance imaging under focus (internal/external), dual task, and move-only conditions. Results revealed higher activation in primary somatosensory and motor cortex for an external compared to an internal focus. The authors conclude that external participants focused on the task-related environment (i.e., the keys) to enhance tactile input to somatosensory areas that closely connect to motor areas.

The mechanisms preventing efficient remyelination in the adult mammalian central nervous system after demyelinating inflammatory diseases, such as multiple sclerosis, are largely unknown. Partial remyelination occurs in early disease stages, but repair capacity diminishes over time and with disease progression. We describe a potent candidate for the negative regulation of oligodendroglial differentiation that may underlie failure to remyelinate. The p57kip2 gene is dynamically regulated in the spinal cord during MOG-induced experimental autoimmune encephalomyelitis. Transient down-regulation indicated that it is a negative regulator of post-mitotic oligodendroglial differentiation. We then applied short hairpin RNA-mediated gene suppression to cultured oligodendroglial precursor cells and demonstrated that downregulation of p57kip2 accelerates morphological maturation and promotes myelin expression. We also provide evidence that p57kip2 interacts with LIMK-1, implying that p57kip2 affects cytoskeletal dynamics during oligodendroglial maturation. These data suggest that sustained down-regulation of p57kip2 is important for oligodendroglial maturation and open perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade in multiple sclerosis.differentiation ͉ intrinsic inhibitor ͉ multiple sclerosis ͉ oligodendrocyte ͉ remyelination