Differential changes in Wnt7 and Dkk1 levels in astrocytes exposed to glutamate or TNFα.

Wnt signaling plays an important role in adult brain function, and its dysregulation has been implicated in the loss of neuronal homeostasis. Despite the existence of many studies on the participation of the Wnt pathway in adult neurons, its regulation in astrocytes has been scarcely explored. Several reports point to the presence of Wnt ligands in astrocytes and their possible impact on neuronal plasticity or neuronal death. We aimed to analyze the effect of the neurotransmitter glutamate and the inflammatory cytokine TNFα on the mRNA and protein levels of the canonical Wnt agonist Wnt7a and the antagonist Dkk1 in cultured astrocytes. Primary astrocyte cultures from rat cerebral cortices were exposed to glutamate or TNFα. Wnt7a and Dkk1 expression was analyzed by RT-qPCR and its protein abundance and distribution was assessed by immunofluorescence. We found high basal expression and protein levels of Wnt7a and Dkk1 in unstimulated astrocytes and overproduction of Dkk1 mRNA induced by the two stimuli. These results reveal the astrocytic source of the canonical Wnt ligands Wnt7a and Dkk1, whose levels are differentially regulated by glutamate and TNFα. Astrocytes are a significant source of Wnt ligands, the production of which can be differentially regulated under excitatory or proinflammatory conditions, thereby impacting neuronal function.

Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum.

Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on MIF gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C MIF SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], P < 0.01; OR: 0.81 [0.74-0.89], P < 0.0001; and OR: 0.81 [0.76-0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], P < 0.01; OR: 0.66 [0.48-0.92], P < 0.0154; and OR: 0.70 [0.60-0.82], P < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], P < 0.0001; OR: 0.77 [0.72-0.83], P < 0.0001; OR: 0.61 [0.44-0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], P < 0.0001; OR: 0.80 [0.75-0.86], P < 0.0001; OR: 0.73 [0.63-0.85], P-value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.

The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases.

Wnt signaling is a highly conserved pathway that participates in multiple aspects of cellular function during development and in adults. In particular, this pathway has been implicated in cell fate determination, proliferation and cell polarity establishment. In the brain, it contributes to synapse formation, axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. The expression and distribution of Wnt components in different organs vary with age, which may have important implications for preserving tissue homeostasis. The dysregulation of Wnt signaling has been implicated in age-associated diseases, such as cancer and some neurodegenerative conditions. This is a relevant research topic, as an important research avenue for therapeutic targeting of the Wnt pathway in regenerative medicine has recently been opened. In this review, we discuss the recent findings on the regulation of Wnt components during aging, particularly in brain functioning, and the implications of Wnt signaling in age-related diseases.