Our results suggest that plasma membrane and

Our results suggest that plasma membrane and a3-containing V-ATPases represent an important and novel target in the development of drugs to limit breast cancer metastasis. That knock-down of a3 has been shown to reduce metastasis of melanoma cells in an in vivo mouse model suggests that this role may not be restricted to breast cancer [55].
Conflict of interest
Acknowledgements This work was supported by NIH grant GM34478 (to MF), Tufts University Sackler Families Collaborative Cancer Biology Awards (to KC and LS), Predoctoral Ruth L. Kirschstein National Research Service AwardsCA192500 (to KC) and CA189321 (to LS), and the Tufts University Sackler Dean's Award (to CM).
Introduction Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS), with onset usually occurring in early adulthood. The etiology and pathogenesis of MS are still unclear, whereas evidence indicates that it is an autoimmune disease in which myelin is attacked by self-aggressive T cells [1]. Myelin is a membranous structure that surrounds neuronal axons, acts as an electrical insulator, and is vital for the process of neurotransmission in neurons. In this way, the demyelination process that occurs in the Danazol leads to a deficiency or complete loss in the neurotransmission and consequently worsens the signaling mediated by neurotransmitters [2]. Na+,K+-ATPase is an enzyme extensively studied for its role as a maintainer of electrolyte and fluid balance gradients in all mammals, because it transports Na+ and K+ across the plasma membrane, creates an electrochemical gradient, and maintains the membrane potential. These processes are essential for depolarization and the transmission of electrical impulses by axons [3]. Previous studies showed that a decrease in the activity or expression of this enzyme directly impaired neuronal signaling, with deleterious consequences on behavior [4]; increased the calcium influx in brain slices [5]; and caused neuronal death in rats [6]. Because this enzyme is widely expressed along the axons, evidence from the literature supports a decrease in both the activity and the expression of this enzyme in the development of axonal loss associated with demyelination and in MS [7]. Reports have associated the role of cholinesterases and acetylcholine (ACh) as modulators of inflammation because acetylcholinesterase (AChE) is able to regulate the immune system, lymphocyte activity, and cytokine production [8], [9]. The nonneuronal ACh regulates immune functions associated with the cholinergic system in the pathogenesis of diseases such as acute and chronic inflammation, local and systemic infection, dementia, and MS [10]. Cholinesterase enzymes have a regulatory role in cholinergic transmission, being responsible for rapid hydrolysis of the ACh. This system is regulated by 2 important enzymes, AChE and butyrylcholinesterase (BuChE). Acetylcholinesterase is distributed in the CNS and also found in mammalian erythrocytes and lymphocytes [11]. Butyrylcholinesterase is found in the brain, blood, and respiratory systems and able to hydrolyze a variety of esters, including ACh [12]. In parallel to the proinflammatory response, the production of reactive oxygen species is implicated in the axonal damage that occurs in MS because they increase dramatically in inflammatory conditions and deplete the antioxidant defense [13], [14]. These events associated with the neuroinflammation process promote an increase in cell damage as well as an increase in inactivated macrophages, astrocytes, and microglia [15]. Recently, natural products have shown potential as therapeutic candidates for neurodegeneration and demyelination [16], [17]. Quercetin is a flavonoid that possesses free radical scavenging properties and can protect from oxidative injury by its ability to modulate intracellular signals and promote cellular survival [18]. Furthermore, quercetin has been appointed as a potent anti-inflammatory compound [19] because it is able to regulate the pathways of lipoxygenase and arachidonic acid metabolism during inflammation [20]. However, there are few bodies of evidence of the quercetin properties on models of demyelination and remyelination.