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  • To understand the impact of

    2022-05-16

    To understand the impact of alterations in syk inhibitor zinc homeostasis, the role of Zn2+ as a neurotransmitter has to be appreciated. Certain regions of the brain including the neocortex and hippocampus harbour so-called “zincergic” (or “gluzinergic”) neurons, where Zn2+ is co-released with glutamate and used in neurotransmission [165]. The pre-synaptic vesicles of these neurons are loaded with Zn2+ by the zinc transporter ZnT3 [166]. Exocytosis of these vesicles leads to temporally and spatially restricted increases of free [Zn2+] to 300–400 μM [167]. These zinc signals are perceived by several receptors of the post-synaptic neurons, and modulate their function [9,75,159], with various downstream effects that ultimately play a role in neuroplasticity and long-term potentiation. The latter insights go syk inhibitor some way to explain the impact of zinc on both mood-related and cognitive disorders. Free zinc concentrations as low as 0.1 μM are toxic to some cell types including neurons [11,168]; hence, the rapid clearance of extracellular zinc ions at hundreds of μM after exocytosis is essential. Although details of mechanisms for clearance are not known, it can be anticipated that these might also involve interactions between zinc and proteins present in the extracellular matrix. Much attention has focused on metallothioneins, in particular MT3 [169]. Yet, with 3 μM, albumin is also the most abundant protein in ISF and CSF [170], and it may be inferred that the Zn:HSA complex is of major importance for zinc speciation in these fluids as well. The total Zn2+ concentration in CSF is 150–380 nM [171], and basal free Zn2+ concentration has been determined at 5–25 nM [172]. Intriguingly, there are indications that basal extracellular zinc concentrations increase with age [159,171]. A higher extracellular free zinc concentration might in itself be harmful, either through outright zinc cytotoxicity, or by interfering with correct zinc signalling for memory and long-term potentiation. In principle, an increase in free Zn2+ in ISF or CSF may result from changes in total zinc, a shift from intra- to extracellular space, or its extracellular speciation, or a combination of all three possibilities. In any case, such increases may promote the development of sporadic AD in several ways [171]. The emerging role of albumin to combat at least one of the molecular mechanisms underlying AD pathology is discussed in Section 7.1. The causes for increases in basal extracellular zinc are as yet unclear; but besides the hypothesis of decreasingly efficient re-uptake of synaptically released Zn2+ and subsequent leakage into surrounding areas, a direct effect of poly-unsaturated fatty acids (PUFAs) has been uncovered recently, highlighted in Section 7.2.
    Conclusions More detailed investigations into the impact of fatty acid binding to albumin on Zn2+ dynamics on a cellular and organismal level may provide insight into downstream implications for health and disease, in the context of energy metabolism, the cardiovascular system, the immune system, and neurochemistry. The first step towards such new insights requires an integrated, quantitative approach that considers FFA-dependent extracellular speciation and Zn2+ cell uptake, and correlates these data with subsequent biochemical and cellular consequences.
    Transparency document
    Introduction The omega-3 fatty acids (n-3 FAs) alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaneoic acid (EPA) are dietary polyunsaturated fatty acids with benefits for human health. Dietary n-3 FAs are nutraceuticals derived from plants; they are also present in high levels in fish oil where they accumulate from consumption of aquatic plants by fish. One aspect of the health benefit of n-3 FAs to humans concerns their potential for cancer prevention and/or treatment [1]. Ovarian cancer is one of the cancers for which epidemiological evidence suggests that consumption of n-3 FAs reduces risk [2]. Experimentally, cell culture studies support an inhibitory effect of n-3 FAs on the proliferation of epithelial ovarian cancer cells [3].