Impact of High Salt Diet on Cerebral Vascular Function and Stroke in Tff3−/−/C57BL/6N Knockout and WT (C57BL/6N) Control Mice

Abstract

High salt (HS) dietary intake leads to impaired vascular endothelium-dependent responses to various physiological stimuli, some of which are mediated by arachidonic acid (AA) metabolites. Transgenic Tff3−/− gene knockout mice (Tff3−/−/C57BL/6N) have changes in lipid metabolism which may affect vascular function and outcomes of stroke. We aimed to study the effects of one week of HS diet (4% NaCl) on vascular function and stroke induced by transient occlusion of middle cerebral artery in Tff3−/− and wild type (WT/C57BL/6N) mice. Flow-induced dilation (FID) of carotid artery was reduced in WT-HS mice, but not affected in Tff3−/−-HS mice. Nitric oxide (NO) mediated FID. NO production was decreased with HS diet. On the contrary, acetylcholine-induced dilation was significantly decreased in Tff3−/− mice on both diets and WT-HS mice. HS intake and Tff3 gene depletion affected the structural components of the vessels. Proteomic analysis revealed a significant effect of Tff3 gene deficiency on HS diet-induced changes in neuronal structural proteins and acute innate immune response proteins’ expression and Tff3 depletion, but HS diet did not increase the stroke volume, which is related to proteome modification and upregulation of genes involved mainly in cellular antioxidative defense. In conclusion, Tff3 depletion seems to partially impair vascular function and worsen the outcomes of stroke, which is moderately affected by HS diet.

Zinc Binding to Tau Influences Aggregation Kinetics and Oligomer Distribution

“…In the case of AD, it is established that metal dyshomeostasis is an altered cellular process that evolves along the pathology and neuronal protein inclusions in diseased human brains and in animal models accumulate metal ions, such as copper, iron, and zinc [23,24]. Several studies have focused on the effects of metal ion to binding Tau and its fragments, including zinc, while also advancing knowledge in the field; these studies have nevertheless opened questions that remain unaddressed [11,14,15,16,17,18]. Eventually, the understanding of the diverse consequences of zinc binding to Tau that has been reported to result in both stoichiometry-dependent effects on the kinetics of fibril formation and its cytotoxicity, as well as in amorphous aggregates, is the most interesting aspect to investigate.…”

“…Moreover, it was observed in in vitro studies that low concentrations of Zn 2+ result in the acceleration of Tau fibril formation [15]. Additionally, it was demonstrated for Tau constructs and mutants with aggregation enhanced properties that, in the presence of zinc ions, Tau aggregation is further promoted with toxicity effects on neuroblastoma cell lines [16,17,18]. There are also studies that suggest what seems to be a tightly regulated Ca 2+ -dependent process of maintaining the state of Tau phosphorylation between physiological levels [19].…”

Bioinformatics Methods for Mass Spectrometry-Based Proteomics Data Analysis

“…An objective of studying signaling networks is to interpret the relationships between enzymes and their substrates. The interactions between kinases and their targets are particularly interesting since they are essential cellular signaling molecules and frequently associated with diseases such as cancers and endocrine disorders [166,167]. MS-based phosphoproteome analysis of kinase signaling also helps reveal the regulatory modification pattern of proteins in bacteria [168][169][170].…”

Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective

“…Furthermore, TFF3 deficiency may also affect vascular function and stroke outcome. In a model of brain injury induced by transient occlusion of the middle cerebral artery, high-salt diet resulted in significant reduction in endothelium-dependent vasodilation of carotid arteries in TFF3 −/− mice, and their cerebral infarction area was larger than that in wild-type mice [20]. Furthermore, compared with wild-type mice, experimental cerebral ischemia/reperfusion TFF3 −/− mice exhibited higher caspase 3 activity and cell death, larger cerebral infarction area, and more severe forelimb motor defects [21].…”