A switch in N-terminal capping of ß-peptides creates novel self-assembled nanoparticles.

Small tripeptides composed entirely of ß3-amino acids have been shown to self-assemble into fibres following acylation of the N-terminus. Given the use of Fmoc as a strategy to initiate self-assembly in α-peptides, we hypothesized that the acyl cap can be replaced by an Fmoc without perturbation to the self-assembly and enable simpler synthetic protocols. We therefore replaced the N-acyl cap for an Fmoc group and herein we show that these Fmoc-protected ß3-peptides produce regular spherical particles, rather than fibrous structures, that are stable and capable of encapsulating cargo. We then demonstrated that these particles were able to deliver cargo to cells without any obvious signs of cytotoxicity. This is the first description of such regular nanoparticles derived from Fmoc-protected ß3-peptides.

IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke.

Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

Diet-induced vitamin D deficiency has no effect on acute post-stroke outcomes in young male mice.

Recent observational studies have reported that patients with low circulating levels of vitamin D experience larger infarct volumes and worse functional outcomes after ischemic stroke compared to those with sufficient levels. However, it is unknown whether a causal relationship exists between low vitamin D levels and poor stroke outcome. This study aimed to assess the effect of vitamin D deficiency on acute outcomes post-stroke. Male C57Bl6 mice (six week old) were assigned to either a control or vitamin D deficient diet for four weeks prior to stroke. Stroke was induced by 1 h middle cerebral artery occlusion (MCAO) with reperfusion. At 24 h, we assessed functional outcomes, infarct volume, quantified immune cells in the brain by immunofluorescence and examined susceptibility to lung infection. ELISAs showed that the plasma level of hydroxyvitamin D3 was 85% lower in mice fed the vitamin D-deficient diet compared with the control group. Despite this, vitamin D deficiency had no impact on functional outcomes or infarct volume after stroke. Further, there were no differences in the numbers of infiltrating immune cells or bacterial load within the lungs. These data suggest that diet-induced vitamin D deficiency has no effect on acute post-stroke outcomes.