Tst, has been causally linked to reduced adiposity and insulin sensitisation. Here we show that macrophages derived from the high-TST expressing Lean line of mice have a reduced inflammatory response to TLR-ligand activation than those from the low-TST expressing Fat line of mice. Furthermore, using the mouse clonal 3T3-L1 adipocytes we describe a positive effect of TST upregulation via its substrates, sodium thiosulfate (STS) and the garlic compound diallyl disulfide (DADS), on palmitate-induced inflammation resulting in significant reduction of inflammatory cytokines and inhibition of reactive oxygen species. Additionally, using an IL1ß-induced insulin resistance 3T3-L1 cell model, upregulation of TST associated with antidiabetic effects. Therefore, we demonstrate that TST-mediated suppression of the inflammatory response protects in vitro cell model of white adipocytes from insulin resistance-induced inflammation. These results encourage the development of potent medicines in the future that specifically target TST in the fat tissue, which could lead to new ways of treating diabetes associated with obesity.
COBISS.SI-ID: 18673923
NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is a multiprotein complex which forms within cells in response to various microbial and self-derived triggers. Mutations in the gene encoding NLRP3 cause rare cryopyrin-associated periodic syndromes (CAPS) and growing evidence links NLRP3 inflammasome to common diseases such as Alzheimer´s disease. In order to modulate different stages of NLRP3 inflammasome assembly nine peptides whose sequences correspond to segments of inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) were selected. Five peptides inhibited IL-1ß release, caspase-1 activation and ASC oligomerization in response to soluble and particulate NLRP3 triggers. Modulatory peptides also attenuated IL-1ß maturation induced by constitutive CAPS-associated NLRP3 mutants. Peptide corresponding to H2-H3 segment of ASC pyrin domain selectively inhibited NLRP3 inflammasome by binding to NLRP3 pyrin domain in the micromolar range. The peptide had no effect on AIM2 and NLRC4 inflammasomes as well as NF-?B pathway. The peptide effectively dampened neutrophil infiltration in the silica-induced peritonitis and when equipped with Antennapedia or Angiopep-2 motifs crossed the blood-brain barrier in a mouse model. Our study demonstrates that peptides represent an important tool for targeting multiprotein inflammatory complexes and can serve as the basis for the development of novel anti-inflammatory strategies for neurodegeneration.
COBISS.SI-ID: 23332355
Response of the adaptive immune system is augmented by multimeric presentation of antigen, resembling viral particles. Several vaccines have been designed based on natural or designed protein scaffolds, which exhibited a potent adaptive immune response to antigens; however antibodies are also generated against the scaffold, which may impair subsequent vaccination. In order to compare polypeptide scaffolds of different size and oligomerization state with respect to their efficiency ,including anti-scaffold immunity we compared several strategies of presentation of the RBD domain of the SARS-CoV-2 spike protein, an antigen aimed to generate neutralizing antibodies. A comparison of several genetic fusions of RBD to different nanoscaffolding domains (foldon, ferritin, lumazine synthase, and ß-annulus peptide) delivered as DNA plasmid demonstrated a strongly augmented immune response, with high titers of neutralizing antibodies and a robust T cell response in mice. Antibody titers and virus neutralization were most potently enhanced by fusion to the small ß-annulus peptide scaffold, which itself triggered a minimal response in contrast to larger scaffolds. The ß-annulus fused RBD protein increased residence in lymph nodes and triggered the most potent viral neutralization in immunization by a recombinant protein. Results of the study support the use of a nanoscaffolding platform using the ß-annulus peptide for vaccine design.
COBISS.SI-ID: 62539779