Cathelicidins are peptide components of the innate immune system of mammals. Apart from exerting a direct antibiotic activity, they can also trigger specific defense responses in the host. Their roles in various pathophysiological conditions have been studied, but there is a lack of published information on their expression and activities in the context of mastitis. The aims of this study were to investigate the expression of the bovine cathelicidins BMAP-27, BMAP-28, Bac5, and indolicidin in healthy and infected mammary tissue and in lipopolysaccharide (LPS)-treated cells, to determine their activities against bacteria isolated from bovine mastitis, and to examine their potentials to trigger defense responses in bovine mammary cells. The genes were found to be upregulated in LPS-stimulated neutrophils, but not in infected quarters or epithelial cells. All peptides showed a variably broad spectrum of activity against 28 bacterial isolates from bovine mastitis (MIC values, 0.5 to 32 M), some of which were antibiotic resistant. The activity of each peptide was significantly enhanced when it was pairwise tested with the other peptides, reaching the synergy threshold when indolicidin was present. The bactericidal activity was sensitive to milk components; BMAP-27 and -28 were highly effective in mastitic bovine milk and inhibited in milk from healthy cows. Both peptides were also active in whey and in blood serum and triggered the expression of tumor necrosis factor alpha (TNF-␣) in bovine mammary epithelial cells. Our results indicate multiple roles for the bovine cathelicidins in mastitis, with complementary and mutually enhanced antimicrobial activities against causative pathogens and the capacity to activate host cells.
Designing
small molecules able to break down G4 structures in mRNA
(RG4s) offers an interesting approach to cancer therapy. Here, we
have studied cationic porphyrins (CPs) bearing an alkyl chain up to
12 carbons, as they bind to RG4s while generating reactive oxygen
species upon photoirradiation. Fluorescence-activated cell sorting
(FACS) and confocal microscopy showed that the designed alkyl CPs
strongly penetrate cell membranes, binding to KRAS and NRAS mRNAs under low-abundance cell conditions.
In Panc-1 cells, alkyl CPs at nanomolar concentrations promote a dramatic
downregulation of KRAS and NRAS expression,
but only if photoactivated. Alkyl CPs also reduce the metabolic activity
of pancreatic cancer cells and the growth of a Panc-1 xenograft in
SCID mice. Propidium iodide/annexin assays and caspase 3, caspase
7, and PARP-1 analyses show that these compounds activate apoptosis.
All these data demonstrate that the designed alkyl CPs are efficient
photosensitizers for the photodynamic therapy of ras-driven cancers.
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