Escherichia coli bacteria into the urinary bladder. The control groups received phosphate-buffered saline or water. C3H/Tif mice were treated with hLF or bLF, and C3H/HeN mice were treated with bLF only. The numbers of bacteria in the kidneys and bladder of C3H/Tif and C3H/HeN mice were significantly reduced 24 h later by the LF treatments compared to the findings for the control group. The hLF-treated group showed the strongest reduction compared with the vehicle-treated-group (P values were 0.009 and 0.0001 for the kidneys and bladder, respectively). The urinary leukocyte response was diminished in the hLF-treated group. The hLF treatment also significantly reduced the urinary interleukin-6 (IL-6) levels at 2 h and the systemic IL-6 levels at 24 h after infection (P values were 0.04 and < 0.002, respectively). In the bLF-treated animals, no such strong antiinflammatory effects were obtained. In another series of experiments, C3H/Tif mice perorally treated with HLD1 or HLD2 also showed reduced numbers of bacteria in the kidneys compared with the vehicle-treated mice, although the results were significantly different only for HLD2 (P < 0.01). Analysis of urine from hLF-fed C3H/ Tif mice showed that hLF was excreted into the urinary tract at 2 h after feeding. Testing of the in vitro bactericidal activity of LF (1 mg/ml) or the peptides (0.1 mg/ml) in mouse urine against the E. coli bacteria revealed moderate killing only by HLD2. In conclusion, these results demonstrate for the first time that oral administration of hLF or peptides thereof is effective in reducing infection and inflammation at a remote site, the urinary tract, possibly through transfer of hLF or its peptides to the site of infection via renal secretion. The antibacterial mechanism is suggested to involve bactericidal capacities of LF, fragments thereof, or its peptides.
Biologically programmed molecular recognition provides the basis of all natural systems and supplies evolution-optimized functional materials from self-assembly of a limited number of molecular building blocks. Biomolecules such as peptides, nucleic acids and carbohydrates represent a diverse supply of structural building blocks for the chemist to design and fabricate new functional nanostructured architectures. In this context, we review here the chemistry we have developed to conjugate peptides with nucleic acids, carbohydrates, and organic molecules, as well as combinations thereof using a template-assembled approach. With this methodology, we have prepared new integrated functional systems exhibiting designed properties in the field of nanovectors, biosensors as well as controlled peptide self-assembly. Thus this molecular engineering approach allows for the rational design of systems with integrated tailor-made properties and paves the way to more elaborate applications by bottom-up design in the domain of nanobiosciences.
In this study, we investigated the anti-inflammatory effects of orally administered human lactoferrin (hLF) and two peptides, based on the bactericidal region of hLF (HLD1 and HLD2), on the course of experimental colitis. Acute colitis was induced in C57Bl/6 mice by giving 5% dextran sulphate (DX) in the drinking water. The mice were killed after 2 or 7 days of DX exposure. The animals were given hLF or the peptides orally twice a day (2 mg/dose/mouse) during the DX exposure. In the control animals, the hLF or the peptides were replaced by bovine serum albumin or water.The appearance of occult blood in the faeces and macroscopic rectal bleeding were significantly delayed and partly reduced in the hLF-treated animals compared with the control animals. The shortening of the colon, a pathological effect of DX exposure, was significantly less pronounced in the hLF-treated group compared with the control group. Also, the interleukin-1b (IL-1b) levels in the blood were significantly diminished in this group after 2 days of DX exposure. A significantly lower crypt score was observed in the distal part of the colon in the hLF-treated group compared with the control group. Also, significantly reduced numbers of CD4 cells, F4/80-positive macrophages and tumour necrosis factor-a-producing cells were detected by immunohistochemistry in the distal colon of the hLF-treated animals compared with the control animals after 7 days of DX exposure. A reduction was also observed concerning the IL-10-producing cells in the middle colonic submucosa. The HLD1 and HLD2 treatment, which was carried out for 2 days, only gave results almost identical to those of hLF, concerning clinical parameters after the 2 days of DX exposure. An even stronger effect was observed for HLD2, regarding decreased occult blood in the faeces and colon length.Our results show that perorally given hLF mediates anti-inflammatory effects on the DX-induced acute colitis, and further suggest that the bactericidal region of the hLF molecule may be involved in these activities.
Amyloid formation and accumulation of the amyloid beta-peptide (Abeta) in the brain is associated with Alzheimer's disease (AD) pathogenesis. Therefore, among the therapeutic approaches in development to fight the disease, the direct inhibition of the Abeta self-assembly process is currently widely investigated and is one of the most promising approaches. In this study we investigated the potential of a multimeric display of quinacrine derivatives, as compared to the monomer quinacrine, as a design principal for a novel class of inhibitors against Abeta fibril formation. The presented multimeric conjugate exhibits a cluster of four quinacrine derivatives on a rigid cyclopeptidic scaffold. Herein is reported the synthesis of the conjugate, together with the in vitro inhibitory evaluation of Abeta(1-40) fibrils using the thioflavin T fluorescence assay, and imaging with atomic force microscopy. Our data show that the multimeric compound inhibits Abeta(1-40) fibril formation with an IC(50) value of 20+/-10 microM, which contrasts with the nonactive monomeric analogue. This work suggests that assembling multiple copies of acridine moieties to a central scaffold, for multiple interactions, is a promising strategy for the engineering of inhibitors against Abeta fibril formation.
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