Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ(2)O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV-vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes 1-4. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound 4, which also shows the most pronounced rate of hydrolysis. Compounds 2 and 4 also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex 2 displayed moderate cytotoxicity when tested on the HeLa cell line.
Background:The lack of cysteine cathepsin inhibitor, stefin B (cystatin B), results in progressive myoclonus epilepsy, type 1. Results: Stefin B deficiency in macrophages resulted in increased inflammasome activation. Conclusion: Stefin B-deficient mice are significantly more sensitive to e LPS-induced sepsis due to increased caspase-11 expression and mitochondrial damage. Significance: Stefin B has an important role in limiting the inflammatory response during LPS-induced sepsis.
Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models.Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro. Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment.
BackgroundIn vivo imaging of orally administered lactic acid bacteria (LAB) and commensal bacteria in mice is shown to provide information on the spatial and temporal distribution of bacteria in the gastrointestinal tract. The bacteria can be detected and monitored using bioluminescence or near-infrared fluorescence.ResultsFluorescence imaging of bacteria was established by expressing the infrared fluorescent protein IRFP713 in Lactococcus lactis, Lactobacillus plantarum and Escherichia coli. All three bacterial species were monitored in live mice and no major differences in transit time were observed. Bacteria passed through the stomach and small intestine in 1 h and the majority were secreted from the large intestine after 6–8 h. Intestinal localization of bacteria was confirmed by imaging the isolated intestines and culturing the intestinal content. The use of fluorescence tomography for spatial localization of fluorescent bacteria has been established. The expression of an additional infrared fluorescent protein IRFP682 enabled concomitant detection of two bacterial populations in live mice.ConclusionsThe present work provides a methodological basis for future studies of probiotic and theranostic actions of LAB in mouse disease models.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-015-0376-4) contains supplementary material, which is available to authorized users.
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