Background: Active vitamin D analogs that are less toxic than calcitriol can be useful in the combined treatment of patients suffering from colon cancer. In the present study we demonstrate, for the first time in anin vivomodel system, the biological effect of combined therapy using 5-fluorouracil (5-FU) along with vitamin D analog PRI-2191 (tacalcitol, 1,24-dihydroxyvitamin D₃) or PRI-2205 (5,6-trans-isomer of calcipotriol) on colon cancer.Methods: We investigated the influence of vitamin D analogs on the anticancer activity of 5-FU or capecitabine in the treatment of mice bearing MC38 mouse colon tumors implanted subcutaneously or orthotopically. The cell cycle distribution, E-cadherin expression and caspase 3/7 activityin vitrowere also evaluated.Results: We observed that both PRI-2191 and PRI-2205 significantly enhanced the antitumor activity of 5-FU; but these results depend on the treatment regimen. Applying the optimal schedule of combined therapy we observed a significant decrease in tumor growth, metastasis and also a prolongation of the survival time of mice, in comparison with the administrations of 5-FU given alone. Both combinations indicated a synergistic effect and did not cause toxicity. Moreover, analogs applied after completed course of administration of 5-FU, prolonged the antitumor effect of the drug. Furthermore, when the prodrug of 5-FU, capecitabine, was used, potentiation of its activity was also observed.Conclusions: Our data suggest that vitamin D analogs (especially PRI-2191) might be potentially applied to clinical use in order to enhance the anticancer effect of 5-FU and also prolong its activity against colon cancer. The activity of PRI-2191 is realized through stopping the cells in the G₀/G₁cell cycle phase and increasing the expression of E-cadherin.

Background: Mesenchymal stem cells (MSCs) secrete a cocktail of growth factors and cytokines, which could promote tissue regeneration and wound healing. Therefore, in clinical practice, post-culture MSC supernatant treatment could be a more attractive alternative to autologous stem cell transplantation. In this study, we compared the regenerative properties of supernatants harvested from four newly established human adipose tissue mesenchymal stem cell lines (HATMSCs) derived from chronic wound patients or healthy donors. Methods: HATMSC supernatants were produced in a serum-free medium under hypoxia and their content was analyzed by a human angiogenesis antibody array. The regenerative effect of HATMSCs supernatants was investigated in an in vitro model of chronic wound, where cells originating from human skin, such as microvascular endothelial cells (HSkMEC.2), keratinocytes (HaCaT), and fibroblasts (MSU-1.1), were cultured in serum-free and oxygen-reduced conditions. The effect of supernatant treatment was evaluated using an MTT assay and light microscopy. In addition, fibroblasts and HATMSCs were labeled with PKH67 and PKH26 dye, respectively, and the effect of supernatant treatment was compared to that obtained when fibroblasts and HATMSCs were co-cultured, using flow cytometry and fluorescent microscopy. Results: A wide panel of angiogenesis-associated cytokines such as angiogenin, growth-regulated oncogene (GRO), interleukin-6 and 8 (IL-6, IL-8), vascular endothelial growth factor (VEGF), insulin growth factor 1 (IGF-1), and matrix metalloproteinase (MMP) were found in all tested HATMSCs supernatants. Moreover, supernatant treatment significantly enhanced the survival of fibroblasts, endothelial cells, and keratinocytes in our chronic wound model in vitro. Importantly, we have shown that in in vitro settings, HATMSC supernatant treatment results in superior fibroblast proliferation than in the case of co-culture with HATMSCs. Conclusions: Our results suggest that therapy based on bioactive factors released by the immortalized atMSC into supernatant has important effect on skin-derived cell proliferation and might preclude the need for a more expensive and difficult cell therapy approach to improve chronic wound healing.

Pseudomonas aeruginosa is an opportunistic human pathogen that has become a nosocomial health problem worldwide. The pathogen has multiple drug removal and virulence secretion systems, is resistant to many antibiotics, and there is no commercial vaccine against it. Yersinia pestis is a zoonotic pathogen that is on the Select Agents list. The bacterium is the deadliest pathogen known to humans and antibiotic-resistant strains are appearing naturally. There is no commercial vaccine against the pathogen, either. In the current work, novel compounds based on metallacarborane cage were studied on strains of Pseudomonas aeruginosa and a Yersinia pestis substitute, Yersinia enterocolitica. The representative compounds had IC₅₀ values below 10 µM against Y. enterocolitica and values of 20–50 μM against P. aeruginosa. Artificial generation of compound-resistant Y. enterocolitica suggested a common mechanism for drug resistance, the first reported in the literature, and suggested N-linked metallacarboranes as impervious to cellular mechanisms of resistance generation. SEM analysis of the compound-resistant strains showed that the compounds had a predominantly bacteriostatic effect and blocked bacterial cell division in Y. enterocolitica. The compounds could be a starting point towards novel anti-Yersinia drugs and the strategy presented here proposes a mechanism to bypass any future drug resistance in bacteria.