No abstract

Metformin is widely used to suppress certain functions of the cells found in diseases including diabetes and obesity. In this study, the effects of metformin on downregulating IL-17-producing T (Th17) cells, activating and upregulating regulatory T (Treg) cells, suppressing osteoclastogenesis, and clinically scoring collagen-induced arthritis (CIA) were investigated. To evaluate the effect of metformin on CIA, mice were orally fed with either metformin or saline as control three times a week for nine weeks. Histological analysis of the joints was performed using immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. Metformin mitigated the severity of CIA, reduced serum immunoglobulin concentrations, and reciprocally regulated Th17/Treg axis. Also, metformin treatment of normal cells cultured in Th17 conditions decreased the number of Th17 cells and increased the number of Treg cells. Metformin decreased gene expression and osteoclastogenic activity in CIA and normal mice. These results indicate that metformin had immunomodulatory actions influencing anti-inflammatory action on CIA through the inhibition of Th17 cell differentiation and the upregulation of Treg cell differentiation along with the suppression of osteoclast differentiation. Our results suggest that metformin may be a potential therapeutic for rheumatoid arthritis.

Salmonella enterica and Escherichia coli O157:H7 are major food-borne pathogens causing serious illness. Phage SFP10, which revealed effective infection of both S. enterica and E. coli O157:H7, was isolated and characterized. SFP10 contains a 158-kb double-stranded DNA genome belonging to the Vi01 phage-like family Myoviridae. In vitro adsorption assays showed that the adsorption constant rates to both Salmonella enterica serovar Typhimurium and E. coli O157:H7 were 2.50 ؋ 10 ؊8 ml/min and 1.91 ؋ 10 ؊8 ml/min, respectively. One-step growth analysis revealed that SFP10 has a shorter latent period (25 min) and a larger burst size (>200 PFU) than ordinary Myoviridae phages, suggesting effective host infection and lytic activity. However, differential development of resistance to SFP10 in S. Typhimurium and E. coli O157:H7 was observed; bacteriophage-insensitive mutant (BIM) frequencies of 1.19 ؋ 10 ؊2 CFU/ml for S. Typhimurium and 4.58 ؋ 10 ؊5 CFU/ml for E. coli O157:H7 were found, indicating that SFP10 should be active and stable for control of E. coli O157:H7 with minimal emergence of SFP10-resistant pathogens but may not be for S. Typhimurium. Specific mutation of rfaL in S. Typhimurium and E. coli O157:H7 revealed the O antigen as an SFP10 receptor for both bacteria. Genome sequence analysis of SFP10 and its comparative analysis with homologous Salmonella Vi01 and Shigella phiSboM-AG3 phages revealed that their tail fiber and tail spike genes share low sequence identity, implying that the genes are major host specificity determinants. This is the first report identifying specific infection and inhibition of Salmonella Typhimurium and E. coli O157:H7 by a single bacteriophage.

Players undergoing microfracture for knee chondral injuries are at risk for not returning to the National Basketball Association postoperatively. With the exception of points per game, athletes returning exhibited similar performance postoperatively compared with matched controls.

Myeloid-derived suppressor cells (MDSCs) are heterogenous populations of immature myeloid progenitor cells with immunoregulatory function. MDSCs play critical roles in controlling the processes of autoimmunity but their roles in rheumatoid arthritis (RA) are controversial. The present study was undertaken to investigate whether MDSCs have therapeutic impact in mice with collagen-induced arthritis (CIA), an animal model of RA. We also examined the mechanisms underlying the anti-arthritic effect of MDSCs. In vitro treatment with MDSCs repressed IL-17 but increased FOXP3 in CD4+ T cells in mice. In vivo infusion of MDSCs markedly ameliorated inflammatory arthritis. Th17 cells and Th1 cells were decreased while Tregs were increased in the spleens of MDSCs-treated mice. MDSCs profoundly inhibited T cell proliferation. Addition of anti-IL-10 almost completely blocked the anti-proliferative effects of MDSCs on T cells. Anti-IL-10 blocked the expansion of Tregs by MDSCs. However, infusion of MDSCs from IL-10 KO mice failed to suppress inflammatory arthritis. MDSCs could reciprocally regulate Th17/Treg cells and suppress CIA via IL-10, suggesting that MDSCs might be a promising therapeutic strategy for T cell mediated autoimmune diseases including RA.