While some earlier reports show Selleckchem PU-H71 that Berenil possesses trypanolytic and trypanostatic properties, some studies show it may also indirectly affect the host immune system. Our recent extensive studies show that treatment with Berenil reduces pro-inflammatory cytokine (IL-6, IL-12 and TNF) production in macrophages in vivo and in vitro following stimulation with Ttypanosoma congolense, lipopolysaccharide (LPS), unmethylated bacterial CpG motifs and Poly I:C This global effect was not due to downregulation of Toll-like receptor (TLR) expression on innate immune cells. Instead, Berenil significantly downregulated phosphorylation of mitogen activated

protein kinases (MAPKs, including ERK, p38 and JNK),

signal transducer and activator of transcription (STAT) proteins (including STAT1 and STAT3) and NF kappa B p65 subunit, key signaling molecules and transcription factors involved in the production of proinflammatory cytokines. The ability of Berenil to downregulate major intracellular signaling pathways that lead to proinflammatory cytokine production suggests that it could be used to treat conditions caused by excessive production of inflammatory RSL3 mouse cytokines. (C) 2014 Elsevier B.V. All rights reserved.”
“L-asparaginase (L-ASP) is a therapeutic enzyme used clinically for the treatment of childhood acute lymphoblastic leukemia. L-ASP’s anticancer activity is believed to be associated primarily with depletion of asparagine, but secondary glutaminase activity has also been implicated in its anticancer mechanism of action. To investigate the effects of L-ASP on amino acid metabolism, we have developed an LC-MS/MS metabolomics platform for high-throughput quantitation of 29 metabolites, including all 20 proteinogenic amino acids, 6 metabolically related amino Selleck ABT737 acid derivatives (ornithine, citrulline, sarcosine, taurine, hypotaurine, and cystine), and 3 polyamines (putrescince, spermidine, and spermine) in adherent cultured cells. When we examined the response of OVCAR-8 ovarian cancer cells in culture to L-ASP, asparagine

was depleted from the medium within seconds. Interestingly, intracellular asparagine was also depleted rapidly, and the mechanism was suggested to involve rapid export of intracellular asparagine followed by rapid conversion to aspartic acid by L-ASP. We also found that L-ASP-induced cell death was more closely associated with glutamine concentration than with asparagine concentration. Time-course analysis revealed the dynamics of amino acid metabolism after feeding cells with fresh medium. Overall, this study provides new insight into L-ASP’s mechanism of action, and the optimized analytical method can be extended, with only slight modification, to other metabolically active amino acids, related compounds, and a range of cultured cell types.