Search

Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD. Results: A thorough analysis of the developed model provided the following results: 1. TG-2 inhibitor treatment leads to insignificant decrease in antibody levels, and hence remains higher than in healthy individuals. 2. TG-2 inhibitor treatment does not lead to any significant increase in villous area. 3. The model predicts that the most effective treatment of CD would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APC. The model predicts that the treatment of CD by such gluten peptide analogs can lead to a decrease in antibody levels to those of normal healthy people, and to a significant increase in villous area. Conclusions: The developed mathematical model of immune response in CD allows prediction of the efficacy of TG-2 inhibitors and other possible drugs for the treatment of CD: their influence on the intestinal villous area and on the antibody levels. The model also allows to understand what processes in the immune response have the strongest influence on the efficacy of different drugs. This model could be applied in the pharmaceutical R&D arena for the design of drugs against autoimmune small intestine disorders and on the design of their corresponding clinical trials. [ABSTRACT FROM AUTHOR]

Background: Putrescine is the intermediate product of arginine decarboxylase pathway in Escherichia coli which can be used as an alternative nitrogen source. Transaminase and dehydrogenase enzymes seem to be implicated in the degradative pathway of putrescine, in which this compound is converted into γ-aminobutyrate. But genes coding for these enzymes have not been identified so far. Results: The 1.8-kbp DNA fragment containing E. coli K12 ygjG gene with aer-ygjG intergenic region was examined. It was found that the fragment contains σ54-depended open reading frame (ORF) of 1,380 nucleotides encoding a 459-amino acid polypeptide of approximately 49.6 kDa. The cytidine (C) residue localized 10 bp downstream of the σ54 promoter sequence was identified as the first mRNA base. The UUG translation initiation codon is situated 36 nucleotides downstream of the mRNA start. The YgjG was expressed as a his6-tag fused protein and purified to homogeneity. The protein catalyzed putrescine:2-oxoglutaric acid (2-OG) aminotransferase reaction (PATase, EC 2.6.1.29). The Km values for putrescine and 2-OG were found to be 9.2 mM and 19.0 mM, respectively. The recombinant enzyme also was able to transaminate cadaverine and, in lower extent, spermidine, and gave maximum activity at pH 9.0. Conclusion: Expression of E. coli K12 ygjG coding region revealed σ54-depended ORF which encodes a 459-amino acid protein with putrescine:2-OG aminotransferase activity. The enzyme also was able to transaminate cadaverine and, in lower extent, spermidine. [ABSTRACT FROM AUTHOR]