Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats.
Stadnicki A. Sartor RB. Janardham R. Majluf-Cruz A. Kettner CA. Adam AA. Colman RW.
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
The kallikrein-kinin (K-K) (contact) system is activated during acute and chronic relapsing phases of enterocolitis induced in genetically susceptible Lewis rats by intramural injection of peptidoglycan-polysaccharide (PG-APS). Using the selective plasma kallikrein inhibitor P8720, we investigate whether activation of the K-K system plays a primary role in chronic granulomatous intestinal and systemic inflammation in this model. Group I (negative control) received human serum albumin intramurally. Group II (treatment) received PG-APS intramurally and P8720 orally. Group III (positive control) received PG-APS intramurally and albumin orally. P8720 attenuated the consumption of the contact proteins, high molecular weight kininogen (P
Prediction-based threading of the hMSH2 DNA mismatch repair protein.
de las Alas MM. de Bruin RA. Ten Eyck L. Los G. Howell SB.
Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla 92093-0058, USA.
Mutations in the genes whose products participate in DNA mismatch repair underlie the increased risk of cancer in families with hereditary nonpolyposis colon carcinoma. Mutations in hMSH2 account for approximately 50% of the mutations found in these families. We sought to predict the 3-dimensional structure of hMSH2 by identifying structural homologues using prediction-based threading and by computer modeling using information from these putative structurally related proteins. Prediction-based threading identified three candidate structural homologues: glycogen phosphorylase (gpb), a 70 kDa soluble lytic transglycosylase, and ribonucleotide reductase protein R1. An independent approach utilizing a potential-based threading program also identified gpb as a structural homologue. The models based on the structures of these proteins suggest that the ATP binding domain and helix-turn-helix domain are exposed on the outside of the protein. All known bacterial MutS and hMSH2 mutations appear to be clustered in similar vicinities in the theoretical models of hMSH2; the major site is within the ATP binding domain and near the carboxyl-terminal end, whereas a smaller number map to the region coding for exon 5 and the amino-terminal domain. All point mutations also appear to affect amino acids that are exposed on the outside surface of the protein.