The release of antimicrobial peptides and growth factors by Paneth cells is thought to play an important role in protecting the small intestine, but the mechanisms involved have remained obscure. Immunohistochemistry and immunofluorescence showed that Paneth cells express Toll-like receptor 9 (TLR9) in the granules. Injection of mice with oligonucleotides containing CpG sequence (CpG-ODNs) led to a down-modulation of TLR9 and a striking decrease in the number of large secretory granules, consistent with degranulation. Moreover CpG-ODN treatment increased resistance to oral challenge with virulent Salmonella typhimurium. Moreover, our findings demonstrate a sentinel role for Paneth cells through TLR9.

No abstract

Two series (A, B) of 2-(2-methyl-5-nitro-1H-imidazolyl)ethyl derivatives (6-9, 18-23) conjugated through an oxygen or an aminomethyl bridge with either a furoxan NO-donor moiety or a furazan substructure, devoid of NO-donor properties, were synthesised. A third group (C) of 2-(2-methyl-5-nitro-1H-imidazolyl)ethyl derivatives conjugated with nitrooxy and dinitrooxy NO-donor functions (35, 38) as well as the corresponding analogue without these functions (40) were prepared. All the compounds were evaluated in vitro for their activity against a number of Helicobacter pylori strains. Metronidazole (1) and its amino analogue (11) were taken as reference compounds. All the synthesised hybrids and their analogues exhibited good anti-H. pylori activity with MIC 50 in the range less than 0.0039-1, resulting in compounds more active than metronidazole. Derivatives 6-9 displayed good potency also against metronidazole-resistant strains. Compounds lacking the 5-nitroimidazole moiety (24-29, 30-33) proved to be inactive against H. pylori with the exception of 33. The lack of significant differences in the antibacterial potency between furoxan and furazan hybrids in both series (A, B) suggest that the role of the N-oxide moiety of the furoxan system either as an inductor of oxidative stress or as a promoter of NO-donor properties is marginal. The substitution of the furoxan substructures with nitrooxy moieties (35, 38) afforded active compounds. In view of their NO-donor properties, NO-metronidazole hybrids could represent potential therapeutic tools both in the treatment of gastric ulcer and in a number of extragastrointestinal disorders such as ischaemic heart diseases and atherosclerosis-related to some H. pylori strains. Drug Dev. Res. 60:225-239, 2003.

Antibiotic susceptibility testing of Helicobacter pylori isolates was performed by broth microdilution method with MegaCell RPMI-1640 Medium (SIGMA). Fifty five clinical isolates of H. pylori were tested against metronidazole, tinidazole, amoxicillin, and clarithromycin. The results were compared to those obtained by standard agar dilution method. The microdilution method performed with new medium, showed excellent correlation with agar dilution results, with 100% agreement for metronidazole, 96.3% for amoxicillin, 90.7% for clarithromycin, and 92.8% for tinidazole. MICs determined by proposed method were highly reproducible: replicate results were variable within one-two-fold dilution by using different inocula and different batches of medium.