The anti-inflammatory activity of a novel fused-cyclopentenone phosphonate and its potential in the local treatment of experimental colitis.

A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and tested in vitro (LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity and in vivo (DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFα and IL-1β.

Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses.

The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.

Synchronized release of Doxil and Nutlin-3 by remote degradation of polysaccharide matrices and its possible use in the local treatment of colorectal cancer.

A novel approach to the prevention of colorectal cancer (CRC) recurrence by the local, luminal application of the combined therapies: Nutlin-3 (NUT) and the liposomal preparation of doxorubicin, Doxil(*) (Doxil) is presented here. The two drug entities were loaded into calcium alginate beads, engineered to erode upon exposure to a de-crosslinking agent, to allow for the controlled, concomitant release of the two. The synchronized release-driven improved cytotoxicity of NUT and Doxil was tested in vitro in RKO (wild-type p53) and HT-29 (mutant p53) CRC cells, by measuring intracellular expression of p53, p21 and Mdm2, as well as monitoring cell proliferation and viable cell numbers.

Enhanced transferrin receptor expression by proinflammatory cytokines in enterocytes as a means for local delivery of drugs to inflamed gut mucosa.

Therapeutic intervention in inflammatory bowel diseases (IBDs) is often associated with adverse effects related to drug distribution into non-diseased tissues, a situation which attracts a rational design of a targeted treatment confined to the inflamed mucosa. Upon activation of immune cells, transferrin receptor (TfR) expression increases at their surface. Because TfR is expressed in all cell types we hypothesized that its cell surface levels are regulated also in enterocytes.

Local treatment of experimental colitis in the rat by negatively charged liposomes of catalase, TMN and SOD.

Superoxide dismutase (SOD), 4-amino tempol (tempamine, denoted as TMN) and catalase were encapsulated into negatively charged liposomes. The activity of the antioxidants against dinitrobenzenesulfonic acid (DNBS) induced colitis was tested in the rat and compared to the anti-inflammatory activity of the native enzymes and free TMN. Inflammation severity was assessed by monitoring tissue myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) amounts and by comparing the weights of the dissected colons.