Peng Cho Tang

Matrix metalloproteinase inhibitors reduce phorbol ester-induced cutaneous inflammation and hyperplasia

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases which play key roles in extracellular matrix remodeling, connective tissue damage, inflammation and cell proliferation in a variety of tissues. Since MMP inhibitors have been recently shown to decrease proliferation of vascular smooth-muscle cells, and to prevent neutrophil infiltration in response to alkali burns, we sought to determine whether MMPs play a role in the pathogenesis of inflammatory or hyperproliferative skin disorders. The effects of a specific MMP inhibitor and its analogues on phorbol dibutyrate (PdiBu)-induced inflammation and epidermal hyperplasia in murine skin were assessed. Topical GM 6001, a hydroxamic acid analog with potent inhibitory activity against several MMPs, markedly inhibited PdiBu-induced increases in both ear thickness and ear punch-biopsy weight in a dose-dependent manner 30 h after topical application of PdiBu. Maximal inhibition (75%) was obtained at a dose of 100 μg/cm2 (P < 0.01). Moreover, histologic analysis revealed that GM 6001 decreased both the inflammatory cellular infiltrates and epidermal hyperplasia induced by PdiBu. Whereas similar results were found for GM 1489, an analog of GM 6001, acetohydroxamic acid, containing the critical metal ligand group but without the amino acid side chains necessary for binding to the MMPs, did not alter the response to PdiBu inflammation/hyperplasia. These results show that the MMP inhibitors, GM 6001 and GM 1489, are effective in reducing both the inflammatory and hyperproliferative responses that occur following topical phorbol ester application, suggesting a potential role for MMPs in cutaneous inflammatory dermatoses. Moreover, the delivery of this class of inhibitors across intact stratum corneum implies that MMP inhibition could provide an approach to the topical treatment of inflammatory dermatoses.

Synthesis of novel fused ring C-glycosides

Abstract Tlie Lewis acid mediated addition of olefins to O -benzyl protected sugars is studied. The results show the formation of C -glycosides witb α selectivity and a propensity to cyclize with loss of a benzyl group.

Chapter 22. Cell Adhesion and Carbohydrates

Publisher Summary The interaction of cell-surface carbohydrates, with protein receptors, is a well accepted phenomenon. For example, cell-surface glycoconjugates, found on red blood cells, determine blood group specificity. These blood group epitopes are the ABO antigens. Recently, the discovery of selectins, a new class of cell adhesion molecules, sparked new enthusiasm in the interaction of cell-surface carbohydrates, with protein receptors. The selectins are now known to be involved in the rolling stage of the previously discovered transendothelial migration of leukocytes. Once out of the blood stream, leukocytes become involved in disorders, ranging from autoimmune diseases to acute respiratory distress syndrome (ARDS). Extravasation of leukocytes also applies to the transendothelial migration of the metastatic cells. The chapter discusses the mechanism of cell adhesion mediated disorders and possible treatments. Research in the area has yielded a wealth of biological information based on neutrophil-endothelial cell interactions. Furthermore, the use of carbohydrate based drugs, as novel therapeutic agents, for the treatment of diseases ranging from ARDS to cancer will provide the basis for future reviews of this emerging field of glycomimetics. Normal inflammation is a protective response, by the immune system, sewing to destroy the injurious materials and organisms as well as a mechanism to remodel the injured tissue. However, when the immune system recognizes the host tissue, as foreign, an inflammatory response may result. A specific example is rheumatoid arthritis that results from the lysosomal digestion of cartilage-lgG complexes.