Epithelium intestinal

Delivery of peptides and proteins via the gastrointestinal tract has not been successful because of poor penetration through the intestinal epithelium and high levels of proteolytic activity in the gastrointestinal tract. Liposomal encapsulation of proteins and peptides will not improve the efficiency and capacity of this absorption pathway considerably (e.g., Ryman et al., 1982 Machy and Leserman, 1987 Weiner and Chia-Ming Chiang, 1988). These difficulties in delivery via the oral route caused the parenteral route to remain the preferred route for the administration of therapeutic peptides... 

Curcumin possesses strong antioxidant capacities, which may explain its effects against degenerative diseases in which oxidative stress plays a major role. As previously described for flavonoids, it is unlikely that curcumin acts as a direct antioxidant outside the digestive tract since its concentration in peripheral blood and organs is very low (near or below 1 pM, even after acute or long-term supplementation). Indeed, it has been shown that the intestinal epithelium limits its entry into the body, as reflected by absorption studies in various models (portal blood perfusion, everted bags). ... 

The surface epithelial cells of the small intestine are renewed rapidly and regularly. It takes about two days for the cells of the duodenum to be renewed completely. As a result of its rapid renewal rate, the intestinal epithelium is susceptible to various factors that may influence proliferation. Exposure of the intestine to ionizing radiation and cytotoxic drugs (such as folic acid antagonists and colchicine) reduces the cell renewal rate. 

Mucin, a viscous mucopolysaccharide that lines and protects the intestinal epithelium, has been thought to bind certain drugs nonspecifically (e.g., quarternary ammonium compounds) and thereby prevent or reduce absorption. This behavior may partially account for the erratic and incomplete absorption of such charged... 

LS Schanker, JJ Jeffrey. Active transport of foreign pyrimidines across the intestinal epithelium. Nature 190 727-728, 1961. 

JV Asperen, OV Tellingen, JH Beijnen. The pharmacological role of / -glycoprotein in the intestinal epithelium. Pharmacol Res 37 429—435, 1998. 

Walter,E. Janich, S. Roessler, B.J. Hilfinger,J.M. Amidon, G. L., HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium In vitro-in vivo correlation with permeability data from rats and humans, J. Pharm. Sci. 85, 1070-1076 (1996). 

JL Madara, JR Pappenheimer. (1987). Structural basis for physiological regulation of paracellular pathways in intestinal epithelium. J Membr Biol 100 149-164. 

Numerous observations of non-linear relationships between PbB concentration and lead intake in humans provide further support for the existence of a saturable absorption mechanism or some other capacity limited process in the distribution of lead in humans (Pocock et al. 1983 Sherlock et al. 1984, 1986). However, in immature swine that received oral doses of lead in soil, lead dose-blood lead relationships were non-linear whereas, dose-tissue lead relationships for bone, kidney and liver were linear. The same pattern (nonlinearity for PbB and linearity for tissues) was observed in swine administered lead acetate intravenously (Casteel et al. 1997). These results suggest that the non-linearity in the lead dose-PbB relationship may derive from an effect of lead dose on some aspect of the biokinetics of lead other than absorption. Evidence from mechanistic studies for capacity-limited processes at the level of the intestinal epithelium is compelling, which would suggest that the intake-uptake relationship for lead is likely to be non-linear these studies are discussed in greater detail in Section 2.4.1. 

The Caco-2 cell line was isolated from a human colon carcinoma, and has been characterized as one of the best in vitro models of intestinal epithelium. Indeed, in contrast to other intestinal cell lines, Caco-2 cells are able to constitute a homogenous monolayer and to spontaneously differentiate into polarized cells, highly similar to human mature enterocytes, after approximately 2 weeks of culture. Furthermore, the Caco-2 cells present microvillosities at the apical side and have a high transmembrane resistivity, which confirms the fact that the cells are confluent and link to one another via gap junctions. Finally, they can absorb different compounds, express many enzymes involved in intestinal metabolic pathways (Pinto et al. 1983, Musto et al. 1995, Salvini et al. 2002), and give reproducible in vitro results consistent with results obtained in in vivo studies (Artursson and Karlsson 1991). 

In summary, the in vivo protective effects of Tyv-specific antibodies, exclusion and immobility, can now be effectively studied using an in vitro model of the intestinal epithelium. Larvae are prevented from entering epithelial cells by caps of immune complexes or by binding of antibody to Tyv in the absence of immune complex formation. These effects would correlate with exclusion of larvae from epitheha observed in passively immunized rats. Larvae are encumbered as they migrate within epithelial monolayers, an effect that may correlate with immobility of larvae observed in vivo. It is reasonable to conclude that in the animal host the different effects work in combination, most iikeiy in cooperation with innate host defences, to cause nematode expuision from the intestine. 

Bland, P.W. and Whiting, C.V. (1992) Induction of MHC class II gene products in rat intestinal epithelium during graft-versus-host disease and effects on the immune function of the epithelium. Immunology 75, 366-371. 

Mucins are also thought to act in cooperation with trefoil proteins in the protection and repair of the epithelium (Kindon et al., 1995). Trefoil factors are expressed along the GI tract and increased levels are noted near sites of inflammation and ulcerative lesions (Babyatsky et al., 1996). Furthermore, it has been demonstrated that mouse intestinal trefoil factor may play a role in the alteration of the physicochemical nature of GC mucins during N. brasiliensis infection (Tomita et al., 1995). Perhaps in GI nematode parasite infection mucins are not aiding in the host s protective expulsion of the parasite, but rather are functioning in the repair of the damaged intestinal epithelium. 

Chong, S., S. A. Dando, and R. A. Morrison. Evaluation of Biocoat intestinal epithelium differentiation environment (3-day cultured Caco-2 cells) as an absorption screening model with improved productivity, Pharm. Res. 1997, 34, 1835-1837... 

Fihn, B. M., A. Sjoqvist, and M. Jodal. Permeability of the rat small intestinal epithelium along the villus-crypt axis effects of glucose transport, Gastroenterology 2000, 119, 1029-1036... 

Culture protocols have been published which describes an accelerated differentiation process where monolayers are ready to be used after 3-7 days of culture [90-92]. One of these systems, the so-called BD BioCoat Intestinal Epithelium Differentiation Environment, is commercially available through BD Bioscience. This system is described to produce monolayers of a quality that are comparable with the typical Caco-2 cells with respect to permeability for drugs transported transcellularly. The paracellular barrier function is however low, as indicated by high mannitol permeability and low TER. The functional capacity for active uptake and efflux is not as thoroughly characterized as for the standard Caco-2 mono-layers. 

Gan, L.-S. L., Thakker, D. R., Applications of the Caco-2 model in the design and development of orally active drugs elucidation of biochemical and physical barriers posed by the intestinal epithelium, Adv. Drug Deliv. Rev. 1997, 23, 77-98. 

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