Search results for "Intestinal mucosa"
showing 10 items of 373 documents
Coexpression of inducible NO synthase and soluble guanylyl cyclase in colonic enterocytes: a pathophysiologic signaling pathway for the initiation of…
1998
Infectious diarrhea is often caused by the exotoxins of gram-negative bacteria such as Escherichia coli. However, these organisms also contain lipopolysaccharide (LPS) endotoxin. LPS induces nitric oxide synthase II (NOS II, inducible NOS) in various types of cells. We now demonstrate by RNase protection analysis, Western blot, and immunohistochemistry that the expression of NOS II mRNA and protein is markedly induced in colonic enterocytes of mice that ingest LPS with their drinking water. Using the same techniques, significant levels of soluble guanylyl cyclase (GC-S), the effector enzyme of NO, were found constitutively expressed in the mucosa. This creates a pathophysiologic autocrine p…
Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C
2016
Objective Congenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing. Design We performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies. Results We identified novel de novo missense mutations in GUCY2C, the gene encod…
Instability of the faecal microbiota in diarrhoea-predominant irritable bowel syndrome
2013
The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with a largely unknown aetiology and a wide range of symptoms. Most cross-sectional studies carried out so far suggest subtle alterations in the structure of the intestinal microbiota that are barely reproduced, partly because of the high inter-subject variation in the community composition and disorder-specific features. We performed a longitudinal study to explore the within-subject variation in the faecal microbiota in two patients with IBS classified into the diarrhoea subtype and the healthy spouse of one of them. Faecal communities were monitored over 6-8 weeks and analysed through metagenomic and metatranscr…
Intestinal drug efflux: formulation and food effects
2001
The intestine, primarily regarded as an absorptive organ, is also prepared for the elimination of certain organic acids, bases and neutral compounds depending on their affinity to intestinal carrier systems. Several of the transport systems known to mediate efflux in the major clearing organs--liver and kidney--are also expressed in the intestine. Examples of secretory transporters in the intestine are P-glycoprotein, members of the multidrug resistance associated protein family, breast cancer resistance protein, organic cation transporters and members of the organic anion polypeptide family. In this communication, the P-glycoprotein mediated intestinal secretion of talinolol, a model compo…
Biopartitioning micellar chromatography: an in vitro technique for predicting human drug absorption.
2001
The main oral drug absorption barriers are fluid cell membranes and generally drugs are absorbed by a passive diffusion mechanism. Biopartitioning micellar chromatography (BMC) is a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 under adequate experimental conditions and can be useful to mimic the drug partitioning process in biological systems. In this paper the usefulness of BMC for predicting oral drug absorption in humans is demonstrated. A hyperbolic model has been obtained using the retention data of a heterogeneous set of 74 compounds, which shows predictive ability for drugs absorbed by passive diffusion. The model obtained in BMC is compared with …
The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC
2013
The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given…
Identification of protein IT of the intestinal cytoskeleton as a novel type I cytokeratin with unusual properties and expression patterns.
1990
A major cytoskeletal polypeptide (Mr approximately 46,000; protein IT) of human intestinal epithelium was characterized by biochemical and immunological methods. The polypeptide, which was identified as a specific and genuine mRNA product by translation in vitro, reacted, in immunoblotting after SDS-PAGE, only with one of numerous cytokeratin (CK) antisera tested but with none of many monoclonal CK antibodies. In vitro, it formed heterotypic complexes with the type II CK 8, as shown by blot binding assays and gel electrophoresis in 4 M urea, and these complexes assembled into intermediate filaments (IFs) under appropriate conditions. A chymotrypsin-resistant Mr approximately 38,000 core fra…
New therapeutic strategies for treatment of inflammatory bowel disease
2008
Although the precise etiology of inflammatory bowel disease (IBD) still remains unclear, considerable progress has been made in the identification of cytokine-mediated signaling pathways involved in the inflammatory process. Recent data have clearly shown that these pathways induce augmented intestinal T-cell activation and thus resistance to apoptosis, which is a central process in disease pathogenesis, as it impairs mucosal homeostasis. Therefore, novel therapeutic strategies aim at restoring activated effector T-cell susceptibility to apoptosis in the gut, based on a pathophysiological rationale. This development is best exemplified by the emergence of agents that target the TNF pathway,…
Quantitative electron microscopic observations on Paneth cells of germfree and ex-germfree Wistar rats.
1986
Ultrastructural changes of Paneth cells of germfree (Gf) rats which had been inoculated with bacteria-containing feces from conventionally-reared (SPF) rats were quantitatively examined. 12 and 24 h after inoculation, the Paneth cells showed a striking decrease in the number of secretory granules and the occurrence of large vacuoles. Phagosomes containing bacteria were not seen. After 4 days, the secretory granules reaccumulated and smooth-surfaced apical vesicles increased in number. It is discussed that the large vacuoles may be related to membrane-retrieval events following the massive extrusion of secretory granules whereas the apical vesicles appear to serve this function when exocytos…
TGF-beta as a T cell regulator in colitis and colon cancer
2005
TGF-beta is a pleiotropic cytokine with powerful immunosuppressive functions. Mice deficient for TGF-beta1 show a dramatic phenotype with severe multiorgan inflammation and die shortly after birth. Recent investigations have highlighted the role of TGF-beta in suppression of T cell mediated autoimmune inflammation and anti-tumor immunity. In addition to its direct anti-inflammatory effects on T cells, TGF-beta has been implicated as central regulator of regulatory T cells. TGF-beta not only mediates the suppression of effector T cells by Tregs, recent evidence also reveals a role for TGF-beta along with TCR stimulation in the peripheral induction of regulatory T cells from naïve CD4+CD25- c…