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PubMed1998

Ultrastructural evidence for combined action of noradrenaline and vasoactive intestinal polypeptide upon neurons, astrocytes, and blood vessels of the rat cerebral cortex.

The intracortical organization of the noradrenaline (NA) and vasoactive intestinal polypeptide (VIP) systems provides ample opportunity for functional convergence, and accumulated evidence indicates that NA and VIP share certain cellular actions upon both neuronal and nonneuronal cortical elements. In the present study, a double immunolabeling method was combined with a silver-gold intensification procedure to examine the ultrastructural relationships of the NA coeruleocortical afferents and the intrinsic VIP neurons with three main constituents of the cortex: neurons, astrocytes, and blood vessels. Electron microscopy of singly or doubly labeled material indicated that NA and VIP boutons are engaged in a variety of anatomical relationships with both neuronal and nonneuronal elements. Dendritic shafts and perikarya of nonpyramidal neurons, some of which are VIP positive, receive combined NA and VIP synapses. A significant number of cortical microvessels are in intimate contact with NA or VIP profiles. NA axons often form perivascular loops, and VIP dendritic shafts of large diameter are frequently observed to bend around the vessel circumference. Serial section examination demonstrates that some NA boutons are directly apposed to the capillary wall at sites of glial end-feet discontinuities, whereas VIP boutons contact astrocytic sleeves of capillaries but never cross the perivascular astroglial barrier. Some VIP dendrites containing coated vesicles make intimate contact with the capillary basal lamina. Astrocytic perikarya, mainly in the supragranular layers, are also directly apposed to NA and/or VIP elements. These complex anatomical relationships provide a structural basis for the known interactions between NA and VIP in the control of cortical metabolism and function.

Animals↗

PubMed1993

Fate and effects of the surfactant sodium dodecyl sulfate.

Sodium dodecyl sulfate is the most widely used of the anionic alkyl sulfate surfactants. Its surface-active properties make it important in hundreds of household and industrial cleaners, personal care products, and cosmetics. It is also used in several types of industrial manufacturing processes, as a delivery aid in pharmaceuticals, and in biochemical research involving electrophoresis. SDS synthesis is a relatively simple process involving the sulfation of 1-dodecanol followed by neutralization with a cation source. Purification is accomplished through repeated extraction. It is available commercially in both broad-cut and purified forms. Although its environmental occurrence arises mainly from its presence in complex domestic and industrial effluents, SDS is also directly released in some applications (e.g., oil dispersants and pesticides). Although surfactants are known to significantly contribute to the toxicity of some effluents, no official water quality standards currently exist. Research has shown SDS to be highly biodegradable by a large number of naturally occurring bacteria, and degradation is generally reported to be > or = 90% within 24 hr. The process involves initial enzymatic sulfate liberation and conversion to dodecanoic acid, followed by either beta-oxidative shortening or elongation and desaturation. All surfactant properties are lost after initial sulfate hydrolysis. SDS can enhance absorption of chemicals through skin, gastrointestinal mucosa, and other mucous membranes. Thus, it is used in transepidermal, nasal, and ocular drug delivery systems and to enhance the intestinal absorption of poorly absorbed drugs; enhancement is concentration dependent. Human exposure is mainly through oral ingestion and dermal contact, although cases of respiratory exposure are known. The main sources of daily intake are ingestion of personal care products, residues on insufficiently rinsed utensils, and contaminated drinking water. Uptake, distribution, and excretion of SDS are all rapid. In fish, uptake in various tissues plateaus within 24-72 hr, with elimination occurring within < 24-48 hr; selective accumulation occurs in the hepatopancreas and gall bladder. In mammals, it is readily absorbed via the intestine, colon, and skin. Metabolism is similar in fish and mammals, proceeding from initial omega-oxidation to a carboxylic acid, then to beta-oxidation to butyric acid 4-sulfate, which is finally nonenzymatically desulfurated to gamma-butyrolactone and inorganic sulfate. SDS elicits both physical and biochemical effects on cells, with the membrane the primary target structure. Effects are concentration dependent and range from loss of barrier function and increased permeability to complete cell lysis. Hemolysis in mammals is pH dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

Probiotics: effects on immunity.

The gastrointestinal tract functions as a barrier against antigens from microorganisms and food. The generation of immunophysiologic regulation in the gut depends on the establishment of indigenous microflora. This has led to the introduction of novel therapeutic interventions based on the consumption of cultures of beneficial live microorganisms that act as probiotics. Among the possible mechanisms of probiotic therapy is promotion of a nonimmunologic gut defense barrier, which includes the normalization of increased intestinal permeability and altered gut microecology. Another possible mechanism of probiotic therapy is improvement of the intestine's immunologic barrier, particularly through intestinal immunoglobulin A responses and alleviation of intestinal inflammatory responses, which produce a gut-stabilizing effect. Many probiotic effects are mediated through immune regulation, particularly through balance control of proinflammatory and anti-inflammatory cytokines. These data show that probiotics can be used as innovative tools to alleviate intestinal inflammation, normalize gut mucosal dysfunction, and down-regulate hypersensitivity reactions. More recent data show that differences exist in the immunomodulatory effects of candidate probiotic bacteria. Moreover, distinct regulatory effects have been detected in healthy subjects and in patients with inflammatory diseases. These results suggest that specific immunomodulatory properties of probiotic bacteria should be characterized when developing clinical applications for extended target populations.

Adjuvants, Immunologic↗

PubMed2002

Impairment of epithelial transport but not of barrier function in idiopathic pouchitis after ulcerative colitis.

BACKGROUND AND AIMS: Little is known of the permeability of ileoanal pouches. Hence the aim of the present study was to determine changes in permeability and mucosal function after ileo-pouchanal anastomosis (IPAA) in patients with ulcerative colitis. MATERIALS AND METHODS: Biopsies were taken from 43 patients (male:female ratio 28:15; mean age 35.2 (12.5) years) prior to colectomy (ileum prior to pouch), prior to closure of ileostomy (deviation), and after closure of ileostomy (intact pouch) in the case of pouchitis, and from 14 healthy controls. Tissues were mounted in a miniaturised Ussing chamber. Epithelial and subepithelial resistance was determined by transmural impedance analysis. Active Na(+)-glucose cotransport was measured as change in short circuit current after stepwise addition of glucose, and active Cl(-) secretion was measured after stimulation with theophylline and prostaglandin E(2). RESULTS: Neither epithelial resistance nor mannitol fluxes were significantly altered compared with intact controls, indicating no barrier defect in pouchitis. Subepithelial resistances of intact pouches and pouchitis were increased compared with deviation (18.2 (1.6) and 24.3 (1.5) v. 13.6 (1.0) Omegaxcm(2)) consistent with an adaptive thickening of the subepithelial layer. In contrast, active Cl(-) secretion of pouchitis tissues was reduced versus intact pouch and controls (1.4 (0.3) v. 4.3 (0.7) and 4.6 (0.7) micromol/h/cm(2)), and Na(+)-glucose cotransport of pouchitis was reduced compared with intact pouch and controls (1.8 (0.5) v. 4.2 (0.8) and 8.8 (1.3) micromol/h/cm(2)). CONCLUSIONS: Ileal mucosa in pouchitis and terminal ileum prior to IPAA exhibit impaired secretory and absorptive transport functions whereas the epithelial barrier function remains unchanged. This differs from findings in ulcerative colitis. Thus the hypothesis that pouchitis represents a remanifestation of ulcerative colitis has to be questioned.

Adult↗

PubMed2000

Tight junctions are membrane microdomains.

Tight junctions (TJ) of polarized epithelial cells regulate barrier function at mucosal surfaces. Structural proteins of TJs include hyperphosphorylated occludin (HO) and the peripheral membrane protein, ZO-1. Since TJs are dynamically regulated, and lipid-modified signal transduction proteins localize to TJs, we considered the possibility that the TJ itself is composed of microdomains with unique structure. Differential detergent extraction and isopycnic sucrose density gradients were utilized to isolate TJ-enriched membranes from a polarized intestinal epithelial cell line, T84. Here we report that major pools of hyperphosphorylated occludin (HO) and ZO-1 are found in raft-like membrane microdomains with characteristics of the previously described detergent-insoluble glycolipid rafts (DIGs). Properties of such gradient fractions included Triton X-100 (TX-100) insolubility, light scattering at 600 nm, buoyant density of approximately 1.08 g/cm(3) and increased cholesterol content compared to high density fractions. Similar results were obtained using natural epithelium. Unlike the TJ proteins HO and ZO-1, other basolateral transmembrane proteins including E-cadherin, c-met and &bgr; 1 integrin were not increased in DIG-like fractions. Immunoprecipitation studies revealed coprecipitation of a pool of occludin with caveolin-1, a scaffolding protein abundant in DIGs. Coprecipitation results were supported by immunofluorescence and immunogold labeling studies demonstrating caveolin-1 localization in the apical membrane and focal colocalization with occludin in TJs. TJ disassembly by calcium chelation resulted in displacement of TJ proteins from the 'raft-like' compartment. Our findings suggest that raft-like compartments play an important role in the spatial organization of TJs and probably in regulation of paracellular permeability in epithelial cells.

Caveolin 1↗

PubMed2006

Membrane transporter proteins: a challenge for CNS drug development.

Drug transporters are membrane proteins present in various tissues such as the lymphocytes, intestine, liver, kidney, testis, placenta, and central nervous system. These transporters play a significant role in drug absorption and distribution to organic systems, particularly if the organs are protected by blood-organ barriers, such as the blood-brain barrier or the maternal-fetal barrier. In contrast to neurotransmitters and receptor-coupled transporters or other modes of interneuronal transmission, drug transporters are not directly involved in specific neuronal functions, but provide global protection to the central nervous system. The lack of capillary fenestration, the low pinocytic activity and the tight junctions between brain capillary and choroid plexus endothelial cells represent further gatekeepers limiting the entrance of endogenous and exogenous compounds into the central nervous system. Drug transport is a result of the concerted action of efflux and influx pumps (transporters) located both in the basolateral and apical membranes of brain capillary and choroid plexus endothelial cells. By regulating efflux and influx of endogenous or exogenous substances, the blood-brain barrier and, to a lesser extent the blood-cerebrospinal barrier in the ventricles, represents the main interface between the central nervous system and the blood, i.e., the rest of the body. As drug distribution to organs is dependent on the affinity of a substrate for a specific transport system, membrane transporter proteins are increasingly recognized as a key determinant of drug disposition. Many drug transporters are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily or the solute-linked carrier (SLC) class. The multidrug resistance protein MDR1 (ABCB1), also called P-glycoprotein, the multidrug resistance-associated proteins MRP1 (ABCC1) and MRP2 (ABCC2), and the breast cancer-resistance protein BCRP (ABCG2) are ATP-dependent efflux transporters expressed in the blood-brain barrier They belong to the superfamily of ABC transporters, which export drugs from the intracellular to the extracellular milieu. Members of the SLC class of solute carriers include, for example, organic ion transporting peptides, organic cation transporters, and organic ion transporters. They are ATP-independent polypeptides principally expressed at the basolateral membrane of brain capillary and choroid plexus endothelial cells that also mediate drug transport through central nervous system barriers.

Animals↗

PubMed1998

Epithelial antimicrobial peptides: review and significance for oral applications.

Epithelial tissues provide the first line of defense between an organism and the environment. Disruption of this barrier leads to bacterial invasion and subsequent inflammation. This is precisely the situation existing in the human oral cavity, where tissues are constantly exposed to a variety of microbial challenges that can lead to bacterially induced periodontal diseases, and to infections of the oral mucosa by bacteria, fungi, and viruses. With the recent discoveries of host-derived peptide antibiotics in mammalian mucosal epithelium, a new line of investigation is emerging to test the hypothesis that one class of these peptides, called "beta-defensins", functions to protect the host against microbial pathogenesis at these critical, confrontational sites. In that light, impairment of beta-defensin activity has recently been implicated in chronic bacterial infections in cystic fibrosis patients. The first direct evidence of expression of defensin peptides in the oral mucosa was the identification of a novel epithelial beta-defensin in mammalian tongue. It was shown to be upregulated in inflammation, suggesting that it participates in host defense. It is theorized that epithelial cell-derived antimicrobial peptides function to keep the natural flora of micro-organisms in a steady state in different niches such as the skin, the intestines, the airway, the endocervix, and the mouth. There is now evidence indicating that normal gingival epithelial cells and tissues express two beta-defensins, hBD-1 and the newly described hBD-2. In addition, a cathelin-class antimicrobial peptide, designated LL-37 and found in human neutrophils, is also expressed in skin and gingiva. It is highly likely that these and/or other epithelial antimicrobial peptides play an important role in determining the outcome of the host-pathogen interaction at the oral mucosal barrier, and that they may have important future applications in antibiotic treatment.

Amino Acid Sequence↗

PubMed2002

Novel probiotics for the management of allergic inflammation.

Several pathologies of the gastrointestinal tract, particularly food allergy, are due to an exaggerated and imbalanced response of the gut mucosal immune system. The intestinal microflora is an important constituent of the gut mucosal barrier against food allergens and there is increasing evidence that one important acquired factor predisposing to food allergy in infants is the gut microflora. Indeed, the balance of bifidobacteria versus Clostridia in the neonatal flora appears to determine the allergic status in infants. In earlier studies, it was shown that the higher prevalence of allergies in infants fed standard formulas, compared to breast-fed infants, correlated with lower frequencies of bifidobacteria in their faeces. Certain Lactobacillus probiotic strains can have an inhibitory impact on allergic inflammation. The mechanisms implicated are still unclear, but it seems that they can involve both proteolytic and/or immunomodulatory functions. One challenge will be to find a probiotic strain that elicits all these functions and that fulfills all safety criteria.

Food Hypersensitivity↗

PubMed2005

Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure.

BACKGROUND & AIMS: Small epithelial wounds heal by purse-string contraction of an actomyosin ring that is regulated by myosin light chain (MLC) kinase (MLCK) and rho kinase (ROCK). These studies aimed to define the roles of these kinases in purse-string wound closure. METHODS: Oligocellular and single-cell wounds were created in intestinal epithelial monolayers. Fluorescence imaging and electrophysiologic data were collected during wound closure. Human biopsies were studied immunohistochemically. RESULTS: Live-cell imaging of enhanced green fluorescent protein-beta-actin defined rapid actin ring assembly within 2 minutes after wounding. This progressed to a circumferential ring within 8 minutes that subsequently contracted and closed the wound. We therefore divided this process into 2 phases: ring assembly and wound contraction. Activated rho and ROCK localized to the wound edge during ring assembly. Consistent with a primary role in the assembly phase, ROCK inhibition prevented actin ring assembly and wound closure. ROCK inhibition after ring assembly was complete had no effect. Recruitment and activation of MLCK occurred after ring assembly was complete and coincided with ring contraction. MLCK inhibition slowed and then stopped contraction but did not prevent ring assembly. MLCK inhibition also delayed barrier function recovery. Studies of human colonic biopsy specimens suggest that purse-string wound closure also occurs in vivo, because MLC phosphorylation was enhanced surrounding oligocellular wounds. CONCLUSIONS: These results suggest complementary roles for these kinases in purse-string closure of experimental and in vivo oligocellular epithelial wounds; rho and ROCK are critical for actin ring assembly, while the activity of MLCK drives contraction.

Actin Cytoskeleton↗

PubMed2002

Functional polymorphisms of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo.

The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. Its physiological role is the protection of cells from toxic substances or metabolites. Many drugs that have been developed for the treatment of human diseases are substrates of Pgp. Because of that, the degree of expression and the functionality of the MDR1 gene product can directly affect the therapeutic effectiveness of such agents. This is of particular importance in cancer therapy where high expression and activity of MDR1 causes cancer cells to become refractory to the treatment with many agents, all of which are Pgp substrates. MDR1 is also expressed on different non-malignant cells in various organs, e.g. in the intestine and at the blood brain barrier. Modulation of MDR1 expression in these normal cell types can also influence the activity and bioavailability of drugs. In the intestine, modulation of MDR1 may control the degree of drug uptake following drug ingestion. At the blood-brain barrier, Pgp may influence the uptake of substrates into the brain: high Pgp levels may limit the uptake of sufficient amounts of desired drugs into the brain, and reduced Pgp activity could lead to abnormally increased accumulation in the brain and undesired side effects of drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Lectin-mediated drug delivery: the second generation of bioadhesives.

This paper reviews some recent developments in the area of bioadhesive drug delivery systems. The area of bioadhesion in drug delivery had started some 20 years ago by using so-called mucoadhesive polymers. Many of these polymers were already used as excipients in pharmaceutical formulations. This has facilitated the development of the first bioadhesive drug products, which are now commercially available. A major disadvantage of the hitherto known mucoadhesives, however, is their non-specificity with respect to the substrate. In particular for gastro-intestinal applications, this may cause some premature inactivation and moreover limits the duration of mucoadhesive bonds to the relatively fast mucus turnover. Nevertheless, for some mucoadhesive polymers other interesting functionalities were discovered, such as their ability to modulate epithelial permeability and to inhibit proteolytic enzymes. In contrast to the mucoadhesive polymers, lectins and some other adhesion molecules specifically recognize receptor-like structures of the cell membrane and therefore bind directly to the epithelial cells themselves ("cytoadhesion") rather than to the mucus gel layer. Furthermore, when bioadhesion is receptor-mediated, it is not only restricted to mere binding, but may subsequently trigger the active transport of large molecules or nanoscalic drug carrier systems by vesicular transport processes (endo-/transcytosis). Rather than only acting as a platform for controlled release systems, the concept of lectin-mediated bioadhesion therefore bears the potential for the controlled delivery of macromolecular biopharmaceuticals at relevant biological barriers, such as the epithelia of the intestinal or respiratory tract.

Adhesives↗

PubMed1999

Enhancement of ovalbumin-induced antibody production and mucosal mast cell response by mercury.

Food contaminants may contribute to the recent increased incidence of food allergies. We have investigated this hypothesis experimentally. It was our objective to determine whether toxicity to the intestinal tissue by orally applied mercury (Hg) could modulate the immune response to food allergens. Effective mechanisms were studied with functional immunological and toxicological parameters. Brown Norway rats were immunized intraperitoneally by ovalbumin (OVA). Before oral challenge with OVA, immunized and non-immunized animals were exposed to HgCl2. Immunological responses were measured by enzyme-linked immunosorbent assays [anti-OVA-IgE and-IgG, rat mast cell protease II (RMCPII), interferon-gamma, interleukin-4, lymphocyte proliferation] and by flow cytometry (lymphocyte subpopulations). Toxicity of Hg to the intestinal barrier was determined by measuring viability, DNA damage and induction of glutathione S-transferase in isolated intestinal epithelial cells and lymph node cells, and by measuring permeability, short-circuit current and tissue conductance of the intact intestinal epithelium. A single high oral dose of HgCl2 enhanced the serum concentrations of anti-OVA-IgE and IgG (P < 0.05) and of RMCPII (P < 0.05) in immunized rats. The treatment resulted in a higher number of CD4/CD25+ T cells in the lymph nodes (P < 0.05). The multiple application of low HgCl2 doses (5 x 0.2 mg/kg body weight) only resulted in an elevated RMCPII serum concentration (P < 0.05). Neither treatment schedules impaired proliferation and cytokine production of lymphocytes. In non-immunized rats only minor immunological changes were observed. Oral HgCl2 induced genotoxic damage in lymph node cells and in jejunal epithelial cells (P < 0.05). Moreover, HgCl2 increased the permeability of intestinal epithelial tissue and of Caco-2 monolayers and was genotoxic and cytotoxic to isolated intestinal epithelial cells in vitro. In conclusion, these studies indicate that the food contaminant Hg can stimulate the immune response to OVA in immunized rats. One possible mechanism could be the toxicity of Hg to the intestinal epithelial and the lymph node cells. Whether humans with allergies respond to high oral doses of Hg in a similar way needs to be investigated in further studies.

Animals↗

PubMed2003

The effect of pelvic organ prolapse on lower urinary tract function.

Pelvic organ prolapse (POP) is a process in which the pelvic contents, including the reproductive organ, bladder, rectum, and/or small intestines become herniated through defects in the vaginal wall. The pelvic organs are closely related to the urinary tract and thus various urinary functions can be affected. The purpose of this study was to evaluate the relationship between pelvic organ prolapse and lower urinary tract function by urodynamic studies. From March 1999 to May 2000, 40 patients with pelvic organ prolapse who underwent urodynamic studies (uroflowmetry, filling cystometry, urethral pressure profile) without barrier reduction of prolapse were analyzed. The majority of the cases of low grade POP involvedpatients with anterior wall prolapse, whereas the higher POP stages were more frequent in women with cervical cuff prolapse. Symptoms of stress urinary incontinence and hesitancy were more frequent in the patients with anterior wall prolapse. The urodynamic study showed a statistically significant increase in MUCP in patients with POP stage IV and the leading point of POP was cervical cuff. The subjective urinary symptoms of patients with POP appear to be less reliable as a diagnostic tool. POP had no adverse effect on the bladder storage function. However, POP affected the voiding function through an increase in MUCP, especially in patients with stage IV prolapse and when the leading point of POP was cervical cuff. Following the surgical correction of POP, an evaluation of the preoperative changes in the urodynamic study parameters should be performed.

Aged↗

PubMed2006

Lysozyme-modified probiotic components protect rats against polymicrobial sepsis: role of macrophages and cathelicidin-related innate immunity.

Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp., with lysozyme. We showed that oral delivery of LzMPC effectively protected rats against lethality from polymicrobial sepsis induced by cecal ligation and puncture. We found that orally administrated LzMPC was engulfed by cells such as macrophages in the liver after crossing the intestinal barrier. Moreover, LzMPC-induced protection was associated with an increase in bacterial clearance in the liver. In vitro, LzMPC up-regulated the expression of cathelicidin-related antimicrobial peptide (CRAMP) in macrophages and enhanced bactericidal activity of these cells. Furthermore, we demonstrated that surgical stress or cecal ligation and puncture caused a decrease in CRAMP expression in the liver, whereas enteral administration of LzMPC restored CRAMP gene expression in these animals. Using a neutralizing Ab, we showed that protection against sepsis by LzMPC treatment required endogenous CRAMP. In addition, macrophages from LzMPC-treated rats had an enhanced capacity of cytokine production in response to LPS or LzMPC stimulation. Together, our data suggest that the protective effect of LzMPC in sepsis is related to an enhanced cathelicidin-related innate immunity in macrophages. Therefore, LzMPC, a novel probiotic product, is a potent immunomodulator for macrophages and may be beneficial for the treatment of sepsis.

Animals↗

PubMed1979

Localization and activities of lysosomal enzymes in jejunal and ileal epithelial cells of the young pig.

The localization and the specific activities of lysosomal enzymes in jejunal and ileal epithelium of suckling pigs were determined. Acid phosphatase was found in pinocytotic vesicles and vacoles at both intestinal sites in pigs examined during (less than or equal to 1 day old) or shortly after (2 days old) closure. These pinocytolically active vesicles and vacuoles were determined to be phagolysosomes. In the ileum, phagolysosomes persisted well after closure, at an age (10 days) when ileal epithelium retains the capacity for pinocytotic uptake of immunoglobulin, but does not transport it to blood. Neither jejunum nor ileum contained phagolysosomes at an age (30 days) when the intestine had lost both uptake and transport capacities. The specific activities of acid phosphatase and cathepsin B-1 in jejunum were similar for all age groups. However, the activities of these enzymes in ileum of 10-day-old pigs were three and five times greater than at any other age or site. The results are consistent with phagolysosomes in the ileum of 10-day-old pigs functioning as a "barrier" which prevents transport of the macromolecules which are taken up pinocytotically by this epithelium. The results do not permit conclusions whether (or not) the phagolysosomes which appear in jejunum and ileum of pigs less than or equal to 1 day old contribute to closure, because the transcellular route for immunoglobulin absorption in pigs has not been precisely defined.

Acid Phosphatase↗

PubMed2003

NAD+ ameliorates inflammation-induced epithelial barrier dysfunction in cultured enterocytes and mouse ileal mucosa.

In the course of other experiments, we serendipitously observed that extracellular nicotinamide adenine dinucleotide (NAD+) ameliorated the development of epithelial hyperpermeability when monolayers of Caco-2 enterocyte-like cells were incubated with cytomix, a mixture containing interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha. We sought to characterize the effects of NAD+ on inflammation-induced epithelial barrier dysfunction using Caco-2 monolayers that were exposed to cytomix in the absence or presence of NAD+ or other purine-containing molecules. Paracellular barrier function measured as the apical-to-basolateral passage of fluorescein isothiocyanate-conjugated dextran (mol. wt. approximately 4000) was preserved in a concentration-dependent manner when immunostimulated Caco-2 cells were exposed to extracellular NAD+. Incubation with NAD+ prevented cytomix-induced derangements in the expression and localization of the tight junction proteins occludin and zonula occludens-1 in Caco-2 cells. Treatment of cytomix-stimulated cells with NAD+ also blocked nuclear factor-kappaB (NF-kappaB) activation, inducible nitric-oxide synthase induction, and increased production of nitric oxide (NO.). Ileal mucosal permeability to fluorescein isothiocyanate-dextran mol. wt. approximately 4000 was increased in mice 18 h after lipopolysaccharide (endotoxin) injection, but treatment of endotoxemic mice with NAD+ ameliorated the development of gut mucosal hyperpermeability. Thus, extracellular NAD+ seems to ameliorate inflammation-induced intestinal epithelial barrier dysfunction by inhibiting NF-kappaB activation and increased NO. production.

Animals↗

PubMed2000

A coumarin-based prodrug strategy to improve the oral absorption of RGD peptidomimetics.

In recent years, major progress has been made in the design and synthesis of fibrinogen antagonists, which are peptidomimetic Arg-Gly-Asp (RGD) analogs. These RGD analogs are very promising antiplatelet agents. However, the clinical development of orally active RGD analogs has been hindered by the low oral bioavailability of many such RGD analogs. Aimed at enhancing their oral bioavailability, we have synthesized several coumarin-based cyclic prodrugs of RGD analogs, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. As expected, these cyclic prodrugs have higher membrane interaction potentials as estimated by determining their partitioning between aqueous buffer and an immobilized artificial membrane than the corresponding RGD analogs. Consequently, these cyclic prodrugs are 5-6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier. Preliminary studies using dog also indicate the promising potential of using this coumarin-based prodrug strategy to improve the oral bioavailability of such RGD analogs.

Animals↗

PubMed2004

MUC1 and MUC2 in pancreatic neoplasia.

MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, participating in cancer progression. In contrast, MUC2 is normally found only in goblet cells, where it contributes to the protective barrier function of these cells. Recently, a tumour suppressor role has been demonstrated for MUC2, and both MUC1 and MUC2 appear to have important roles in pancreatic neoplasia. MUC1 appears to be a marker of aggressive phenotype and may facilitate the vascular spread of carcinoma cells. In contrast, MUC2 is rarely detectable in aggressive pancreatic tumours, but is commonly expressed in intraductal papillary mucinous neoplasms (IPMNs), which are rare, indolent tumours, in intestinal IPMNs, and in indolent colloid carcinomas. MUC2 appears to be not only a marker of this indolent pathway, but also partly responsible for its less aggressive nature. Thus, in pancreatic neoplasia, MUC1 and MUC2 have potential diagnostic and prognostic value as markers of aggressive and indolent phenotypes, respectively, and have potential as therapeutic targets.

Cell Transformation, Neoplastic↗