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Sample records for abnormal intestinal permeability

  1. Intestinal permeability, leaky gut, and intestinal disorders.

    PubMed

    Hollander, D

    1999-10-01

    A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called permeability. Clinicians can use inert, nonmetabolized sugars such as mannitol, rhamnose, or lactulose to measure the permeability barrier or the degree of leakiness of the intestinal mucosa. Ample evidence indicates that permeability is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. The abnormal leakiness of the mucosa in Crohn's patients and their relatives can be greatly amplified by aspirin preadministration. Permeability measurements in Crohn's patients reflect the activity, extent, and distribution of the disease and may allow us to predict the likelihood of recurrence after surgery or medically induced remission. Permeability is also increased in celiac disease and by trauma, burns, and nonsteroidal anti-inflammatory drugs. The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. As we broaden our understanding of the mechanisms and agents that control the degree of leakiness of the tight junctions, we will be increasingly able to use permeability measurements to study the etiology and pathogenesis of various disorders and to design or monitor therapies for their management.

  2. Genetic aspects of intestinal permeability in inflammatory bowel disease.

    PubMed

    Takeuchi, Ken; Maiden, Laurence; Bjarnason, Ingvar

    2004-01-01

    There is a long-standing belief that disruption of the intestinal barrier function may lead to systemic and local intestinal disease. The role of increased intestinal permeability in Crohn's disease is reviewed here. What is not in doubt is that intestinal permeability in patients with Crohn's disease is increased proportional to disease activity; it can be used to predict clinical relapse of disease and prognosis; and a small proportion of first-degree relatives have increased intestinal permeability. This last finding has been subject to much speculation. In particular it has been suggested that it represents a genetically determined abnormality. If so it might play an important pathogenic process in the disease. However this permeability change in relatives does not conform to a classical inheritance pattern and in some studies it is found in the patients' spouses. This suggests an environmental cause for the changes. However proponents of an environmental factor have been singularly inactive in attempting to identify this agent(s). In view of recent research it seems likely that the increased intestinal permeability in relatives of Crohn's patients may be secondary to sub-clinical intestinal inflammation. This inflammation conforms to an inherited additive trait. The genetic basis for this inflammation is being studied.

  3. Alterations in Intestinal Permeability After Thermal Injury,

    DTIC Science & Technology

    1992-01-01

    disaccharide with a The cause of the altered intestinal permeability in our molecular weight of 342, and mannitol, a monosaccharide patients who...and linear regression analyses were used as indicated. Differences •P<.01 vs controls and uninfected patients by analysis of were considered

  4. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    ERIC Educational Resources Information Center

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  5. ABNORMAL GASTRIC AND COLONIC PERMEABILITY IN CHILDREN WITH RECURRENT ABDOMINAL PAIN (RAP)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent histologic studies have suggested evidence of low grade inflammation in many patients with irritable bowel syndrome (IBS). Additionally, small intestinal permeability recently has been reported to be abnormal in some adults with IBS. Whether the same is true for children with RAP, a condition...

  6. Perturbed zinc homeostasis in rural 3-5-y-old Malawian children is associated with abnormalities in intestinal permeability attributed to tropical enteropathy.

    PubMed

    Manary, Micah J; Abrams, Steven A; Griffin, Ian J; Quimper, Megan M; Shulman, Robert J; Hamzo, Maria G; Chen, Zhensheng; Maleta, Kenneth; Manary, Mark J

    2010-06-01

    Tropical enteropathy and zinc deficiency are major public health problems worldwide. Tropical enteropathy is characterized by reduced mannitol absorption with normal or increased lactulose absorption when a dual sugar absorption test is administered, the results of which are reported as the lactulose:mannitol ratio (L:M). Zinc homeostasis is quantified with a dual stable isotope test. This study tested the hypothesis that endogenous fecal zinc (EFZ) was correlated with the L:M. A dual sugar absorption test and dual stable isotope test were performed on 25 asymptomatic Malawian children aged 3-5 y at risk for tropical enteropathy and zinc deficiency. EFZ and net zinc retention were estimated and correlated with the L:M. Twenty-two children (88%) had an abnormal L:M (L:M>0.10), and the L:M was 0.24+/-0.10 (mean+/-SD). EFZ was 1.68+/-1.06 mg/d, a quantity greater than is seen in healthy populations from the developed world. EFZ was positively correlated with the L:M (r=0.62, p<0.001). Net zinc retention (0.67+/-1.6 mg/d) was negatively correlated with the L:M (r=-0.47, p=0.02). This suggests that perturbed zinc homeostasis is associated with subclinical enteropathy in these children.

  7. Intestinal permeability defects: is it time to treat?

    PubMed

    Odenwald, Matthew A; Turner, Jerrold R

    2013-09-01

    An essential role of the intestinal epithelium is to separate luminal contents from the interstitium, a function primarily determined by the integrity of the epithelium and the tight junction that seals the paracellular space. Intestinal tight junctions are selectively permeable, and intestinal permeability can be increased physiologically in response to luminal nutrients or pathologically by mucosal immune cells and cytokines, the enteric nervous system, and pathogens. Compromised intestinal barrier function is associated with an array of clinical conditions, both intestinal and systemic. Although most available data are correlative, some studies support a model where cycles of increased intestinal permeability, intestinal immune activation, and subsequent immune-mediated barrier loss contribute to disease progression. This model is applicable to intestinal and systemic diseases. However, it has not been proven, and both mechanistic and therapeutic studies are ongoing. Nevertheless, the correlation between increased intestinal permeability and disease has caught the attention of the public, leading to a rise in popularity of the diagnosis of "leaky gut syndrome," which encompasses a range of systemic disorders. Proponents claim that barrier restoration will cure underlying disease, but this has not been demonstrated in clinical trials. Moreover, human and mouse studies show that intestinal barrier loss alone is insufficient to initiate disease. It is therefore uncertain whether increased permeability in these patients is a cause or effect of the underlying disorder. Although drug targets that may mediate barrier restoration have been proposed, none have been proven effective. As such, current treatments for barrier dysfunction should target the underlying disease.

  8. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium.

    PubMed

    Purohit, Vishnudutt; Bode, J Christian; Bode, Christiane; Brenner, David A; Choudhry, Mashkoor A; Hamilton, Frank; Kang, Y James; Keshavarzian, Ali; Rao, Radhakrishna; Sartor, R Balfour; Swanson, Christine; Turner, Jerrold R

    2008-08-01

    This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram-negative bacteria in the intestine, which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram-negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan, which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram-negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, l-glutamine, oats supplementation, or zinc, thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram-negative bacteria

  9. Measurement of the intestinal permeability in chronic kidney disease

    PubMed Central

    Terpstra, Matty L; Singh, Ramandeep; Geerlings, Suzanne E; Bemelman, Frederike J

    2016-01-01

    AIM: To evaluate methods measuring the intestinal per-meability in chronic kidney disease (CKD) and clarify whether there is an increased intestinal permeability in CKD. METHODS: We reviewed the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and performed a systematic literature search through MEDline and EMBASE. All controlled trials and cohort studies using non-invasive methods to assess intestinal permeability in CKD patients were included. Excluded were: Conference abstracts and studies including patients younger than 18 years or animals. From the included studies we summarized the used methods and their advantages and disadvantages. For the comparison of their results we divided the included studies in two categories based on their included patient population, either assessing the intestinal permeability in mild to moderate CKD patients or in end stage renal disease (ESRD) patients. Results were graphically displayed in two plots, one comparing the intestinal permeability in mild to moderate CKD patients to healthy controls and one comparing the intestinal permeability in ESRD patients to healthy controls. RESULTS: From the 480 identified reports, 15 met our inclusion criteria. Methods that were used to assess the intestinal permeability varied from markers measured in plasma to methods based on calculating the urinary excretion of an orally administered test substance. None of the applied methods has been validated in CKD patients and the influence of decreased renal function on the different methods remains unclear to a certain extent. Methods that seem the least likely to be influenced by decreased renal function are the quantitative PCR (qPCR) for bacterial DNA in blood and D-lactate. Considering the results published by the included studies; the studies including patients with mild to moderate CKD conducted conflicting results. Some studies did report an increase in intestinal

  10. Regulation of intestinal permeability: The role of proteases

    PubMed Central

    Van Spaendonk, Hanne; Ceuleers, Hannah; Witters, Leonie; Patteet, Eveline; Joossens, Jurgen; Augustyns, Koen; Lambeir, Anne-Marie; De Meester, Ingrid; De Man, Joris G; De Winter, Benedicte Y

    2017-01-01

    The gastrointestinal barrier is - with approximately 400 m2 - the human body’s largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.

  11. Increased pulmonary and intestinal permeability in Crohn's disease.

    PubMed Central

    Adenis, A; Colombel, J F; Lecouffe, P; Wallaert, B; Hecquet, B; Marchandise, X; Cortot, A

    1992-01-01

    We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis. PMID:1612487

  12. Intestinal permeability in a patient with liver cirrhosis

    PubMed Central

    Aguirre Valadez, Jonathan Manuel; Rivera-Espinosa, Liliana; Méndez-Guerrero, Osvely; Chávez-Pacheco, Juan Luis; García Juárez, Ignacio; Torre, Aldo

    2016-01-01

    Liver cirrhosis is a worldwide public health problem, and patients with this disease are at high risk of developing complications, bacterial translocation from the intestinal lumen to the mesenteric nodes, and systemic circulation, resulting in the development of severe complications related to high mortality rate. The intestinal barrier is a structure with a physical and biochemical activity to maintain balance between the external environment, including bacteria and their products, and the internal environment. Patients with liver cirrhosis develop a series of alterations in different components of the intestinal barrier directly associated with the severity of liver disease that finally increased intestinal permeability. A “leaky gut” is an effect produced by damaged intestinal barrier; alterations in the function of tight junction proteins are related to bacterial translocation and their products. Instead, increasing serum proinflammatory cytokines and hemodynamics modification, which results in the appearance of complications of liver cirrhosis such as hepatic encephalopathy, variceal hemorrhage, bacterial spontaneous peritonitis, and hepatorenal syndrome. The intestinal microbiota plays a fundamental role in maintaining the proper function of the intestinal barrier; bacterial overgrowth and dysbiosis are two phenomena often present in people with liver cirrhosis favoring bacterial translocation. Increased intestinal permeability has an important role in the genesis of these complications, and treating it could be the base for prevention and partial treatment of these complications. PMID:27920543

  13. Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc.

    PubMed Central

    Rodriguez, P; Darmon, N; Chappuis, P; Candalh, C; Blaton, M A; Bouchaud, C; Heyman, M

    1996-01-01

    BACKGROUND: Zinc has been shown to have beneficial effects in vitro on epithelial barrier function, and in vivo to reduce intestinal permeability in malnourished children with diarrhoea. AIMS: To determine whether malnutrition alters intestinal paracellular permeability, and whether zinc prevents such alterations. METHODS: Guinea pigs were fed a normal protein diet (NP group), a low protein diet (LP group), or a low protein diet enriched with 1800 ppm zinc (LPZn group) for three weeks. Intestinal permeability was measured on jejunal segments mounted in Ussing chambers by measuring ionic conductance and mucosal to serosal fluxes of 14C-mannitol, 22Na, and horseradish peroxidase. Tight junction morphology was assessed on cryofracture replicas. RESULTS: Mannitol and Na fluxes and ionic conductance increased in the LP group compared with the NP group but remained normal in the LPZn group. Accordingly, jejunal epithelia from the LP group, but not from the LPZn group, showed a small decrease in number of tight junctional strands compared with epithelia from the NP group. Neither malnutrition nor zinc treatment modified horseradish peroxidase fluxes. CONCLUSIONS: Malnutrition is associated with increased intestinal paracellular permeability to small molecules, and pharmacological doses of zinc prevent such functional abnormality. Images Figure 3 PMID:8949647

  14. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV and their relation to diarrhoea.

    PubMed Central

    Keating, J; Bjarnason, I; Somasundaram, S; Macpherson, A; Francis, N; Price, A B; Sharpstone, D; Smithson, J; Menzies, I S; Gazzard, B G

    1995-01-01

    Intestinal function is poorly defined in patients with HIV infection. Absorptive capacity and intestinal permeability were assessed using 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose in 88 HIV infected patients and the findings were correlated with the degree of immunosuppression (CD4 counts), diarrhoea, wasting, intestinal pathogen status, and histomorphometric analysis of jejunal biopsy samples. Malabsorption of 3-O-methyl-D-glucose and D-xylose was prevalent in all groups of patients with AIDS but not in asymptomatic, well patients with HIV. Malabsorption correlated significantly (r = 0.34-0.56, p < 0.005) with the degree of immune suppression and with body mass index. Increased intestinal permeability was found in all subgroups of patients. The changes in absorption-permeability were of comparable severity to those found in patients with untreated coeliac disease. Jejunal histology, however, showed only mild changes in the villus height/crypt depth ratio as compared with subtotal villus atrophy in coeliac disease. Malabsorption and increased intestinal permeability are common in AIDS patients. Malabsorption, which has nutritional implications, relates more to immune suppression than jejunal morphological changes. PMID:8549936

  15. Amorphous azithromycin with improved aqueous solubility and intestinal membrane permeability.

    PubMed

    Aucamp, Marique; Odendaal, Roelf; Liebenberg, Wilna; Hamman, Josias

    2015-01-01

    Azithromycin (AZM) is a poorly soluble macrolide antibacterial agent. Its low solubility is considered as the major contributing factor to its relatively low oral bioavailability. The aim of this study was to improve the solubility of this active pharmaceutical ingredient (API) by preparing an amorphous form by quench cooling of the melt and to study the influence of the improved solubility on membrane permeability. The amorphous azithromycin (AZM-A) exhibited a significant increase in water solubility when compared to the crystalline azithromycin dihydrate (AZM-DH). The influence that the improved solubility could have on membrane permeability was also studied. The apparent permeability coefficient (Papp) values of AZM-A were statistically significantly higher (p < 0.05) than crystalline AZM-DH at pH values of 6.8 and 7.2. The results therefore indicated that the improved solubility of AZM in the amorphous form also produced improved permeability across excised intestinal tissue at physiological pH values found in the small intestine.

  16. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.

    PubMed

    Hu, Bo; Arpag, Sezgi; Zhang, Xuebao; Möbius, Wiebke; Werner, Hauke; Sosinsky, Gina; Ellisman, Mark; Zhang, Yang; Hamilton, Audra; Chernoff, Jonathan; Li, Jun

    2016-09-01

    Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it "functional demyelination", a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.

  17. Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP

    PubMed Central

    Hu, Bo; Zhang, Xuebao; Möbius, Wiebke; Werner, Hauke; Sosinsky, Gina; Ellisman, Mark; Zhang, Yang; Hamilton, Audra; Chernoff, Jonathan; Li, Jun

    2016-01-01

    Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it “functional demyelination”, a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP. PMID:27583434

  18. The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model

    PubMed Central

    Kwak, Dong Shin; Lee, Oh Young; Lee, Kang Nyeong; Jun, Dae Won; Lee, Hang Lak; Yoon, Byung Chul; Choi, Ho Soon

    2016-01-01

    Background/Aims DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. Methods Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. Results The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. Conclusions DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway. PMID:27114435

  19. Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions

    PubMed Central

    Baranwal, Somesh

    2015-01-01

    Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico-basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis. PMID:25792565

  20. Sodium alginate decreases the permeability of intestinal mucus.

    PubMed

    Mackie, Alan R; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M; Parker, Roger; Channell, Guy A; Harding, Stephen E; Bajka, Balazs H

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia.

  1. Sodium alginate decreases the permeability of intestinal mucus

    PubMed Central

    Mackie, Alan R.; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M.; Parker, Roger; Channell, Guy A.; Harding, Stephen E.; Bajka, Balazs H.

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia. PMID:26726279

  2. Permeability Profiles and Intestinal Toxicity Assessment of Hydrochlorothiazide and Its Inclusion Complex with β-Cyclodextrin Loaded into Chitosan Nanoparticles.

    PubMed

    Onnainty, R; Schenfeld, E M; Petiti, J P; Longhi, M R; Torres, A; Quevedo, M A; Granero, G E

    2016-11-07

    Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:βCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:βCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na(+/)K(+)-ATPase channel. Thus, it is postulated that the CS/HCT:βCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium; consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.

  3. A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability.

    PubMed

    Rodríguez-Berna, Guillermo; Mangas-Sanjuán, Víctor; Gonzalez-Alvarez, Marta; Gonzalez-Alvarez, Isabel; García-Giménez, José Luis; Díaz Cabañas, María José; Bermejo, Marival; Corma, Avelino

    2014-08-18

    Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.

  4. Intestinal permeability of forskolin by in situ single pass perfusion in rats.

    PubMed

    Liu, Zhen-Jun; Jiang, Dong-bo; Tian, Lu-Lu; Yin, Jia-Jun; Huang, Jian-Ming; Weng, Wei-Yu

    2012-05-01

    The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 µg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability.

  5. Intestinal permeability and bacterial translocation following small bowel transplantation in the rat

    SciTech Connect

    Grant, D.; Hurlbut, D.; Zhong, R.; Wang, P.Z.; Chen, H.F.; Garcia, B.; Behme, R.; Stiller, C.; Duff, J. )

    1991-08-01

    In addition to its role in absorbing nutrients, the intestinal mucosa provides an important barrier against toxins and bacteria in the bowel lumen. The present study evaluated gut barrier function following orthotopic (in continuity) intestinal grafting in rats. Graft histology, intestinal permeability, and bacterial translocation to the grafted mesenteric lymph nodes, the host's liver, and the host's spleen were assessed on the 3rd, 5th, and 7th postoperative days. The study group received no immunosuppression after allotransplantation. The two control groups included rats with isografts and rats with cyclosporine-treated allografts. On the 7th POD, the study animals had moderate transmural inflammation due to rejection, with normal histology in the isografts and CsA-treated allografts; increased intestinal permeability, measured by urinary excretion of oral 51Cr-EDTA (P less than 0.01); and increased number of bacteria in the MLN and spleen (P less than 0.05). The number of bacteria in the MLN and spleen of the study group positively correlated with the changes in intestinal permeability (P less than 0.05). Rejection of the orthotopic intestinal graft leads to increased intestinal permeability and bacterial translocation from the lumen of the graft to the host's reticuloendothelial system. Measures to improve gut barrier function and antibiotic therapy during rejection episodes may help reduce the incidence of septic complications after intestinal grafting.

  6. Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids.

    PubMed

    Naderkhani, Elenaz; Vasskog, Terje; Flaten, Gøril Eide

    2015-06-20

    A prerequisite for successful oral drug therapy is the drug's ability to cross the gastrointestinal barrier. Considering the increasing number of new chemical entities in modern drug discovery, reliable and fast in vitro models are required for early and efficient prediction of intestinal permeability. To mimic the intestinal environment, use of biorelevant media may provide valuable information on in vivo drug permeation. The present study aims at improving the novel biomimetic phospholipid vesicle-based permeation assay's (PVPAbiomimetic) biorelevance by investigating the applicability of the biorelevant media; fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF). The FaSSIF and FeSSIF's influence on the permeability of the model drugs acyclovir, indomethacin, griseofulvin and nadolol was then assessed. The barriers' robustness in terms of storage stability was also evaluated. The barriers were found to maintain their integrity in presence of FaSSIF and FeSSIF. The model drugs showed changes in permeability in presence of the different simulated intestinal fluids that were in agreement with previous reports. Moreover, the barrier showed improved storage stability by maintaining its integrity for 6months. Altogether, this study moves the PVPAbiomimetic an important step towards a better in vitro permeability model for use in drug development.

  7. Rhodamine 123 permeability through the catfish intestinal wall: Relationship to thermal acclimation and acute temperature change.

    PubMed

    Kleinow, Kevin M; Johnston, Brad D; Holmes, Earnestine P; McCarrol, Matthew E

    2006-11-01

    Temperature is known to influence xenobiotic retention in fish. The effect of acute and acclimatory temperature change upon Rhodamine 123 (Rho123) permeability through an in vitro catfish multi-segment (3) everted sac intestinal wall model was examined in a 9 cell matrix of acclimation and assay temperatures (10, 20 and 30 degrees C). Changes in Rho123 permeability were examined in context with membrane fluidity, xenobiotic solubility and intestinal morphology. When assayed at the acclimation temperature greater Rho123 permeability was noted at warmer acclimation temperatures for the proximal and middle intestinal segments, while the distal segment exhibited little change and apparent compensation across temperatures. Rho123 permeability was increased as assay temperatures were elevated above the acclimation temperature for most comparisons. Cold acclimation significantly increased total intestinal length (43.2%) and proximal intestine weights while total body weights did not differ. Brush border membranes (BBM) increased fluidity with increased assay temperatures, however, composite anisotropy lines were not significantly different between acclimation treatments. In an additive manner, the membrane probe DPH exhibited increased solubility in BBM with increases in acclimation and assay temperatures. Compositely, these results suggest that acclimation and acute temperature change may differentially influence xenobiotic permeability among intestinal segments with interacting mechanisms.

  8. Intestinal permeability measurements: general aspects and possible pitfalls.

    PubMed

    Salles Teixeira, Tatiana Fiche; Boroni Moreira, Ana Paula; Silva Souza, Nilian Carla; Frias, Rafael; Gouveia Peluzio, Maria do Carmo

    2014-02-01

    Introducción: Alteraciones funcionales de la barrera intestinal se han relacionado con una variedad de enfermedades intestinales y también con enfermedades no intestinales. Las pruebas de permeabilidad intestinal son consideradas herramientas útiles para evaluar la gravedad de la enfermedad para el posterior seguimiento de los pacientes después de una intervención terapéutica. Objetivo: El objeto de esta revisión ha sido destacar los posibles factores que pueden estar asociados a una mayor permeabilidad intestinal y revisar condiciones clínicas que han sido asociadas en individuos de diferentes edades. También revisar ciertos aspectos metodológicos de las pruebas de permeabilidad intestinal. Resultados y discusión: Las uniones estrechas entre los enterocitos son las principales estructuras encargadas de la regulación de la barrera intestinal. Una alteración de éstas, resulta en una deficiencia en la permeabilidad intestinal y una mayor penetración de las sustancias marcadoras de permeabilidad intestinal. La lactulosa y el manitol son las sustancias marcadoras más utilizadas. La inocuidad y facilidad de los test de permeabilidad han sido de ayuda para explorar y ampliar el conocimiento de muchas condiciones clínicas en las que la disfunción de la barrera intestinal ha sido un sello distintivo. Muchos factores pueden influir en los resultados de los test de permeabilidad. Sin embargo, los investigadores y los clínicos han de tratar de eludir los posibles inconvenientes de las pruebas de permeabilidad intestinal para poder producir evidencias más consistentes. El uso de otras sustancias marcadoras de la fisiología intestinal también puede contribuir a comprender mejor el papel de la barrera intestinal en diferentes enfermedades.

  9. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut.

    PubMed

    Michielan, Andrea; D'Incà, Renata

    2015-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

  10. An improved prediction of the human in vivo intestinal permeability and BCS class of drugs using the in vitro permeability ratio obtained for rat intestine using an Ussing chamber system.

    PubMed

    Li, Hong; Jin, Hyo-Eon; Shim, Won-Sik; Shim, Chang-Koo

    2013-10-01

    The Biopharmaceutics Classification System (BCS) was developed to facilitate estimation of the in vivo pharmacokinetic performance of drugs from human intestinal permeability and solubility. However, the measurement of human in vivo intestinal permeability, unlike that of solubility, is problematic and inefficient. Thus, rat in vitro intestinal permeability results obtained via the Ussing chamber technique are often used instead. However, these data could be unreliable due to difficulty in maintaining the viability of the dissected intestinal membrane in the Ussing chamber. Therefore, a more efficient method to obtain a reliable in vitro permeability is mandatory. Here, we propose a new approach by introducing a novel factor called the permeability ratio (PR). Basically, PR is a rat in vitro intestinal permeability obtained from the Ussing chamber, which is then corrected by the permeability of lucifer yellow, a paracellular permeability marker. To prove the validity of the method, 12 model drugs representing different BCS classes were tested, and the correlation with human in vivo intestinal permeability was high. More importantly, the new method perfectly classified all 12 model drugs. The results indicate that PR is a reliable factor with high correlation to human in vivo intestinal permeability, which can further be used to accurately predict the BCS classification.

  11. Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea

    PubMed Central

    Istrate, Claudia; Hagbom, Marie; Vikström, Elena; Magnusson, Karl-Eric

    2014-01-01

    ABSTRACT The disease mechanisms associated with onset and secondary effects of rotavirus (RV) diarrhea remain to be determined and may not be identical. In this study, we investigated whether onset of RV diarrhea is associated with increased intestinal permeability and/or motility. To study the transit time, fluorescent fluorescein isothiocyanate (FITC)-dextran was given to RV-infected adult and infant mice. Intestinal motility was also studied with an opioid receptor agonist (loperamide) and a muscarinic receptor antagonist (atropine). To investigate whether RV increases permeability at the onset of diarrhea, fluorescent 4- and 10-kDa dextran doses were given to infected and noninfected mice, and fluorescence intensity was measured subsequently in serum. RV increased transit time in infant mice. Increased motility was detected at 24 h postinfection (h p.i.) and persisted up to 72 h p.i in pups. Both loperamide and atropine decreased intestinal motility and attenuated diarrhea. Analysis of passage of fluorescent dextran from the intestine into serum indicated unaffected intestinal permeability at the onset of diarrhea (24 to 48 h p.i.). We show that RV-induced diarrhea is associated with increased intestinal motility via an activation of the myenteric nerve plexus, which in turn stimulates muscarinic receptors on intestinal smooth muscles. IMPORTANCE We show that RV-infected mice have increased intestinal motility at the onset of diarrhea, and that this is not associated with increased intestinal permeability. These new observations will contribute to a better understanding of the mechanisms involved in RV diarrhea. PMID:24371070

  12. Possible Links between Intestinal Permeablity and Food Processing: A Potential Therapeutic Niche for Glutamine

    PubMed Central

    Rapin, Jean Robert; Wiernsperger, Nicolas

    2010-01-01

    Increased intestinal permeability is a likely cause of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Intestinal permeability is found in many severe clinical situations and in common disorders such as irritable bowel syndrome. In these conditions, substances that are normally unable to cross the epithelial barrier gain access to the systemic circulation. To illustrate the potential harmfulness of leaky gut, we present an argument based on examples linked to protein or lipid glycation induced by modern food processing. Increased intestinal permeability should be largely improved by dietary addition of compounds, such as glutamine or curcumin, which both have the mechanistic potential to inhibit the inflammation and oxidative stress linked to tight junction opening. This brief review aims to increase physician awareness of this common, albeit largely unrecognized, pathology, which may be easily prevented or improved by means of simple nutritional changes. PMID:20613941

  13. Development of an advanced intestinal in vitro triple culture permeability model to study transport of nanoparticles.

    PubMed

    Schimpel, Christa; Teubl, Birgit; Absenger, Markus; Meindl, Claudia; Fröhlich, Eleonore; Leitinger, Gerd; Zimmer, Andreas; Roblegg, Eva

    2014-03-03

    Intestinal epithelial cell culture models, such as Caco-2 cells, are commonly used to assess absorption of drug molecules and transcytosis of nanoparticles across the intestinal mucosa. However, it is known that mucus strongly impacts nanoparticle mobility and that specialized M cells are involved in particulate uptake. Thus, to get a clear understanding of how nanoparticles interact with the intestinal mucosa, in vitro models are necessary that integrate the main cell types. This work aimed at developing an alternative in vitro permeability model based on a triple culture: Caco-2 cells, mucus-secreting goblet cells and M cells. Therefore, Caco-2 cells and mucus-secreting goblet cells were cocultured on Transwells and Raji B cells were added to stimulate differentiation of M cells. The in vitro triple culture model was characterized regarding confluence, integrity, differentiation/expression of M cells and cell surface architecture. Permeability of model drugs and of 50 and 200 nm polystyrene nanoparticles was studied. Data from the in vitro model were compared with ex vivo permeability results (Ussing chambers and porcine intestine) and correlated well. Nanoparticle uptake was size-dependent and strongly impacted by the mucus layer. Moreover, nanoparticle permeability studies clearly demonstrated that particles were capable of penetrating the intestinal barrier mainly via specialized M cells. It can be concluded that goblet cells and M cells strongly impact nanoparticle uptake in the intestine and should thus be integrated in an in vitro permeability model. The presented model will be an efficient tool to study intestinal transcellular uptake of particulate systems.

  14. Design of vancomycin RS-100 nanoparticles in order to increase the intestinal permeability

    PubMed Central

    Loveymi, Badir Delf; Jelvehgari, Mitra; Zakeri-Milani, Parvin; Valizadeh, Hadi

    2012-01-01

    Purpose: The purpose of this work was to preparation of vancomycin (VCM) biodegradable nanoparticles to improve the intestinal permeability, using water-in-oil-in-water (W/O/W) multiple emulsion method. Methods: The vancomycin-loaded nanoparticles were created using double-emulsion solvent evaporation method. Using Eudragit RS100 as a coating material. The prepared nanoparticles were identifyed for their micromeritic and crystallographic properties, drug loading, particle size, drug release, Zeta potential, effective permeability (Peff) and oral fractional absorption. Intestinal permeability of VCM nanoparticles was figured out, in different concentrations using SPIP technique in rats. Results: Particle sizes were between 362 and 499 nm for different compositions of VCM-RS-100 nanoparticles. Entrapment efficiency expansed between 63%-94.76%. The highest entrapment efficiency 94.76% was obtained when the ratio of drug to polymer was 1:3. The in vitro release studies were accomplished in pH 7.4. The results showed that physicochemical properties were impressed by drug to polymer ratio. The FT-IR, XRPD and DSC results ruled out any chemical interaction betweenthe drug and RS-100. Effective intestinal permeability values of VCM nanoparticles in concentrations of 200, 300 and 400 μg/ml were higher than that of solutions at the same concentrations. Oral fractional absorption was achieved between 0.419-0.767. Conclusion: Our findings suggest that RS-100 nanoparticles could provide a delivery system for VCM, with enhanced intestinal permeability. PMID:24312770

  15. Self-Microemulsifying Drug Delivery System: Formulation and Study Intestinal Permeability of Ibuprofen in Rats

    PubMed Central

    Subudhi, Bharat Bhushan; Mandal, Surjyanarayan

    2013-01-01

    The study was aimed at developing a self-microemulsifying drug delivery system (SMEDDS) of Ibuprofen for investigating its intestinal transport behavior using the single-pass intestinal perfusion (SPIP) method in rat. Methods. Ibuprofen loaded SMEDDS (ISMEDDS) was developed and was characterized. The permeability behavior of Ibuprofen over three different concentrations (20, 30, and 40 µg/mL) was studied in each isolated region of rat intestine by SPIP method at a flow rate of 0.2 mL/min. The human intestinal permeability was predicted using the Lawrence compartment absorption and transit (CAT) model since effective permeability coefficients (Peff) values for rat are highly correlated with those of human, and comparative intestinal permeability of Ibuprofen was carried out with plain drug suspension (PDS) and marketed formulation (MF). Results. The developed ISMEDDS was stable, emulsified upon mild agitation with 44.4 nm ± 2.13 and 98.86% ± 1.21 as globule size and drug content, respectively. Higher Peff in colon with no significant Peff difference in jejunum, duodenum, and ileum was observed. The estimated human absorption of Ibuprofen for the SMEDDS was higher than that for PDS and MF (P < 0.01). Conclusion. Developed ISMEDDS would possibly be advantageous in terms of minimized side effect, increased bioavailability, and hence the patient compliance. PMID:26555973

  16. Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

    PubMed

    Togami, Kohei; Hayashi, Yoshiaki; Chono, Sumio; Morimoto, Kazuhiro

    2014-09-01

    The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.

  17. JAM-A regulates permeability and inflammation in the intestine in vivo.

    PubMed

    Laukoetter, Mike G; Nava, Porfirio; Lee, Winston Y; Severson, Eric A; Capaldo, Christopher T; Babbin, Brian A; Williams, Ifor R; Koval, Michael; Peatman, Eric; Campbell, Jacquelyn A; Dermody, Terence S; Nusrat, Asma; Parkos, Charles A

    2007-12-24

    Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A-deficient (JAM-A(-/-)) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A(-/-) mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A(-/-) mice. The in vivo observations were epithelial specific, because monolayers of JAM-A(-/-) epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A(-/-) mice and in JAM-A small interfering RNA-treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A(-/-) mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A(-/-) animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.

  18. Cold exposure increases intestinal paracellular permeability to nutrients in the mouse.

    PubMed

    Price, Edwin R; Ruff, Lisa J; Guerra, Alberto; Karasov, William H

    2013-11-01

    In situations of increased energy demand and food intake, animals can often acclimate within several days. The intestine generally responds to elevated digestive demand by increasing in size. However, there is likely a limit to how quickly the intestine can grow to meet the new demand. We investigated the immediate and longer-term changes to intestinal properties of the mouse when suddenly exposed to 4°C. We hypothesized that paracellular permeability to nutrients would increase as part of an immediate response to elevated absorptive demand. We measured absorption of l-arabinose, intestinal size and gene expression of several tight junction proteins (claudin-2, claudin-4, claudin-15 and ZO-1) at three time points: pre-exposure, and after 1 day and 2 weeks of cold exposure. Cold exposure increased food intake by 62% after 2 weeks but intake was not significantly increased after 1 day. Intestinal wet mass was elevated after 1 day and throughout the experiment. Absorption of arabinose rose by 20% after 1 day in the cold and was 33% higher after 2 weeks. Expression of claudin-2 increased after 1 day of cold exposure, but there were no changes in expression of any claudin genes when normalized to ZO-1 expression. Our results indicate that intestinal mass can respond rapidly to increased energy demand and that increased paracellular permeability is also part of that response. Increased paracellular permeability may be a consequence of enterocyte hyperplasia, resulting in more tight junctions across which molecules can absorb.

  19. Enhancement of intestinal permeability utilizing solid lipid nanoparticles increases γ-tocotrienol oral bioavailability.

    PubMed

    Abuasal, Bilal S; Lucas, Courtney; Peyton, Breanne; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal

    2012-05-01

    γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.

  20. The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract.

    PubMed

    Zur, Moran; Cohen, Noa; Agbaria, Riad; Dahan, Arik

    2015-07-15

    The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form.

  1. Identification of intestinal wall abnormalities and ischemia by modeling spatial uncertainty in computed tomography imaging findings.

    PubMed

    Tsunoyama, Taichiro; Pham, Tuan D; Fujita, Takashi; Sakamoto, Tetsuya

    2014-10-01

    Intestinal abnormalities and ischemia are medical conditions in which inflammation and injury of the intestine are caused by inadequate blood supply. Acute ischemia of the small bowel can be life-threatening. Computed tomography (CT) is currently a gold standard for the diagnosis of acute intestinal ischemia in the emergency department. However, the assessment of the diagnostic performance of CT findings in the detection of intestinal abnormalities and ischemia has been a difficult task for both radiologists and surgeons. Little effort has been found in developing computerized systems for the automated identification of these types of complex gastrointestinal disorders. In this paper, a geostatistical mapping of spatial uncertainty in CT scans is introduced for medical image feature extraction, which can be effectively applied for diagnostic detection of intestinal abnormalities and ischemia from control patterns. Experimental results obtained from the analysis of clinical data suggest the usefulness of the proposed uncertainty mapping model.

  2. From Intestinal Permeability to Dysmotility: The Biobreeding Rat as a Model for Functional Gastrointestinal Disorders

    PubMed Central

    Vanheel, Hanne; Masaoka, Tatsuhiro; Salim Rasoel, Shadea; Tóth, Joran; Houben, Els; Verbeke, Kristin; De Hertogh, Gert; Berghe, Pieter Vanden; Tack, Jan; Farré, Ricard

    2014-01-01

    Background Impaired intestinal barrier function, low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. However, the sequence of and causal relation between these events is unclear, necessitating a spontaneous animal model. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat. Methods Normoglycemic BB-diabetes prone (DP) and control rats were sacrificed at different ages and jejunum was harvested to characterize intestinal permeability, inflammation and neuromuscular function. Results Both structural and functional evidence of increased intestinal permeability was found in young BB-DP rats from the age of 50 days. In older animals, starting in the mucosa from 70 days and in half of the animals also in the muscularis propria from 110 days, an inflammatory reaction, characterized by an influx of polymorphonuclear cells and higher myeloperoxidase activity, was observed. Finally, in animals older than 110 days, coinciding with a myenteric ganglionitis, a loss of nitrergic neurons and motor function was demonstrated. Conclusion In the BB-rat, mucosal inflammatory cell infiltration is preceded by intestinal barrier dysfunction and followed by myenteric ganglionitis and loss of nitrergic function. This sequence supports a primary role for impaired barrier function and provides an insightful model for the pathogenesis of functional gastrointestinal disorders. PMID:25354336

  3. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.

    PubMed

    Karwad, Mustafa A; Macpherson, Tara; Wang, Bo; Theophilidou, Elena; Sarmad, Sarir; Barrett, David A; Larvin, Michael; Wright, Karen L; Lund, Jonathan N; O'Sullivan, Saoirse E

    2017-02-01

    Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography-tandem mass spectrometry. OEA (applied apically, logEC50 -5.4) and PEA (basolaterally, logEC50 -4.9; apically logEC50 -5.3) increased Caco-2 resistance by 20-30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001-0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation.-Karwad, M. A., Macpherson, T., Wang, B., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.

  4. cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .

    PubMed

    Marelli, Udaya Kiran; Ovadia, Oded; Frank, Andreas Oliver; Chatterjee, Jayanta; Gilon, Chaim; Hoffman, Amnon; Kessler, Horst

    2015-10-19

    Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco-2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta- and hexapeptides possess an N-methylated cis-peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri-N-methylated analogue of the Veber-Hirschmann peptide. Based on these observations it appears that the presence of N-methylated cis-peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization.

  5. Effects of soybean agglutinin on intestinal barrier permeability and tight junction protein expression in weaned piglets.

    PubMed

    Zhao, Yuan; Qin, Guixin; Sun, Zewei; Che, Dongsheng; Bao, Nan; Zhang, Xiaodong

    2011-01-01

    This study was developed to provide further information on the intestinal barrier permeability and the tight junction protein expression in weaned piglets fed with different levels of soybean agglutinin (SBA). Twenty-five weaned crossbred barrows (Duroc × Landrace × Yorkshire) were selected and randomly allotted to five groups, each group with five replicates. The piglets in the control group were not fed with leguminous products. 0.05, 0.1, 0.15 and 0.2% SBA was added to the control diet to form four experimental diets, respectively. After the experimental period of 7 days (for each group), all the piglets were anesthetized with excess procaine and slaughtered. The d-lactic acid in plasma and the Ileal mucosa diamine oxidase (DAO) was analyzed to observe the change in the intestinal permeability. The tight junction proteins occludin and ZO-1 in the jejunum tissue distribution and relative expression were detected by immunohistochemistry and Western Blot. The results illustrated that a high dose of SBA (0.1-0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no significant affects. The contents of DAO, d-lactic acid, occludin or ZO-1, had a linear relationship with the SBA levels (0-0.2%) in diets. The high dose SBA (0.1-0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no affects.

  6. The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression

    SciTech Connect

    Pinton, Philippe; Nougayrede, Jean-Philippe; Del Rio, Juan-Carlos; Moreno, Carolina; Marin, Daniela E.; Ferrier, Laurent; Bracarense, Ana-Paula; Kolf-Clauw, Martine; Oswald, Isabelle P.

    2009-05-15

    'The gastrointestinal tract represents the first barrier against food contaminants as well as the first target for these toxicants. Deoxynivalenol (DON) is a mycotoxin that commonly contaminates cereals and causes various toxicological effects. Through consumption of contaminated cereals and cereal products, human and pigs are exposed to this mycotoxin. Using in vitro, ex vivo and in vivo approaches, we investigated the effects of DON on the intestinal epithelium. We demonstrated that, in intestinal epithelial cell lines from porcine (IPEC-1) or human (Caco-2) origin, DON decreases trans-epithelial electrical resistance (TEER) and increases in a time and dose-dependent manner the paracellular permeability to 4 kDa dextran and to pathogenic Escherichia coli across intestinal cell monolayers. In pig explants treated with DON, we also observed an increased permeability of intestinal tissue. These alterations of barrier function were associated with a specific reduction in the expression of claudins, which was also seen in vivo in the jejunum of piglets exposed to DON-contaminated feed. In conclusion, DON alters claudin expression and decreases the barrier function of the intestinal epithelium. Considering that high levels of DON may be present in food or feed, consumption of DON-contaminated food/feed may induce intestinal damage and has consequences for human and animal health.

  7. Normal and abnormal electrical propagation in the small intestine.

    PubMed

    Lammers, W J E P

    2015-02-01

    As in other muscular organs, small intestinal motility is determined to a large degree by the electrical activities that occur in the smooth muscle layers of the small intestine. In recent decades, the interstitial cells of Cajal, located in the myenteric plexus, have been shown to be responsible for the generation and propagation of the electrical impulse: the slow wave. It was also known that the slow waves as such do not cause contraction, but that the action potentials ('spikes') that are generated by the slow waves are responsible for the contractions. Recording from large number of extracellular electrodes simultaneously is one method to determine origin and pattern of propagation of these electrical signals. This review reports the characteristics of slow wave propagation through the intestinal tube, the occurrence of propagation blocks along its length, which explains the well-known decrease in frequency, and the specific propagation pattern of the spikes that follow the slow waves. But the value of high-resolution mapping is highest in discovering and analysing mechanisms of arrhythmias in the gut. Most recently, circus movements (also called 're-entries') have been described in the small intestine in several species. Moreover, several types of re-entries have now been described, some similar to what may occur in the heart, such as functional re-entries, but others more unique to the small intestine, such as circumferential re-entry. These findings seem to suggest the possibilities of hitherto unknown pathologies that may be present in the small intestine.

  8. Evaluation of physicochemical properties and intestinal permeability of six dietary polyphenols in human intestinal colon adenocarcinoma Caco-2 cells.

    PubMed

    Rastogi, Himanshu; Jana, Snehasis

    2016-02-01

    Phenolic compounds are common ingredients in many dietary supplements and functional foods. However, data concerning physicochemical properties and permeability of polyphenols on the intestinal epithelial cells are scarce. The aims of this study were to determine the experimental partition coefficient (Log P), and parallel artificial membrane permeability assay (PAMPA), to characterize the bi-directional transport of six phenolic compounds viz. caffeic acid, chrysin, gallic acid, quercetin, resveratrol and rutin in Caco-2 cells. The experimental Log P values of six polyphenols were correlated (R (2) = 0.92) well with the calculated Log P values. The apparent permeability (P app) range of all polyphenols in PAMPA for the apical (AP) to basolateral (BL) was 1.18 ± 0.05 × 10(-6) to 5.90 ± 0.16 × 10(-6) cm/s. The apparent Caco-2 permeability (P app) range for the AP-BL was 0.96 ± 0.03 × 10(-6) to 3.80 ± 0.45 × 10(-6) cm/s. The efflux ratio of P app (BL → AP) to P app (AP → BL) for all phenolics was <2, suggesting greater permeability in the absorptive direction. Six compounds exhibited strong correlations between Log P and PAMPA/Caco-2 cell monolayer permeation data. Dietary six polyphenols were poorly absorbed through PAMPA and Caco-2 cells, and their transepithelial transports were mainly by passive diffusion.

  9. Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats

    PubMed Central

    Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy; Molet, Jenny; Million, Mulugeta; Mayer, Emeran; Taché, Yvette

    2016-01-01

    A few studies indicate that limited nesting stress (LNS) alters maternal behavior and the hypothalamic pituitary adrenal (HPA) axis of dams and offspring in male Sprague Dawley rats. In the present study, we evaluated the impact of LNS on maternal behavior in Wistar rats, and on the HPA axis, glycemia and in vivo intestinal permeability of male and female offspring. Intestinal permeability is known to be elevated during the first week postnatally and influenced by glucocorticoids. Dams and neonatal litters were subjected to LNS or normal nesting conditions (control) from days 2 to 10 postnatally. At day 10, blood was collected from pups for determination of glucose and plasma corticosterone by enzyme immunoassay and in vivo intestinal permeability by oral gavage of fluorescein isothiocyanate–dextran 4kDa. Dams exposed to LNS compared to control showed an increase in the percentage of time spent building a nest (118%), self-grooming (69%), and putting the pups back to the nest (167%). LNS male and female pups exhibited a reduction of body weight by 5% and 4%, adrenal weights/100g body weight by 17% and 18%, corticosterone plasma levels by 64% and 62% and blood glucose by 11% and 12% respectively compared to same sex control pups. In male LNS pups, intestinal permeability was increased by 2.7-fold while no change was observed in females compared to same sex control. There was no sex difference in any of the parameters in control pups except the body weight. These data indicate that Wistar dams subjected to LNS during the first postnatal week have an altered repertoire of maternal behaviors which affects the development of the HPA axis in both sexes and intestinal barrier function in male offspring. PMID:27149676

  10. Methods to determine intestinal permeability and bacterial translocation during liver disease

    PubMed Central

    Wang, Lirui; Llorente, Cristina; Hartmann, Phillipp; Yang, An-Ming; Chen, Peng; Schnabl, Bernd

    2015-01-01

    Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis). It is therefore important to assess and monitor gut barrier dysfunction during hepatic disease. We review methods to assess intestinal barrier disruption and discuss advantages and disadvantages. We will in particular focus on methods that we have used to measure increased intestinal permeability and bacterial translocation during experimental liver disease models. PMID:25595554

  11. Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiologic stress.

    PubMed

    Karl, J Philip; Margolis, Lee M; Madslien, Elisabeth H; Murphy, Nancy E; Castellani, John W; Gundersen, Yngvar; Hoke, Allison V; Levangie, Michael W; Kumar, Raina; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Martini, Svein; Montain, Scott J; Pasiakos, Stefan M

    2017-03-23

    The magnitude, temporal dynamics, and physiologic effects of intestinal microbiome responses to physiologic stress are poorly characterized. This study used a systems biology approach and multiple-stressor military training environment to determine the effects of physiologic stress on intestinal microbiota composition and metabolic activity, and intestinal permeability (IP). 73 Soldiers were provided three rations/d with or without protein- or carbohydrate-based supplements during a four day cross-country ski march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62%±57% (mean±SD, P<0.001) during STRESS independent of diet group, and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased α-diversity, and changes in the relative abundance of >50% of identified genera, including increased abundances of less dominant taxa at the expense of more dominant taxa such as Bacteroides. Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Pre-STRESS Actinobacteria relative abundance, and changes in serum IL-6 and stool cysteine concentrations, collectively, accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation, and with intestinal microbiota composition and metabolism. Observed associations between IP, the pre-stress microbiota, and microbiota metabolites suggest targeting the intestinal microbiota could provide novel strategies for preserving IP during physiologic stress.

  12. Intestinal permeability and orocaecal transit time in elderly patients with Parkinson's disease.

    PubMed Central

    Davies, K. N.; King, D.; Billington, D.; Barrett, J. A.

    1996-01-01

    The aetiology of weight loss in patients with Parkinson's disease is likely to be multifactorial. We studied 15 patients with Parkinson's disease and 15 age- and sex-matched controls and looked for evidence of malabsorption due to small bowel bacterial overgrowth or alteration of intestinal permeability. There was a marked increase in orocaecal transit time in the patients with Parkinson's disease, although lactulose hydrogen breath testing did not show evidence of small bowel bacterial contamination. Intestinal permeability measured by the differential sugar absorption test was also deranged. There was reduced absorption of mannitol in patients with Parkinson's disease while lactulose absorption was similar in both groups, suggesting decreased non-mediated uptake across the enterocyte brush border membrane in patients with Parkinson's disease. PMID:8731708

  13. [Alteration of intestinal permeability: the missing link between gut microbiota modifications and inflammation in obesity?].

    PubMed

    Genser, Laurent; Poitou, Christine; Brot-Laroche, Édith; Rousset, Monique; Vaillant, Jean-Christophe; Clément, Karine; Thenet, Sophie; Leturque, Armelle

    2016-05-01

    The increasing incidence of obesity and associated metabolic complications is a worldwide public health issue. The role of the gut in the pathophysiology of obesity, with an important part for microbiota, is becoming obvious. In rodent models of diet-induced obesity, the modifications of gut microbiota are associated with an alteration of the intestinal permeability increasing the passage of food or bacterial antigens, which contribute to low-grade inflammation and insulin resistance. In human obesity, intestinal permeability modification, and its role in the crosstalk between gut microbiota changes and inflammation at systemic and tissular levels, are still poorly documented. Hence, further characterization of the triggering mechanisms of such inflammatory responses in obese subjects could enable the development of personalized intervention strategies that will help to reduce the risk of obesity-associated diseases.

  14. Plasma albumin concentrations and intestinal permeability in Bangladeshi children infected with Ascaris lumbricoides.

    PubMed

    Northrop, C A; Lunn, P G; Wainwright, M; Evans, J

    1987-01-01

    Plasma albumin concentration and intestinal permeability have been investigated in Bangladeshi children before and 9-14 d after successful treatment for ascariasis. Children infected with A. lumbricoides had lower plasma albumin concentrations than counterparts not harbouring this worm and values increased with successful treatment. Intestinal permeability tests indicated that the children had impaired gastrointestinal function and some loss of mucosal integrity; these factors had not improved 9-14 d after A. lumbricoides expulsion. The lowered nitrogen nutritional status implied by the reduced plasma albumin values in infected children, and the improvement following treatment, are in keeping with previous reports that A. lumbricoides impairs protein digestion or absorption. This may be the basis of the better growth rates of dewormed children in this area.

  15. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics

    PubMed Central

    Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J.; Keshavarzian, Ali

    2015-01-01

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = −0.39, P = 0.03; urinary sucralose, r = −0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID:25907689

  16. Chlorogenic Acid Decreases Intestinal Permeability and Increases Expression of Intestinal Tight Junction Proteins in Weaned Rats Challenged with LPS

    PubMed Central

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21±1 d of age; 62.26±2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS. PMID:24887396

  17. Chlorogenic acid decreases intestinal permeability and increases expression of intestinal tight junction proteins in weaned rats challenged with LPS.

    PubMed

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21 ± 1 d of age; 62.26 ± 2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS.

  18. (51Cr)EDTA intestinal permeability in children with cow's milk intolerance

    SciTech Connect

    Schrander, J.J.; Unsalan-Hooyen, R.W.; Forget, P.P.; Jansen, J. )

    1990-02-01

    Making use of ({sup 51}Cr)EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. ({sup 51}Cr)EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the ({sup 51}Cr)EDTA test can be helpful for the diagnosis of cow's milk intolerance.

  19. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders.

    PubMed

    Kelly, John R; Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Clarke, Gerard; Hyland, Niall P

    2015-01-01

    The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a "leaky gut" may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function.

  20. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

    PubMed Central

    Kelly, John R.; Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Hyland, Niall P.

    2015-01-01

    The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID:26528128

  1. Small intestinal mucosal abnormalities in post-perinatal deaths.

    PubMed Central

    Variend, S; Sunderland, R

    1984-01-01

    Examination of small intestinal mucosa from cases of post-perinatal death in Sheffield between September 1980 and September 1981 showed mucosal changes before death in 18 of 78 cases (20%). There was no significant difference in prevalence between explained and unexplained deaths, nor was there any positive association with viral isolation from the small intestine. The lesion was much more common in males than females and showed a strong association with bottle feeding--no infant wholly breast fed showed an enteropathy. There was a low incidence of symptoms referrable to the gastrointestinal tract among affected infants, and no appreciable evidence of failure to thrive, as reflected by the postmortem body weight, was present. Mucosal changes of the small intestine in cases of sudden infant death syndrome have previously been reported and attributed to heatstroke. Although the finding of similar lesions in infants who died explicably does not appear to support this view, overheating is difficult to exclude as most of the explained deaths with a mucosal lesion occurred at home. Images PMID:6699191

  2. Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement.

    PubMed

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon; Strauss, Holger M; Rahbek, Ulrik L; Andresen, Thomas L

    2015-10-01

    Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate its influence on intestinal cell translocation and membrane interaction. We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain provides 6- or 9-fold increase in peptide translocation at pH 7.4 and 5.5, respectively. Prolonging the chain length appears to hamper translocation, possibly due to self-association or aggregation, although the long chain acylated analogues remain superior to the unacylated peptide. For K(18)-acylation a short chain provides a moderate improvement, whereas medium and long chain analogues are highly efficient, with a 12-fold increase in permeability compared to the unacylated peptide backbone, on par with currently employed oral permeation enhancers. For K(18)-acylation the medium chain acylation appears to be optimal, as elongating the chain causes greater binding to the cell membrane but similar permeability, and we speculate that increasing the chain length further may

  3. Optimization of the Caco-2 permeability assay to screen drug compounds for intestinal absorption and efflux.

    PubMed

    Press, Barry

    2011-01-01

    In vitro permeability assays are a valuable tool for scientists during lead compound optimization. As a majority of discovery projects are focused on the development of orally bioavailable drugs, correlation of in vitro permeability data to in vivo absorption results is critical for understanding the structural-physicochemical relationship (SPR) of drugs exhibiting low levels of absorption. For more than a decade, the Caco-2 screening assay has remained a popular, in vitro system to test compounds for both intestinal permeability and efflux liability. Despite advances in artificial membrane technology and in silico modeling systems, drug compounds still benefit from testing in cell-based epithelial monolayer assays for lead optimization. This chapter provides technical information for performing and optimizing the Caco-2 assay. In addition, techniques are discussed for dealing with some of the most pressing issues surrounding in vitro permeability assays (i.e., low aqueous solubility of test compounds and low postassay recovery). Insights are offered to help researchers avoid common pitfalls in the interpretation of in vitro permeability data, which can often lead to the perception of misleading results for correlation to in vivo data.

  4. Maintenance of superior mesenteric arterial perfusion prevents increased intestinal mucosal permeability in endotoxic pigs

    SciTech Connect

    Fink, M.P.; Kaups, K.L.; Wang, H.L.; Rothschild, H.R. )

    1991-08-01

    Lipopolysaccharide increases intestinal mucosal permeability to hydrophilic compounds such as chromium 51-labeled edetate (51Cr-EDTA). The authors sought to determine whether this phenomenon is partly mediated by lipopolysaccharide-induced mesenteric hypoperfusion. They assessed permeability in an isolated segment of ileum by measuring plasma-to-lumen clearances (C) for two probes, 51Cr-EDTA and urea, and expressing the results as a ratio (CEDTA/CUREA). In control pigs (n = 6) resuscitated with Ringer's lactate (RL), mucosal permeability was unchanged during the 210-minute period of observation. In pigs (n = 7) infused with lipopolysaccharide (50 micrograms/kg) and similarly resuscitated with RL, mesenteric perfusion (Qsma) decreased significantly and permeability increased progressively and significantly. When endotoxic pigs (n = 6) were resuscitated with a regimen (RL plus hetastarch plus dobutamine) that preserved normal Qsma, lipopolysaccharide-induced mucosal hyperpermeability was prevented. Resuscitation of endotoxic pigs (n = 6) with RL plus hetastarch provided intermediate protection against both mesenteric hypoperfusion and increased permeability. These data suggest that diminished Qsma contributes to impaired ileal mucosal barrier function in experimental endotoxicosis.

  5. Studies with inulin-type fructans on intestinal infections, permeability, and inflammation.

    PubMed

    Guarner, Francisco

    2007-11-01

    Symbiosis between host and gut bacteria can be optimized by prebiotics. Inulin-type fructans have been shown to improve the microbial balance of the intestinal ecosystem by stimulating the growth of bifidobacteria and lactobacilli. These changes have been associated with several health benefits, including the prevention of gastrointestinal and systemic infections in animal models and human studies. Inulin-type fructans induce changes of the intestinal mucosa characterized by higher villi, deeper crypts, increased number of goblet cells, and a thicker mucus layer on the colonic epithelium. Bacterial antagonism and competition of bifidobacteria and lactobacilli with pathogens, as well as the trophic effects on the intestinal epithelium, may explain the protective role of inulin against enteric infections. In contrast, studies with rats fed a low-calcium diet suggested a negative effect of prebiotics on intestinal barrier function. However, the adverse effect was clearly ascribed to the strong reduction of dietary calcium, as it could be reversed by oral administration of calcium. The adverse effect of a low-calcium diet on intestinal permeability has not been observed in humans. Inulin and oligofructose are now being tested in human studies aimed at prevention of bacterial translocation in critical health conditions. Mixtures of probiotics and prebiotics including inulin or oligofructose significantly reduced the rate of postoperative infections in liver transplant patients. Finally, inulin and oligofructose have proven useful to prevent mucosal inflammatory disorders in animal models and in patients with inflammatory bowel disease.

  6. Intestinal permeability to (/sup 51/Cr)EDTA in children with Crohn's disease and celiac disease

    SciTech Connect

    Turck, D.; Ythier, H.; Maquet, E.; Deveaux, M.; Marchandise, X.; Farriaux, J.P.; Fontaine, G.

    1987-07-01

    (/sup 51/Cr)EDTA was used as a probe molecule to assess intestinal permeability in 7 healthy control adults, 11 control children, 17 children with Crohn's disease, and 6 children with untreated celiac disease. After subjects fasted overnight, 75 kBq/kg (= 2 microCi/kg) /sup 51/Cr-labeled EDTA was given by mouth; 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the total oral dose. Mean and SD were as follows: control adults 1.47 +/- 0.62, control children 1.59 +/- 0.55, and patients with Crohn's disease or celiac disease 5.35 +/- 1.94. The difference between control children and patients was statistically significant (p less than 0.001). These results show that intestinal permeability to (/sup 51/Cr)EDTA is increased among children with active or inactive Crohn's disease affecting small bowel only or small bowel and colon, and with untreated celiac disease. The (/sup 51/Cr)EDTA permeability test could facilitate the decision to perform more extensive investigations in children suspected of small bowel disease who have atypical or poor clinical and biological symptomatology.

  7. Permeability of milk protein antigens across the intestinal epithelium in vitro.

    PubMed

    Marcon-Genty, D; Tomé, D; Dumontier, A M; Kheroua, O; Desjeux, J F

    1989-01-01

    Degradations by proteolytic enzymes and intestinal epithelial permeability represent two major drawbacks to the transfer of food protein antigens to blood. These steps were studied in vitro for the milk protein antigens beta-lactoglobulin (beta-Lg), alpha-Lactalbumin (alpha-La) and beta-casein (beta-cas). Pepsin-trypsin hydrolysis and permeability in isolated rabbit ileum in Ussing chamber were suited by ELISA and radiolabelled-protein measurement. Pepsin-trypsin hydrolysis showed an increasing resistance in the order beta-cas less than alpha-La less than beta-Lg. The rate of absorption of the antigenic proteins by isolated rabbit ileum was in the same order, and the rate of absorption of the whole proteins (degraded and antigenic forms) was significantly higher for beta-Lg than for alpha-La and beta-cas. These results suggest a selective intestinal permeability for milk protein antigens. This selectivity is probably important in the mechanism of food protein sensitization via the oral route.

  8. Antibiotic Treatment Affects Intestinal Permeability and Gut Microbial Composition in Wistar Rats Dependent on Antibiotic Class.

    PubMed

    Tulstrup, Monica Vera-Lise; Christensen, Ellen Gerd; Carvalho, Vera; Linninge, Caroline; Ahrné, Siv; Højberg, Ole; Licht, Tine Rask; Bahl, Martin Iain

    2015-01-01

    Antibiotics are frequently administered orally to treat bacterial infections not necessarily related to the gastrointestinal system. This has adverse effects on the commensal gut microbial community, as it disrupts the intricate balance between specific bacterial groups within this ecosystem, potentially leading to dysbiosis. We hypothesized that modulation of community composition and function induced by antibiotics affects intestinal integrity depending on the antibiotic administered. To address this a total of 60 Wistar rats (housed in pairs with 6 cages per group) were dosed by oral gavage with either amoxicillin (AMX), cefotaxime (CTX), vancomycin (VAN), metronidazole (MTZ), or water (CON) daily for 10-11 days. Bacterial composition, alpha diversity and caecum short chain fatty acid levels were significantly affected by AMX, CTX and VAN, and varied among antibiotic treatments. A general decrease in diversity and an increase in the relative abundance of Proteobacteria was observed for all three antibiotics. Additionally, the relative abundance of Bifidobacteriaceae was increased in the CTX group and both Lactobacillaceae and Verrucomicrobiaceae were increased in the VAN group compared to the CON group. No changes in microbiota composition or function were observed following MTZ treatment. Intestinal permeability to 4 kDa FITC-dextran decreased after CTX and VAN treatment and increased following MTZ treatment. Plasma haptoglobin levels were increased by both AMX and CTX but no changes in expression of host tight junction genes were found in any treatment group. A strong correlation between the level of caecal succinate, the relative abundance of Clostridiaceae 1 family in the caecum, and the level of acute phase protein haptoglobin in blood plasma was observed. In conclusion, antibiotic-induced changes in microbiota may be linked to alterations in intestinal permeability, although the specific interactions remain to be elucidated as changes in permeability did

  9. Intestinal permeability to (/sup 51/Cr)EDTA in children with cystic fibrosis

    SciTech Connect

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-05-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of (/sup 51/Cr)EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of (/sup 51/Cr)EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

  10. Botulinum Toxin Complex Increases Paracellular Permeability in Intestinal Epithelial Cells via Activation of p38 Mitogen-Activated Protein Kinase

    PubMed Central

    MIYASHITA, Shin-ichiro; SAGANE, Yoshimasa; INUI, Ken; HAYASHI, Shintaro; MIYATA, Keita; SUZUKI, Tomonori; OHYAMA, Tohru; WATANABE, Toshihiro; NIWA, Koichi

    2013-01-01

    ABSTRACT Clostridium botulinum produces a large toxin complex (L-TC) that increases paracellular permeability in intestinal epithelial cells by a mechanism that remains unclear. Here, we show that mitogen-activated protein kinases (MAPKs) are involved in this permeability increase. Paracellular permeability was measured by FITC-dextran flux through a monolayer of rat intestinal epithelial IEC-6 cells, and MAPK activation was estimated from western blots. L-TC of C. botulinum serotype D strain 4947 increased paracellular dextran flux and activated extracellular signal-regulated kinase (ERK), p38, but not c-Jun N-terminal kinase (JNK) in IEC-6 cells. The permeability increase induced by L-TC was abrogated by the p38 inhibitor SB203580. These results indicate that L-TC increases paracellular permeability by activating p38, but not JNK and ERK. PMID:23884081

  11. [The role of intestinal permeability in the pathogenesis of ankylosing spondylitis].

    PubMed

    Liu, Y; Xu, B; Cai, X

    1995-02-01

    By use of low molecular weight polyethlene glycol (PEG400) as tracer, a revised Chedwick method with capillary gas chromatography was used to examine the intestinal permeability in 49 subjects including patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) and healthy controls. Recovery percentage, maximal recovery percentage [Rmax(%)] and Rmax(w) were used to find the effect of bowel permeability in the pathogenesis and disease flare up of AS, as well as the role of HLA-B27 for the bowel permeability. The results showed that in AS group, the recovery of first component (242D) was higher and the Rmax(%) was lower than those in the controls. No statistical difference was found with other indexes. The results indicated that bowel permeability is not elevated in AS. The passage of enteral bacteria antigen into the host may not result from the process of nonspecific penetration. We postulate that there may somehow be a process of "active transportation" in the pathogenesis of AS. More studies of the process are necessary to clarify its importance in the early stage of AS.

  12. MicroRNA 29 Targets Nuclear Factor-κB–Repressing Factor and Claudin 1 to Increase Intestinal Permeability

    PubMed Central

    Zhou, QiQi; Costinean, Stefan; Croce, Carlo M.; Brasier, Alan R.; Merwat, Shehzad; Larson, Scott A.; Basra, Sarpreet; Verne, G. Nicholas

    2014-01-01

    BACKGROUND & AIMS Some patients with irritable bowel syndrome with diarrhea (IBS-D) have intestinal hyperpermeability, which contributes to their diarrhea and abdominal pain. MicroRNA 29 (MIR29) regulates intestinal permeability in patients with IBS-D. We investigated and searched for targets of MIR29 and investigated the effects of disrupting Mir29 in mice. METHODS We investigated expression MIR29A and B in intestinal biopsies collected during endoscopy from patients with IBS (n = 183) and without IBS (controls) (n = 36). Levels were correlated with disease phenotype. We also generated and studied Mir29−/− mice, in which expression of Mir29a and b, but not c, is lost. Colitis was induced by administration of 2,4,6-trinitrobenzenesulfonic acid; intestinal tissues were collected and permeability was assessed. Microarray analysis was performed using tissues from Mir29−/− mice. Changes in levels of target genes were measured in human colonic epithelial cells and small intestinal epithelial cells after knockdown of MIR29 with anti-MIRs. RESULTS Intestinal tissues from patients with IBS-D (but not IBS with constipation or controls) had increased levels of MIR29A and B, but reduced levels of Claudin-1 (CLDN1) and nuclear factor-κB–repressing factor (NKRF). Induction of colitis and water avoidance stress increased levels of Mir29a and Mir29b and intestinal permeability in wild-type mice; these increased intestinal permeability in colons of far fewer Mir29−/− mice. In microarray and knockdown experiments, MIR29A and B were found to reduce levels of NKRF and CLDN1 messenger RNA, and alter levels of other messenger RNAs that regulate intestinal permeability. CONCLUSIONS Based on experiments in knockout mice and analyses of intestinal tissue samples from patients with IBS-D, MIR29 targets and reduces expression of CLDN1 and NKRF to increase intestinal permeability. Strategies to block MIR29 might be developed to restore intestinal permeability in patients with

  13. The intestinal permeability of neolignans from the seeds of Myristica fragrans in the Caco-2 cell monolayer model.

    PubMed

    Yang, Xiu-Wei; Huang, Xin; Ma, Lian; Wu, Qi; Xu, Wei

    2010-10-01

    The intestinal permeability and transport of 10 neolignans isolated from MYRISTICA FRAGRANS were studied by using the Caco-2 cell monolayer model. The 10 neolignans were measured by HPLC. Transport parameters and permeability coefficients were then calculated and compared with those of the model compounds, propranolol and atenolol. Among the 10 neolignans, the 8- O-4'-type neolignans demonstrated high permeability while the benzofuran-type neolignans were of poor to moderate permeability. Among them, eight neolignans were transported mainly VIA passive diffusion. These findings indicate that the 8- O-4'-type neolignans are well-absorbed compounds and can be used as oral leading compounds in drug discovery.

  14. [Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

    PubMed

    Liu, Yang; Wang, Gang; Dong, Ling; Tang, Ming-Min; Zhu, Mei-Ling; Dong, Hong-Huant; Hou, Cheng-Bo

    2014-12-01

    The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.

  15. Low Dosage of Chitosan Supplementation Improves Intestinal Permeability and Impairs Barrier Function in Mice

    PubMed Central

    Peng, Hanhui; Li, Guanya

    2016-01-01

    The purpose of this study was to explore relationships between low dose dietary supplementation with chitosan (COS) and body weight, feed intake, intestinal barrier function, and permeability in mice. Twenty mice were randomly assigned to receive an unadulterated control diet (control group) or a dietary supplementation with 30 mg/kg dose of chitosan (COS group) for two weeks. Whilst no significant differences were found between the conditions for body weight or food and water intake, mice in the COS group had an increased serum D-lactate content (P < 0.05) and a decreased jejunal diamine oxidase (DAO) activity (P < 0.05). Furthermore, mice in COS group displayed a reduced expression of occludin and ZO-1 (P < 0.05) and a reduced expression of occludin in the ileum (P < 0.05). The conclusion drawn from these findings showed that although 30 mg/kg COS-supplemented diet had no effect on body weight or feed intake in mice, this dosage may compromise intestinal barrier function and permeability. This research will contribute to the guidance on COS supplements. PMID:27610376

  16. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury.

    PubMed

    Frazier, Thomas H; DiBaise, John K; McClain, Craig J

    2011-09-01

    Obesity and its metabolic complications are major health problems in the United States and worldwide, and increasing evidence implicates the microbiota in these important health issues. Indeed, it appears that the microbiota function much like a metabolic "organ," influencing nutrient acquisition, energy homeostasis, and, ultimately, the control of body weight. Moreover, alterations in gut microbiota, increased intestinal permeability, and metabolic endotoxemia likely play a role in the development of a chronic low-grade inflammatory state in the host that contributes to the development of obesity and associated chronic metabolic diseases such as nonalcoholic fatty liver disease. Supporting these concepts are the observations that increased gut permeability, low-grade endotoxemia, and fatty liver are observed in animal models of obesity caused by either high-fat or high-fructose feeding. Consistent with these observations, germ-free mice are protected from obesity and many forms of liver injury. Last, many agents that affect gut flora/permeability, such as probiotics/prebiotics, also appear to affect obesity and certain forms of liver injury in animal model systems. Here the authors review the role of the gut microbiota and metabolic endotoxemia-induced inflammation in the development of obesity and liver injury, with special reference to the intensive care unit setting.

  17. Intestinal permeability and P-glycoprotein-mediated efflux transport of ticagrelor in Caco-2 monolayer cells.

    PubMed

    Marsousi, Niloufar; Doffey-Lazeyras, Fabienne; Rudaz, Serge; Desmeules, Jules A; Daali, Youssef

    2016-12-01

    Ticagrelor is the unique reversible oral antiplatelet drug commercialized today. During this study, the intestinal permeability of ticagrelor and its potential P-glycoprotein (P-gp)-mediated active transport were assessed. To this end, bidirectional transport of ticagrelor was performed across Caco-2 (human epithelial colorectal adenocarcinoma) monolayer model in the presence and absence of potent P-gp inhibitor valspodar. Ticagrelor presented an apical-basolateral apparent permeability coefficient (Papp ) of 6.0 × 10(-6) cm/s. On the other hand, mean efflux ratio (ER) of 2.71 was observed for ticagrelor describing a higher efflux permeability compared to the influx component. Valspodar showed a significant inhibitory effect on the efflux of ticagrelor suggesting involvement of P-gp in its oral disposition. Co-incubation of the P-gp inhibitor decreased the efflux Papp of ticagrelor from 1.60 × 10(-5) to 1.13 × 10(-5) cm/s and decreased its ER by 70%. Results suggest a modest active transport of ticagrelor by P-gp across the Caco-2 cell monolayer. The co-administration of ticagrelor with a P-gp inhibitor seems altogether unlikely to have an extended impact on pharmacokinetics of ticagrelor and cause bleeding events in patients.

  18. Is the sugar intestinal permeability test a reliable investigation for coeliac disease screening?

    PubMed Central

    Catassi, C; Fabiani, E; Rätsch, I M; Bonucci, A; Dotti, M; Coppa, G V; Giorgi, P L

    1997-01-01

    BACKGROUND: The lactulose/mannitol (L/M) intestinal permeability test is a simple, non-invasive screening test for coeliac disease. The reliability of the L/M test has so far only been tested in selected groups of patients with coeliac disease. AIM: To evaluate the reliability of the L/M test in a group of patients with coeliac disease who had been diagnosed during mass serological screening of the general population. PATIENTS AND METHODS: Twenty nine patients with coeliac disease detected by screening and 54 age matched coeliac disease free controls aged 11-15 years underwent an L/M test with 5 g lactulose and 2 g mannitol in isotonic aqueous solution. Urinary sugars were measured by high performance liquid chromatography. RESULTS: The median % urinary recovery of lactulose (lactulose UR) was significantly higher in patients with coeliac disease than in controls (0.63 v 0.18, p < 0.001). The mean mannitol % UR was lower in patients with coeliac disease than in controls (17.6 v 18.5) but the difference was not significant. The median urinary L%/M% ratio was significantly higher in patients with coeliac disease than in controls (0.038 v 0.014, p < 0.001). However, 16 of the 29 patients with coeliac disease showed an L%/M% ratio within normal limits (< 0.044). CONCLUSIONS: The L/M intestinal permeability test is not a valuable tool for screening of coeliac disease in the general population. The pattern of the urinary probe recovery suggests that many patients with coeliac disease could remain symptomless because the extent of their intestinal mucosal damage is small ("short" coeliac disease). PMID:9071934

  19. Nano-reservoir Bioadhesive Tablets Enhance Protein Drug Permeability Across the Small Intestine.

    PubMed

    Yin, Lifang; Wang, Yong; Wang, Cuifeng; Feng, Min

    2017-01-23

    Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time. In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs.

  20. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases

    SciTech Connect

    Jenkins, R.T.; Jones, D.B.; Goodacre, R.L.; Collins, S.M.; Coates, G.; Hunt, R.H.; Bienenstock, J.

    1987-11-01

    Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered /sup 51/Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of /sup 51/Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease.

  1. Study of the Biotransformation of Tongmai Formula by Human Intestinal Flora and Its Intestinal Permeability across the Caco-2 Cell Monolayer.

    PubMed

    Wu, Shuai; Xu, Wei; Wang, Fu-Rong; Yang, Xiu-Wei

    2015-10-15

    Tongmai formula (TMF) is a well-known Chinese medicinal preparation that contains isoflavones as its major bioactive constituents. As traditional Chinese medicines (TCMs) are usually used by oral administration, their fate inside the intestinal lumen, including their biotransformation by human intestinal flora (HIF) and intestinal absorption deserves study. In this work TMF extract was incubated with human intestinal bacteria under anaerobic conditions and the changes in the twelve main constituents of TMF were then investigated. Their intestinal permeabilities, i.e., the transport capability across the intestinal brush border were investigated with a human colon carcinoma cell line (Caco-2) cell monolayer model to predict the absorption mechanism. Meanwhile, rapid HPLC-DAD methods were established for the assay. According to the biotransformation curves of the twelve constituents and the permeability coefficients, the intestinal absorption capacity of the typical compounds was elevated from the levels of 10(-7) cm/s to 10(-5) cm/s from those of the original compounds in TMF. Among them the main isoflavone glycosides puerarin (4), mirificin (6) and daidzin (7) were transformed into the same aglycone, daidzein (10). Therefore it was predicted that the aglycone compounds might be the real active ingredients in TMF. The models used can represent a novel path for the TCM studies.

  2. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

    PubMed Central

    Nighot, Prashant; Al-Sadi, Rana; Guo, Shuhong; Watterson, D. Martin; Ma, Thomas

    2015-01-01

    Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9−/− mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9−/− mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9−/− mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK−/− mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9−/− mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK. PMID:26514773

  3. Expressions of Tight Junction Proteins Occludin and Claudin-1 Are under the Circadian Control in the Mouse Large Intestine: Implications in Intestinal Permeability and Susceptibility to Colitis

    PubMed Central

    Oh-oka, Kyoko; Kono, Hiroshi; Ishimaru, Kayoko; Miyake, Kunio; Kubota, Takeo; Ogawa, Hideoki; Okumura, Ko; Shibata, Shigenobu; Nakao, Atsuhito

    2014-01-01

    Background & Aims The circadian clock drives daily rhythms in behavior and physiology. A recent study suggests that intestinal permeability is also under control of the circadian clock. However, the precise mechanisms remain largely unknown. Because intestinal permeability depends on tight junction (TJ) that regulates the epithelial paracellular pathway, this study investigated whether the circadian clock regulates the expression levels of TJ proteins in the intestine. Methods The expression levels of TJ proteins in the large intestinal epithelium and colonic permeability were analyzed every 4, 6, or 12 hours between wild-type mice and mice with a mutation of a key clock gene Period2 (Per2; mPer2m/m). In addition, the susceptibility to dextran sodium sulfate (DSS)-induced colitis was compared between wild-type mice and mPer2m/m mice. Results The mRNA and protein expression levels of Occludin and Claudin-1 exhibited daily variations in the colonic epithelium in wild-type mice, whereas they were constitutively high in mPer2m/m mice. Colonic permeability in wild-type mice exhibited daily variations, which was inversely associated with the expression levels of Occludin and Claudin-1 proteins, whereas it was constitutively low in mPer2m/m mice. mPer2m/m mice were more resistant to the colonic injury induced by DSS than wild-type mice. Conclusions Occludin and Claudin-1 expressions in the large intestine are under the circadian control, which is associated with temporal regulation of colonic permeability and also susceptibility to colitis. PMID:24845399

  4. Role of free radicals and poly(ADP-ribose) synthetase in intestinal tight junction permeability.

    PubMed Central

    Cuzzocrea, S.; Mazzon, E.; De Sarro, A.; Caputi, A. P.

    2000-01-01

    BACKGROUND: Small intestine permeability is frequently altered in inflammatory bowel disease and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJ) and adherence (1,2). The role of hydrogen peroxide (H2O2), and nitric oxide (NO) and PARS in the permeability and structure of small intestine TJ is not clearly understood. MATERIALS AND METHODS: In vitro study, MDCK (Madin-Darby Canine Kidney) cells were exposed to H2O2 (100 microM for 2h), or zymosan (200 microl of stock solution 1 mg/ml for 4h), in the presence or absence of a treatment with poly(ADP-ribose) synthetase (PARS) inhibitor 3-aminobenzamide (3-AB: 3 mM) or with n-acetylcysteine (NAC 10 mM). In vivo study, wild-type mice (WT) and mice lacking (KO) of the inducible (or type 2) nitric oxide synthase (iNOS) were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.). In addition INOSWT mice were treated with 3-AB (10 mg/kg, i.p.) or with NAC (40 mg/kg, i.p.) 1 hour and 6 h after zymosan administration. RESULTS: Exposure of MDCK cells to hydrogen peroxide caused a significant impairment in mitochondrial respiration that was associated with a reduction of cells adherence as well as derangement of the junctional proteins. A significant increase of nitrate and nitrite levels, stable metabolites of nitric oxide (NO), were found in MDCK supernatant after zymosan incubation. NO production was associated with a significant reduction of cell adherence and impairment of occludin protein. Pre-treatment of the cells with 3-AB or with NAC caused a significant prevention of H2O2-mediated occludin junctional damage as well as reduced the NO-induced occludin damage. In addition, H2O2 and NO are able to induce a significant derangement of beta-catenin and Zonula Ocludence-1 (ZO-1). We found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the terminal ileal TJs in zymosan-treated iNOSWT mice compared with

  5. Intestinal permeability in Hymenolepis nana as reflected by non invasive lactulose/mannitol dual permeability test and its impaction on nutritional parameters of patients.

    PubMed

    Mohammad, Mahmoud A; Hegazi, Mai A

    2007-12-01

    Assessment of Hymenolepis nana infection among 102 children and adults of both sexes (5-16 years) residing 2 Welfare Institutes (Giza and Cairo) showed a prevalence of 22.33%. The effect of H. nana on intestinal permeability and on nutritional parameters of patients was studied. A total of 46 subjects were divided into 2 groups: GI (20 H. nana patients) and GII (26 parasite-free control). Both groups were subjected to lactulose/mannitol dual permeability test, anthropometric study, estimation of vitamin B12 and folate levels in plasma and estimation of haemoglobin (HB)%, RBCs and WBCs counts and haematocrite value (HCT%) for anaemia. The H. nana patients showed significant higher percent (P = 0.04) of altered intestinal permeability versus controls denoting intestinal leakage, significant means lower levels of vitamin B12 (P = 0.01) and folate (P < 0.04) in blood plasma versus control denoting liability to vitamin B12 & folate deficiencies. Means value of HB%, RBC & WBC counts and HCT% showed generalized decrease but without significant difference in H. nana patients and control denoting anaemia liability. The percent of stunting (HAZ < or =2) and of wasting (WAZ < or =2) were higher among H. nana patients versus controls but without significant difference (P = 0.19 & P = 0.47 respectively).

  6. Ameliorative effect of melatonin against increased intestinal permeability in diabetic rats: possible involvement of MLCK-dependent MLC phosphorylation.

    PubMed

    Yang, Xiaoping; Zou, Duobing; Tang, Songtao; Fan, Tingting; Su, Huan; Hu, Ruolei; Zhou, Qing; Gui, Shuyu; Zuo, Li; Wang, Yuan

    2016-05-01

    The increased intestinal permeability and functional impairment play an important role in type 2 diabetes (T2D), and melatonin may possess enteroprotection properties. Therefore, we used streptozotocin-induced diabetic rat model to investigate the regulation of intestinal permeability by melatonin. Rats were randomly divided into three groups, including control, diabetes mellitus (DM), and DM rats treated with melatonin. Melatonin was administered (10 mg/kg/day) by gavage for 24 weeks. The DM rats significantly increased the serum fasting blood glucose and lipid levels, which were alleviated by melatonin treatment. Importantly, the intestinal epithelial permeability was significantly increased in DM rats but was ameliorated following treatment with melatonin. These findings also indicated the expression of myosin light chain kinase (MLCK) and phosphorylation of MLC targeting subunit (MYPT) induced myosin light chain (MLC) phosphorylation level was markedly elevated in hyperglycemic and hyperlipidemic status. They were partly associated with down-regulated membrane type 1 and 2 (MT1 and MT2) expression, and up-regulated Rho-associated protein kinase (ROCK) expression and increased extracellular signal-regulated kinase (ERK) phosphorylation. However, the changes in target protein expression were reversed by melatonin. In conclusion, our results show melatonin beneficial effects on impaired intestinal epithelial permeability in T2D by suppressing ERK/MLCK- and ROCK/MCLP-dependent MLC phosphorylation.

  7. Short term effects of indomethacin on rat small intestinal permeability. Role of eicosanoids and platelet activating factor.

    PubMed Central

    Mion, F; Cuber, J C; Minaire, Y; Chayvialle, J A

    1994-01-01

    Short term effects of indomethacin on intestinal permeability were studied on a model of rat isolated vascularly perfused terminal ileum. The objectives of this study were (a) to assess the effects of indomethacin on intestinal permeability and histology; (b) to assess the effects of prostaglandins, leukotrienes, and platelet activating factor (PAF) on the same parameters; (c) to evaluate the role of these inflammation mediators on indomethacin induced permeability modifications. Intravascular administration of 1.25 and 2.5 mM indomethacin induced a significant increase of 51Cr-EDTA transfer rate. Histological analysis showed only mucosal oedema. Pretreatment with 16,16 dimethyl-prostaglandin E2 did not reverse these changes. Intravascular administration of PAF, leukotrienes B4 and D4 provoked a significant rise in 51Cr-EDTA transfer rate and intraluminal protein leakage, with an intense vascocongestion of the mucosal capillaries. These changes were completely prevented by perfusion of the respective specific antagonists (BN52021 for PAF, LY255,583 for leukotriene B4 and MK571 for leukotriene D4). None of these three antagonists, however, or MK886, a selective 5'-lipo-oxygenase inhibitor, could reverse the indomethacin induced permeability changes. Indomethacin induced increased intestinal permeability at these high concentrations does not seem to be a result of changed prostanoid or PAF metabolism. Alternative mechanisms of the initial damage of non-steroid anti-inflammatory drugs should be sought. Images Figure 2 Figure 3 Figure 5 PMID:8174986

  8. Zonulin Regulates Intestinal Permeability and Facilitates Enteric Bacteria Permeation in Coronary Artery Disease

    PubMed Central

    Li, Chuanwei; Gao, Min; Zhang, Wen; Chen, Caiyu; Zhou, Faying; Hu, Zhangxu; Zeng, Chunyu

    2016-01-01

    Several studies have reported an association between enteric bacteria and atherosclerosis. Bacterial 16S ribosomal RNA (rRNA) gene belong to Enterobacteriaceae have been detected in atherosclerotic plaques. How intestinal bacteria go into blood is not known. Zonulin reversibly modulate intestinal permeability (IP), the circulating zonulin levels were increased in diabetes, obesity, all of which are risk factors for atherosclerosis. It is unclear whether the circulating zonulin levels were changed in coronary artery disease (CAD) patients and modulate IP. The 16S rRNA gene of bacteria in blood sample was checked by 454 pyrosequencing. The zonulin levels were determined by enzyme-linked immunosorbent assay (ELISA) methods. The distribution of zonulin was detected by confocal immunofluorescence microscopy. Bacteria and Caco-2 cell surface micro-structure were checked by transmission electron microscopy. A high diversity of bacterial 16S rRNA gene can be detected in samples from CAD patients, most of them (99.4%) belong to Enterobacteriaceaes, eg. Rahnella. The plasma zonulin levels were significantly higher in CAD patients. Pseudomonas fluorescens exposure significantly increased zonulin expression and decreased IP in a time dependent manner. The elevated zonulin increase IP and may facilitate enteric translocation by disassembling the tight junctions, which might explain the observed high diversity of bacterial 16S rRNA genes in blood samples. PMID:27353603

  9. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    NASA Astrophysics Data System (ADS)

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-11-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO.

  10. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    PubMed Central

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-01-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO. PMID:26611622

  11. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds.

    PubMed

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-11-27

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO.

  12. Alanyl-glutamine dipeptide-supplemented parenteral nutrition improves intestinal metabolism and prevents increased permeability in rats.

    PubMed Central

    Haque, S M; Chen, K; Usui, N; Iiboshi, Y; Okuyama, H; Masunari, A; Cui, L; Nezu, R; Takagi, Y; Okada, A

    1996-01-01

    OBJECTIVE: The authors determined the effects of alanyl-glutamine-supplemented total parenteral nutrition (TPN) on mucosal metabolism, integrity, and permeability of the small intestine in rats. METHODS: Male Sprague-Dawley rats were randomized to receive TPN supplemented with a conventional amino acids mixture (STD group) or the same solution supplemented with alanyl-glutamine; both solutions were isocaloric and isonitrogenous. On the seventh day of TPN, D-xylose and fluorescein isothiocyanate (FITC)-dextran were administered orally. One hour later, superior mesenteric vein (SMV) D-xylose and plasma FITC-dextran concentration were measured. Intestinal blood flow and calculated intestinal substrates flux were measured with ultrasonic transit time flowmetery. RESULTS: Plasma FITC-dextran increased significantly in the STD group. Intestinal blood flow and SMV D-xylose concentration did not differ between the groups. Mucosa weight, villus height, mucosal wall thickness, mucosal protein, and DNA and RNA content in jejunal mucosa were significantly increased in the alanyl-glutamine group. Jejunal mucosal glutaminase activity and net intestinal uptake of glutamine (glutamine flux) were significantly higher in the alanyl-glutamine group as compared with the STD group. CONCLUSION: Addition of alanyl-glutamine dipeptide to the TPN solution improves intestinal glutamine metabolism and prevents mucosal atrophy and deterioration of permeability. PMID:8604914

  13. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats.

    PubMed

    Chiu, Wan-Chun; Huang, Ya-Li; Chen, Ya-Ling; Peng, Hsiang-Chi; Liao, Wei-Hsiang; Chuang, Hsiao-Li; Chen, Jiun-Rong; Yang, Suh-Ching

    2015-05-01

    Clinical and animal experiments indicated that gut-derived endotoxin and imbalanced intestinal microbiota contribute to the pathogenesis of alcoholic liver disease (ALD). In this study, we investigated whether synbiotic supplementation could improve ALD in rats by altering the intestinal microbial composition and improving the intestinal integrity. Male Wistar rats were divided into four groups according to plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and subjected to either a normal liquid diet (C), a normal liquid diet with synbiotic supplementation (C + S), an ethanol liquid diet (E), or an ethanol liquid diet with synbiotic supplementation (E + S) for 12 weeks. Results revealed that the ethanol-fed group showed increases in plasma AST and ALT activities, the endotoxin level, the hepatic triglyceride (TG) level, and hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels, and a decrease in the hepatic IL-10 level. Ethanol-feeding also contributed to increased intestinal permeability and decreased fecal bifidobacteria and lactobacilli amounts. However, synbiotic supplementation effectively attenuated the plasma endotoxin, hepatic TG and TNF-α levels, and increased the hepatic IL-10 level. Furthermore, synbiotic supplementation protected the rats against ethanol-induced hyperpermeability of the intestine, and significantly increased amounts of bifidobacteria and lactobacilli in the feces. This study demonstrated that synbiotics possess a novel hepatoprotective function by improving the intestinal permeability and microbiota in rats with ethanol-induced liver injury.

  14. Contributions of altered permeability of intestinal barrier and defecation behavior to toxicity formation from graphene oxide in nematode Caenorhabditis elegans.

    PubMed

    Wu, Qiuli; Yin, Li; Li, Xing; Tang, Meng; Zhang, Tao; Wang, Dayong

    2013-10-21

    Graphene oxide (GO) has been extensively studied for potential biomedical applications. Meanwhile, potential GO toxicity arises in both biomedical applications and non-biomedical products where environmental exposures may occur. In the present study, we examined the potential adverse effects of GO and the underlying mechanism using nematode Caenorhabditis elegans as the assay system. We compared the in vivo effects of GO between acute exposure and prolonged exposure, and found that prolonged exposure to 0.5-100 mg L(-1) of GO caused damage on functions of both primary (intestine) and secondary (neuron and reproductive organ) targeted organs. In the intestine, ROS production was significantly correlated with the formation of adverse effects on functions of both primary and secondary targeted organs. GO could be translocated into intestinal cells with loss of microvilli, and distributed to be adjacent to or surrounding mitochondria. Prolonged exposure to GO resulted in a hyper-permeable state of the intestinal barrier, an increase in mean defecation cycle length, and alteration of genes required for intestinal development and defecation behavior. Thus, our data suggest that prolonged exposure to GO may cause potential risk to environmental organisms after release into the environment. GO toxicity may be due to the combinational effects of oxidative stress in the intestinal barrier, enhanced permeability of the biological barrier, and suppressed defecation behavior in C. elegans.

  15. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease.

    PubMed

    Lerner, Aaron; Matthias, Torsten

    2015-06-01

    The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade. Future research on food additives exposure-intestinal permeability-autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression.

  16. Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers.

    PubMed

    Ingels, F; Beck, B; Oth, M; Augustijns, P

    2004-04-15

    Presently, the Caco-2 cell culture model is widely used during drug discovery and development as a predictive tool for the oral absorption of drug candidates. For transport experiments in the Caco-2 system, HBSS-like buffered salt solutions are commonly used, although different shortcomings have been associated with the use of these buffers. In this paper, we investigated the effect of using fasted state simulated intestinal fluid (FaSSIF) as potential biorelevant medium for the drug permeability estimation across Caco-2 monolayers. The transport characteristics of 19 model compounds were determined in the Caco-2 cell culture model in the presence of FaSSIF as compared to classic transport medium. A sigmoidal relation was obtained when the estimated P(app), s of the apical to basolateral transport were plotted versus the reported values of the fraction absorbed in man. Although no effect of FaSSIF as compared to classic transport medium (TM) was observed on the total predictability of the model, an impact was demonstrated (1) on the bi-directional transport of actively transported drugs (including talinolol, digoxin and doxorubicin), (2) on recovery and (3) on the solubility and permeability estimation of poorly water-soluble drugs. The observed differences may be attributed to a P-gp inhibitory effect of sodium taurocholate (NaTC), micellar encapsulation by the NaTC/lecithin mixed micelles and/or an increase of the solubility of lipophilic drugs. As the experimental conditions should mimic the physiological in vivo conditions, the use of FaSSIF as medium during Caco-2 experiments may improve the biorelevance of the model.

  17. Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon.

    PubMed

    Pade, D; Jamei, M; Rostami-Hodjegan, A; Turner, D B

    2017-03-01

    A major component of physiologically based pharmacokinetic (PBPK) models is the prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff ) is essential. Single-pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents, while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters. The 'MechPeff' model, built-in to the Simcyp Rat and Mouse Simulators, predicts transcellular, paracellular and mucus layer permeabilities and combines these to give the overall Peff . The jejunal and/or ileal Peff was predicted for 12 (4) acidic, 13 (12) basic, 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logPo:w , and compared with experimental Peff obtained using SPIP. A key input is the intrinsic transcellular permeability (Ptrans,0 ) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The Peff predictions were reasonably good when experimentally derived Ptrans,0 was used; from 42 Peff,rat values, 24 (57%) were within 3-fold, and of 19 Peff,mouse values, 12 (63%) were within 3-fold, of observed Peff . Considering the lack of alternative models to predict Peff in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis.

    PubMed

    Julian, Mark W; Bao, Shengying; Knoell, Daren L; Fahy, Ruairi J; Shao, Guohong; Crouser, Elliott D

    2011-10-01

    Mitochondrial morphology and function are altered in intestinal epithelia during endotoxemia. However, it is unclear whether mitochondrial abnormalities occur in lung epithelial cells during acute sepsis or whether mitochondrial dysfunction corresponds with altered epithelial barrier function. Thus, we hypothesized that the intestinal epithelium is more susceptible to mitochondrial injury than the lung epithelium during acute sepsis and that mitochondrial dysfunction precedes impaired barrier function. Using a resuscitated feline model of Escherichia coli-induced sepsis, lung and ileal tissues were harvested after 6 h for histological and mitochondrial ultrastructural analyses in septic (n = 6) and time-matched controls (n = 6). Human lung epithelial cells (HLEC) and Caco-2 monolayers (n = 5) were exposed to 'cytomix' (TNFα: 40 ng/ml, IL-1β: 20 ng/ml, IFNγ: 10 ng/ml) for 24-72 h, and measurements of transepithelial electrical resistance (TER), epithelial permeability and mitochondrial membrane potential (ΔΨ) were taken. Lung epithelial morphology, mitochondrial ultrastructure and pulmonary gas exchange were unaltered in septic animals compared to matching controls. While histologically intact, ileal epithelia demonstrated marked mitochondrial ultrastructural damage during sepsis. Caco-2 monolayers treated with cytomix showed a significant decrease in mitochondrial ΔΨ within 24 h, which was associated with a progressive reduction in TER and increased epithelial permeability over the subsequent 48 h. In contrast, mitochondrial ΔΨ and epithelial barrier functions were preserved in HLEC following cytomix. These findings indicate that intestinal epithelium is more susceptible to mitochondrial damage and dysfunction than the lung epithelium in the context of sepsis. Early alterations in mitochondrial function portend subsequent epithelial barrier dysfunction.

  19. Effect of vitamin A deficiency on permeability of the small intestinal mucosa for macromolecules in adult rats

    SciTech Connect

    Gmoshinskii, I.V.; Khvylya, S.I.; Kon', I.Ya.

    1987-07-01

    The authors study the effect of experimental vitamin A deficiency on absorption of macromolecules of hen's ovalbumin in the intestine. An electron-microscopic study of permeability of small intestine enterocytes for particles of colloidal lanthanum hydroxide La(OH)/sub 3/ was carried out at the same time. The concentration of unsplit hen's ovalbumin in the blood of the rats used in the experiment was determined by competitive radioimmunoassay. Samples of serum were incubated with indicator doses of /sup 125/I-OA. Radioactivity of the precipitates was measured.

  20. Liquid Chromatography-Tandem Mass Spectrometry for Analysis of Intestinal Permeability of Loperamide in Physiological Buffer

    PubMed Central

    Rubelt, Miriam S.; Amasheh, Salah; Grobosch, Thomas; Stein, Christoph

    2012-01-01

    Analysis of in vitro samples with high salt concentrations represents a major challenge for fast and specific quantification with liquid chromatography-tandem mass spectrometry (LC-MS/MS). To investigate the intestinal permeability of opioids in vitro employing the Ussing chamber technique, we developed and validated a fast, sensitive and selective method based on LC–MS/MS for the determination of loperamide in HEPES-buffered Ringer's solution. Chromatographic separation was achieved with an Atlantis dC18 column, 2.1 mm×20 mm, 3 µm particle size and a gradient consisting of methanol/0.1% formic acid and ammonium acetate. The flow rate was 0.7 ml/min, and the total run time was 3 min. For quantification, two mass transitions for loperamide and a deuterated internal standard (methadone-d3) were used. The lower limit of loperamide quantification was 0.2 ng/ml. This new LC-MS/MS method can be used for the detection of loperamide in any experimental setup using HEPES-buffered Ringer's solution as a matrix compound. PMID:23144895

  1. Use of rubidium, manganese, and zinc as tracers to measure intestinal permeability by PIXE analysis: basal study in an experimental enteritis model.

    PubMed

    Nakao, Keitaro; Suzuki, Yasuo; Imaseki, Hitoshi; Joshima, Hisamasa; Tamanoi, Itsuro; Saito, Yasushi

    2004-04-01

    Intestinal permeability has been suggested to be closely linked with the etiology or activity of Crohn's disease. However, current methods for measurement of intestinal permeability are too laborious for routine examination, as they require urine collection and/or use of radioisotopes. The present study was performed to develop a more convenient and safer method for assessing intestinal permeability using blood samples rather than urine. Rats with indomethacin-induced enteritis were orally administered Rb, Mn, and Zn as tracers. Intestinal permeability was determined by assaying the levels of Rb, Mn, and Zn in blood samples by particle-induced X-ray emission (PIXE). The distributions of Rb, Mn, and Zn in the small intestine after administration were analyzed by micro-PIXE. The conventional PIXE analysis showed that the levels of Rb and Zn in the blood in the enteritis group were correlated with the grade of enteritis. The micro-PIXE analysis showed that Rb, Mn, and Zn were translocated into the wall of the proximal small intestine 5 min after administration, and this effect was more conspicuous in the enteritis group than in controls. Analysis of blood or small intestine tissue samples using the PIXE allows determination of both intestinal permeability and the route of permeation.

  2. Fish Oil Reduces Hepatic Injury by Maintaining Normal Intestinal Permeability and Microbiota in Chronic Ethanol-Fed Rats

    PubMed Central

    Chen, Jiun-Rong; Chen, Ya-Ling; Peng, Hsiang-Chi; Lu, Yu-An; Chuang, Hsiao-Li; Chang, Hsiao-Yun; Wang, Hsiao-Yun; Su, Yu-Ju; Yang, Suh-Ching

    2016-01-01

    The aim of this study was to investigate the ameliorative effects of fish oil on hepatic injury in ethanol-fed rats based on the intestinal permeability and microbiota. Rats were assigned to 6 groups and fed either a control diet or an ethanol diet such as C (control), CF25 (control with 25% fish oil), CF57 (control with 57% fish oil), E (ethanol), EF25 (ethanol with 25% fish oil), and EF57 (ethanol with 57% fish oil) groups. Rats were sacrificed at the end of 8 weeks. Plasma aspartate aminotransferase (AST) and aminotransferase (ALT) activities, hepatic cytokines, and plasma endotoxin levels were significantly higher in the E group. In addition, hepatic histopathological analysis scores in the E group were significantly elevated. Rats in the E group also showed increased intestinal permeability and decreased numbers of fecal Bifidobacterium. However, plasma AST and ALT activities and hepatic cytokine levels were significantly lower in the EF25 and EF57 groups. Histological changes and intestinal permeability were also improved in the EF25 and EF57 groups. The fecal Escherichia coli numbers were significantly lower, but fecal Bifidobacterium numbers were significantly higher in the EF25 and EF57 groups. PMID:27143963

  3. Ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age-dependent oral drug absorption.

    PubMed

    Annaert, Pieter; Brouwers, Joachim; Bijnens, Ann; Lammert, Frank; Tack, Jan; Augustijns, Patrick

    2010-01-31

    The possible influence of advanced age on intestinal drug absorption was investigated by determining the effects of aging on (i) solubility of model drugs in human intestinal fluids (HIF) obtained from two age groups (18-25 years; 62-72 years); and (ii) transepithelial permeation of model drugs across intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of intestinal tissue (rather than age-dependent luminal drug solubility) may contribute to altered intestinal drug absorption in older patients compared to young adults.

  4. CONCEPTUAL MODEL FOR ORIGIN OF ABNORMALLY PRESSURED GAS ACCUMULATIONS IN LOW-PERMEABILITY RESERVOIRS.

    USGS Publications Warehouse

    Law, B.E.; Dickinson, W.W.

    1985-01-01

    The paper suggests that overpressured and underpressured gas accumulations of this type have a common origin. In basins containing overpressured gas accumulations, rates of thermogenic gas accumulation exceed gas loss, causing fluid (gas) pressure to rise above the regional hydrostatic pressure. Free water in the larger pores is forced out of the gas generation zone into overlying and updip, normally pressured, water-bearing rocks. While other diagenetic processes continue, a pore network with very low permeability develops. As a result, gas accumulates in these low-permeability reservoirs at rates higher than it is lost. In basins containing underpressured gas accumulations, rates of gas generation and accumulation are less than gas loss. The basin-center gas accumulation persists, but because of changes in the basin dynamics, the overpressured accumulation evolves into an underpressured system.

  5. Development of a biomimetic phospholipid vesicle-based permeation assay for the estimation of intestinal drug permeability.

    PubMed

    Naderkhani, Elenaz; Isaksson, Johan; Ryzhakov, Alexey; Flaten, Gøril Eide

    2014-06-01

    Permeability is a crucial property of orally administered drugs. Therefore, in drug discovery, it is important to employ methods suitable for rapidly and reliably screening the permeability of large numbers of new drug candidates. The phospholipid vesicle-based permeation assay (PVPA), a model consisting of a tight layer of liposomes immobilized on a filter, offers potential advantages unmet by other methods and has been successfully used in permeability testing of novel active substances as well as formulations. In this study, the PVPA was developed into a more robust, biomimetic model by employing a lipid composition matching that of the intestinal permeation barrier and performing the experiments at the more biologically relevant pH 6.2. As expected, positively charged basic compounds demonstrated increased permeability through the negatively charged biomimetic barriers, and the degree of correct classification according to in vivo absorption was comparable between the original PVPA and the biomimetic PVPA. The biomimetic PVPA further proved to be tremendously more robust toward the presence of tensides compared with the original PVPA; this is a promising finding that renders the biomimetic PVPA an enhanced ability to estimate the permeability of poorly soluble compounds. Hence, the PVPA model developed in this study has evolved an important step forward.

  6. In-situ single pass intestinal permeability and pharmacokinetic study of developed Lumefantrine loaded solid lipid nanoparticles.

    PubMed

    Garg, Anuj; Bhalala, Kripal; Tomar, Devendra Singh; Wahajuddin

    2017-01-10

    The present investigation aims to develop lumefantrine loaded binary solid lipid nanoparticles (LF-SLNs) to improve its poor and variable oral bioavailability. The oral bioavailability of LF is poor and variable due to its limited aqueous solubility and P-gp mediated efflux occurring in small intestine. LF-SLNs were prepared using binary lipid mixture of stearic acid and caprylic acid stabilized with TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) and Poloxamer 188. Developed LF-SLNs were characterized for particle size distribution, zeta potential, entrapment efficiency, solid state properties and biopharmaceutical properties including in situ intestinal permeability and oral bioavailability. The particle size distribution, zeta potential and entrapment efficiency of optimized batch (LF-SLN7) was found to be 357.7±43.27nm, 25.29±1.15mV and 97.35±0.30%, respectively. DSC thermographs showed loss of crystalline nature of lumefantrine in LF-SLNs. In situ single pass intestinal permeability study (SPIP) study indicated significant enhancement in the effective intestinal permeability of LF from LF-SLN7 as compared to that of control. Pharmacokinetic study also showed significant increase in Cmax and area under curve (AUC0-∞) from LF-SLN7 (3860±521ng/mL and 43181±2557h×ng/mL, respectively) as compared to that of LF-control suspension (1425±563ng/mL and 19586±1537h×ng/mL, respectively). Thus, developed LF-SLNs can be promising to overcome P-gp efflux pump and enhance the oral bioavailability of lumefantrine.

  7. Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review.

    PubMed

    Angkathunyakul, Napat; Treepongkaruna, Suporn; Molagool, Sani; Ruangwattanapaisarn, Nichanan

    2015-06-14

    Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2(nd) to 4(th) middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed.

  8. Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review

    PubMed Central

    Angkathunyakul, Napat; Treepongkaruna, Suporn; Molagool, Sani; Ruangwattanapaisarn, Nichanan

    2015-01-01

    Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2nd to 4th middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed. PMID:26078585

  9. Effects of glutamine on markers of intestinal inflammatory response and mucosal permeability in abdominal surgery patients: A meta-analysis

    PubMed Central

    Shu, Xiao-Liang; Yu, Ting-Ting; Kang, Kai; Zhao, Jian

    2016-01-01

    The present meta-analysis was carried out to determine whether supplementation with glutamine (Gln) would reduce the intestinal inflammatory response and mucosal permeability in patients undergoing abdominal surgery. The PubMed, EMBASE, Web of Science, and The Cochrane Library databases were searched for randomized controlled trials on the effects of supplementation with Gln, and published from August, 1966 to June 2014. Inclusion criteria for the meta-analysis were: i) Study design was a randomized controlled trial, ii) study included patients undergoing abdominal surgery, iii) study patients received a supplementation with Gln peptide (Ala-Gln or Gly-Gln) whereas control patients did not use any supplements, and iv) study outcomes included inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, and IL-2 receptor] and markers of intestinal permeability [lactulose/mannitol, diamine oxidase, D(−)lactic acid, and endotoxin]. Qualities of controlled trials were assessed using the Jadad score. Meta-analyses were performed with fixed- or random-effect models depending on the heterogeneity of studies. There were 21 trials meeting the inclusion criteria. The meta-analysis revealed that the levels of CRP, TNF-α, and IL-6 in patients supplemented with Gln were significantly lower than those in control patients, whereas the levels of IL-2 receptor were increased by Gln supplementation. Gln also significantly decreased the lactulose/mannitol ratio, the levels of diamine oxidase and endotoxin, and tended to decrease the levels of cyclic D-lactic acid. In conclusion, Gln appears to effectively reduce the inflammatory response and intestinal mucosal permeability in patients after abdominal surgery. PMID:28105083

  10. In vitro studies of intestinal permeability and hepatic and intestinal metabolism of 8-prenylnaringenin, a potent phytoestrogen from hops (Humulus lupulus L.)

    PubMed Central

    Nikolic, Dejan; Li, Yongmei; Chadwick, Lucas R.; van Breemen, Richard B.

    2006-01-01

    Purpose The absorption potential and metabolism of 8-prenylnaringenin (8-PN) from hops (Humulus lupulus L.) were investigated. 8-PN is a potent estrogen with the potential to be used for the relief of menopausal symptoms in women. Methods Monolayers of the human intestinal epithelial cancer cell line Caco-2 and human hepatocytes were incubated with 8-PN to model its intestinal absorption and hepatic metabolism, respectively. Results The apparent permeability coefficients for 8-PN in the apical-to-basolateral and basolateral-to-apical directions of a Caco-2 monolayer were 5.2 ± 0.7 x 10−5 cm/sec and 4.9 ± 0.5 x 10−5 cm/sec, respectively, indicating good intestinal absorption via passive diffusion. Both glucuronide and sulfate conjugates of 8-PN were detected in the Caco-2 cell incubations. The 4′-O-glucuronide was the predominant Caco-2 cell metabolite, followed by 7-O-sulfate and 4′-O-sulfate. Both phase I and phase II metabolites of 8-PN were formed by human hepatocytes. The 7-O-glucuronide was the most abundant hepatocyte metabolite, and no sulfate conjugates were detected. Incubations with various cDNA-expressed UDP-glucuronosyl transferases indicated that the isozymes UGT1A1, UGT1A6, UGT1A8, and UGT1A9 were responsible for glucuronidation of 8-PN. Conclusions Although orally administered 8-PN should be readily absorbed from the intestine, its bioavailability should be reduced significantly by intestinal and hepatic metabolism. PMID:16715376

  11. The "perfect storm" for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity.

    PubMed

    Vaarala, Outi; Atkinson, Mark A; Neu, Josef

    2008-10-01

    It is often stated that type 1 diabetes results from a complex interplay between varying degrees of genetic susceptibility and environmental factors. While agreeing with this principal, our desire is that this Perspectives article will highlight another complex interplay potentially associated with this disease involving facets related to the gut, one where individual factors that, upon their interaction with each another, form a "perfect storm" critical to the development of type 1 diabetes. This trio of factors includes an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness. Studies examining the microecology of the gastrointestinal tract have identified specific microorganisms whose presence appears related (either quantitatively or qualitatively) to disease; in type 1 diabetes, a role for microflora in the pathogenesis of disease has recently been suggested. Increased intestinal permeability has also been observed in animal models of type 1 diabetes as well as in humans with or at increased-risk for the disease. Finally, an altered mucosal immune system has been associated with the disease and is likely a major contributor to the failure to form tolerance, resulting in the autoimmunity that underlies type 1 diabetes. Herein, we discuss the complex interplay between these factors and raise testable hypotheses that form a fertile area for future investigations as to the role of the gut in the pathogenesis and prevention of type 1 diabetes.

  12. Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88

    PubMed Central

    Guo, Shuhong; Nighot, Meghali; Al-Sadi, Rana; Alhmoud, Tarik; Nighot, Prashant; Ma, Thomas Y.

    2015-01-01

    Gut-derived bacterial lipopolysaccharides (LPS) play an essential role in inducing intestinal and systemic inflammatory responses and have been implicated as a pathogenic factor of necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD). The defective intestinal tight junction (TJ) barrier has been shown to be an important factor contributing to the development of intestinal inflammation. LPS, at physiological concentrations, cause an increase in intestinal tight junction permeability (TJP) via a TLR-4 dependent process; however the intracellular mechanisms that mediate LPS regulation of intestinal TJP remain unclear. The aim of this study was to investigate the adaptor proteins and the signaling interactions that mediate LPS modulation of intestinal TJ barrier using an in-vitro and in-vivo model system. LPS caused a TLR-4 dependent activation of membrane-associated adaptor protein FAK in Caco-2 monolayers. LPS caused an activation of both MyD88-dependent and –independent pathways. SiRNA silencing of MyD88 prevented LPS-induced increase in TJP. LPS caused a MyD88-dependent activation of IRAK4. TLR-4, FAK and MyD88 were co-localized. SiRNA silencing of TLR-4 inhibited TLR-4 associated FAK activation; and FAK knockdown prevented MyD88 activation. In-vivo studies also confirmed that LPS-induced increase in mouse intestinal permeability was associated with FAK and MyD88 activation; knockdown of intestinal epithelial FAK prevented LPS-induced increase in intestinal permeability. Additionally, high dose LPS-induced intestinal inflammation was also dependent on TLR-4/FAK/MyD88 signal-transduction axis. Our data show for the first time that LPS-induced increase in intestinal TJP and intestinal inflammation was regulated by TLR-4 dependent activation of FAK-MyD88-IRAK4 signaling pathway. PMID:26466961

  13. Zidovudine-poly(L-lactic acid) solid dispersions with improved intestinal permeability prepared by supercritical antisolvent process.

    PubMed

    Yoshida, Valquíria M H; Balcão, Victor M; Vila, Marta M D C; Oliveira Júnior, José M; Aranha, Norberto; Chaud, Marco V; Gremião, Maria P D

    2015-05-01

    A supercritical antisolvent (SAS) process for obtaining zidovudine-poly(L-lactic acid) (PLLA) solid dispersions (SDs) was used to attain a better intestinal permeation of this drug. A 3(2) factorial design was used, having as independent variables the ratio 3'-azido-2'3'-dideoxythymidine (AZT)-PLLA and temperature/pressure conditions, as dependent variables the process yield and particle macroscopic morphology. AZT-PLLA production batches were carried out by the SAS process, and the resulting products evaluated via scanning electron microscope, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared analyses. From the nine possible combinations of tests performed experimentally, only one combination did not produced a solid. The L3 batch of SD, produced with 1:2 (AZT-PLLA) ratio, resulted in a 91.54% yield, with 40% AZT content. Intestinal permeability studies using the AZT-PLLA from L3 batch led to an AZT permeability of approximately 9.87%, which was higher than that of pure AZT (∼3.84%). AZT remained in crystalline form, whereas PLLA remained in semicrystalline form. AZT release is controlled by a diffusion mechanism. It has been demonstrated that it is possible to use PLLA carrier and SAS process to obtain SD, in a single step.

  14. Circulating Zonulin, a Marker of Intestinal Permeability, Is Increased in Association with Obesity-Associated Insulin Resistance

    PubMed Central

    Moreno-Navarrete, José María; Sabater, Mònica; Ortega, Francisco; Ricart, Wifredo; Fernández-Real, José Manuel

    2012-01-01

    Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA) was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity). Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002) contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01) contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase. PMID:22629362

  15. Ball-milled solid dispersions of BCS Class IV drugs: Impact on the dissolution rate and intestinal permeability of acyclovir.

    PubMed

    Nart, Viviane; França, Maria Terezinha; Anzilaggo, Daiane; Riekes, Manoela Klüppel; Kratz, Jadel Müller; de Campos, Carlos Eduardo Maduro; Simões, Cláudia Maria Oliveira; Stulzer, Hellen Karine

    2015-08-01

    Acyclovir, an analog of 2'-deoxyguanosine, is one of the most important drugs in the current approved antiviral treatment. However, it's biopharmaceutical properties, contribute to acyclovir's poor oral bioavailability, which restricts the clinical use of the drug. In this view, the aim of this work was to improve the dissolution rate and intestinal permeability of acyclovir through the development of ball milling solid dispersions with the hydrophilic carriers Pluronic F68®, hydroxypropylmethyl cellulose K100M® and chitosan. Solid dispersions were obtained and completely characterized through different solid state techniques. The solid state data demonstrated a decrease in the crystallinity (amorphous phase and defects) and the presence of hydrogen bonds for SD HPMC and SD CTS. The enhancement of dissolution rates was observed for all SDs developed. In addition, no detrimental effects over the in vitro antiviral activity were detected. The solid dispersions with Pluronic F68® significantly improved the intestinal permeability of acyclovir across Caco-2 cells. In summary, the SDs developed in this study could be considered as potential systems for solid dosage forms containing acyclovir with superior biopharmaceutical properties.

  16. Sotalol permeability in cultured-cell, rat intestine and PAMPA system

    PubMed Central

    LIU, WEI; OKOCHI, HIDEAKI; BENET, LESLIE Z.; ZHAI, SUO-DI

    2014-01-01

    Purpose To clarify sotalol’s classification in the BCS versus BDDCS systems through cellular, rat everted sac and PAMPA permeability studies. Methods Studies were carried out in Madin Darby canine kidney (MDCK) and MDR1-transfected MDCK (MDCK-MDR1) cell lines, rat everted gut sacs and the Parallel Artificial Membrane Permeability Assay (PAMPA) system. Three-hour transport studies were conducted in MDCK cell lines (with apical pH changes) and MDCK-MDR1 cells (with and without the P-glycoprotein inhibitor GG918); male Sprague-Dawley rats (300 ~ 350 g) were used to prepare everted sacs. In the PAMPA studies, drug solutions at different pH’s were dosed in each well and incubated for 5 hours. Samples were measured by LC-MS/MS, or liquid scintillation counting and apparent permeability (Papp) was calculated. Results Sotalol showed low permeability in all of the cultured-cell lines, everted sacs and PAMPA systems. It might be a border line P-glycoprotein substrate. The PAMPA study showed that sotalol’s permeability increased with a higher apical pH, while much less change was found in MDCK cells. Conclusion The low permeability rate for sotalol correlates with its Class 3 BDDCS assignment and lack of in vivo metabolism. PMID:22350803

  17. Acylation of Glucagon-Like Peptide-2: Interaction with Lipid Membranes and In Vitro Intestinal Permeability

    PubMed Central

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon; Andresen, Thomas Lars; Rahbek, Ulrik Lytt

    2014-01-01

    Background Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation as well as increasing enzymatic stability without disrupting biological potency. Acylation has furthermore been shown to increase interactions with the lipid membranes of mammalian cells. The extent to which such interactions hinder or benefit delivery of acylated peptide drugs across cellular barriers such as the intestinal epithelia is currently unknown. The present study investigates the effect of acylating peptide drugs from a drug delivery perspective. Purpose We hypothesize that the membrane interaction is an important parameter for intestinal translocation, which may be used to optimize the acylation chain length for intestinal permeation. This work aims to characterize acylated analogues of the intestinotrophic Glucagon-like peptide-2 by systematically increasing acyl chain length, in order to elucidate its influence on membrane interaction and intestinal cell translocation in vitro. Results Peptide self-association and binding to both model lipid and cell membranes was found to increase gradually with acyl chain length, whereas translocation across Caco-2 cells depended non-linearly on chain length. Short and medium acyl chains increased translocation compared to the native peptide, but long chain acylation displayed no improvement in translocation. Co-administration of a paracellular absorption enhancer was found to increase translocation irrespective of acyl chain length, whereas a transcellular enhancer displayed increased synergy with the long chain acylation. Conclusions These results show that membrane interactions play a prominent role during intestinal translocation of an acylated peptide. Acylation benefits permeation for shorter and medium chains due to increased membrane interactions, however, for longer chains insertion in the membrane becomes dominant and hinders translocation, i.e. the peptides get ‘stuck’ in the cell

  18. Loss of organic anion transporting polypeptide 1a1 increases deoxycholic acid absorption in mice by increasing intestinal permeability.

    PubMed

    Zhang, Youcai; Csanaky, Iván L; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2011-12-01

    Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)α/β, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice.

  19. Loss of Organic Anion Transporting Polypeptide 1a1 Increases Deoxycholic Acid Absorption in Mice by Increasing Intestinal Permeability

    PubMed Central

    Zhang, Youcai; Csanaky, Iván L.; Lehman-McKeeman, Lois D.; Klaassen, Curtis D.

    2011-01-01

    Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)α/β, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice. PMID:21914718

  20. Brief Report: Normal Intestinal Permeability at Elevated Platelet Serotonin Levels in a Subgroup of Children with Pervasive Developmental Disorders in Curacao (The Netherlands Antilles)

    ERIC Educational Resources Information Center

    Kemperman, Ramses F. J.; Muskiet, Fred D.; Boutier, A. Inge; Kema, Ido P.; Muskiet, Frits A. J.

    2008-01-01

    This study investigated the relationship between platelet (PLT) serotonin (5-HT) and intestinal permeability in children with pervasive developmental disorders (PDD). Differential sugar absorption and PLT 5-HT were determined in 23 children with PDD. PLT 5-HT (2.0-7.1 nmol/10[to the ninth power] PLT) was elevated in 4/23 patients. None exhibited…

  1. Mast cells and histamine alter intestinal permeability during malaria parasite infection.

    PubMed

    Potts, Rashaun A; Tiffany, Caitlin M; Pakpour, Nazzy; Lokken, Kristen L; Tiffany, Connor R; Cheung, Kong; Tsolis, Renée M; Luckhart, Shirley

    2016-03-01

    Co-infections with malaria and non-typhoidal Salmonella serotypes (NTS) can present as life-threatening bacteremia, in contrast to self-resolving NTS diarrhea in healthy individuals. In previous work with our mouse model of malaria/NTS co-infection, we showed increased gut mastocytosis and increased ileal and plasma histamine levels that were temporally associated with increased gut permeability and bacterial translocation. Here, we report that gut mastocytosis and elevated plasma histamine are also associated with malaria in an animal model of falciparum malaria, suggesting a broader host distribution of this biology. In support of mast cell function in this phenotype, malaria/NTS co-infection in mast cell-deficient mice was associated with a reduction in gut permeability and bacteremia. Further, antihistamine treatment reduced bacterial translocation and gut permeability in mice with malaria, suggesting a contribution of mast cell-derived histamine to GI pathology and enhanced risk of bacteremia during malaria/NTS co-infection.

  2. Cell-permeable intrinsic cellular inhibitors of apoptosis protect and rescue intestinal epithelial cells from radiation-induced cell death

    PubMed Central

    Matsuzaki-Horibuchi, Shiori; Yasuda, Takeshi; Sakaguchi, Nagako; Yamaguchi, Yoshihiro; Akashi, Makoto

    2015-01-01

    One of the important mechanisms for gastrointestinal (GI) injury following high-dose radiation exposure is apoptosis of epithelial cells. X-linked inhibitor of apoptosis (XIAP) and cellular IAP2 (cIAP2) are intrinsic cellular inhibitors of apoptosis. In order to study the effects of exogenously added IAPs on apoptosis in intestinal epithelial cells, we constructed bacterial expression plasmids containing genes of XIAP (full-length, BIR2 domain and BIR3-RING domain with and without mutations of auto-ubiquitylation sites) and cIAP2 proteins fused to a protein-transduction domain (PTD) derived from HIV-1 Tat protein (TAT) and purified these cell-permeable recombinant proteins. When the TAT-conjugated IAPs were added to rat intestinal epithelial cells IEC6, these proteins were effectively delivered into the cells and inhibited apoptosis, even when added after irradiation. Our results suggest that PTD-mediated delivery of IAPs may have clinical potential, not only for radioprotection but also for rescuing the GI system from radiation injuries. PMID:25359904

  3. Cell-permeable intrinsic cellular inhibitors of apoptosis protect and rescue intestinal epithelial cells from radiation-induced cell death.

    PubMed

    Matsuzaki-Horibuchi, Shiori; Yasuda, Takeshi; Sakaguchi, Nagako; Yamaguchi, Yoshihiro; Akashi, Makoto

    2015-01-01

    One of the important mechanisms for gastrointestinal (GI) injury following high-dose radiation exposure is apoptosis of epithelial cells. X-linked inhibitor of apoptosis (XIAP) and cellular IAP2 (cIAP2) are intrinsic cellular inhibitors of apoptosis. In order to study the effects of exogenously added IAPs on apoptosis in intestinal epithelial cells, we constructed bacterial expression plasmids containing genes of XIAP (full-length, BIR2 domain and BIR3-RING domain with and without mutations of auto-ubiquitylation sites) and cIAP2 proteins fused to a protein-transduction domain (PTD) derived from HIV-1 Tat protein (TAT) and purified these cell-permeable recombinant proteins. When the TAT-conjugated IAPs were added to rat intestinal epithelial cells IEC6, these proteins were effectively delivered into the cells and inhibited apoptosis, even when added after irradiation. Our results suggest that PTD-mediated delivery of IAPs may have clinical potential, not only for radioprotection but also for rescuing the GI system from radiation injuries.

  4. Improvement of the intestinal membrane permeability of low molecular weight heparin by complexation with stem bromelain.

    PubMed

    Grabovac, V; Bernkop-Schnürch, A

    2006-12-01

    The aim of this study was to investigate the influence of the proteolytic enzyme bromelain on the permeation of heparin across the gastrointestinal epithelial barrier. Stability of the complex and effect of heparin on the enzymatic activity of bromelain was analysed photometrically by measuring bromelain enzymatic activity in complex with the heparin. In vitro permeation studies were performed with Caco-2 cell monolayer and rat small intestinal mucosa in Ussing-type chambers, respectively. Results revealed that enzymatic activity of bromelain remained uninfluenced by the immobilization of heparin on it. Transport studies across Caco-2 cell monolayer and rat small intestine showed that the permeation of heparin could be significantly increased in presence of bromelain. In the study with Caco-2 cells, the most effective molar ratio of bromelain to heparin was 2:1, leading to 6.7-fold improvement in uptake, whereas the molar ratio 1:1 showed the highest permeation enhancing effect in the study on intestinal mucosa. This study provides evidence that heparin and bromelain form stable complexes leading to a significantly improved uptake of heparin.

  5. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity.

    PubMed

    Leclercq, Sophie; Matamoros, Sébastien; Cani, Patrice D; Neyrinck, Audrey M; Jamar, François; Stärkel, Peter; Windey, Karen; Tremaroli, Valentina; Bäckhed, Fredrik; Verbeke, Kristin; de Timary, Philippe; Delzenne, Nathalie M

    2014-10-21

    Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.

  6. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity

    PubMed Central

    Leclercq, Sophie; Matamoros, Sébastien; Cani, Patrice D.; Neyrinck, Audrey M.; Jamar, François; Stärkel, Peter; Windey, Karen; Tremaroli, Valentina; Bäckhed, Fredrik; Verbeke, Kristin; de Timary, Philippe; Delzenne, Nathalie M.

    2014-01-01

    Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut–brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence. PMID:25288760

  7. Intestinal Fluid Permeability in Atlantic Salmon (Salmo salar L.) Is Affected by Dietary Protein Source

    PubMed Central

    Hu, Haibin; Kortner, Trond M.; Gajardo, Karina; Chikwati, Elvis; Tinsley, John; Krogdahl, Åshild

    2016-01-01

    In Atlantic salmon (Salmo salar L.), and also in other fish species, certain plant protein ingredients can increase fecal water content creating a diarrhea-like condition which may impair gut function and reduce fish growth. The present study aimed to strengthen understanding of the underlying mechanisms by observing effects of various alternative plant protein sources when replacing fish meal on expression of genes encoding proteins playing key roles in regulation of water transport across the mucosa of the distal intestine (DI). A 48-day feeding trial was conducted with five diets: A reference diet (FM) in which fish meal (72%) was the only protein source; Diet SBMWG with a mix of soybean meal (30%) and wheat gluten (22%); Diet SPCPM with a mix of soy protein concentrate (30%) and poultry meal (6%); Diet GMWG with guar meal (30%) and wheat gluten (14.5%); Diet PM with 58% poultry meal. Compared to fish fed the FM reference diet, fish fed the soybean meal containing diet (SBMWG) showed signs of enteritis in the DI, increased fecal water content of DI chyme and higher plasma osmolality. Altered DI expression of a battery of genes encoding aquaporins, ion transporters, tight junction and adherens junction proteins suggested reduced transcellular transport of water as well as a tightening of the junction barrier in fish fed the SBMWG diet, which may explain the observed higher fecal water content and plasma osmolality. DI structure was not altered for fish fed the other experimental diets but alterations in target gene expression and fecal water content were observed, indicating that alterations in water transport components may take place without clear effects on intestinal structure. PMID:27907206

  8. Effect of dexamethasone in feed on intestinal permeability, differential white blood cell counts, and immune organs in broiler chicks.

    PubMed

    Vicuña, E A; Kuttappan, V A; Galarza-Seeber, R; Latorre, J D; Faulkner, O B; Hargis, B M; Tellez, G; Bielke, L R

    2015-09-01

    We have previously shown that intestinal barrier function can be adversely affected by poorly digested diets or feed restriction, resulting in increased intestinal inflammation-associated permeability. Three experiments were conducted in broilers to evaluate the effect of dexamethasone (DEX) treatment on systemic fluorescein isothiocyanate-dextran (FITC-D; 3-5 kDa) levels, indicative of increased gut epithelial leakage. Experiment 1 compared DEX injections of 1 mg/kg, once per day on d 3, 5, and 9, with feed administration at 0.57, 1.7, or 5.1 ppm d 4 to 10, with FITC-D serum concentrations 2.5 h after gavage with 4.16 mg/kg FITC-D. All DEX treatments resulted in marked (2 to 6X; P<0.05) increased serum FITC-D levels. Feed DEX administration resulted in greater (P<0.05) gut permeability than injection at any dose, with numerically optimal effects at the lowest dose tested. In experiments 2 and 3, chicks were randomly assigned to a starter ration containing either control (CON) or DEX treated feed (0.57 ppm/kg; d 3 to 10 experiment 2, d 4 to 10 experiment 3). At d 10, all chicks were treated by oral gavage with FITC-D and serum samples were obtained as described above. Samples of the liver were aseptically collected, homogenized, diluted 1:4 wt/vol in sterile saline, and serial dilutions were plated on tryptic soy agar to evaluate total numbers of aerobic bacteria in the liver as an index of bacterial translocation (BT). In both experiments, FITC-D absorption was significantly enhanced (P<0.05) in DEX-treated chicks, again indicating increased paracellular leakage across the gut epithelium associated with dissolution of tight junctions. Experiment 2 differential cell counts showed an increased heterophil/lymphocyte ratio, and immune organ (spleen and bursa of Fabricius) weights for experiments 2 and 3 were decreased (P<0.05) from controls. In experiments 2 and 3, dietary DEX administration resulted in numerically (experiment 2) or significantly (P<0.05) increased

  9. Simultaneous determination of nine model compounds in permeability samples using RP-HPLC: application to prove the cassette administration principle in single pass intestinal perfusion study in rats.

    PubMed

    Wahajuddin; Singh, Sheelendra Pratap; Raju, K S R; Nafis, Asad; Jain, Girish Kumar

    2012-01-01

    A simple, sensitive and specific reversed phase high performance liquid chromatographic (RP-HPLC) method for simultaneous determination of atenolol, paracetamol, hydrochlorothiazide, caffeine, cephalexin, metoprolol, propranolol, ketoprofen along with phenol red (a non-absorbable compound) in samples obtained from intestinal in situ single-pass perfusion studies, was developed and validated. Chromatography was carried out on RP18 column with mobile phase comprising of 10 mM phosphate buffer (pH 2.5) and methanol in gradient mode. The calibration curves were linear for all nine permeability model compounds (r² > 0.999) across the concentration range of 1.25-40 μg/ml. The coefficient of variation for intra and inter-day assay precision was between 0.04 and 3.08% and the accuracy was between 98.39 and 109.45%. Stability studies were carried out at different storage conditions and all the analytes were found to be stable. The method was successfully applied for analysing the permeability samples obtained from in situ single pass perfusion studies. The effective permeability (P(eff)) values obtained upon cassette administration were in close proximity to the permeability values obtained upon single administration of model compounds. In conclusion, the developed RP-HPLC method can be used for high throughput cassette validation of rat in situ perfusion model for intestinal permeability assessment.

  10. Intestine.

    PubMed

    Smith, J M; Skeans, M A; Horslen, S P; Edwards, E B; Harper, A M; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    Intestine and intestine-liver transplant plays an important role in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2014, 210 new patients were added to the intestine transplant waiting list. Among prevalent patients on the list at the end of 2014, 65% were waiting for an intestine transplant and 35% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was highest for adult candidates, at 22.1 per 100 waitlist years compared with less than 3 per 100 waitlist years for pediatric candidates, and notably higher for candidates for intestine-liver transplant than for candidates for intestine transplant without a liver. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 67 in 2014. Intestine-liver transplants increased from a low of 44 in 2012 to 72 in 2014. Short-gut syndrome (congenital and other) was the main cause of disease leading to both intestine and intestine-liver transplant. Graft survival improved over the past decade. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients.

  11. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model

    PubMed Central

    2011-01-01

    Background Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models. Methods To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice. Results By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated. Conclusions This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin. PMID:21977944

  12. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics.

    PubMed

    Buyukozturk, Fulden; Benneyan, James C; Carrier, Rebecca L

    2010-02-25

    Lipid based drug delivery systems, and in particular self-emulsifying drug delivery systems (SEDDS), show great potential for enhancing oral bioavailability but have not been broadly applied, largely due to lack of general formulation guidance. To help understand how formulation design influences physicochemical emulsion properties and associated function in the gastrointestinal environment, a range of twenty-seven representative self-emulsifying formulations were investigated. Two key functions of emulsion-based drug delivery systems, permeability enhancement and drug release, were studied and statistically related to three formulation properties - oil structure, surfactant hydrophilic liphophilic balance (HLB) values, and surfactant-to-oil ratio. Three surfactants with HLB values ranging from 10 to 15 and three structurally different oils (long chain triglyceride, medium chain triglyceride, and propylene glycol dicaprylate/dicaprate) were combined at three different weight ratios (1:1, 5:1, 9:1). Unstable formulations of low HLB surfactant (HLB=10) had a toxic effect on cells at high (1:1) surfactant concentrations, indicating the importance of formulation stability for minimizing toxicity. Results also indicate that high HLB surfactant (Tween 80) loosens tight junction at high (1:1) surfactant concentrations. Release coefficients for each emulsion system were calculated. Incorporation of a long chain triglyceride (Soybean oil) as the oil phase increased the drug release rate constant. These results help establish an initial foundation for relating emulsion function to formulation design and enabling bioavailability optimization across a broad, representative range of SEDDS formulations.

  13. Altered intestinal microbiota in patients with chronic pancreatitis: implications in diabetes and metabolic abnormalities

    PubMed Central

    Jandhyala, Sai Manasa; Madhulika, A.; Deepika, G.; Rao, G. Venkat; Reddy, D. Nageshwar; Subramanyam, Chivukula; Sasikala, Mitnala; Talukdar, Rupjyoti

    2017-01-01

    Intestinal dysbiosis and its functional implications in chronic pancreatitis (CP) have not been elaborately studied. We evaluated the taxonomic and functional alterations in intestinal microbiota in 30 well-characterised patients with CP (16 without, 14 with diabetes) and 10 healthy controls. The patients with CP and diabetes had significantly longer disease duration and greater degree of malnutrition. There was increase in plasma endotoxin concentrations from controls to CP non-diabetics to CP diabetics. We observed significant differences in richness and alpha diversity between the groups. We also observed increase in the Firmicutes:Bacteroidetes ratio in CP patients without and with diabetes. There was reduction in abundance of Faecalibacterium prausnitzii and Ruminococcus bromii from controls to CP non-diabetics to CP diabetics. On the other hand, there was increase in LPS (endotoxin) synthetic pathways (KEGG orthology) in the groups. Faecalibacterium prausnitzii abundance correlated negatively with plasma endotoxin and glycemic status; while plasma endotoxin correlated positively with blood glucose and negatively with plasma insulin. Our results have important implications for future studies exploring mechanistic insights on secondary diabetes in CP. PMID:28255158

  14. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease.

    PubMed

    Anders, Hans-Joachim; Andersen, Kirstin; Stecher, Bärbel

    2013-06-01

    Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of 'endotoxin tolerance' or 'immune paralysis' in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent the associated complications.

  15. Flos Lonicera Ameliorates Obesity and Associated Endotoxemia in Rats through Modulation of Gut Permeability and Intestinal Microbiota

    PubMed Central

    Wang, Jing-Hua; Bose, Shambhunath; Kim, Gi-Cheol; Hong, Seung-Ug; Kim, Ji-Hun; Kim, Jai-eun; Kim, Hojun

    2014-01-01

    Background and Aim Increasing evidence has indicated a close association of host-gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia. Methods Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models. Results In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-α, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin-1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes. Conclusion This evidence collectively demonstrates that Flos Lonicera ameliorates obesity

  16. Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen-activated protein kinases in pigs.

    PubMed

    Hu, C H; Xiao, K; Luan, Z S; Song, J

    2013-03-01

    Although weaning stress has been reported to impair intestinal barrier function, the mechanisms have not yet been elucidated. In the present study, the intestinal morphology and permeability and mRNA expressions of tight junction proteins and cytokines in the intestine of piglets during the 2 wk after weaning were assessed. The phosphorylated (activated) ratios of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular regulated kinases (ERK1/2) were determined to investigate whether mitogen-activated protein kinase (MAPK) signaling pathways are involved in the early weaning process. A shorter villus and deeper crypt were observed on d 3 and 7 postweaning. Although damaged intestinal morphology recovered to preweaning values on d 14 postweaning, the intestinal mucosal barrier, which was reflected by transepithelial electrical resistance (TER) and paracellular flux of dextran (4 kDa) in the Ussing chamber and tight junction protein expression, was not recovered. Compared with the preweaning stage (d 0), jejunal TER and mRNA expressions of occludin and claudin-1 on d 3, 7, and 14 postweaning and Zonula occludens-1 (ZO-1) mRNA on d 3 and 7 postweaning were reduced, and paracellular flux of dextran on d 3, 7, and 14 postweaning was increased. An increase (P < 0.05) of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA on d 3 and d 7 postweaning and an increase (P < 0.05) of interferon-γ (IFN-γ) mRNA on d 3 postweaning were observed compared with d 0. No significant increase of transforming growth factor β1 (TGF-β1) and interleukin-10 (IL-10) mRNA after weaning was observed. The phosphorylated (activated) ratios of JNK and p38 on d 3 and 7 postweaning and the phosphorylated ratio of ERK1/2 on d 3 postweaning were increased (P < 0.05) compared with d 0. The results indicated that early weaning induced sustained impairment in the intestinal barrier, decreased mRNA expression of tight junction proteins, and upregulated the expression of proinflammatory

  17. Glutamine Supplementation of Parenteral Nutrition Does Not Improve Intestinal Permeability, Nitrogen Balance, or Outcome in Newborns and Infants Undergoing Digestive-Tract Surgery

    PubMed Central

    Albers, Marcel J. I. J.; Steyerberg, Ewout W.; Hazebroek, Frans W. J.; Mourik, Marjan; Borsboom, Gerard J. J. M.; Rietveld, Trinet; Huijmans, Jan G. M.; Tibboel, Dick

    2005-01-01

    Objective: To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery. Summary Background Data: Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability, attenuate nitrogen loss, improve survival, and lower the incidence of nosocomial infections. Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results. Methods: Eighty newborns and infants were included in a double-blind, randomized trial comparing standard parenteral nutrition (sPN; n = 39) to glutamine-supplemented parenteral nutrition (GlnPN; glutamine target intake, 0.4 g kg−1 day−1; n = 41), starting on day 2 after major digestive-tract surgery. Primary endpoints were intestinal permeability, as assessed by the urinary excretion ratio of lactulose and rhamnose (weeks 1 through 4); nitrogen balance (days 4 through 6), and urinary 3-methylhistidine excretion (day 5). Secondary endpoints were mortality, length of stay in the ICU and the hospital, number of septic episodes, and usage of antibiotics and ICU resources. Results: Glutamine intake plateaued at 90% of the target on day 4. No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints. Glutamine supplementation was not associated with adverse effects. Conclusions: In newborns and infants after major digestive-tract surgery, we did not identify beneficial effects of isonitrogenous, isocaloric glutamine supplementation of parenteral nutrition. Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise. PMID:15798461

  18. Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex

    PubMed Central

    Moussaoui, Nabila; Jacobs, Jonathan P; Larauche, Muriel; Biraud, Mandy; Million, Mulugeta; Mayer, Emeran; Taché, Yvette

    2017-01-01

    Background/Aims Wistar rat dams exposed to limited nesting stress (LNS) from post-natal days (PND) 2 to 10 display erratic maternal behavior, and their pups show delayed maturation of the hypothalamic-pituitary-adrenal axis and impaired epithelial barrier at PND10 and a visceral hypersensitivity at adulthood. Little is known about the impact of early life stress on the offspring before adulthood and the influence of sex. We investigated whether male and female rats previously exposed to LNS displays at weaning altered corticosterone, intestinal permeability, and microbiota. Methods Wistar rat dams and litters were maintained from PND2 to 10 with limited nesting/bedding materials and thereafter reverted to normal housing up to weaning (PND21). Control litters had normal housing. At weaning, we monitored body weight, corticosterone plasma levels (enzyme immunoassay), in vivo intestinal to colon permeability (fluorescein isothiocyanate-dextran 4 kDa) and fecal microbiota (DNA extraction and amplification of the V4 region of the 16S ribosomal RNA gene). Results At weaning, LNS pups had hypercorticosteronemia and enhanced intestinal permeability with females > males while body weights were similar. LNS decreased fecal microbial diversity and induced a distinct composition characterized by increased abundance of Gram positive cocci and reduction of fiber-degrading, butyrate-producing, and mucus-resident microbes. Conclusions These data indicate that chronic exposure to LNS during the first week post-natally has sustained effects monitored at weaning including hypercorticosteronemia, a leaky gut, and dysbiosis. These alterations may impact on the susceptibility to develop visceral hypersensitivity in adult rats and have relevance to the development of irritable bowel syndrome in childhood. PMID:27829577

  19. Osmotic water permeability of rat intestinal brush border membrane vesicles: involvement of aquaporin-7 and aquaporin-8 and effect of metal ions.

    PubMed

    Tritto, Simona; Gastaldi, Giulia; Zelenin, Sergey; Grazioli, Monica; Orsenigo, Maria Novella; Ventura, Ulderico; Laforenza, Umberto; Zelenina, Marina

    2007-12-01

    Water channels AQP7 and AQP8 may be involved in transcellular water movement in the small intestine. We show that both AQP7 and AQP8 mRNA are expressed in rat small intestine. Immunoblot and immunohistochemistry experiments demonstrate that AQP7 and AQP8 proteins are present in the apical brush border membrane of intestinal epithelial cells. We investigated the effect of several metals and pH on the osmotic water permeability (Pf) of brush border membrane vesicles (BBMVs) and of AQP7 and AQP8 expressed in a cell line. Hg2+, Cu2+, and Zn2+ caused a significant decrease in the BBMV Pf, whereas Ni2+ and Li+ had no effect. AQP8-transfected cells showed a reduction in Pf in the presence of Hg2+ and Cu2+, whereas AQP7-transfected cells were insensitive to all tested metals. The Pf of both BBMVs and cells transfected with AQP7 and AQP8 was not affected by pH changes within the physiological range, and the Pf of BBMVs alone was not affected by phlorizin or amiloride. Our results indicate that AQP7 and AQP8 may play a role in water movement via the apical domain of small intestine epithelial cells. AQP8 may contribute to the water-imbalance-related clinical symptoms apparent after ingestion of high doses of Hg2+ and Cu2+.

  20. Altered hepatic gene expression profiles associated with improved fatty liver, insulin resistance, and intestinal permeability after hydroxypropyl methylcellulose (HPMC) supplementation in diet-induced obese mice.

    PubMed

    Kim, Hyunsook; Bartley, Glenn E; Young, Scott A; Seo, Kun-Ho; Yokoyama, Wallace

    2013-07-03

    The effect of hydroxypropyl methylcellulose (HPMC) on hepatic gene expression was analyzed by exon microarray and real-time PCR from livers of diet-induced obese (DIO) mice fed a high-fat (HF) diet supplemented with either 6% HPMC or 6% microcrystalline cellulose (MCC). HPMC-fed mice exhibited significantly reduced body weight gain (55% lower compared to MCC), liver weight (13%), plasma LDL-cholesterol concentration (45%), and HF diet-increased intestinal permeability (48%). HPMC significantly reduced areas under the curve for 2 h insulin and glucose responses, indicating enhanced insulin sensitivity and glucose metabolism. HPMC up-regulated hepatic genes related to fatty acid oxidation, cholesterol and bile acid synthesis, and cellular activation of glucocorticoid (bile acid recycling) and down-regulated genes related to oxidative stress, triglyceride synthesis, and polyunsaturated fatty acid elongation. In conclusion, HPMC consumption ameliorates the effects of a HF diet on intestinal permeability, insulin resistance, hepatic lipid accumulation, glucocorticoid-related bile acid recycling, oxidative stress, and weight gain in DIO mice.

  1. Development and validation of a HPLC method using a monolithic column for quantification of trans-resveratrol in lipid nanoparticles for intestinal permeability studies.

    PubMed

    Neves, Ana Rute; Reis, Salette; Segundo, Marcela A

    2015-04-01

    The development of nanodelivery systems that protect trans-resveratrol is extremely important to preserve its bioactive properties in the development of further applications as nutraceuticals to supplement foods and beverages. In this work, a validated HPLC method was developed for the quantification of trans-resveratrol in lipid nanoparticles for application in studies of in vitro intestinal permeability. The chromatographic separation was achieved in a C18 monolithic column connected to a fluorometric detector (330/374 nm), by isocratic elution consisting of 2% acetic acid/acetonitrile (80:20). Two calibration ranges were established (0.020-0.200 and 0.200-2.00 μmol L(-1)), and low quantification limits (2-6 nmol L(-1), 23-69 pg) were achieved. Stability studies showed that trans-resveratrol is stable for 24 h at 4 °C, and storage at room temperature and freeze-thaw cycles are not recommended. The proposed method was applied to in vitro intestinal permeability studies, in which values between 0.05 ± 0.01 and 1.8 ± 0.3 μmol L(-1) were found.

  2. High in situ rat intestinal permeability of artemisinin unaffected by multiple dosing and with no evidence of P-glycoprotein involvement.

    PubMed

    Svensson, U S; Sandström, R; Carlborg, O; Lennernäs, H; Ashton, M

    1999-02-01

    The objective of this study was to investigate whether the decrease in artemisinin bioavailability after repeated oral dosing in humans can be a result of increased efflux of artemisinin by P-glycoprotein or decreased membrane transport at the intestinal barrier. The effective jejunal permeability (Peff) of artemisinin was investigated using an in situ rat perfusion model. Fifty-four rats were randomized to one of three treatment arms: no pretreatment, pretreatment with artemisinin emulsion for 5 days (60 mg/kg/day, p.o. ), or pretreatment with emulsion vehicle for 5 days. The rats within each treatment arm were randomized further to be jejunally perfused with either low (500 ng/ml) or high (5000 ng/ml) artemisinin concentration or low artemisinin concentration plus the P-glycoprotein inhibitor R,S-verapamil (400 microg/ml). Perfusate samples were assayed for content of artemisinin, R,S-verapamil, and perfusion viability markers. Artemisinin Peff was 1.44 +/- 0.38, 1. 17 +/- 0.32, and 1.71 +/- 0.29 (.10(-4), cm/s) in rats receiving no pretreatment and perfused with low, high, or low artemisinin concentration plus verapamil, respectively. Multiple oral dosing of artemisinin did not affect the jejunal permeability of artemisinin. R,S-verapamil Peff was similar in artemisinin-pretreated rats (1.09 +/- 0.54. 10(-4), cm/s) and rats pretreated with only vehicle (1.07 +/- 0.37. 10(-4), cm/s). The decrease in artemisinin bioavailability after multiple oral dosing in human is probably not a result of changes in P-glycoprotein expression or general intestinal transport. It seems more likely attributed to increased hepatocellular activity. Furthermore, artemisinin exhibits high jejunal permeability and is neither a substrate nor inducer of P-glycoprotein.

  3. Crosstalk between Inflammation and ROCK/MLCK Signaling Pathways in Gastrointestinal Disorders with Intestinal Hyperpermeability

    PubMed Central

    Du, Lijun; Kim, John J.; Shen, Jinhua

    2016-01-01

    The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn's disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability. PMID:27746814

  4. Evaluation of a selected lactic acid bacteria-based probiotic on Salmonella enterica serovar Enteritidis colonization and intestinal permeability in broiler chickens.

    PubMed

    Prado-Rebolledo, Omar F; Delgado-Machuca, Jaime de Jesus; Macedo-Barragan, Rafael J; Garcia-Márquez, Luis J; Morales-Barrera, Jesus E; Latorre, Juan D; Hernandez-Velasco, Xochitl; Tellez, Guillermo

    2017-02-01

    Two experiments were conducted to evaluate the effect of a lactic acid bacteria-based probiotic (FloraMax-B11(®)) against Salmonella enterica serovar Enteritidis intestinal colonization and intestinal permeability in broiler chickens. Experiment 1 consisted of two independent trials. In each trial, day-old broiler chicks were assigned to one of two groups: control + S. Enteritidis or probiotic + S. Enteritidis. At 72 h post-S. Enteritidis challenge, haematology and caecal content were evaluated for S. Enteritidis colonization. In Experiment 2, day-old broiler chicks were assigned to one of four groups: negative control; probiotic; control + S. Enteritidis; or probiotic + S. Enteritidis. At 72 h post-S. Enteritidis challenge, chickens in all groups were given an oral gavage dose of fluorescein isothiocyanate dextran (FITC-d). In both trials of Experiment 1, a significant reduction (P < 0.05) in colony-forming units/gram of S. Enteritidis in caecal content and a reduction in the incidence of S. Enteritidis enriched caecal samples were observed in probiotic + S. Enteritidis chickens. In addition, significant heterophilia and lymphopaenia were observed in control + S. Enteritidis chickens. In Experiment 2, a decrease in numbers of S. Enteritidis in caeca were observed in probiotic + S. Enteritidis chickens when compared to control + S. Enteritidis. Also, an increase in serum FITC-d concentration was detected in control + S. Enteritidis. These results suggest that early infection with S. Enteritidis can increase intestinal permeability, but the adverse effects can be prevented by the administration of the probiotic tested.

  5. Bovine colostrum increases pore-forming claudin-2 protein expression but paradoxically not ion permeability possibly by a change of the intestinal cytokine milieu.

    PubMed

    Bodammer, Peggy; Kerkhoff, Claus; Maletzki, Claudia; Lamprecht, Georg

    2013-01-01

    An impaired intestinal barrier function is involved in the pathogenesis of inflammatory bowel disease (IBD). Several nutritional factors are supposed to be effective in IBD treatment but scientific data about the effects on the intestinal integrity remain scarce. Bovine colostrum was shown to exert beneficial effects in DSS-induced murine colitis, and the present study was undertaken to explore the underlying molecular mechanisms. Western blot revealed increased claudin-2 expression in the distal ileum of healthy mice after feeding with colostrum for 14 days, whereas other tight junction proteins (claudin-3, 4, 10, 15) remained unchanged. The colostrum-induced claudin-2 induction was confirmed in differentiated Caco-2 cells after culture with colostrum for 48 h. Paradoxically, the elevation of claudin-2, which forms a cation-selective pore, was neither accompanied by increased ion permeability nor impaired barrier function. In an in situ perfusion model, 1 h exposure of the colonic mucosa to colostrum induced significantly increased mRNA levels of barrier-strengthening cytokine transforming growth factor-β, while interleukine-2, interleukine-6, interleukine-10, interleukine-13, and tumor-necrosis factor-α remained unchanged. Thus, modulation of the intestinal transforming growth factor-β expression might have compensated the claudin-2 increase and contributed to the observed barrier strengthening effects of colostrum in vivo and in vitro.

  6. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L.) extract polyphenols and terpenoids in Caco-2 cell monolayers

    PubMed Central

    Arráez-Román, David; González-Álvarez, Isabel; Ibáñez, Elena; Segura-Carretero, Antonio; Bermejo, Marival; Micol, Vicente

    2017-01-01

    Rosemary (Rosmarinus officinalis) is grown throughout the world and is widely used as a medicinal herb and to season and preserve food. Rosemary polyphenols and terpenoids have attracted great interest due to their potential health benefits. However, complete information regarding their absorption and bioavailability in Caco-2 cell model is scarce. The permeation properties of the bioactive compounds (flavonoids, diterpenes, triterpenes and phenylpropanoids) of a rosemary extract (RE), obtained by supercritical fluid extraction, was studied in Caco-2 cell monolayer model, both in a free form or liposomed. Compounds were identified and quantitated by liquid chromatography coupled to quadrupole time-of-flight with electrospray ionization mass spectrometry analysis (HPLC-ESI-QTOF-MS), and the apparent permeability values (Papp) were determined, for the first time in the extract, for 24 compounds in both directions across cell monolayer. For some compounds, such as triterpenoids and some flavonoids, Papp values found were reported for the first time in Caco-2 cells.Our results indicate that most compounds are scarcely absorbed, and passive diffusion is suggested to be the primary mechanism of absorption. The use of liposomes to vehiculize the extract resulted in reduced permeability for most compounds. Finally, the biopharmaceutical classification (BCS) of all the compounds was achieved according to their permeability and solubility data for bioequivalence purposes. BCS study reveal that most of the RE compounds could be classified as classes III and IV (low permeability); therefore, RE itself should also be classified into this category. PMID:28234919

  7. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L.) extract polyphenols and terpenoids in Caco-2 cell monolayers.

    PubMed

    Pérez-Sánchez, Almudena; Borrás-Linares, Isabel; Barrajón-Catalán, Enrique; Arráez-Román, David; González-Álvarez, Isabel; Ibáñez, Elena; Segura-Carretero, Antonio; Bermejo, Marival; Micol, Vicente

    2017-01-01

    Rosemary (Rosmarinus officinalis) is grown throughout the world and is widely used as a medicinal herb and to season and preserve food. Rosemary polyphenols and terpenoids have attracted great interest due to their potential health benefits. However, complete information regarding their absorption and bioavailability in Caco-2 cell model is scarce. The permeation properties of the bioactive compounds (flavonoids, diterpenes, triterpenes and phenylpropanoids) of a rosemary extract (RE), obtained by supercritical fluid extraction, was studied in Caco-2 cell monolayer model, both in a free form or liposomed. Compounds were identified and quantitated by liquid chromatography coupled to quadrupole time-of-flight with electrospray ionization mass spectrometry analysis (HPLC-ESI-QTOF-MS), and the apparent permeability values (Papp) were determined, for the first time in the extract, for 24 compounds in both directions across cell monolayer. For some compounds, such as triterpenoids and some flavonoids, Papp values found were reported for the first time in Caco-2 cells.Our results indicate that most compounds are scarcely absorbed, and passive diffusion is suggested to be the primary mechanism of absorption. The use of liposomes to vehiculize the extract resulted in reduced permeability for most compounds. Finally, the biopharmaceutical classification (BCS) of all the compounds was achieved according to their permeability and solubility data for bioequivalence purposes. BCS study reveal that most of the RE compounds could be classified as classes III and IV (low permeability); therefore, RE itself should also be classified into this category.

  8. Intestinal and Blood-Brain Barrier Permeability of Ginkgolides and Bilobalide: In Vitro and In Vivo Approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study intestinal and blood brain barrier (BBB) transport of ginkgolides A, B, C, J and bilobalide, isolated from Ginkgo biloba (Family-Ginkgoaceae), was evaluated in Caco-2 and MDR1-MDCK cell monolayer models. Transepithelial transport was examined for 2 hours in both absorptive and secretor...

  9. Comparison of 51chromium-labeled ethylenediamine tetra-acetic acid and iohexol as blood markers for intestinal permeability testing in Beagle dogs.

    PubMed

    Frias, Rafael; Strube, Katrin; Ternes, Waldemar; Collado, M Carmen; Spillmann, Thomas; Sankari, Satu; Westermarck, Elias

    2012-04-01

    (51)Chromium-labeled ethylenediamine tetra-acetic acid ((51)Cr-EDTA) is the gold standard probe for assessing intestinal permeability (IP) in dogs, but exposure to radioactivity is a disadvantage. Iohexol is a safe contrast medium commonly used for medical imaging purposes and has been successfully applied more recently for the assessment of IP in animal models and humans. This study aimed at comparing (51)Cr-EDTA and iohexol as IP blood markers in dogs. A test solution containing (51)Cr-EDTA and iohexol was administered intragastrically to seven healthy laboratory Beagle dogs, and percentage recoveries in serum were calculated. The strong linear association (correlation, r=0.76 and linear regression, y=0.03+5.04x) between (51)Cr-EDTA and iohexol supports the potential usefulness of iohexol as an IP blood marker in dogs.

  10. Modern approach for determination of lactulose, mannitol and sucrose in human urine using HPLC-MS/MS for the studies of intestinal and upper digestive tract permeability.

    PubMed

    Kubica, Paweł; Kot-Wasik, Agata; Wasik, Andrzej; Namieśnik, Jacek; Landowski, Piotr

    2012-10-15

    A new analytical procedure was described for the simultaneous determination of lactulose, mannitol and sucrose in urine, in which HILIC chromatography and tandem mass spectrometry detection are used. Sugars are orally administered for the estimation of intestinal permeability in children digestive tract. Samples were purified by dispersive solid phase extraction (d-SPE) using Amberlite MB150 resin. Raffinose was selected as an internal standard. The chosen chromatographic separation was carried out on ZIC(®)-HILIC column in 10 min at a flow rate of 0.3 mL/min, using mixture of acetonitrile (ACN) and ammonium acetate (NH(4)Ac) in water (H(2)O) as the mobile phase. Within-run precision (CV) measured at three concentrations was 1.08%, 0.32% and 0.49% for lactulose; 1.88%, 0.47% and 0.75% for mannitol, 2.95%, 1.31% and 0.6% for sucrose. Between-run CVs were 0.75%, 1.1% and 1.2% for lactulose; 1.1%, 1.02% and 1.01% for mannitol; 1.17%, 1.4% and 1.05% for sucrose. Analytical recovery of all three sugar probes was 95.06-99.92%. The detection limits were: 15.94 ng/mL for lactulose, 17.10 ng/mL for sucrose and 11.48 ng/mL for mannitol. The proposed method is rapid, simple, sensitive and suitable for the determination of intestinal permeability of the sugar derivatives in children.

  11. Permeability of the small intestine to (/sup 51/Cr)EDTA in children with acute gastroenteritis or eczema

    SciTech Connect

    Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1985-06-01

    Increased gut permeability to macromolecules is thought to be an important factor in the development of food hypersensitivity. The latter can develop in the course of acute gastroenteritis and could play a role in infantile eczema. The authors studied gut permeability in 10 normal adults, 11 control children, 7 children with acute gastroenteritis, and 8 patients with infantile eczema, making use of (/sup 51/Cr)EDTA as probe molecule. (/sup 51/Cr)EDTA was given orally (50-100 microCi); 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the oral dose. Mean and standard error were 2.35 +/- 0.24, 2.51 +/- 0.21, 9.96 +/- 3.44, and 10.90 +/- 2.05 in normal adults, control children, and gastroenteritis and eczema patients, respectively. Differences between controls and either gastroenteritis (p less than 0.001) or eczema (p less than 0.001) patients are significant. The results support the hypothesis that increased gut permeability could play a role in food hypersensitivity.

  12. Intestinal permeability to chromium-51 ethylenediamine tetraacetic acid in children with chronic obstructive respiratory disease: relationship with clinical and duodenal biopsy findings

    SciTech Connect

    Hoyoux, C.; Forget, P.P.; Borlee-Hermans, G.; Geubelle, F.

    1988-01-01

    Intestinal permeability (IP) to /sup 51/Cr ethylenediamine tetraacetic acid was investigated in 47 children with chronic obstructive respiratory disease (CORD). Endoscopic duodenal biopsies were performed in 22 of these patients. IP was significantly increased in CORD patients when compared to either control children or adults (P less than 0.001). Mean +/- 1 SD were 4.3 +/- 1.71%, 2.5 +/- 0.78%, and 2.3 +/- 0.77% in the three groups, respectively. IP was not related to the presence of atopy. Significant differences in IP results were found between CORD children with abdominal pain (4.5 +/- 1.4%) and both control children and CORD patients without abdominal pain (2.5 +/- 0.78% and 3.2 +/- 1.49%, respectively). A significant correlation was found between small bowel injury on the one hand and IP on the other hand (P less than 0.02). Furthermore, small bowel injury was significantly related to the presence of abdominal pain (P less than 0.05). We speculate that in CORD patients with abdominal pain, a factor exists that causes small bowel injury responsible for both abdominal pain and increased small bowel permeability. Food intolerance could, presumably, play a role in the mucosal damage-linked IP increase found in the subset of CORD patients who complain of abdominal pain.

  13. Glucagon-like peptide-2 reduces intestinal permeability but does not modify the onset of type 1 diabetes in the nonobese diabetic mouse.

    PubMed

    Hadjiyanni, Irene; Li, Kunmin Karen; Drucker, Daniel J

    2009-02-01

    The development of type 1 diabetes (T1D) has been linked to environmental factors and dietary components. Increasing evidence indicates that the integrity of the gut mucosa plays a role in the development of autoimmune diseases, and evidence from both preclinical and clinical studies demonstrates that increased leakiness of the intestinal epithelium precedes the development of type 1 diabetes. However, there is limited information on modulation of gut barrier function and its relationship to diabetes development. Here we show that the nonobese diabetic (NOD) mouse, a model of T1D, exhibits enhanced intestinal transcellular permeability before the development of autoimmune diabetes. Treatment of NOD mice with a glucagon-like peptide 2 (GLP-2) analog, synthetic human [Gly(2)] glucagon-like peptide-2 (h[Gly(2)]GLP-2, increased the length and weight of the small bowel and significantly improved jejunal transepithelial resistance. However, chronic administration of once daily h[Gly(2)]GLP-2 failed to delay or reverse the onset of T1D when treatment was initiated in young, normoglycemic female NOD mice. Furthermore, h[Gly(2)]GLP-2 administration had no significant effect on lymphocyte subpopulations in NOD mice. These findings demonstrate that h[Gly(2)]GLP-2-mediated enhancement of gut barrier function in normoglycemic NOD mice disease is not sufficient to prevent or delay the development of experimental T1D.

  14. Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in association with regulation of intestinal permeability and microbiota in rats

    PubMed Central

    Wang, Jing-Hua; Bose, Shambhunath; Kim, Hyung-Gu; Han, Kyung-Sun; Kim, Hojun

    2015-01-01

    Accumulating evidence suggests the anti-inflammatory and anti-obesity activities of Rhizoma Atractylodis Macrocephalae (RAM). Here, we evaluated the anti-obesity impact of unfermented (URAM) versus fermented RAM (FRAM) using both in vitro and in vivo models. Both URAM and FRAM exhibited marked anti-inflammatory, anti-adipogenic, and anti-obesity activities, and modulation of the gut microbial distribution. However, FRAM, compared to URAM, resulted in more efficient suppression of NO production and normalization of transepithelial electrical resistance in LPS-treated RAW 264.7 and HCT 116 cells, respectively. Compared to URAM, FRAM more effectively reduced the adipose tissue weight; ameliorated the serum triglyceride and aspartate transaminase levels; restored the serum HDL level and intestinal epithelial barrier function in the LPS control group. The relative abundance of Bifidobacterium and Akkermansia as well as Bacteriodetes/Firmicutes ratio in the gut of the LPS control group was significantly enhanced by both URAM and FRAM. However, FRAM, but not URAM, resulted in a significant increase in the distribution of Bacteriodetes and Lactobacillus in the gut of the HFD + LPS group. Our results suggest that FRAM with probiotics can exert a greater anti-obesity effect than URAM, which is probably mediated at least in part via regulation of the intestinal microbiota and gut permeability. PMID:25684573

  15. Effect of immunologic reactions on rat intestinal epithelium. Correlation of increased permeability to chromium 51-labeled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis

    SciTech Connect

    Ramage, J.K.; Stanisz, A.; Scicchitano, R.; Hunt, R.H.; Perdue, M.H.

    1988-06-01

    In these studies we compared jejunal permeability to two probes--chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)--under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (less than 0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p less than 0.005), (b) increased approximately 20-fold at day 10 (p less than 0.005 and less than 0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values approximately 10-fold those in controls (p less than 0.001 and less than 0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens.

  16. Effects of ε-viniferin, a dehydrodimer of resveratrol, on transepithelial active ion transport and ion permeability in the rat small and large intestinal mucosa.

    PubMed

    Karaki, Shin-Ichiro; Ishikawa, Junji; Tomizawa, Yuka; Kuwahara, Atsukazu

    2016-05-01

    ε-Viniferin is a dehydrodimer of resveratrol, a polyphenol synthesized in many plants, including grapevine. The present study investigated the effects of ε-viniferin and resveratrol on epithelial secretory and barrier functions in isolated rat small and large intestinal mucosa. Mucosa-submucosa tissue preparations of various segments of the rat large and small intestines were mounted on Ussing chambers, and short-circuit current (Isc) and tissue conductance (Gt) were continuously measured. The mucosal addition of ε-viniferin (>10(-5) mol/L) and resveratrol (>10(-4) mol/L) to the cecal mucosa, which was the most sensitive region, induced an increase in Isc and a rapid phase decrease (P-1) followed by rapid (P-2) and broad (P-3) peak increases in Gt in concentration-dependent manners. Mucosal ε-viniferin (10(-4) mol/L), but not resveratrol (10(-4) mol/L), increased the permeability of FITC-conjugated dextran (4 kDa). The mucosal ε-viniferin-evoked changes in Isc (Cl(-) secretion), but not in Gt, were attenuated by a selective cyclooxygenase (COX)-1 inhibitor and a selective EP4 prostaglandin receptor. The mucosal ε-viniferin-evoked increase in Isc was partially attenuated, and P-2, but not P-1 or P-3, change in Gt was abolished by a transient receptor potential cation channel, subfamily A, member 1 (TRPA1) inhibitor. Moreover, the mucosal ε-viniferin concentration-dependently attenuated the mucosal propionate (1 mmol/L)-evoked increases in Isc and Gt Immunohistochemical studies revealed COX-1-immunoreactive epithelial cells in the cecal crypt. The present study showed that mucosal ε-viniferin modulated transepithelial ion transport and permeability, possibly by activating sensory epithelial cells expressing COX-1 and TRPA1. Moreover, mucosal ε-viniferin decreased mucosal sensitivity to other luminal molecules such as short-chain fatty acids. In conclusion, these results suggest that ε-viniferin modifies intestinal mucosal transport and barrier

  17. Intestinal transport of bis(12)-hupyridone in Caco-2 cells and its improved permeability by the surfactant Brij-35.

    PubMed

    Yu, Hua; Hu, Yue Qing; Ip, Fanny C F; Zuo, Zhong; Han, Yi Fan; Ip, Nancy Y

    2011-04-01

    The objective of the present study was to elucidate the mechanisms of intestinal transport of bis(12)-hupyridone (B12H) to predict its oral bioavailability. The effect of the B12H concentration and the contribution of the drug efflux transporters, P-glycoprotein (P-gp or ABCB1) and multidrug resistance-associated proteins (MRPs or ABCC) on B12H absorption were measured and evaluated using the human intestinal epithelial Caco-2 cell monolayer in the presence of transporter inhibitors. The results indicated that B12H was absorbed in a dose-dependent manner at concentrations ranging from 132 to 264 µM. However, only apical efflux was observed in the directional transport studies for B12H below 88 µM (P(app) (AP-to-BL): virtually zero; P(app) (BL-to-AP): 1.591 ± 0.071 × 10(-5)  cm s(-1) ). P-gp and mixed P-gp/MRP inhibitors significantly increased the absorptive transport (P(app) (AP-to-BL)) to 0.619 ± 0.018 × 10(-5) and 0.608 ± 0.025 × 10(-5)  cm s(-1) , respectively, while decreasing secretory transport (P(app) (BL-to-AP)) by >75%. A multiple-MRP inhibitor, probenecid, increased the P(app) (AP-to-BL) to 0.329 ± 0.015 × 10(-5)  cm s(-1) while decreasing the P(app) (BL-to-AP) by 50%. Another multiple-MRP inhibitor, indomethacin, only modestly decreased the P(app) (BL-to-AP) by ∼30% and had no effect on the absorptive transport (P(app) (AP-to-BL): virtually zero). In addition, the effect of various pharmaceutical excipients (e.g. Pluronic F-68, Tween-80 and Brij-35) on B12H transport was determined and compared. Among them, Brij-35 effectively enhanced B12H absorption at a concentration lower than its critical micelle concentration (CMC, 60 µM). Therefore, Brij-35 can be used as a potential enhancer to improve intestinal absorption of B12H for oral administration.

  18. Usefulness of Caco-2/HT29-MTX and Caco-2/HT29-MTX/Raji B Coculture Models To Predict Intestinal and Colonic Permeability Compared to Caco-2 Monoculture.

    PubMed

    Lozoya-Agullo, Isabel; Araújo, Francisca; González-Álvarez, Isabel; Merino-Sanjuán, Matilde; González-Álvarez, Marta; Bermejo, Marival; Sarmento, Bruno

    2017-04-03

    The Caco-2 cellular monolayer is a widely accepted in vitro model to predict human permeability but suffering from several and critical limitations. Therefore, some alternative cell cultures to mimic the human intestinal epithelium, as closely as possible, have been developed to achieve more physiological conditions, as the Caco-2/HT29-MTX coculture and the triple Caco-2/HT29-MTX/Raji B models. In this work the permeability of 12 model drugs of different Biopharmaceutical Classification System (BCS) characteristics, in the coculture and triple coculture models was assessed. Additionally, the utility of both models to classify compounds according to the BCS criteria was scrutinized. The obtained results suggested that the coculture of Caco-2/HT29-MTX and the triple coculture of Caco-2/HT29-MTX/Raji B were useful models to predict intestinal permeability and to classify the drugs in high or low permeability according to BCS. Moreover, to study thoroughly the transport mechanism of a specific drug, using a more complex model than Caco-2 monocultures is more suitable because coculture and triple coculture are more physiological models, so the results obtained with them will be closer to those obtained in the human intestine.

  19. Fecal Markers of Intestinal Inflammation and Permeability Associated with the Subsequent Acquisition of Linear Growth Deficits in Infants

    PubMed Central

    Kosek, Margaret; Haque, Rashidul; Lima, Aldo; Babji, Sudhir; Shrestha, Sanjaya; Qureshi, Shahida; Amidou, Samie; Mduma, Estomih; Lee, Gwenyth; Yori, Pablo Peñataro; Guerrant, Richard L.; Bhutta, Zulfiqar; Mason, Carl; Kang, Gagandeep; Kabir, Mamun; Amour, Caroline; Bessong, Pascal; Turab, Ali; Seidman, Jessica; Olortegui, Maribel Paredes; Quetz, Josiane; Lang, Dennis; Gratz, Jean; Miller, Mark; Gottlieb, Michael

    2013-01-01

    Enteric infections are associated with linear growth failure in children. To quantify the association between intestinal inflammation and linear growth failure three commercially available enzyme-linked immunosorbent assays (neopterin [NEO], alpha-anti-trypsin [AAT], and myeloperoxidase [MPO]) were performed in a structured sampling of asymptomatic stool from children under longitudinal surveillance for diarrheal illness in eight countries. Samples from 537 children contributed 1,169 AAT, 916 MPO, and 954 NEO test results that were significantly associated with linear growth. When combined to form a disease activity score, children with the highest score grew 1.08 cm less than children with the lowest score over the 6-month period following the tests after controlling for the incidence of diarrheal disease. This set of affordable non-invasive tests delineates those at risk of linear growth failure and may be used for the improved assessments of interventions to optimize growth during a critical period of early childhood. PMID:23185075

  20. Escherichia coli strain Nissle 1917 ameliorates experimental colitis by modulating intestinal permeability, the inflammatory response and clinical signs in a faecal transplantation model.

    PubMed

    Souza, Éricka L; Elian, Samir D; Paula, Laís M; Garcia, Cristiana C; Vieira, Angélica T; Teixeira, Mauro M; Arantes, Rosa M; Nicoli, Jacques R; Martins, Flaviano S

    2016-03-01

    Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the gut that include ulcerative colitis and Crohn's disease. Probiotics are live micro-organisms that may be used as adjuvant therapy for patients with IBD. The aim of this study was to evaluate the effect of prophylactic ingestion of Escherichia coli strain Nissle 1917 (EcN) in a murine model of colitis. For induction of colitis, mice were given a 3.5% dextran sodium sulfate (DSS) solution for 7 days in drinking water. EcN administration to mice subjected to DSS-induced colitis resulted in significant reduction in clinical and histopathological signs of disease and preservation of intestinal permeability. We observed reduced inflammation, as assessed by reduced levels of neutrophils, eosinophils, chemokines and cytokines. We observed an increase in the number of regulatory T-cells in Peyer's patches. Germ-free mice received faecal content from control or EcN-treated mice and were then subjected to DSS-induced colitis. We observed protection from colitis in animals that were colonized with faecal content from EcN-treated mice. These results suggest that preventative oral administration of EcN or faecal microbiota transplantation with EcN-containing microbiota ameliorates DSS-induced colitis by modifying inflammatory responsiveness to DSS.

  1. Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice

    PubMed Central

    Isoda, Takuro; Nakatsu, Yoshimichi; Yamauchi, Kazumi; Piao, Jingshu; Yao, Takashi; Honda, Hiroshi; Nakabeppu, Yusaku; Tsuzuki, Teruhisa

    2014-01-01

    MUTYH is a DNA glycosylase that excises adenine paired with 8-oxoguanine to prevent mutagenesis in mammals. Biallelic germline mutations of MUTYH have been found in patients predisposed to a recessive form of familial adenomatous polyposis (MAP: MUTYH-associated polyposis). We previously reported that Mutyh-deficient mice showed a high susceptibility to spontaneous and oxidative stress-induced intestinal adenoma/carcinoma. Here, we performed mutation analysis of the tumor-associated genes including Apc, Ctnnb1, Kras and Trp53 in the intestinal tumors of Mutyh-deficient mice. In the 62 tumors, we identified 25 mutations in Apc of 18 tumors and 36 mutations in Ctnnb1 of 36 tumors. Altogether, 54 out of the 62 tumors (87.1%) had a mutation in either Apc or Ctnnb1; no tumor displayed mutations simultaneously in the both genes. Similar to MAP, 60 out of 61 mutations (98.3%) were identified as G:C to T:A transversions of which 85% occurred at either AGAA or TGAA sequences. Immunohistochemical analyses revealed the accumulation of β-catenin in the nuclei of tumors. No mutation was found in either Kras or Trp53 in the tumors. These results indicate that the uncontrolled activation of Wnt signaling pathway is causatively associated with oxidative stress-induced intestinal tumorigenesis in the Mutyh-deficient mice. PMID:25170306

  2. An explanation of large-scale coal and gas outbursts in underground coal mines: the effect of low-permeability zones on abnormally abundant gas

    NASA Astrophysics Data System (ADS)

    An, F. H.; Cheng, Y. P.

    2013-09-01

    Large-scale coal and gas outbursts post a risk of fatal disasters in underground mines. Large-scale outbursts (outburst of coal and rock greater than 500 t) in recent years in China indicate that there is abundant gas in areas of outbursts containing large amounts of potential energy. The adequate sealing properties of the roof and floor of a coal seam are required for local abundant gas around the site of an outburst, but an annular low-permeability zone in a coal seam, which prevents the loss by gas migration through the coal seam itself, is also required. The distribution of coal gas with this annular zone of low permeability is described, and it is proposed that the annular zone of low permeability creates conditions for confining the coal gas. The effect of this low-permeability zone on the gas distribution is analyzed after allowing for simplifications in the model. The results show that the permeability and length of the low-permeability zone have a great impact on the gas distribution. A steep gradient of gas pressure in the low-permeability zone and the high gas pressure in the abundant zone of gas can promote coal mass failure and coal wall deformation, thereby accelerating the coal and gas outburst. The high pressure gas in abundant zone of gas will lead to a large-scale outburst if an outburst occurs.

  3. An explanation of large-scale coal and gas outbursts in underground coal mines: the effect of low-permeability zones on abnormally abundant gas

    NASA Astrophysics Data System (ADS)

    An, F. H.; Cheng, Y. P.

    2014-08-01

    Large-scale coal and gas outbursts pose a risk of fatal disasters in underground mines. Large-scale outbursts (outburst of coal and rock greater than 500 t) in recent years in China indicate that there is abundant gas in areas of outbursts containing large amounts of potential energy. The adequate sealing properties of the roof and floor of a coal seam are required for local abundant gas around the site of an outburst, but an annular low-permeability zone in a coal seam, which prevents the loss by gas migration through the coal seam itself, is also required. The distribution of coal gas with this annular zone of low permeability is described, and it is proposed that the annular zone of low permeability creates conditions for confining the coal gas. The effect of this low-permeability zone on the gas distribution is analyzed after allowing for simplifications in the model. The results show that the permeability and length of the low-permeability zone have a great impact on the gas distribution, and the permeability is required to be several orders of magnitude less than that of normal coal and enough length is also in demand. A steep gradient of gas pressure in the low-permeability zone and the high-pressure gas in the abundant zone of gas can promote coal mass failure and coal wall deformation, thereby accelerating the coal and gas outburst. The high-pressure gas in abundant zone of gas will lead to a large-scale outburst if an outburst occurs.

  4. Viscosity-mediated negative food effect on oral absorption of poorly-permeable drugs with an absorption window in the proximal intestine: In vitro experimental simulation and computational verification.

    PubMed

    Cvijić, Sandra; Parojčić, Jelena; Langguth, Peter

    2014-09-30

    Concomitant food intake can diminish oral absorption of drugs with limited permeability and an absorption window in the proximal intestine, due to viscosity-mediated decrease in dosage form disintegration time and drug dissolution rate. Three poorly-permeable drugs (atenolol, metformin hydrochloride, and furosemide) exhibiting negative food effect, and one highly-soluble and highly-permeable (metoprolol tartrate), serving as a negative control, were selected for the study. In vitro and in silico tools were used to evaluate the influence of media viscosity on drug bioperformance under fasted and fed conditions. The obtained results demonstrated that increased medium viscosity in the presence of food is one of the key factors limiting oral absorption of drugs with limited permeability and absorption restricted to the upper parts of the intestine, while having negligible effect on pharmacokinetic profile of drugs with pH- and site-independent absorption. Dissolution medium pH 4.6 with the addition of hydroxypropyl methylcellulose was suggested to simulate postprandial gastric conditions for drugs whose solubility under these conditions is not the limiting factor for drug absorption. In addition, drug formulation was found to be an interfering factor in relation to the impact of medium viscosity on the rate and extent of drug absorption.

  5. Intestinal lymphangiectasia in adults.

    PubMed

    Freeman, Hugh James; Nimmo, Michael

    2011-02-15

    Intestinal lymphangiectasia in the adult may be characterized as a disorder with dilated intestinal lacteals causing loss of lymph into the lumen of the small intestine and resultant hypoproteinemia, hypogammaglobulinemia, hypoalbuminemia and reduced number of circulating lymphocytes or lymphopenia. Most often, intestinal lymphangiectasia has been recorded in children, often in neonates, usually with other congenital abnormalities but initial definition in adults including the elderly has become increasingly more common. Shared clinical features with the pediatric population such as bilateral lower limb edema, sometimes with lymphedema, pleural effusion and chylous ascites may occur but these reflect the severe end of the clinical spectrum. In some, diarrhea occurs with steatorrhea along with increased fecal loss of protein, reflected in increased fecal alpha-1-antitrypsin levels, while others may present with iron deficiency anemia, sometimes associated with occult small intestinal bleeding. Most lymphangiectasia in adults detected in recent years, however, appears to have few or no clinical features of malabsorption. Diagnosis remains dependent on endoscopic changes confirmed by small bowel biopsy showing histological evidence of intestinal lymphangiectasia. In some, video capsule endoscopy and enteroscopy have revealed more extensive changes along the length of the small intestine. A critical diagnostic element in adults with lymphangiectasia is the exclusion of entities (e.g. malignancies including lymphoma) that might lead to obstruction of the lymphatic system and "secondary" changes in the small bowel biopsy. In addition, occult infectious (e.g. Whipple's disease from Tropheryma whipplei) or inflammatory disorders (e.g. Crohn's disease) may also present with profound changes in intestinal permeability and protein-losing enteropathy that also require exclusion. Conversely, rare B-cell type lymphomas have also been described even decades following initial

  6. Abnormally High Content of Free Glucosamine Residues Identified in a Preparation of Commercially Available Porcine Intestinal Heparan Sulfate

    PubMed Central

    2016-01-01

    Heparan sulfate (HS) polysaccharides are ubiquitous in animal tissues as components of proteoglycans, and they participate in many important biological processes. HS carbohydrate chains are complex and can contain rare structural components such as N-unsubstituted glucosamine (GlcN). Commercially available HS preparations have been invaluable in many types of research activities. In the course of preparing microarrays to include probes derived from HS oligosaccharides, we found an unusually high content of GlcN residue in a recently purchased batch of porcine intestinal mucosal HS. Composition and sequence analysis by mass spectrometry of the oligosaccharides obtained after heparin lyase III digestion of the polysaccharide indicated two and three GlcN in the tetrasaccharide and hexasaccharide fractions, respectively. 1H NMR of the intact polysaccharide showed that this unusual batch differed strikingly from other HS preparations obtained from bovine kidney and porcine intestine. The very high content of GlcN (30%) and low content of GlcNAc (4.2%) determined by disaccharide composition analysis indicated that N-deacetylation and/or N-desulfation may have taken place. HS is widely used by the scientific community to investigate HS structures and activities. Great care has to be taken in drawing conclusions from investigations of structural features of HS and specificities of HS interaction with proteins when commercial HS is used without further analysis. Pending the availability of a validated commercial HS reference preparation, our data may be useful to members of the scientific community who have used the present preparation in their studies. PMID:27295282

  7. Assessment of the Effect of Intestinal Permeability Probes (Lactulose And Mannitol) and Other Liquids on Digesta Residence Times in Various Segments of the Gut Determined by Wireless Motility Capsule: A Randomised Controlled Trial

    PubMed Central

    Sequeira, Ivana R.; Lentle, Roger G.; Kruger, Marlena C.; Hurst, Roger D.

    2015-01-01

    Background Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time. Methods Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms. Results The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity. Conclusions Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between

  8. Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics.

    PubMed

    Cao, Feng; Gao, Yahan; Wang, Meng; Fang, Lei; Ping, Qineng

    2013-04-01

    In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (P(eff)) of the prodrugs. P(eff) of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, P(eff) of the other prodrugs containing 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), P(eff) of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (P(app)) of OA with Caco-2 cell monolayer, significant enhancement of the P(app) of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that P(app) of 7a, 9b, and

  9. Development and validation of RP-HPLC-UV method for simultaneous determination of buparvaquone, atenolol, propranolol, quinidine and verapamil: a tool for the standardization of rat in situ intestinal permeability studies.

    PubMed

    Venkatesh, Gantala; Ramanathan, S; Mansor, S M; Nair, N K; Sattar, Munavvar Abdul; Croft, Simon L; Navaratnam, V

    2007-03-12

    A simple, sensitive and specific reversed phase high performance liquid chromatographic (RP-HPLC) method with UV detection at 251 nm was developed for simultaneous quantitation of buparvaquone (BPQ), atenolol, propranolol, quinidine and verapamil. The method was applicable in rat in situ intestinal permeability study to assess intestinal permeability of BPQ, a promising lead compound for Leishmania donovani infections. The method was validated on a C-4 column with mobile phase comprising ammonium acetate buffer (0.02 M, pH 3.5) and acetonitrile in the ratio of 30:70 (v/v) at a flow rate of 1.0 ml/min. The retention times for atenolol, quinidine, propranolol, verapamil and BPQ were 4.30, 5.96, 6.55, 7.98 and 8.54 min, respectively. The calibration curves were linear (correlation coefficient > or =0.996) in the selected range of each analyte. The method is specific and sensitive with limit of quantitation of 15 microg/ml for atenolol, 0.8 microg/ml for quinidine, 5 microg/ml for propranolol, 10 microg/ml for verapamil and 200 ng/ml for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and all the analytes were found to be stable. This method is simple, reliable and can be routinely used for accurate permeability characterization.

  10. Undernutrition, Vitamin A and Iron Deficiency Are Associated with Impaired Intestinal Mucosal Permeability in Young Bangladeshi Children Assessed by Lactulose/Mannitol Test

    PubMed Central

    Hossain, Md. Iqbal; Haque, Rashidul; Mondal, Dinesh; Mahfuz, Mustafa; Ahmed, AM Shamsir; Islam, M. Munirul; Guerrant, Richard L.; Petri, William A.; Ahmed, Tahmeed

    2016-01-01

    Background Lactulose/mannitol (L:M) test has been used as a non-invasive marker of intestinal mucosal -integrity and -permeability (enteropathy). We investigated the association of enteropathy with anthropometrics, micronutrient- status, and morbidity in children. Methods The urine and blood samples were collected from 925 children aged 6–24 months residing in Mirpur slum of Dhaka, Bangladesh during November 2009 to April 2013. L:M test and micronutrient status were assessed in the laboratory of International Centre for Diarrhoeal Diseases Research, Bangladesh (icddr,b) following standard procedure. Results Mean±SD age of the children was 13.2±5.2 months and 47.8% were female. Urinary- lactulose recovery was 0.264±0.236, mannitol recovery was 3.423±3.952, and L:M was 0.109±0.158. An overall negative correlation (Spearman’s-rho) of L:M was found with age (rs = -0.087; p = 0.004), weight-for-age (rs = -0.077; p = 0.010), weight-for-length (rs = -0.060; p = 0.034), mid-upper-arm-circumference (rs = -0.098; p = 0.001) and plasma-retinol (rs = -0.105; p = 0.002); and a positive correlation with plasma α-1-acid glycoprotein (rs = 0.066; p = 0.027). However, most of the correlations were not very strong. Approximately 44% of children had enteropathy as reflected by L:M of ≥0.09. Logistic regression analysis revealed that younger age (infancy) (adjusted odds ratio (AOR) = 1.35; p = 0.027), diarrhea (AOR = 4.00; p = 0.039) or fever (AOR = 2.18; p = 0.003) within previous three days of L:M test were the risk factors of enteropathy (L:M of ≥0.09). Conclusions Enteropathy (high L:M) is associated with younger age, undernutrition, low vitamin A and iron status, and infection particularly diarrhea and fever. PMID:27906964

  11. Catalase and superoxide dismutase conjugated with platelet-endothelial cell adhesion molecule antibody distinctly alleviate abnormal endothelial permeability caused by exogenous reactive oxygen species and vascular endothelial growth factor.

    PubMed

    Han, Jingyan; Shuvaev, Vladimir V; Muzykantov, Vladimir R

    2011-07-01

    Reactive oxygen species (ROS) superoxide anion (O(2)()) and hydrogen peroxide (H(2)O(2)) produced by activated leukocytes and endothelial cells in sites of inflammation or ischemia cause endothelial barrier dysfunction that may lead to tissue edema. Antioxidant enzymes (AOEs) catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically bind to endothelium, quench the corresponding ROS, and alleviate vascular oxidative stress and inflammation. In the present work, we studied the effects of anti-PECAM/catalase and anti-PECAM/SOD conjugates on the abnormal permeability manifested by transendothelial electrical resistance decline, increased fluorescein isothiocyanate-dextran influx, and redistribution of vascular endothelial-cadherin in human umbilical vein endothelial cell (HUVEC) monolayers. Anti-PECAM/catalase protected HUVEC monolayers against H(2)O(2)-induced endothelial barrier dysfunction. Polyethylene glycol-conjugated catalase exerted orders of magnitude lower endothelial uptake and no protective effect, similarly to IgG/catalase. Anti-PECAM/catalase, but not anti-PECAM/SOD, alleviated endothelial hyperpermeability caused by exposure to hypoxanthine/xanthine oxidase, implicating primarily H(2)O(2) in the disruption of the endothelial barrier in this model. Thrombin-induced endothelial permeability was not affected by treatment with anti-PECAM/AOEs or the NADPH oxidase inhibitor apocynin or overexpression of AOEs, indicating that the endogenous ROS play no key role in thrombin-mediated endothelial barrier dysfunction. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase, inhibited a vascular endothelial growth factor (VEGF)-induced increase in endothelial permeability, identifying a key role of endogenous O(2)() in the VEGF-mediated regulation of endothelial barrier function. Therefore, AOEs targeted to endothelial cells provide versatile molecular tools for testing the roles of

  12. "Green" synthesized and coated nanaosilver alters the membrance permeability of barrier (intestinal, brain, endothelial) cells and stimulates oxidative stress pathways in neurons.

    EPA Science Inventory

    Nanosilver's (nanoAg) use in medical applications and consumer products is increasing. Because of this, its "green" synthesis and surface modification with beneficial coatings are desirable. Given nanoAg's potential exposure routes (e.g., dermal, intestin...

  13. An evaluation of the relative roles of the unstirred water layer and receptor sink in limiting the in-vitro intestinal permeability of drug compounds of varying lipophilicity.

    PubMed

    Katneni, Kasiram; Charman, Susan A; Porter, Christopher J H

    2008-10-01

    The roles of the unstirred water layer (UWL) and receptor sink on the in-vitro transmembrane permeability of an increasingly lipophilic series of compounds (mannitol (MAN), diazepam (DIA) and cinnarizine (CIN)) have been assessed. Altered carbogen bubbling rates were used as a means to change the UWL thickness and polysorbate-80 (PS-80), bovine serum albumin (BSA) and alpha-1-acid glycoprotein (AAG) were employed to alter sink conditions. After correction for solubilisation, Papp data for MAN, DIA and CIN were consistent across varying donor PS-80 concentrations suggesting that for the drugs examined here, the donor UWL did not limit in-vitro permeability. Similarly, altered bubbling rates and receptor sink conditions had no impact on the permeability of MAN. In contrast, decreasing the size of the receptor UWL or adding solubilising agents to the receptor sink resulted in modest enhancements to the permeability of the more lipophilic probe DIA. For the most lipophilic compound, CIN, very significant changes to measured permeability (>30 fold) were possible, but were most evident only after concomitant changes to both the UWL and sink conditions, suggesting that the effectiveness of enhanced sink conditions were dependent on a decrease in the width of the UWL.

  14. Small intestine contrast injection (image)

    MedlinePlus

    ... and throat, through the stomach into the small intestine. When in place, contrast dye is introduced and ... means of demonstrating whether or not the small intestine is normal when abnormality is suspected.

  15. Reevaluation of the non-lesional dry skin in atopic dermatitis by acute barrier disruption: an abnormal permeability barrier homeostasis with defective processing to generate ceramide.

    PubMed

    Sugiura, Ayumi; Nomura, Tsuyoshi; Mizuno, Atsuko; Imokawa, Genji

    2014-07-01

    Atopic dermatitis is characterized by disruption of the cutaneous barrier due to reduced ceramide levels even in non-lesional dry skin. Following further acute barrier disruption by repeated tape strippings, we re-characterized the non-lesional dry skin of subjects with atopic dermatitis, which shows significantly reduced levels of barrier function and ceramide but not of beta-glucocerebrosidase activity. For the first time, we report an abnormal trans-epidermal water loss homeostasis in which delayed recovery kinetics of trans-epidermal water loss occurred on the first day during the 4 days after acute barrier disruption compared with healthy control skin. Interestingly, whereas the higher ceramide level in the stratum corneum of healthy control skin was further significantly up-regulated at 4 days post-tape stripping, the lower ceramide level in the stratum corneum of subjects with atopic dermatitis was not significantly changed. In a parallel study, whereas beta-glucocerebrosidase activity at 4 days post-tape stripping was significantly up-regulated in healthy control skin compared with before tape stripping, the level of that activity remained substantially unchanged in atopic dermatitis. These findings indicate that subjects with atopic dermatitis have a defect in sphingolipid-metabolic processing that generates ceramide in the interface between the stratum corneum and the epidermis. The results also support the notion that the continued disruption of barrier function in atopic dermatitis non-lesional skin is associated with the impaired homeostasis of a ceramide-generating process, which underscores an atopy-specific inflammation-triggered ceramide deficiency that is distinct from other types of dermatitis.

  16. Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation.

    PubMed

    Yoon, Jung H; Choi, Sung S; Kim, Olga; Choi, Won S; Park, Yong K; Nam, Suk W; Lee, Jung Y; Park, Won S

    2016-02-01

    Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS(NKX6.3) and MKN1(NKX6.3) cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6.3 inactivation may result in intestinal metaplasia in gastric epithelial cells.

  17. Crustal permeability

    USGS Publications Warehouse

    Gleeson, Tom; Ingebritsen, Steven E.

    2016-01-01

    Permeability is the primary control on fluid flow in the Earth’s crust and is key to a surprisingly wide range of geological processes, because it controls the advection of heat and solutes and the generation of anomalous pore pressures.  The practical importance of permeability – and the potential for large, dynamic changes in permeability – is highlighted by ongoing issues associated with hydraulic fracturing for hydrocarbon production (“fracking”), enhanced geothermal systems, and geologic carbon sequestration.  Although there are thousands of research papers on crustal permeability, this is the first book-length treatment.  This book bridges the historical dichotomy between the hydrogeologic perspective of permeability as a static material property and the perspective of other Earth scientists who have long recognized permeability as a dynamic parameter that changes in response to tectonism, fluid production, and geochemical reactions. 

  18. Differential permeability of the proximal and distal rabbit small bowel

    PubMed Central

    Ross, Allan; Rubin, Allen W.; Deren, Julius J.

    1972-01-01

    The permeability of the proximal and distal rabbit intestine for two to six carbon polyhydric alcohols was compared. Intestinal segments were mounted in chambers that permitted the measurement of the unidirectional flux across the brush border membrane. For both proximal and distal intestine, the permeability for a series of polyhydric alcohols decreased with increasing size. The proximal intestine was more permeable for four, five, and six carbon polyhydric alcohols than distal intestine. This regional permeability difference can be attributed to variations in the permeability characteristics of the brush border specifically. The uptake of alcohols was nonsaturable and was not inhibited by phlorizine or n-ethylmaleimide. The results are compatible with the concept that the brush border membrane has properties similar to artificial porous membranes and that the equivalent radius of the pores of the proximal intestine exceeds that of the distal gut. PMID:4639025

  19. Intestinal Barrier and Behavior.

    PubMed

    Julio-Pieper, M; Bravo, J A

    2016-01-01

    The intestinal barrier function contributes to gut homeostasis by modulating absorption of water, electrolytes, and nutrients from the lumen into the circulation while restricting the passage of noxious luminal substances and microorganisms. Chronic conditions such as rheumatoid arthritis, inflammatory bowel disease, and celiac disease are associated to intestinal barrier dysfunction. Here, the hypothesis is that a leaky intestinal wall allowing for indiscriminate passage of intraluminal compounds to the vascular compartment could in turn lead to systemic inflammation. An increasing number of studies are now investigating the association between gut permeability and CNS disorders, under the premise that translocation of intestinal luminal contents could affect CNS function, either directly or indirectly. Still, it is unknown whether disruption of intestinal barrier is a causative agent or a consequence in these situations. Here, we discuss the latest evidence pointing to an association between increased gut permeability and disrupted behavioral responses.

  20. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  1. Intestinal microbiota in pathophysiology and management of irritable bowel syndrome.

    PubMed

    Lee, Kang Nyeong; Lee, Oh Young

    2014-07-21

    Irritable bowel syndrome (IBS) is a functional bowel disorder without any structural or metabolic abnormalities that sufficiently explain the symptoms, which include abdominal pain and discomfort, and bowel habit changes such as diarrhea and constipation. Its pathogenesis is multifactorial: visceral hypersensitivity, dysmotility, psychosocial factors, genetic or environmental factors, dysregulation of the brain-gut axis, and altered intestinal microbiota have all been proposed as possible causes. The human intestinal microbiota are composed of more than 1000 different bacterial species and 10(14) cells, and are essential for the development, function, and homeostasis of the intestine, and for individual health. The putative mechanisms that explain the role of microbiota in the development of IBS include altered composition or metabolic activity of the microbiota, mucosal immune activation and inflammation, increased intestinal permeability and impaired mucosal barrier function, sensory-motor disturbances provoked by the microbiota, and a disturbed gut-microbiota-brain axis. Therefore, modulation of the intestinal microbiota through dietary changes, and use of antibiotics, probiotics, and anti-inflammatory agents has been suggested as strategies for managing IBS symptoms. This review summarizes and discusses the accumulating evidence that intestinal microbiota play a role in the pathophysiology and management of IBS.

  2. Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson’s Disease

    PubMed Central

    Hasegawa, Satoru; Goto, Sae; Tsuji, Hirokazu; Okuno, Tatsuya; Asahara, Takashi; Nomoto, Koji; Shibata, Akihide; Fujisawa, Yoshiro; Minato, Tomomi; Okamoto, Akira; Ohno, Kinji; Hirayama, Masaaki

    2015-01-01

    Background The intestine is one of the first affected organs in Parkinson’s disease (PD). PD subjects show abnormal staining for Escherichia coli and α-synuclein in the colon. Methods We recruited 52 PD patients and 36 healthy cohabitants. We measured serum markers and quantified the numbers of 19 fecal bacterial groups/genera/species by quantitative RT-PCR of 16S or 23S rRNA. Although the six most predominant bacterial groups/genera/species covered on average 71.3% of total intestinal bacteria, our analysis was not comprehensive compared to metagenome analysis or 16S rRNA amplicon sequencing. Results In PD, the number of Lactobacillus was higher, while the sum of analyzed bacteria, Clostridium coccoides group, and Bacteroides fragilis group were lower than controls. Additionally, the sum of putative hydrogen-producing bacteria was lower in PD. A linear regression model to predict disease durations demonstrated that C. coccoides group and Lactobacillus gasseri subgroup had the largest negative and positive coefficients, respectively. As a linear regression model to predict stool frequencies showed that these bacteria were not associated with constipation, changes in these bacteria were unlikely to represent worsening of constipation in the course of progression of PD. In PD, the serum lipopolysaccharide (LPS)-binding protein levels were lower than controls, while the levels of serum diamine oxidase, a marker for intestinal mucosal integrity, remained unchanged in PD. Conclusions The permeability to LPS is likely to be increased without compromising the integrity of intestinal mucosa in PD. The increased intestinal permeability in PD may make the patients susceptible to intestinal dysbiosis. Conversely, intestinal dysbiosis may lead to the increased intestinal permeability. One or both of the two mechanisms may be operational in development and progression of PD. PMID:26539989

  3. Leaky gut and mycotoxins: Aflatoxin B1 does not increase gut permeability in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies conducted in our laboratory have demonstrated that intestinal barrier function can be adversely affected by diet ingredients or feed restriction, resulting in increased intestinal inflammation-associated permeability. Two experiments were conducted in broilers to evaluate the effect...

  4. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  5. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  6. Claudins in intestines

    PubMed Central

    Lu, Zhe; Ding, Lei; Lu, Qun; Chen, Yan-Hua

    2013-01-01

    Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases. PMID:24478939

  7. Intestinal Lesions Are Associated with Altered Intestinal Microbiome and Are More Frequent in Children and Young Adults with Cystic Fibrosis and Cirrhosis

    PubMed Central

    Flass, Thomas; Tong, Suhong; Frank, Daniel N.; Wagner, Brandie D.; Robertson, Charles E.; Kotter, Cassandra Vogel; Sokol, Ronald J.; Zemanick, Edith; Accurso, Frank; Hoffenberg, Edward J.; Narkewicz, Michael R.

    2015-01-01

    Background and Aims Cirrhosis (CIR) occurs in 5–7% of cystic fibrosis (CF) patients. We hypothesized that alterations in intestinal function in CF contribute to the development of CIR. Aims: Determine the frequency of macroscopic intestinal lesions, intestinal inflammation, intestinal permeability and characterize fecal microbiome in CF CIR subjects and CF subjects with no liver disease (CFnoLIV). Methods 11 subjects with CFCIR (6 M, 12.8 yrs ± 3.8) and 19 matched with CFnoLIV (10 M, 12.6 yrs ± 3.4) underwent small bowel capsule endoscopy, intestinal permeability testing by urinary lactulose: mannitol excretion ratio, fecal calprotectin determination and fecal microbiome characterization. Results CFCIR and CFnoLIV did not differ in key demographics or CF complications. CFCIR had higher GGT (59±51 U/L vs 17±4 p = 0.02) and lower platelet count (187±126 vs 283±60 p = 0.04) and weight (-0.86 ± 1.0 vs 0.30 ± 0.9 p = 0.002) z scores. CFCIR had more severe intestinal mucosal lesions on capsule endoscopy (score ≥4, 4/11 vs 0/19 p = 0.01). Fecal calprotectin was similar between CFCIR and CFnoLIV (166 μg/g ±175 vs 136 ± 193 p = 0.58, nl <120). Lactulose:mannitol ratio was elevated in 27/28 subjects and was slightly lower in CFCIR vs CFnoLIV (0.08±0.02 vs 0.11±0.05, p = 0.04, nl ≤0.03). Small bowel transit time was longer in CFCIR vs CFnoLIV (195±42 min vs 167±68 p<0.001, nl 274 ± 41). Bacteroides were decreased in relative abundance in CFCIR and were associated with lower capsule endoscopy score whereas Clostridium were more abundant in CFCIR and associated with higher capsule endoscopy score. Conclusions CFCIR is associated with increased intestinal mucosal lesions, slower small bowel transit time and alterations in fecal microbiome. Abnormal intestinal permeability and elevated fecal calprotectin are common in all CF subjects. Disturbances in intestinal function in CF combined with changes in the microbiome may contribute to the development of

  8. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  9. Rifaximin Alters Intestinal Bacteria and Prevents Stress-Induced Gut Inflammation and Visceral Hyperalgesia in Rats

    PubMed Central

    Xu, Dabo; Gao, Jun; Gillilland, Merritt; Wu, Xiaoyin; Song, Il; Kao, John Y.; Owyang, Chung

    2014-01-01

    Background & Aims Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. Methods We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction and 454 pyrosequencing were used to analyze bacterial 16S rRNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. Results Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. Conclusions Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress. PMID:24161699

  10. Intestinal Cancer

    MedlinePlus

    ... connects your stomach to your large intestine. Intestinal cancer is rare, but eating a high-fat diet ... increase your risk. Possible signs of small intestine cancer include Abdominal pain Weight loss for no reason ...

  11. Intestinal leiomyoma

    MedlinePlus

    Leiomyoma - intestine ... McLaughlin P, Maher MM. The duodenum and small intestine. In: Adam A, Dixon AK, Gillard JH, Schaefer- ... Roline CE, Reardon RF. Disorders of the small intestine. In: Marx JA, Hockberger RS, Walls RM, et ...

  12. Intestinal obstruction

    MedlinePlus

    Paralytic ileus; Intestinal volvulus; Bowel obstruction; Ileus; Pseudo-obstruction - intestinal; Colonic ileus ... objects that are swallowed and block the intestines) Gallstones (rare) Hernias Impacted stool Intussusception (telescoping of 1 ...

  13. Intestinal Obstruction

    MedlinePlus

    An intestinal obstruction occurs when food or stool cannot move through the intestines. The obstruction can be complete or partial. ... abdomen Inability to pass gas Constipation A complete intestinal obstruction is a medical emergency. It often requires surgery. ...

  14. Exercise, intestinal barrier dysfunction and probiotic supplementation.

    PubMed

    Lamprecht, Manfred; Frauwallner, Anita

    2012-01-01

    Athletes exposed to high-intensity exercise show an increased occurrence of gastrointestinal (GI) symptoms like cramps, diarrhea, bloating, nausea, and bleeding. These problems have been associated with alterations in intestinal permeability and decreased gut barrier function. The increased GI permeability, a so-called 'leaky gut', also leads to endotoxemia, and results in increased susceptibility to infectious and autoimmune diseases, due to absorption of pathogens/toxins into tissue and the bloodstream. Key components that determine intestinal barrier function and GI permeability are tight junctions, protein structures located in the paracellular channels between epithelial cells of the intestinal wall. The integrity of tight junctions depends on sophisticated interactions between the gut residents and their expressed substances, the intestinal epithelial cell metabolism and the activities of the gut-associated lymphoid tissue. Probiotic supplements are an upcoming group of nutraceuticals that could offer positive effects on athlete's gut and entire health. Some results demonstrate promising benefits for probiotic use on the athlete's immune system. There is also evidence that probiotic supplementation can beneficially influence intestinal barrier integrity in acute diseases. With regard to exercise-induced GI permeability problems, there is still a lack of studies with appropriate data and a gap to understand the underlying mechanisms to support such health beneficial statements implicitly. This article refers (i) to exercise-induced intestinal barrier dysfunction, (ii) provides suggestions to estimate increased gut barrier permeability in athletes, and (iii) discusses the potential of probiotic supplementation to counteract an exercise-induced leaky gut.

  15. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  16. Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.

    PubMed

    Holmstock, Nico; De Bruyn, Tom; Bevernage, Jan; Annaert, Pieter; Mols, Raf; Tack, Jan; Augustijns, Patrick

    2013-04-11

    Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.

  17. Intestinal Obstruction

    MedlinePlus

    ... Wall Hernias Inguinal Hernia Acute Mesenteric Ischemia Appendicitis Ileus Intestinal Obstruction Ischemic Colitis Perforation of the Digestive ... Wall Hernias Inguinal Hernia Acute Mesenteric Ischemia Appendicitis Ileus Intestinal Obstruction Ischemic Colitis Perforation of the Digestive ...

  18. Permeability of Clay Concretes

    NASA Astrophysics Data System (ADS)

    Solomon, F.; Ekolu, S. O.

    2015-11-01

    This paper presents an investigation on the effect of clay addition on water permeability and air permeability of concretes. Clay concrete mixes consisted of 0 to 40% clay content incorporated as cement replacement. Flow methods using triaxial cells and air permeameters were used for measuring the injected water and air flows under pressure. It was found that the higher the clay content in the mixture, the greater the permeability. At higher water-cement ratios (w/c), the paste matrix is less dense and easily allows water to ingress into concrete. But at high clay contents of 30 to 40% clay, the variation in permeability was significantly diminished among different concrete mixtures. It was confirmed that air permeability results were higher than the corresponding water permeability values when all permeability coefficients were converted to intrinsic permeability values.

  19. EPA Permeable Surface Research

    EPA Science Inventory

    EPA recognizes permeable surfaces as an effective post-construction infiltration-based Best Management Practice to mitigate the adverse effects of stormwater runoff. The professional user community conceptually embraces permeable surfaces as a tool for making runoff more closely...

  20. Film Permeability Determination Using Static Permeability Cells

    EPA Pesticide Factsheets

    The permeability of tarps to soil fumigant pesticides varies depending on the active ingredient chemical: dimethyl disulfide (DMDS), methyl bromide, chloropicrin, or other. The diffusion rate can be represented by the mass transfer coefficient (MTC).

  1. Permeability assessment of poorly water-soluble compounds under solubilizing conditions: the reciprocal permeability approach.

    PubMed

    Katneni, Kasiram; Charman, Susan A; Porter, Christopher J H

    2006-10-01

    The objective of this study was to develop a general method to assess the intestinal permeability of poorly water-soluble drugs where low-aqueous drug solubility requires conduct of experiments under solubilizing experimental conditions. The permeability (Papp) of diazepam (DIA) was assessed across excised rat jejunum in the absence (Pappcontrol) and presence (Pappuncorr) of polysorbate-80 (PS-80). The micellar association constant (Ka) of DIA, estimated via equilibrium solubility studies, was used to correct Pappuncorr data and obtain an estimate of the true permeability coefficient (Pappcorr). An alternate approach was also developed (the reciprocal permeability approach) to allow direct estimation of Pappcorr without the need for independent estimation of Ka. The approach was further examined experimentally using a range of model drugs. DIA Pappcorr values obtained using the Ka from equilibrium solubility studies deviated from Papp(control) values, especially at PS-80 concentrations above 0.1% w/v. In contrast, data obtained using the reciprocal permeability method were consistent with Pappcontrol across the PS-80 concentration range. Similar trends were observed with propranolol (PRO), antipyrine (ANT), naproxen (NAP), and cinnarizine (CIN). The reciprocal permeability approach therefore provides a simple and accurate method by which the permeability of poorly water-soluble compounds may be estimated under solubilizing conditions.

  2. Investigation of Small Bowel Abnormalities in HIV-Infected Patients Using Capsule Endoscopy

    PubMed Central

    Sakai, Eiji; Higurashi, Takuma; Ohkubo, Hidenori; Hosono, Kuhihiro; Ueda, Atsuhisa

    2017-01-01

    HIV infection is reportedly associated with an increased permeability of the intestinal epithelium and can cause HIV enteropathy, which occurs independently of opportunistic infections. However, the characteristics of small bowel abnormalities attributable to HIV infection are rarely investigated. In the present study, we assessed the intestinal mucosal changes found in HIV-infected patients and compared them with the mucosa of healthy control subjects using capsule endoscopy (CE). Three of the 27 HIV-infected patients harbored gastrointestinal opportunistic infections and were thus excluded from subsequent analyses. The endoscopic findings of CE in HIV-infected patients were significantly higher than those in control subjects (55% versus 10%, P = 0.002); however, most lesions, such as red spots or tiny erosions, were unlikely to cause abdominal symptoms. After validating the efficacy of CE for the diagnosis of villous atrophy, we found that the prevalence of villous atrophy was 54% (13/24) among HIV-infected patients. Interestingly, villous atrophy persisted in patients receiving long-term antiretroviral therapy, though most of them exhibited reconstituted peripheral blood CD4+ T cells. Although we could not draw any conclusions regarding the development of small bowel abnormalities in HIV-infected patients, our results may provide some insight regarding the pathogenesis of HIV enteropathy.

  3. Intestinal flora, probiotics, and cirrhosis.

    PubMed

    Guerrero Hernández, Ignacio; Torre Delgadillo, Aldo; Vargas Vorackova, Florencia; Uribe, Misael

    2008-01-01

    Intestinal microflora constitutes a symbiotic ecosystem in permanent equilibrium, composed mainly of anaerobic bacteria. However, such equilibrium may be altered by daily conditions as drug use or pathologies interfering with intestinal physiology, generating an unfavorable environment for the organism. Besides, there are factors which may cause alterations in the intestinal wall, creating the conditions for translocation or permeation of substances or bacteria. In cirrhotic patients, there are many conditions that combine to alter the amount and populations of intestinal bacteria, as well as the functional capacity of the intestinal wall to prevent the permeation of substances and bacteria. Nowadays, numerous complications associated with cirrhosis have been identified, where such mechanisms could play an important role. There is evidence that some probiotic microorganisms could restore the microbiologic and immunologic equilibrium in the intestinal wall in cirrhotic patients and help in the treatment of complications due to cirrhosis. This article has the objective to review the interactions between intestinal flora, gut permeability, and the actual role of probiotics in the field of cirrhotic patients.

  4. Distinguishing between the Permeability Relationships with Absorption and Metabolism To Improve BCS and BDDCS Predictions in Early Drug Discovery

    PubMed Central

    2015-01-01

    The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug–drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption. PMID:24628254

  5. Intestinal Parasitoses.

    ERIC Educational Resources Information Center

    Lagardere, Bernard; Dumburgier, Elisabeth

    1994-01-01

    Intestinal parasites have become a serious public health problem in tropical countries because of the climate and the difficulty of achieving efficient hygiene. The objectives of this journal issue are to increase awareness of the individual and collective repercussions of intestinal parasites, describe the current conditions of contamination and…

  6. Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption.

    PubMed

    Newby, Danielle; Freitas, Alex A; Ghafourian, Taravat

    2015-01-27

    Oral absorption of compounds depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of the relationship between these parameters are not well understood. In this study a large dataset of human intestinal absorption was collated along with in vitro permeability, aqueous solubility, melting point, and maximum dose for the same compounds. The dataset allowed a permeability threshold to be established objectively to predict high or low intestinal absorption. Using this permeability threshold, classification decision trees incorporating a solubility-related parameter such as experimental or predicted solubility, or the melting point based absorption potential (MPbAP), along with structural molecular descriptors were developed and validated to predict oral absorption class. The decision trees were able to determine the individual roles of permeability and solubility in oral absorption process. Poorly permeable compounds with high solubility show low intestinal absorption, whereas poorly water soluble compounds with high or low permeability may have high intestinal absorption provided that they have certain molecular characteristics such as a small polar surface or specific topology.

  7. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.

    PubMed

    Wu, Shaoping; Yi, Jianxun; Zhang, Yong-Guo; Zhou, Jingsong; Sun, Jun

    2015-04-01

    Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3-5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1(G93A)), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.

  8. Permeability of Dentine

    PubMed Central

    Ghazali, Farid Bin Che

    2003-01-01

    This is an update on the present integrated knowledge regarding dentine permeability that assumed a role in dentine sensitivity and contribute clinically to the effective bonding properties of restorative dental materials. This paper will attempt to refer to in vivo and in vitro studies of dentine permeability and the various interrelated factors governing it. PMID:23365497

  9. Beneficial effects of milk oligosaccharides on gut permeability, microbial dysbiosis and the obese phenotype in high-fat diet-induced obesity in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Microbial dysbiosis and increased intestinal permeability is a target for prevention or reversal of weight gain in high-fat (HF) diet-induced obesity (DIO); however, it is not known whether decreased intestinal permeability is necessary or sufficient for weight loss. Prebiotic milk oligos...

  10. Plasmodium berghei ANKA causes intestinal malaria associated with dysbiosis.

    PubMed

    Taniguchi, Tomoyo; Miyauchi, Eiji; Nakamura, Shota; Hirai, Makoto; Suzue, Kazutomo; Imai, Takashi; Nomura, Takahiro; Handa, Tadashi; Okada, Hiroko; Shimokawa, Chikako; Onishi, Risa; Olia, Alex; Hirata, Jun; Tomita, Haruyoshi; Ohno, Hiroshi; Horii, Toshihiro; Hisaeda, Hajime

    2015-10-27

    Gastrointestinal symptoms, such as abdominal pain and diarrhea, are frequently observed in patients with Plasmodium falciparum malaria. However, the correlation between malaria intestinal pathology and intestinal microbiota has not been investigated. In the present study, infection of C57BL/6 mice with P. berghei ANKA (PbA) caused intestinal pathological changes, such as detachment of epithelia in the small intestines and increased intestinal permeability, which correlated with development with experimental cerebral malaria (ECM). Notably, an apparent dysbiosis occurred, characterized by a reduction of Firmicutes and an increase in Proteobacteria. Furthermore, some genera of microbiota correlated with parasite growth and/or ECM development. By contrast, BALB/c mice are resistant to ECM and exhibit milder intestinal pathology and dysbiosis. These results indicate that the severity of cerebral and intestinal pathology coincides with the degree of alteration in microbiota. This is the first report demonstrating that malaria affects intestinal microbiota and causes dysbiosis.

  11. Permeability of porour rhyolite

    NASA Astrophysics Data System (ADS)

    Cashman, K.; Rust, A.; Wright, H.; Roberge, J.

    2003-04-01

    The development of permeability in bubble-bearing magmas determines the efficiency of volatile escape during their ascent through volcanic conduits, which, in turn, controls their explosive potential. As permeability requires bubble connectivity, relationships between permeability and porosity in silicic magmas must be controlled by the formation, growth, deformation and coalescence of their constituent bubbles. Although permeability data on porous volcanic pyroclasts are limited, the database can be greatly extended by including data for ceramic and metallic foams1. Several studies indicate that a single number does not adequately describe the permeability of a foam because inertial effects, which predominate at high flow rates, cause deviations from Darcy's law. These studies suggest that permeability is best modeled using the Forschheimer equation to determine both the Darcy permeability (k1) and the non-Darcian (k2) permeability. Importantly, at the high porosities of ceramic foams (75-95%), both k1 and k2 are strongly dependent on pore size and geometry, suggesting that measurement of these parameters provides important information on foam structure. We determined both the connected porosity (by He-pycnometry) and the permeability (k1 and k2) of rhyolitic samples having a wide range in porosity (22-85%) and vesicle textures. In general, these data support previous observations of a power law relationship between connected porosity and Darcy permeability2. In detail, variations in k1 increase at higher porosities. Similarly, k2 generally increases in both mean and standard deviation with increasing porosity. Measurements made on three mutually perpendicular cores from individual pumice clasts suggest that some of the variability can be explained by anisotropy in the vesicle structure. By comparison with ceramic foams, we suggest that the remaining variability results from differences either in average vesicle size or, more likely, in the size of apertures

  12. The intestinal lesion of autistic spectrum disorder.

    PubMed

    Jass, Jeremy R

    2005-08-01

    This editorial briefly reviews the significance of lymphoid nodular hyperplasia in the intestinal tract of children with autistic spectrum disorder. The distinction between physiological and pathological lymphoid hyperplasia of the intestinal tract is of importance in the context of a possible causative link with autism. A primary intestinal lesion may occur as part of the broad spectrum of immunological disorders to which autistic children are prone. This could result in increased intestinal permeability to peptides of dietary origin which may then lead to disruption of neuroregulatory mechanisms required for normal brain development. Alternatively, there could be a primary defect in the translocation and processing of factors derived from the intestinal lumen. These possibilities deserve further investigation and should not be lost in the fog of the controversy regarding the role of measles/mumps/rubella vaccination in the aetiology of autistic spectrum disorder.

  13. Intestinal Capillariasis

    DTIC Science & Technology

    1987-12-01

    bhIll inenais, the tiny nematode causing Intestinal capillariasis In humans, Is a Iunique parasite. It is one of the newest parasites that has been...Capillariaphilippinensis, the tiny nematode causing intestinal capillariasis in humans, is a unique parasite. It is one of the newest parasites that has been shown to...stichocytes surrounding the oesophagus. The posterior half of the nematode is wider than the anterior half and contains the digestive tract and the

  14. Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage.

    PubMed

    Yu, Chao; Tan, Shanjun; Zhou, Chunyu; Zhu, Cuilin; Kang, Xin; Liu, Shuai; Zhao, Shuang; Fan, Shulin; Yu, Zhen; Peng, Ai; Wang, Zhen

    2016-11-01

    Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.

  15. Permeability of edible coatings.

    PubMed

    Mishra, B; Khatkar, B S; Garg, M K; Wilson, L A

    2010-01-01

    The permeabilities of water vapour, O2 and CO2 were determined for 18 coating formulations. Water vapour transmission rate ranged from 98.8 g/m(2).day (6% beeswax) to 758.0 g/m(2).day (1.5% carboxymethyl cellulose with glycerol). O2 permeability at 14 ± 1°C and 55 ± 5% RH ranged from 1.50 to 7.95 cm(3)cm cm(-2)s(-1)Pa(-1), with CO2 permeability 2 to 6 times as high. Permeability to noncondensable gases (O2 and CO2) was higher for hydrophobic (peanut oil followed by beeswax) coatings as compared to hydrophilic (whey protein concentrate and carboxymethyl cellulose).

  16. Seismic waves increase permeability.

    PubMed

    Elkhoury, Jean E; Brodsky, Emily E; Agnew, Duncan C

    2006-06-29

    Earthquakes have been observed to affect hydrological systems in a variety of ways--water well levels can change dramatically, streams can become fuller and spring discharges can increase at the time of earthquakes. Distant earthquakes may even increase the permeability in faults. Most of these hydrological observations can be explained by some form of permeability increase. Here we use the response of water well levels to solid Earth tides to measure permeability over a 20-year period. At the time of each of seven earthquakes in Southern California, we observe transient changes of up to 24 degrees in the phase of the water level response to the dilatational volumetric strain of the semidiurnal tidal components of wells at the Piñon Flat Observatory in Southern California. After the earthquakes, the phase gradually returns to the background value at a rate of less than 0.1 degrees per day. We use a model of axisymmetric flow driven by an imposed head oscillation through a single, laterally extensive, confined, homogeneous and isotropic aquifer to relate the phase response to aquifer properties. We interpret the changes in phase response as due to changes in permeability. At the time of the earthquakes, the permeability at the site increases by a factor as high as three. The permeability increase depends roughly linearly on the amplitude of seismic-wave peak ground velocity in the range of 0.21-2.1 cm s(-1). Such permeability increases are of interest to hydrologists and oil reservoir engineers as they affect fluid flow and might determine long-term evolution of hydrological and oil-bearing systems. They may also be interesting to seismologists, as the resulting pore pressure changes can affect earthquakes by changing normal stresses on faults.

  17. The microbiota modulates gut physiology and behavioral abnormalities associated with autism

    PubMed Central

    Hsiao, Elaine Y.; McBride, Sara W.; Hsien, Sophia; Sharon, Gil; Hyde, Embriette R.; McCue, Tyler; Codelli, Julian A.; Chow, Janet; Reisman, Sarah E.; Petrosino, Joseph F.; Patterson, Paul H.; Mazmanian, Sarkis K.

    2014-01-01

    SUMMARY Although autism spectrum disorder (ASD) is defined by core behavioral impairments, gastrointestinal (GI) symptoms are commonly reported. Subsets of ASD individuals display dysbiosis of the gut microbiota, and some exhibit increased intestinal permeability. Here we demonstrate GI barrier defects and microbiota alterations in a mouse model displaying features of ASD, maternal immune activation (MIA). Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition and ameliorates ASD-related defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naïve mice with a metabolite that is increased by MIA and restored by B. fragilis causes behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in ASD and identify a potential probiotic therapy for GI and behavioral symptoms of autism. PMID:24315484

  18. Nutritional Keys for Intestinal Barrier Modulation

    PubMed Central

    De Santis, Stefania; Cavalcanti, Elisabetta; Mastronardi, Mauro; Jirillo, Emilio; Chieppa, Marcello

    2015-01-01

    The intestinal tract represents the largest interface between the external environment and the human body. Nutrient uptake mostly happens in the intestinal tract, where the epithelial surface is constantly exposed to dietary antigens. Since inflammatory response toward these antigens may be deleterious for the host, a plethora of protective mechanisms take place to avoid or attenuate local damage. For instance, the intestinal barrier is able to elicit a dynamic response that either promotes or impairs luminal antigens adhesion and crossing. Regulation of intestinal barrier is crucial to control intestinal permeability whose increase is associated with chronic inflammatory conditions. The cross talk among bacteria, immune, and dietary factors is able to modulate the mucosal barrier function, as well as the intestinal permeability. Several nutritional products have recently been proposed as regulators of the epithelial barrier, even if their effects are in part contradictory. At the same time, the metabolic function of the microbiota generates new products with different effects based on the dietary content. Besides conventional treatments, novel therapies based on complementary nutrients are now growing. Fecal therapy has been recently used for the clinical treatment of refractory Clostridium difficile infection instead of the classical antibiotic therapy. In the present review, we will outline the epithelial response to nutritional components derived from dietary intake and microbial fermentation focusing on the consequent effects on the integrity of the epithelial barrier. PMID:26697008

  19. Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice

    PubMed Central

    Laval, L; Martin, R; Natividad, JN; Chain, F; Miquel, S; de Maredsous, C Desclée; Capronnier, S; Sokol, H; Verdu, EF; van Hylckama Vlieg, JET; Bermúdez-Humarán, LG; Smokvina, T; Langella, P

    2015-01-01

    Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities. PMID:25517879

  20. Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice.

    PubMed

    Laval, L; Martin, R; Natividad, J N; Chain, F; Miquel, S; Desclée de Maredsous, C; Capronnier, S; Sokol, H; Verdu, E F; van Hylckama Vlieg, J E T; Bermúdez-Humarán, L G; Smokvina, T; Langella, P

    2015-01-01

    Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.

  1. High-fat Diet-induced Intestinal Hyperpermeability is Associated with Increased Bile Acids in the Large Intestine of Mice.

    PubMed

    Murakami, Yuki; Tanabe, Soichi; Suzuki, Takuya

    2016-01-01

    Metabolic syndrome is characterized by low-grade chronic systemic inflammation, which is associated with intestinal hyperpermeability. This study examined the effects of 3 high-fat diets (HFDs) composed of different fat sources (soybean oil and lard) on the intestinal permeability, tight junction (TJ) protein expression, and cecal bile acid (BA) concentrations in mice, and then analyzed their interrelations. C57/BL6 mice were fed the control diet, HFD (soybean oil), HFD (lard), and HFD (mix; containing equal concentrations of soybean oil and lard) for 8 wk. Glucose tolerance, intestinal permeability, TJ protein expression, and cecal BA concentration were evaluated. Feeding with the 3 HDFs similarly increased body weight, liver weight, and fat pad weight, and induced glucose intolerance and intestinal hyperpermeability. The expression of TJ proteins, zonula occludens-2 and junctional adhesion molecule-A, were lower in the colons of the 3 HFD groups than in the control group (P < 0.05), and these changes appeared to be related to intestinal hyperpermeability. Feeding with HFDs increased total secondary BA (SBA) and total BA concentrations along with increases in some individual BAs in the cecum. Significant positive correlations between intestinal permeability and the concentrations of most SBAs, such as deoxycholic acid and ω-muricholic acids, were detected (P < 0.05). These results suggest that the HFD-induced intestinal hyperpermeability is associated with increased BA secretion. The abundance of SBAs in the large intestine may be responsible for the hyperpermeability.

  2. Intestinal microbiota and obesity.

    PubMed

    Blaut, Michael; Klaus, Susanne

    2012-01-01

    The human gut harbors a highly diverse microbial ecosystem of approximately 400 different species, which is characterized by a high interindividual variability. The intestinal microbiota has recently been suggested to contribute to the development of obesity and the metabolic syndrome. Transplantation of gut microbiota from obese mice to nonobese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. Proposed mechanisms for the role of gut microbiota include the provision of additional energy by the conversion of dietary fiber to short-chain fatty acids, effects on gut-hormone production, and increased intestinal permeability causing elevated systemic levels of lipopolysaccharides (LPS). This metabolic endotoxemia is suggested to contribute to low-grade inflammation, a characteristic trait of obesity and the metabolic syndrome. Finally, activation of the endocannabinoid system by LPS and/or high-fat diets is discussed as another causal factor. In conclusion, there is ample evidence for a role of gut microbiota in the development of obesity in rodents. However, the magnitude of its contribution to human obesity is still unknown.

  3. Dysbiosis-induced intestinal inflammation activates TNFRI and mediates alcoholic liver disease in mice

    PubMed Central

    Chen, Peng; Stärkel, Peter; Turner, Jerrold R.; Ho, Samuel B.; Schnabl, Bernd

    2014-01-01

    Intestinal barrier dysfunction is an important contributor to alcoholic liver disease. Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption following chronic alcohol feeding. A Lieber-DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of TNFα producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with non-absorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced alcoholic liver disease in mice. TNF-receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and alcoholic liver disease. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and alcoholic liver disease, we used TNFRI mutant mice carrying a conditional gain-of-function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light chain kinase (MLCK) is a downstream target of TNFα and was phosphorylated in intestinal epithelial cells following alcohol administration. Using MLCK deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease following chronic alcohol feeding. In conclusion, dysbiosis-induced intestinal inflammation and TNFRI signaling on intestinal epithelial cells are mediating a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of alcoholic liver disease

  4. Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children.

    PubMed

    Gabriele, Stefano; Sacco, Roberto; Altieri, Laura; Neri, Cristina; Urbani, Andrea; Bravaccio, Carmela; Riccio, Maria Pia; Iovene, Maria Rosaria; Bombace, Francesca; De Magistris, Laura; Persico, Antonio M

    2016-07-01

    The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752-759. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  5. Urine - abnormal color

    MedlinePlus

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  6. Tooth - abnormal colors

    MedlinePlus

    ... medlineplus.gov/ency/article/003065.htm Tooth - abnormal colors To use the sharing features on this page, please enable JavaScript. Abnormal tooth color is any color other than white to yellowish- ...

  7. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  8. Skeletal limb abnormalities

    MedlinePlus

    ... medlineplus.gov/ency/article/003170.htm Skeletal limb abnormalities To use the sharing features on this page, please enable JavaScript. Skeletal limb abnormalities refers to a variety of bone structure problems ...

  9. [Intestinal microbiota].

    PubMed

    Debré, Patrice; Le Gall, Jean-Yves

    2014-12-01

    The human body normally lives in symbiosis with a considerable microscopic environment present on all interfaces with the external environment; it hosts ten times more microbes (microbiota) that it has somatic or germ cells, representing a gene diversity (microbiome) 100-150 times higher than the human genome. These germs are located mainly in the gut, where they represent a mass of about one kilogram. The primary colonization of the gastrointestinal tract depends on the delivery route, the bacterial flora rewarding then depending on the environment, food hygiene, medical treatments. The intestinal microbiota plays an important role in the maturation of the immune system and in different physiological functions: digestion of polysaccharides, glycosaminoglycans and glycoproteins, vitamins biosynthesis, bile salt metabolism of some amino acids and xenobiotics. Quantitative and qualitative changes in the microbiota are observed in a wide range of diseases: obesity, colorectal cancer, liver cancer, inflammatory bowel disease, autoimmune diseases, allergies... pharmacobiotics aim to modify the intestinal microbiota in a therapeutic goal and this by various means: prebiotics, probiotics, antibiotics or fecal transplants. Intestinal flora also plays a direct role in the metabolism of certain drugs and the microbiota should be considered as a predictive parameter of response to some chemotherapies.

  10. EPA Permeable Surface Research - Poster

    EPA Science Inventory

    EPA recognizes permeable surfaces as an effective post-construction infiltration-based Best Management Practice to mitigate the adverse effects of stormwater runoff. The professional user community conceptually embraces permeable surfaces as a tool for making runoff more closely...

  11. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... PROBLEMS Abnormal Uterine Bleeding • What is a normal menstrual cycle? • When is bleeding abnormal? • At what ages is ... treat abnormal bleeding? •Glossary What is a normal menstrual cycle? The normal length of the menstrual cycle is ...

  12. Liquid-permeable electrode

    DOEpatents

    Folser, George R.

    1980-01-01

    Electrodes for use in an electrolytic cell, which are liquid-permeable and have low electrical resistance and high internal surface area are provided of a rigid, porous, carbonaceous matrix having activated carbon uniformly embedded throughout. The activated carbon may be catalyzed with platinum for improved electron transfer between electrode and electrolyte. Activated carbon is mixed with a powdered thermosetting phenolic resin and compacted to the desired shape in a heated mold to melt the resin and form the green electrode. The compact is then heated to a pyrolyzing temperature to carbonize and volatilize the resin, forming a rigid, porous structure. The permeable structure and high internal surface area are useful in electrolytic cells where it is necessary to continuously remove the products of the electrochemical reaction.

  13. Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats

    PubMed Central

    van Ampting, Marleen TJ; Schonewille, Arjan J; Vink, Carolien; Brummer, Robert Jan M; Meer, Roelof van der; Bovee-Oudenhoven, Ingeborg MJ

    2009-01-01

    Background Glutathione, the main antioxidant of intestinal epithelial cells, is suggested to play an important role in gut barrier function and prevention of inflammation-related oxidative damage as induced by acute bacterial infection. Most studies on intestinal glutathione focus on oxidative stress reduction without considering functional disease outcome. Our aim was to determine whether depletion or maintenance of intestinal glutathione changes susceptibility of rats to Salmonella infection and associated inflammation. Rats were fed a control diet or the same diet supplemented with buthionine sulfoximine (BSO; glutathione depletion) or cystine (glutathione maintenance). Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability. At day 4 after oral gavage with Salmonella enteritidis (or saline for non-infected controls), Salmonella translocation was determined by culturing extra-intestinal organs. Liver and ileal mucosa were collected for analyses of glutathione, inflammation markers and oxidative damage. Faeces was collected to quantify diarrhoea. Results Glutathione depletion aggravated ileal inflammation after infection as indicated by increased levels of mucosal myeloperoxidase and interleukin-1β. Remarkably, intestinal permeability and Salmonella translocation were not increased. Cystine supplementation maintained glutathione in the intestinal mucosa but inflammation and oxidative damage were not diminished. Nevertheless, cystine reduced intestinal permeability and Salmonella translocation. Conclusion Despite increased infection-induced mucosal inflammation upon glutathione depletion, this tripeptide does not play a role in intestinal permeability, bacterial translocation and diarrhoea. On the other hand, cystine enhances gut barrier function by a mechanism unlikely to be related to glutathione. PMID:19374741

  14. Stainless Steel Permeability

    SciTech Connect

    Buchenauer, Dean A.; Karnesky, Richard A.

    2015-09-01

    An understanding of the behavior of hydrogen isotopes in materials is critical to predicting tritium transport in structural metals (at high pressure), estimating tritium losses during production (fission environment), and predicting in-vessel inventory for future fusion devices (plasma driven permeation). Current models often assume equilibrium diffusivity and solubility for a class of materials (e.g. stainless steels or aluminum alloys), neglecting trapping effects or, at best, considering a single population of trapping sites. Permeation and trapping studies of the particular castings and forgings enable greater confidence and reduced margins in the models. For FY15, we have continued our investigation of the role of ferrite in permeation for steels of interest to GTS, through measurements of the duplex steel 2507. We also initiated an investigation of the permeability in work hardened materials, to follow up on earlier observations of unusual permeability in a particular region of 304L forgings. Samples were prepared and characterized for ferrite content and coated with palladium to prevent oxidation. Issues with the poor reproducibility of measurements at low permeability were overcome, although the techniques in use are tedious. Funding through TPBAR and GTS were secured for a research grade quadrupole mass spectrometer (QMS) and replacement turbo pumps, which should improve the fidelity and throughput of measurements in FY16.

  15. The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

    PubMed Central

    Bansal, Vishal; Ryu, Seok Yong; Blow, Chelsea; Costantini, Todd; Loomis, William; Eliceiri, Brian; Baird, Andrew; Wolf, Paul

    2010-01-01

    Abstract Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 μg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-α. Permeability increased in the TBI group compared to the sham group (109.7 ± 21.8 μg/mL vs. 32.2 ± 10.1 μg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 ± 4.2 μg/mL vs. 109.7 ± 21.8 μg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group (p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-α increased following TBI compared to the sham group (46.2 ± 7.1 pg/mL vs. 24.4 ± 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-α to sham levels (29.2 ± 5.0 pg/mL; p = NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-α. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities. PMID:20858122

  16. Human Intestinal Barrier Function in Health and Disease

    PubMed Central

    König, Julia; Wells, Jerry; Cani, Patrice D; García-Ródenas, Clara L; MacDonald, Tom; Mercenier, Annick; Whyte, Jacqueline; Troost, Freddy; Brummer, Robert-Jan

    2016-01-01

    The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed. PMID:27763627

  17. The low/high BCS permeability class boundary: physicochemical comparison of metoprolol and labetalol.

    PubMed

    Zur, Moran; Gasparini, Marisa; Wolk, Omri; Amidon, Gordon L; Dahan, Arik

    2014-05-05

    Although recognized as overly conservative, metoprolol is currently the common low/high BCS permeability class boundary reference compound, while labetalol was suggested as a potential alternative. The purpose of this study was to identify the various characteristics that the optimal marker should exhibit, and to investigate the suitability of labetalol as the permeability class reference drug. Labetalol's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Labetalol was found to be unequivocally a high-solubility compound. In the pH range throughout the small intestine (6.5-7.5), labetalol exhibited pH-dependent permeability, with higher permeability at higher pH values. While in vitro octanol-buffer partitioning (Log D) values of labetalol were significantly higher than those of metoprolol, the opposite was evident in the in vitro PAMPA permeability assay. The results of the in vivo perfusion studies in rats lay between the two contradictory in vitro studies; metoprolol was shown to have moderately higher rat intestinal permeability than labetalol. Theoretical distribution of the ionic species of the drugs was in corroboration with the experimental in vitro and the in vivo data. We propose three characteristics that the optimal permeability class reference drug should exhibit: (1) fraction dose absorbed in the range of 90%; (2) the optimal marker drug should be absorbed largely via passive transcellular permeability, with no/negligible carrier-mediated active intestinal transport (influx or efflux); and (3) the optimal marker drug should preferably be nonionizable. The data presented in this paper demonstrate that neither metoprolol nor labetalol can be regarded as optimal low/high-permeability class boundary standard. While metoprolol is too conservative due to its complete absorption

  18. Transepithelial Transport of PAMAM Dendrimers Across Isolated Human Intestinal Tissue.

    PubMed

    Hubbard, Dallin; Enda, Michael; Bond, Tanner; Moghaddam, Seyyed Pouya Hadipour; Conarton, Josh; Scaife, Courtney; Volckmann, Eric; Ghandehari, Hamidreza

    2015-11-02

    Poly(amido amine) (PAMAM) dendrimers have shown transepithelial transport across intestinal epithelial barrier in rats and across Caco-2 cell monolayers. Caco-2 models innately lack mucous barriers, and rat isolated intestinal tissue has been shown to overestimate human permeability. This study is the first report of transport of PAMAM dendrimers across isolated human intestinal epithelium. It was observed that FITC labeled G4-NH2 and G3.5-COOH PAMAM dendrimers at 1 mM concentration do not have a statistically higher permeability compared to free FITC controls in isolated human jejunum and colonic tissues. Mannitol permeability was increased at 10 mM concentrations of G3.5-COOH and G4-NH2 dendrimers. Significant histological changes in human colonic and jejunal tissues were observed at G3.5-COOH and G4-NH2 concentrations of 10 mM implying that dose limiting toxicity may occur at similar concentrations in vivo. The permeability through human isolated intestinal tissue in this study was compared to previous rat and Caco-2 permeability data. This study implicates that PAMAM dendrimer oral drug delivery may be feasible, but it may be limited to highly potent drugs.

  19. Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats.

    PubMed

    Shan, C Y; Yang, J H; Kong, Y; Wang, X Y; Zheng, M Y; Xu, Y G; Wang, Y; Ren, H Z; Chang, B C; Chen, L M

    2013-09-01

    For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.

  20. Establishment of novel prediction system of intestinal absorption in humans using human intestinal tissues.

    PubMed

    Miyake, Masateru; Toguchi, Hajime; Nishibayashi, Toru; Higaki, Kazutaka; Sugita, Akira; Koganei, Kazutaka; Kamada, Nobuhiko; Kitazume, Mina T; Hisamatsu, Tadakazu; Sato, Toshiro; Okamoto, Susumu; Kanai, Takanori; Hibi, Toshifumi

    2013-08-01

    The objective of this study was to establish a novel prediction system of drug absorption in humans by utilizing human intestinal tissues. Based on the transport index (TI), a newly defined parameter, calculated by taking account of the change in drug concentrations because of precipitation on the apical side and the amounts accumulated in the tissue and transported to the basal side, the absorbability of drugs in rank order as well as the fraction of dose absorbed (Fa) in humans were estimated. Human intestinal tissues taken from ulcerative colitis or Crohn's disease patients were mounted in a mini-Ussing chamber and transport studies were performed to evaluate the permeation of drugs, including FD-4, a very low permeable marker, atenolol, a low permeable marker, and metoprolol, a high permeable marker. Although apparent permeability coefficients calculated by the conventional equation did not reflect human Fa values for FD-4, atenolol, and metoprolol, TI values were well correlated with Fa values, which are described by 100 · [1 - e (- f · (TI - α)) ]. Based on this equation, Fa values in humans for other test drugs were predicted successfully, indicating that our new system utilizing human intestinal tissues would be valuable for predicting oral drug absorption in humans.

  1. Intestinal capillariasis.

    PubMed Central

    Cross, J H

    1992-01-01

    Intestinal capillariasis caused by Capillaria philippinensis appeared first in the Philippines and subsequently in Thailand, Japan, Iran, Egypt, and Taiwan, but most infections occur in the Philippines and Thailand. As established experimentally, the life cycle involves freshwater fish as intermediate hosts and fish-eating birds as definitive hosts. Embryonated eggs from feces fed to fish hatch and grow as larvae in the fish intestines. Infective larvae fed to monkeys, Mongolian gerbils, and fish-eating birds develop into adults. Larvae become adults in 10 to 11 days, and the first-generation females produce larvae. These larvae develop into males and egg-producing female worms. Eggs pass with the feces, reach water, embryonate, and infect fish. Autoinfection is part of the life cycle and leads to hyperinfection. Humans acquire the infection by eating small freshwater fish raw. The parasite multiplies, and symptoms of diarrhea, borborygmus, abdominal pain, and edema develop. Chronic infections lead to malabsorption and hence to protein and electrolyte loss, and death results from irreversible effects of the infection. Treatment consists of electrolyte replacement and administration of an antidiarrheal agent and mebendazole or albendazole. Capillariasis philippinensis is considered a zoonotic disease of migratory fish-eating birds. The eggs are disseminated along flyways and infect the fish, and when fish are eaten raw, the disease develops. Images PMID:1576584

  2. Intestinal capillariasis.

    PubMed

    Cross, J H

    1992-04-01

    Intestinal capillariasis caused by Capillaria philippinensis appeared first in the Philippines and subsequently in Thailand, Japan, Iran, Egypt, and Taiwan, but most infections occur in the Philippines and Thailand. As established experimentally, the life cycle involves freshwater fish as intermediate hosts and fish-eating birds as definitive hosts. Embryonated eggs from feces fed to fish hatch and grow as larvae in the fish intestines. Infective larvae fed to monkeys, Mongolian gerbils, and fish-eating birds develop into adults. Larvae become adults in 10 to 11 days, and the first-generation females produce larvae. These larvae develop into males and egg-producing female worms. Eggs pass with the feces, reach water, embryonate, and infect fish. Autoinfection is part of the life cycle and leads to hyperinfection. Humans acquire the infection by eating small freshwater fish raw. The parasite multiplies, and symptoms of diarrhea, borborygmus, abdominal pain, and edema develop. Chronic infections lead to malabsorption and hence to protein and electrolyte loss, and death results from irreversible effects of the infection. Treatment consists of electrolyte replacement and administration of an antidiarrheal agent and mebendazole or albendazole. Capillariasis philippinensis is considered a zoonotic disease of migratory fish-eating birds. The eggs are disseminated along flyways and infect the fish, and when fish are eaten raw, the disease develops.

  3. Relative permeability through fractures

    SciTech Connect

    Diomampo, Gracel, P.

    2001-08-01

    The mechanism of two-phase flow through fractures is of importance in understanding many geologic processes. Currently, two-phase flow through fractures is still poorly understood. In this study, nitrogen-water experiments were done on both smooth and rough parallel plates to determine the governing flow mechanism for fractures and the appropriate methodology for data analysis. The experiments were done using a glass plate to allow visualization of flow. Digital video recording allowed instantaneous measurement of pressure, flow rate and saturation. Saturation was computed using image analysis techniques. The experiments showed that gas and liquid phases flow through fractures in nonuniform separate channels. The localized channels change with time as each phase path undergoes continues breaking and reforming due to invasion of the other phase. The stability of the phase paths is dependent on liquid and gas flow rate ratio. This mechanism holds true for over a range of saturation for both smooth and rough fractures. In imbibition for rough-walled fractures, another mechanism similar to wave-like flow in pipes was also observed. The data from the experiments were analyzed using Darcy's law and using the concept of friction factor and equivalent Reynold's number for two-phase flow. For both smooth- and rough-walled fractures a clear relationship between relative permeability and saturation was seen. The calculated relative permeability curves follow Corey-type behavior and can be modeled using Honarpour expressions. The sum of the relative permeabilities is not equal one, indicating phase interference. The equivalent homogeneous single-phase approach did not give satisfactory representation of flow through fractures. The graphs of experimentally derived friction factor with the modified Reynolds number do not reveal a distinctive linear relationship.

  4. Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice

    PubMed Central

    Cheng, Yijun; Wei, Yongxu; Yang, Wenlei; Cai, Yu; Chen, Bin; Yang, Guoyuan; Shang, Hanbing; Zhao, Weiguo

    2016-01-01

    Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy. PMID:27929421

  5. Clinical Characteristics Associated with Post-Operative Intestinal Epithelial Barrier Dysfunction in Children with Congenital Heart Disease

    PubMed Central

    Typpo, Katri V; Larmonier, Claire B.; Deschenes, Jendar; Redford, Daniel; Kiela, Pawel R.; Ghishan, Fayez K.

    2014-01-01

    Objective Children with congenital heart disease (CHD) have loss of intestinal epithelial barrier function (EBF), which increases their risk for post-operative sepsis and organ dysfunction. We do not understand how post-operative cardiopulmonary support or the inflammatory response to cardiopulmonary bypass (CPB) might alter intestinal EBF. We examined variation in a panel of plasma biomarkers to reflect intestinal EBF (cellular and paracellular structure and function) after CPB and in response to routine ICU care. Design Prospective cohort Setting University medical center cardiac intensive care unit Patients Twenty children aged newborn to 18 years undergoing repair or palliation of CHD with CPB. Interventions We measured baseline and repeated plasma FABP2, citrulline, claudin 3, and dual sugar permeability test (DSPT) to reflect intestinal epithelial integrity, epithelial function, paracellular integrity, and paracellular function, respectively. We measured baseline and repeated plasma pro-inflammatory (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL4, IL10) cytokines, known to modulate intestinal EBF in murine models of CPB. Measurements and Main Results All patients had abnormal baseline FABP2 concentrations (mean 3815.5 pg/mL), (normal 41–336 pg/mL). Cytokine response to CPB was associated with early, but not late changes in plasma concentrations of FABP2 and citrulline. Variation in biomarker concentrations over time were associated with aspects of ICU care indicating greater severity of illness: claudin 3, FABP2, and DSPT ratio were associated with symptoms of feeding intolerance (p<0.05) while FABP2 was positively associated with vasoactive-inotrope score (VIS) (p=0.04). Citrulline was associated with larger arteriovenous O2 saturation difference (p=0.04) and had a complex relationship with VIS. Conclusions Children undergoing CPB for repair or palliation of CHD are at risk for intestinal injury and often present with evidence for loss of intestinal

  6. Basolateral potassium (IKCa) channel inhibition prevents increased colonic permeability induced by chemical hypoxia.

    PubMed

    Loganathan, A; Linley, J E; Rajput, I; Hunter, M; Lodge, J P A; Sandle, G I

    2011-01-01

    Major liver resection is associated with impaired intestinal perfusion and intestinal ischemia, resulting in decreased mucosal integrity, increased bacterial translocation, and an increased risk of postoperative sepsis. However, the mechanism by which ischemia impairs intestinal mucosal integrity is unclear. We therefore evaluated the role of Ca(2+)-sensitive, intermediate-conductance (IK(Ca)) basolateral potassium channels in enhanced intestinal permeability secondary to chemical hypoxia. The effects of chemical hypoxia induced by 100 μM dinitrophenol (DNP) and 5 mM deoxyglucose (DG) on basolateral IK(Ca) channel activity and whole cell conductance in intact human colonic crypts, and paracellular permeability (G(S)) in isolated colonic sheets, were determined by patch-clamp recording and transepithelial electrical measurements, respectively. DNP and DG rapidly stimulated IK(Ca) channels in cell-attached basolateral membrane patches and elicited a twofold increase (P = 0.004) in whole cell conductance in amphotericin B-permeabilized membrane patches, changes that were inhibited by the specific IK(Ca) channel blockers TRAM-34 (100 nM) and clotrimazole (CLT; 10 μM). In colonic sheets apically permeabilized with nystatin, DNP elicited a twofold increase (P = 0.005) in G(S), which was largely inhibited by the serosal addition of 50 μM CLT. We conclude that, in intestinal epithelia, chemical hypoxia increases G(S) through a mechanism involving basolateral IK(Ca) channel activation. Basolateral IK(Ca) channel inhibition may prevent or limit increased intestinal permeability during liver surgery.

  7. Intestinal protozoa.

    PubMed

    Juckett, G

    1996-06-01

    Giardia is the best known cause of protozoal gastrointestinal disease in North America, producing significant but not life-threatening gastrointestinal distress and diarrhea. Although diagnosis of giardiasis may be challenging, treatment is usually successful. Entamoeba histolytica poses a rarer but far more difficult clinical challenge. Dysentery caused by E. histolytica may be the most feared intestinal protozoal infection, although Cryptosporidium parvum, Balantidium coli, Isospora belli, Sarcocystis species and other newly described protozoa also may cause diarrhea in healthy individuals and may result in intractable, life-threatening illness in patients with acquired immunodeficiency syndrome or other immunosuppressive diseases. Certain protozoa once considered relatively unimportant, such as Cryptosporidium, are now recognized as significant causes of morbidity even in the United States, since transmission readily occurs through contaminated water.

  8. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  9. Morphological abnormalities among lampreys

    USGS Publications Warehouse

    Manion, Patrick J.

    1967-01-01

    The experimental control of the sea lamprey (Petromyzon marinus) in the Great Lakes has required the collection of thousands of lampreys. Representatives of each life stage of the four species of the Lake Superior basin were examined for structural abnormalities. The most common aberration was the presence of additional tails. The accessory tails were always postanal and smaller than the normal tail. The point of origin varied; the extra tails occurred on dorsal, ventral, or lateral surfaces. Some of the extra tails were misshaped and curled, but others were normal in shape and pigment pattern. Other abnormalities in larval sea lampreys were malformed or twisted tails and bodies. The cause of the structural abnormalities is unknown. The presence of extra caudal fins could be genetically controlled, or be due to partial amputation or injury followed by abnormal regeneration. Few if any lampreys with structural abnormalities live to sexual maturity.

  10. Rocks of low permeability

    NASA Astrophysics Data System (ADS)

    The 17th International Congress of the IAH (International Association of Hydrogeologists) will meet in Tucson, Ariz., January 7-10, 1985. The deadline for abstracts is March 1, 1984, and final papers are due October 15, 1984.The topic of the congress will be “Hydrogeology of Rocks of Low Permeability,” and speakers will include W. Back, J. F. Bredehoeft, G. de Marsily, J. E. Gale, P. Fritz, L. W. Gelhar, G. E. Grisak, C. W. Kreitler, M. R. Llamas, T. N. Narasimhan, I. Neretnieks, and E. P. Weeks. The congress will conclude with a panel discussion moderated by S. P. Neuman. Panelists include S. N. Davis, G. de Marsily, R. A. Freeze, P. A. Witherspoon, and I. Neretnieks.

  11. Placental Permeability of Lead

    PubMed Central

    Carpenter, Stanley J.

    1974-01-01

    The detection of lead in fetal tissues by chemical analysis has long been accepted as prima facie evidence for the permeability of the placenta to this nonessential trace metal. However, only a few investigations, all on lower mammalian species, have contributed any direct experimental data bearing on this physiological process. Recent radioactive tracer and radioautographic studies on rodents have shown that lead crosses the placental membranes rapidly and in significant amounts even at relatively low maternal blood levels. While it is not possible to extrapolate directly the results of these experiments to humans because of differences in placental structure and other factors, the results do serve as a warning of the possible hazard to the human embryo and fetus of even low levels of lead in the maternal system. PMID:4857497

  12. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

    PubMed Central

    Rodiño-Janeiro, Bruno K; Alonso-Cotoner, Carmen; Pigrau, Marc; Lobo, Beatriz; Vicario, María; Santos, Javier

    2015-01-01

    The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions. PMID:25537677

  13. Relative ion permeability of normal and cystic fibrosis nasal epithelium.

    PubMed Central

    Knowles, M; Gatzy, J; Boucher, R

    1983-01-01

    The raised transepithelial electric potential difference (PD) across respiratory epithelia in cystic fibrosis (CF) has suggested an abnormality in ion permeation. We characterized this abnormality further by measuring in the nasal epithelia of CF and normal subjects the concentration-PD relationship for amiloride, an inhibitor of cell Na+ permeability, and PD responses to superfusion with solutions of different composition. Amiloride was more efficacious in the CF subjects but the ED50 was not different from that of normals (approximately 2 X 10(-6) M). Na+ replacement by choline induced effects similar to those of amiloride, i.e. a greater depolarization in CF subjects. A 10-fold increase in the K+ concentration of the perfusate induced a small (less than 10 mV) depolarization in both subject populations. When Cl- in the perfusate was replaced by gluconate or SO2-(4) the nasal PD of normal subjects hyperpolarized (lumen became more negative) by approximately 35 mV. A significantly smaller response (less than 17 mV) was induced in CF homozygotes but not in heterozygotes (38 mV). The smaller response of CF subjects appears to reflect an absolute decrease in luminal surface Cl- permeability because pretreatment with amiloride did not increase the response to Cl- free solution (7 mV). Accordingly, three abnormalities (decreased Cl- permeability, raised PD, greater amiloride efficacy) have been identified in CF respiratory epithelia. Whereas "excessive" active Na+ transport can account for these abnormalities and the dessication of airway surface liquid, it is possible that a lower lumenal cell membrane Cl- permeability and inhibition of a potential path of Cl- secretion can also explain the observations. PMID:6853720

  14. High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity

    PubMed Central

    Park, Mi-Young; Kim, Min Young; Seo, Young Rok; Kim, Jong-Sang; Sung, Mi-Kyung

    2016-01-01

    Background: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in ApcMin/+ mice. Methods: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. Results: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2′-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). Conclusions: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis. PMID:27390738

  15. [Intestinal microbiota].

    PubMed

    Perez, Horacio Joaquín; Menezes, Maria Elisabeth; d'Acâmpora, Armando José

    2014-01-01

    There is accumulative evidence on the multiple functions of the intestinal microflora in relation to the homeostasis of the host. At first considered as a simple mutualism, today this relationship proves to be essential to the health and to pathologic processes, particularly metabolic (eg, obesity) and gastrointestinal (eg, inflammatory bowel disease and functional disorders). The first studies were conducted on the microbiota from fecal material cultured anaerobically. With the advent of molecular biology, it has become possible to determine qualitative and quantitatively the dominant, subdominant and transients species. In recent years, there were advances in the understanding of the relationship betwen the microbiota and the host, as well as among the microorganisms in their respective niches. These advances result from translational integration of microbiology with specialities such as molecular biology, cell phisiology, immunology and ecology. There are few studies on the spatial distribution of the microflora in the gut. Unravelling the topography of the microflora in mammals is a way to validate new animal models for the study of microflora.

  16. [Intestinal enzymopathies of children (author's transl)].

    PubMed

    Schreier, K

    1976-12-24

    In recent years it has been successfully demonstrated that, in relation to congenital metabolic abnormalities, every enzyme of the gastro-intestinal tract may be absent or inactive.. In serious diseases of the intestinal tract, secondary inactivation of numerous enzymes may result. In this comprehensive presentation the pathology of the disaccharidases, the peptidases and lypolysis is described, the physiology being gone into briefly in each case. Furthermore, all known disturbances of absorption of sugar, aminoacids and fats are briefly dealt with. Finally, congenital chloridorrhea is described.

  17. Permeable Boundaries in Organizational Learning

    NASA Astrophysics Data System (ADS)

    Hazy, James K.; Tivnan, Brian F.; Schwandt, David R.

    The nature of the organizational boundary is investigated in the context of organizational learning. Boundary permeability is defined and hypotheses relating it to performance are tested computationally using data from 5,500 artificial organizations. We find that matching boundary permeability to the environment predicts both agent and organization survival.

  18. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  19. Permeable membrane experiment

    NASA Technical Reports Server (NTRS)

    Slavin, Thomas J.; Cao, Tuan Q.; Kliss, Mark H.

    1993-01-01

    The purpose of the Permeable Membrane Experiment is to gather flight data on three areas of membrane performance that are influenced by the presence of gravity. These areas are: (1) Liquid/gas phase separation, (2) gas bubble interference with diffusion through porous membranes and (3) wetting characteristics of hydrophilic membrane surfaces. These data are important in understaning the behavior of membrane/liquid/gas interfaces where surface tension forces predominate. The data will be compared with 1-g data already obtained and with predicted micrograviity behavior. The data will be used to develop designs for phase separation and plant nutrient delivery systems and will be available to the life support community for use in developing technologies which employ membranes. A conceptual design has been developed to conduct three membrane experiments, in sequence, aboard a single Complex Autonomous Payload (CAP) carrier to be carried in the Shuttle Orbiter payload bay. One experiment is conducted for each of the three membrane performance areas under study. These experiments are discussed in this paper.

  20. Relative Permeability of Fractured Rock

    SciTech Connect

    Mark D. Habana

    2002-06-30

    Contemporary understanding of multiphase flow through fractures is limited. Different studies using synthetic fractures and various fluids have yielded different relative permeability-saturation relations. This study aimed to extend the understanding of multiphase flow by conducting nitrogen-water relative permeability experiments on a naturally-fractured rock from The Geysers geothermal field. The steady-state approach was used. However, steady state was achieved only at the endpoint saturations. Several difficulties were encountered that are attributed to phase interference and changes in fracture aperture and surface roughness, along with fracture propagation/initiation. Absolute permeabilities were determined using nitrogen and water. The permeability values obtained change with the number of load cycles. Determining the absolute permeability of a core is especially important in a fractured rock. The rock may change as asperities are destroyed and fractures propagate or st rain harden as the net stresses vary. Pressure spikes occurred in water a solute permeability experiments. Conceptual models of an elastic fracture network can explain the pressure spike behavior. At the endpoint saturations the water relative permeabilities obtained are much less than the nitrogen gas relative permeabilities. Saturations were determined by weighing and by resistivity calculations. The resistivity-saturation relationship developed for the core gave saturation values that differ by 5% from the value determined by weighing. Further work is required to complete the relative permeability curve. The steady-state experimental approach encountered difficulties due to phase interference and fracture change. Steady state may not be reached until an impractical length of time. Thus, unsteady-state methods should be pursued. In unsteady-state experiments the challenge will be in quantifying rock fracture change in addition to fluid flow changes.

  1. DENTAL ABNORMALITIES OF EIGHT WILD QINLING GIANT PANDAS (AILUROPODA MELANOLEUCA QINLINGENSIS), SHAANXI PROVINCE, CHINA.

    PubMed

    Jin, Yipeng; Chen, Si; Chao, Yanqiao; Pu, Tianchun; Xu, Hongqian; Liu, Xiaobin; Zhao, Kaihui; Nie, Yonggang; Wei, Wei; Lin, Degui

    2015-10-01

    Eight adult (six male and two female) wild Qinling giant pandas (Ailuropoda melanoleuca qinlingensis) from China National Foping Nature Reserve were tracked, and their dental data collected and recorded from October 2010 to April 2014. Each panda had dental abnormalities of varying severity. Dental wear and fracture were the most common conditions. Absent teeth were common, with premolars missing most often. Mild caries were present in five molar teeth between two animals. Different degrees of dental plaque and calculus occurred in all animals but without severe periodontal disease. Two animals with severe dental abnormalities died due to intestinal problems. Large segments of bamboo were found in their intestinal tracts, and intestinal perforation and ulcers were evident, indicating dental abnormalities can be an important factor in the health of wild giant pandas and may lead to death. Further research with larger sample sizes of wild and captive giant pandas will be required to substantiate the relationship between dental abnormalities and mortality in giant pandas.

  2. Small Intestine Disorders

    MedlinePlus

    Your small intestine is the longest part of your digestive system - about twenty feet long! It connects your stomach to ... many times to fit inside your abdomen. Your small intestine does most of the digesting of the foods ...

  3. Small intestine (image)

    MedlinePlus

    The small intestine is the portion of the digestive system most responsible for absorption of nutrients from food into the ... the duodenum. This short first portion of the small intestine is followed by the jejunum and the ileum. ...

  4. Geothermal Permeability Enhancement - Final Report

    SciTech Connect

    Joe Beall; Mark Walters

    2009-06-30

    The overall objective is to apply known permeability enhancement techniques to reduce the number of wells needed and demonstrate the applicability of the techniques to other undeveloped or under-developed fields. The Enhanced Geothermal System (EGS) concept presented in this project enhances energy extraction from reduced permeability zones in the super-heated, vapor-dominated Aidlin Field of the The Geysers geothermal reservoir. Numerous geothermal reservoirs worldwide, over a wide temperature range, contain zones of low permeability which limit the development potential and the efficient recovery of heat from these reservoirs. Low permeability results from poorly connected fractures or the lack of fractures. The Enhanced Geothermal System concept presented here expands these technologies by applying and evaluating them in a systematic, integrated program.

  5. Permeability of soils in Mississippi

    USGS Publications Warehouse

    O'Hara, Charles G.

    1994-01-01

    The permeability of soils in Mississippi was determined and mapped using a geographic information system (GIS). Soil permeabilities in Mississippi were determined to range in value from nearly 0.0 to values exceeding 5.0 inches per hour. The U.S. Soil Conservation Service's State Soil Geographic Data Base (STATSGO) was used as the primary source of data for the determination of area-weighted soil permeability. STATSGO provides soil layer properties that are spatially referenced to mapped areas. These mapped areas are referred to as polygons in the GIS. The polygons arc boundaries of soils mapped as a group and are given unique Map Unit Identifiers (MUIDs). The data describing the physical characteristics of the soils within each polygon are stored in a tabular data base format and are referred to as attributes. The U.S. Soil Conservation Service developed STATSGO to be primarily used as a guide for regional resource planning, management, and monitoring. STATSGO was designed so that soil information could be extracted from properties tables at the layer level, combined by component, and statistically expanded to cover the entire map unit. The results of this study provide a mapped value for permeability which is representative of the vertical permeability of soils in that area. The resultant permeability map provides a representative vertical soil permeability for a given area sufficient for county, multi- county, and area planning, and will be used as the soil permeability data component in the evaluation of the susceptibility of major aquifers to contami- nation in Mississippi.

  6. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis.

    PubMed

    Czaja, Albert J

    2016-11-14

    The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.

  7. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

    PubMed Central

    Czaja, Albert J

    2016-01-01

    The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies. PMID:27895415

  8. Permeability of cork to gases.

    PubMed

    Faria, David P; Fonseca, Ana L; Pereira, Helen; Teodoro, Orlando M N D

    2011-04-27

    The permeability of gases through uncompressed cork was investigated. More than 100 samples were assessed from different plank qualities to provide a picture of the permeability distribution. A novel technique based on a mass spectrometer leak detector was used to directly measure the helium flow through the central area of small disks 10 mm in diameter and 2 mm thick. The permeability for nitrogen, oxygen, and other gases was measured by the pressure rise technique. Boiled and nonboiled cork samples from different sections were evaluated. An asymmetric frequency distribution ranging 3 orders of magnitude (roughly from 1 to 1000 μmol/(cm·atm·day)) for selected samples without macroscopic defects was found, having a peak below 100 μmol/(cm·atm·day). Correlation was found between density and permeability: higher density samples tend to show lower permeability. However, boiled cork showed a mean lower permeability despite having a lower density. The transport mechanism of gases through cork was also examined. Calculations suggest that gases permeate uncompressed cork mainly through small channels between cells under a molecular flow regime. The diameter of such channels was estimated to be in the range of 100 nm, in agreement with the plasmodesmata size in the cork cell walls.

  9. Permeability theory and Palace Athena.

    PubMed

    Stamps, Arthur E

    2013-06-01

    Permeability theory suggests that safety in environments depends on how far and how easily one can perceive or move through environments. Parts of environments that limit perception or retard locomotion elicit impressions of being enclosed, so properties of environments that influence perceived enclosure are important in permeability theory. One prediction of permeability theory is that the more permeable the boundary, the less enclosed the region within that boundary will seem to be. Another prediction is that boundary depth will have little influence on perceived enclosure. These predictions were tested in the venue of Greek temples. 30 participants were tested (14 men, 16 women; M age = 40 yr.), who rated perceived enclosure for 18 stimuli. The stimuli were constructed using a virtual scene from the Tholos in Delphi with the positions of the columns forming the boundaries. The boundaries were designed to have different levels of permeability and depth. Data were analyzed in terms of effect sizes and focused comparisons. Results indicated that perceived enclosure was most strongly influenced by the visual permeability of the boundary, while depth of boundary had a much smaller effect on perceived enclosure.

  10. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease?

    PubMed Central

    Brandl, Katharina

    2016-01-01

    Changes in the intestinal microbiota composition contribute to the pathogenesis of many disorders including gastrointestinal and liver diseases. Recent studies have broadened our understanding of the “gut-liver” axis. Dietary changes, other environmental and genetic factors can lead to alterations in the microbiota. Dysbiosis can further disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In this article, the authors dissect the different steps involved in disease pathogenesis to further refine approaches for the medical management of liver diseases. The authors will specifically discuss the role of dysbiosis in inducing intestinal inflammation and increasing intestinal permeability. PMID:26088524

  11. L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice.

    PubMed

    Leocádio, Paola C L; Antunes, Maísa M; Teixeira, Lílian G; Leonel, Alda J; Alvarez-Leite, Jacqueline I; Machado, Denise C C; Generoso, Simone V; Cardoso, Valbert N; Correia, Maria Isabel T D

    2015-01-01

    Beneficial effects of L-arginine on immune responses and bowel function have been reported. Mucositis is a side effect of chemotherapy treatment that affects approximately 40% of patients. This complication is characterized by inflammation that affects the gastrointestinal tract, increasing permeability and causing abdominal pain, nausea, vomiting, and diarrhea, which worsen the patient's nutritional status and increases morbimortality. The aim of this study was to evaluate the effect of pretreating with 2% L-arginine supplementation in water on mucositis as induced by 5-fluorouracil (5-FU; a single dose of 200 mg/kg body weight) in Swiss male mice. The effect of L-arginine on weight, intestinal permeability, morphology, and the histopathological score of the small intestine (from 0 to 12), oxidative stress, myeloperoxidase (MPO), and N-acetylglucosaminidase (NAG) activities were evaluated. Intestinal length improvement was observed, in addition to the partial recovery of the mucosal architecture. L-arginine attenuated the histopathological score and MPO activity. There was also an improvement in intestinal permeability, despite weight loss after 5-FU administration. In conclusion, L-arginine can positively impact intestinal mucositis by promoting partial mucosal recovery, reducing inflammation and improving intestinal permeability.

  12. [The relativity of abnormity].

    PubMed

    Nilson, Annika

    2006-01-01

    In the late 19th century and in the beginning of the 20th century, mental diseases and abnormal behavior was considered to be a great danger to culture and society. "Degeneration" was the buzzword of the time, used and misused by artists and scientists alike. At the same time, some scientists saw abnormity as the key to unlock the mysteries of the ordinary mind. Naturalistic curiosity left Pandoras box open when religion declined in Darwins wake. Two swedish scientists, the physician Bror Gadelius (1862-1938) and his friend the philosopher Axel Herrlin (1870-1937), inspired by the French psychologist Theodule Ribots (1839-1916) "psychology without a soul", denied all fixed demarcation lines between abnormity and normality. All humans are natures creatures ruled by physiological laws, not ruled by God or convention. Even ordinary morality was considered to be an utterly backward explanation and guideline for complex human behavior. Different forms of therapy, not various kinds of penalties for wicked and disturbing behavior, are the now the solution for lots of people, "normal" as well as "abnormal". Psychiatry is expanding.

  13. Abnormalities of gonadal differentiation.

    PubMed

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  14. Establishment of Intestinal Bacteriology

    PubMed Central

    MITSUOKA, Tomotari

    2014-01-01

    Research on intestinal bacteria began around the end of the 19th century. During the last 5 decades of the 20th century, research on the intestinal microbiota made rapid progress. At first, in my work, I first developed a method of comprehensive analysis of the intestinal microbiota, and then I established classification and identification methods for intestinal anaerobes. Using these methods I discovered a number of ecological rules governing the intestinal microbiota and the role of the intestinl microbiota in health and disease. Moreover, using germfree animals, it was proven that the intestinal microbiota has a role in carcinogenesis and aging in the host. Thus, a new interdisciplinary field, “intestinal bacteriology” was established. PMID:25032084

  15. Host Responses to Intestinal Microbial Antigens in Gluten-Sensitive Mice

    PubMed Central

    Natividad, Jane M.; Huang, Xianxi; Slack, Emma; Jury, Jennifer; Sanz, Yolanda; David, Chella; Denou, Emmanuel; Yang, Pinchang; Murray, Joseph

    2009-01-01

    Background and Aims Excessive uptake of commensal bacterial antigens through a permeable intestinal barrier may influence host responses to specific antigen in a genetically predisposed host. The aim of this study was to investigate whether intestinal barrier dysfunction induced by indomethacin treatment affects the host response to intestinal microbiota in gluten-sensitized HLA-DQ8/HCD4 mice. Methodology/Principal Findings HLA-DQ8/HCD4 mice were sensitized with gluten, and gavaged with indomethacin plus gluten. Intestinal permeability was assessed by Ussing chamber; epithelial cell (EC) ultra-structure by electron microscopy; RNA expression of genes coding for junctional proteins by Q-real-time PCR; immune response by in-vitro antigen-specific T-cell proliferation and cytokine analysis by cytometric bead array; intestinal microbiota by fluorescence in situ hybridization and analysis of systemic antibodies against intestinal microbiota by surface staining of live bacteria with serum followed by FACS analysis. Indomethacin led to a more pronounced increase in intestinal permeability in gluten-sensitized mice. These changes were accompanied by severe EC damage, decreased E-cadherin RNA level, elevated IFN-γ in splenocyte culture supernatant, and production of significant IgM antibody against intestinal microbiota. Conclusion Indomethacin potentiates barrier dysfunction and EC injury induced by gluten, affects systemic IFN-γ production and the host response to intestinal microbiota antigens in HLA-DQ8/HCD4 mice. The results suggest that environmental factors that alter the intestinal barrier may predispose individuals to an increased susceptibility to gluten through a bystander immune activation to intestinal microbiota. PMID:19649259

  16. Intestinal endocrine cells in radiation enteritis

    SciTech Connect

    Pietroletti, R.; Blaauwgeers, J.L.; Taat, C.W.; Simi, M.; Brummelkamp, W.H.; Becker, A.E. )

    1989-08-01

    In this study, the intestinal endocrine cells were investigated in 13 surgical specimens affected by radiation enteritis. Endocrine cells were studied by means of Grimelius' silver staining and immunostaining for chromogranin, a general marker of endocrine cells. Positively stained cells were quantified by counting their number per unit length of muscularis mucosa. Results in radiation enteritis were compared with matched control specimens by using Student's t test. Chromogranin immunostaining showed a statistically significant increase of endocrine cells in radiation enteritis specimens compared with controls both in small and large intestine (ileum, 67.5 +/- 23.5 cells per unit length of muscularis mucosa in radiation enteritis versus 17.0 +/- 6.1 in controls; colon, 40.9 +/- 13.7 cells per unit length of muscularis mucosa in radiation enteritis versus 9.5 +/- 4.1 in controls--p less than 0.005 in both instances). Increase of endocrine cells was demonstrated also by Grimelius' staining; however, without reaching statistical significance. It is not clear whether or not the increase of endocrine cells in radiation enteritis reported in this study is caused by a hyperplastic response or by a sparing phenomenon. We should consider that increased endocrine cells, when abnormally secreting their products, may be involved in some of the clinical features of radiation enteropathy. In addition, as intestinal endocrine cells produce trophic substances to the intestine, their increase could be responsible for the raised risk of developing carcinoma of the intestine in long standing radiation enteritis.

  17. Berberine Attenuates Intestinal Mucosal Barrier Dysfunction in Type 2 Diabetic Rats.

    PubMed

    Gong, Jing; Hu, Meilin; Huang, Zhaoyi; Fang, Ke; Wang, Dingkun; Chen, Qingjie; Li, Jingbin; Yang, Desen; Zou, Xin; Xu, Lijun; Wang, Kaifu; Dong, Hui; Lu, Fuer

    2017-01-01

    Background: Intestinal mucosal barrier dysfunction plays an important role in the development of diabetes mellitus (DM). Berberine (BBR), a kind of isoquinoline alkaloid, is widely known to be effective for both DM and diarrhea. Here, we explored whether the anti-diabetic effect of BBR was related to the intestine mucosal barrier. Methods and Results: The rat model of T2DM was established by high glucose and fat diet feeding and intravenous injection of streptozocin. Then, those diabetic rats were treated with BBR at different concentrations for 9 weeks. The results showed, in addition to hyperglycemia and hyperlipidemia, diabetic rats were also characterized by proinflammatory intestinal changes, altered gut-derived hormones, and 2.77-fold increase in intestinal permeability. However, the treatment with BBR significantly reversed the above changes in diabetic rats, presenting as the improvement of the high glucose and triglyceride levels, the relief of the inflammatory changes of intestinal immune system, and the attenuation of the intestinal barrier damage. BBR treatment at a high concentration also decreased the intestinal permeability by 27.5% in diabetic rats. Furthermore, BBR regulated the expressions of the molecules involved in TLR4/MyD88/NF-κB signaling pathways in intestinal tissue of diabetic rats. Conclusion: The hypoglycemic effects of BBR might be related to the improvement in gut-derived hormones and the attenuation of intestinal mucosal mechanic and immune barrier damages.

  18. Berberine Attenuates Intestinal Mucosal Barrier Dysfunction in Type 2 Diabetic Rats

    PubMed Central

    Gong, Jing; Hu, Meilin; Huang, Zhaoyi; Fang, Ke; Wang, Dingkun; Chen, Qingjie; Li, Jingbin; Yang, Desen; Zou, Xin; Xu, Lijun; Wang, Kaifu; Dong, Hui; Lu, Fuer

    2017-01-01

    Background: Intestinal mucosal barrier dysfunction plays an important role in the development of diabetes mellitus (DM). Berberine (BBR), a kind of isoquinoline alkaloid, is widely known to be effective for both DM and diarrhea. Here, we explored whether the anti-diabetic effect of BBR was related to the intestine mucosal barrier. Methods and Results: The rat model of T2DM was established by high glucose and fat diet feeding and intravenous injection of streptozocin. Then, those diabetic rats were treated with BBR at different concentrations for 9 weeks. The results showed, in addition to hyperglycemia and hyperlipidemia, diabetic rats were also characterized by proinflammatory intestinal changes, altered gut-derived hormones, and 2.77-fold increase in intestinal permeability. However, the treatment with BBR significantly reversed the above changes in diabetic rats, presenting as the improvement of the high glucose and triglyceride levels, the relief of the inflammatory changes of intestinal immune system, and the attenuation of the intestinal barrier damage. BBR treatment at a high concentration also decreased the intestinal permeability by 27.5% in diabetic rats. Furthermore, BBR regulated the expressions of the molecules involved in TLR4/MyD88/NF-κB signaling pathways in intestinal tissue of diabetic rats. Conclusion: The hypoglycemic effects of BBR might be related to the improvement in gut-derived hormones and the attenuation of intestinal mucosal mechanic and immune barrier damages. PMID:28217099

  19. Obesity, fatty liver disease and intestinal microbiota

    PubMed Central

    Arslan, Nur

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations. PMID:25469013

  20. Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability

    PubMed Central

    de Punder, Karin; Pruimboom, Leo

    2015-01-01

    Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here, we hypothesize that stresses (defined as homeostatic disturbances) can induce low-grade inflammation by increasing the availability of water, sodium, and energy-rich substances to meet the increased metabolic demand induced by the stressor. One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation. In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammation and its related diseases. PMID:26029209

  1. Intestinal microbiota in functional bowel disorders: a Rome foundation report

    PubMed Central

    Barbara, Giovanni; Flint, Harry J; Spiegel, Brennan M R; Spiller, Robin C; Vanner, Stephen; Verdu, Elena F; Whorwell, Peter J; Zoetendal, Erwin G

    2013-01-01

    It is increasingly perceived that gut host–microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host–microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS. PMID:22730468

  2. Platelets can enhance vascular permeability.

    PubMed

    Cloutier, Nathalie; Paré, Alexandre; Farndale, Richard W; Schumacher, H Ralph; Nigrovic, Peter A; Lacroix, Steve; Boilard, Eric

    2012-08-09

    Platelets survey blood vessels, searching for endothelial damage and preventing loss of vascular integrity. However, there are circumstances where vascular permeability increases, suggesting that platelets sometimes fail to fulfill their expected function. Human inflammatory arthritis is associated with tissue edema attributed to enhanced permeability of the synovial microvasculature. Murine studies have suggested that such vascular leak facilitates entry of autoantibodies and may thereby promote joint inflammation. Whereas platelets typically help to promote microvascular integrity, we examined the role of platelets in synovial vascular permeability in murine experimental arthritis. Using an in vivo model of autoimmune arthritis, we confirmed the presence of endothelial gaps in inflamed synovium. Surprisingly, permeability in the inflamed joints was abrogated if the platelets were absent. This effect was mediated by platelet serotonin accumulated via the serotonin transporter and could be antagonized using serotonin-specific reuptake inhibitor antidepressants. As opposed to the conventional role of platelets to microvascular leakage, this demonstration that platelets are capable of amplifying and maintaining permeability adds to the rapidly growing list of unexpected functions for platelets.

  3. Pyrotechnic deflagration velocity and permeability

    SciTech Connect

    Begeal, D R; Stanton, P L

    1982-01-01

    Particle size, porosity, and permeability of the reactive material have long been considered to be important factors in propellant burning rates and the deflagration-to-detonation transition in explosives. It is reasonable to assume that these same parameters will also affect the deflagration velocity of pyrotechnics. This report describes an experimental program that addresses the permeability of porous solids (particulate beds), in terms of particle size and porosity, and the relationship between permeability and the behavior of pyrotechnics and explosives. The experimental techniques used to acquire permeability data and to characterize the pyrotechnic burning are discussed. Preliminary data have been obtained on the burning characteristics of titanium hydride/potassium perchlorate (THKP) and boron/calcium chromate (BCCR). With THKP, the velocity of a pressure wave (from hot product gases) in the unburned region shows unsteady behavior which is related to the initial porosity or permeability. Simultaneous measurements with pressure gauges and ion gauges reveal that the pressure wave precedes the burn front. Steady burning of BCCR was observed with pressure gauge diagnostics and with a microwave interferometry technique.

  4. Abdominal Problems in Children with Congenital Cardiovascular Abnormalities

    PubMed Central

    Güney, Lütfi Hakan; Araz, Coşkun; Beyazpınar, Deniz Sarp; Arda, İrfan Serdar; Arslan, Esra Elif; Hiçsönmez, Akgün

    2015-01-01

    Background: Congenital cardiovascular abnormality is an important cause of morbidity and mortality in childhood. Both the type of congenital cardiovascular abnormality and cardiopulmonary bypass are responsible for gastrointestinal system problems. Aims: Intra-abdominal problems, such as paralytic ileus, necrotizing enterocolitis, and intestinal perforation, are common in patients who have been operated or who are being followed for congenital cardiovascular abnormalities. Besides the primary congenital cardiovascular abnormalities, ischemia secondary to cardiac catheterization or surgery contributes to the incidence of these problems. Study Design: Cross-sectional study. Methods: In this study, we aimed to screen the intra-abdominal problems seen in patients with congenital cardiovascular abnormalities who had undergone surgical or angiographical intervention(s). Patients with congenital cardiovascular abnormalities who had been treated medically or surgically between 2000 and 2014 were analyzed retrospectively in terms of intra-abdominal problems. The patients’ demographic data, type of congenital cardiovascular abnormalities, the intervention applied (surgical, angiographic), the incidence of intra-abdominal problem(s), the interventions applied for the intra-abdominal problems, and the results were evaluated. Results: Fourteen (Group I) of the 76 patients with congenital cardiovascular abnormalities diagnosis were operated due to intra-abdominal problems, and 62 (Group II) were followed-up clinically for intra-abdominal problems. In Group I (10 boys and 4 girls), 11 patients were aged between 0 and 12 months, and three patients were older than 12 months. Group II included 52 patients aged between 0 and 12 months and 10 patients older than 12 months. Cardiovascular surgical interventions had been applied to six patients in Group I and 40 patients in Group II. The most frequent intra-abdominal problems were necrotizing enterocolitis and intestinal perforation

  5. Heritable bovine fetal abnormalities.

    PubMed

    Whitlock, B K; Kaiser, L; Maxwell, H S

    2008-08-01

    The etiologies for congenital bovine fetal anomalies can be divided into heritable, toxic, nutritional, and infectious categories. Although uncommon in most herds, inherited congenital anomalies are probably present in all breeds of cattle and propagated as a result of specific trait selection that inadvertently results in propagation of the defect. In some herds, the occurrence of inherited anomalies has become frequent, and economically important. Anomalous traits can affect animals in a range of ways, some being lethal or requiring euthanasia on humane grounds, others altering structure, function, or performance of affected animals. Veterinary practitioners should be aware of the potential for inherited defects, and be prepared to investigate and report animals exhibiting abnormal characteristics. This review will discuss the morphologic characteristics, mode of inheritance, breeding lines affected, and the availability of genetic testing for selected heritable bovine fetal abnormalities.

  6. Liver abnormalities in pregnancy.

    PubMed

    Than, Nwe Ni; Neuberger, James

    2013-08-01

    Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.

  7. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed.

  8. Permeability enhancement by shock cooling

    NASA Astrophysics Data System (ADS)

    Griffiths, Luke; Heap, Michael; Reuschlé, Thierry; Baud, Patrick; Schmittbuhl, Jean

    2015-04-01

    The permeability of an efficient reservoir, e.g. a geothermal reservoir, should be sufficient to permit the circulation of fluids. Generally speaking, permeability decreases over the life cycle of the geothermal system. As a result, is usually necessary to artificially maintain and enhance the natural permeability of these systems. One of the methods of enhancement -- studied here -- is thermal stimulation (injecting cold water at low pressure). This goal of this method is to encourage new thermal cracks within the reservoir host rocks, thereby increasing reservoir permeability. To investigate the development of thermal microcracking in the laboratory we selected two granites: a fine-grained (Garibaldi Grey granite, grain size = 0.5 mm) and a course-grained granite (Lanhelin granite, grain size = 2 mm). Both granites have an initial porosity of about 1%. Our samples were heated to a range of temperatures (100-1000 °C) and were either cooled slowly (1 °C/min) or shock cooled (100 °C/s). A systematic microstructural (2D crack area density, using standard stereological techniques, and 3D BET specific surface area measurements) and rock physical property (porosity, P-wave velocity, uniaxial compressive strength, and permeability) analysis was undertaken to understand the influence of slow and shock cooling on our reservoir granites. Microstructurally, we observe that the 2D crack surface area per unit volume and the specific surface area increase as a result of thermal stressing, and, for the same maximum temperature, crack surface area is higher in the shock cooled samples. This observation is echoed by our rock physical property measurements: we see greater changes for the shock cooled samples. We can conclude that shock cooling is an extremely efficient method of generating thermal microcracks and modifying rock physical properties. Our study highlights that thermal treatments are likely to be an efficient method for the "matrix" permeability enhancement of

  9. Heat Stress Reduces Intestinal Barrier Integrity and Favors Intestinal Glucose Transport in Growing Pigs

    PubMed Central

    Pearce, Sarah C.; Mani, Venkatesh; Boddicker, Rebecca L.; Johnson, Jay S.; Weber, Thomas E.; Ross, Jason W.; Rhoads, Robert P.; Baumgard, Lance H.; Gabler, Nicholas K.

    2013-01-01

    Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35–50% humidity; n = 8) or HS conditions (35°C; 24–43% humidity; n = 8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P = 0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-α (P = 0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na+/K+ ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P = 0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport. PMID:23936392

  10. Anatomical Abnormalities in Autism?

    PubMed

    Haar, Shlomi; Berman, Sigal; Behrmann, Marlene; Dinstein, Ilan

    2016-04-01

    Substantial controversy exists regarding the presence and significance of anatomical abnormalities in autism spectrum disorders (ASD). The release of the Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an unprecedented opportunity to conduct large-scale comparisons of anatomical MRI scans across groups and to resolve many of the outstanding questions. Comprehensive univariate analyses using volumetric, thickness, and surface area measures of over 180 anatomically defined brain areas, revealed significantly larger ventricular volumes, smaller corpus callosum volume (central segment only), and several cortical areas with increased thickness in the ASD group. Previously reported anatomical abnormalities in ASD including larger intracranial volumes, smaller cerebellar volumes, and larger amygdala volumes were not substantiated by the current study. In addition, multivariate classification analyses yielded modest decoding accuracies of individuals' group identity (<60%), suggesting that the examined anatomical measures are of limited diagnostic utility for ASD. While anatomical abnormalities may be present in distinct subgroups of ASD individuals, the current findings show that many previously reported anatomical measures are likely to be of low clinical and scientific significance for understanding ASD neuropathology as a whole in individuals 6-35 years old.

  11. Interactions between the intestinal microbiome and helminth parasites.

    PubMed

    Zaiss, M M; Harris, N L

    2016-01-01

    Throughout evolution, both helminths and bacteria have inhabited our intestines. As intestinal helminths and bacteria inhabit the same environmental niche, it is likely that these organisms interact with, and impact on, each other. In addition, intestinal helminths are well known to alter intestinal physiology, permeability, mucous secretion and the production of antimicrobial peptides - all of which may impact on bacterial survival and spatial organization. Yet despite rapid advances in our understanding of host-intestinal bacteria interactions, the impact of helminths on this relationship has remained largely unexplored. Moreover, although intestinal helminths are generally accepted to possess potent immuno-modulatory activity, it is unknown whether this capacity requires interactions with intestinal bacteria. We propose that this 'ménage à trois' situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Whilst such pressures remain in developing countries, the eradication of helminths in industrialized countries has shifted this evolutionary balance, possibly underlying the increased development of chronic inflammatory diseases. Thus, helminth-bacteria interactions may represent a key determinant of healthy homoeostasis.

  12. Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.

    PubMed

    Kadono, Keitaro; Akabane, Takafumi; Tabata, Kenji; Gato, Katsuhiko; Terashita, Shigeyuki; Teramura, Toshio

    2010-07-01

    This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.

  13. Diet, Microbiome, and the Intestinal Epithelium: An Essential Triumvirate?

    PubMed Central

    Guzman, Javier Rivera; Conlin, Victoria Susan; Jobin, Christian

    2013-01-01

    The intestinal epithelium represents a critical barrier protecting the host against diverse luminal noxious agents, as well as preventing the uncontrolled uptake of bacteria that could activate an immune response in a susceptible host. The epithelial monolayer that constitutes this barrier is regulated by a meshwork of proteins that orchestrate complex biological function such as permeability, transepithelial electrical resistance, and movement of various macromolecules. Because of its key role in maintaining host homeostasis, factors regulating barrier function have attracted sustained attention from the research community. This paper will address the role of bacteria, bacterial-derived metabolism, and the interplay of dietary factors in controlling intestinal barrier function. PMID:23586037

  14. Intestinal M cells

    PubMed Central

    Ohno, Hiroshi

    2016-01-01

    We have an enormous number of commensal bacteria in our intestine, moreover, the foods that we ingest and the water we drink is sometimes contaminated with pathogenic microorganisms. The intestinal epithelium is always exposed to such microbes, friend or foe, so to contain them our gut is equipped with specialized gut-associated lymphoid tissue (GALT), literally the largest peripheral lymphoid tissue in the body. GALT is the intestinal immune inductive site composed of lymphoid follicles such as Peyer’s patches. M cells are a subset of intestinal epithelial cells (IECs) residing in the region of the epithelium covering GALT lymphoid follicles. Although the vast majority of IEC function to absorb nutrients from the intestine, M cells are highly specialized to take up intestinal microbial antigens and deliver them to GALT for efficient mucosal as well as systemic immune responses. I will discuss recent advances in our understanding of the molecular mechanisms of M-cell differentiation and functions. PMID:26634447

  15. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  16. [Molecular abnormalities in lymphomas].

    PubMed

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  17. Impact of cremophor-EL and polysorbate-80 on digoxin permeability across rat jejunum: delineation of thermodynamic and transporter related events using the reciprocal permeability approach.

    PubMed

    Katneni, Kasiram; Charman, Susan A; Porter, Christopher J H

    2007-02-01

    The effect of Cremophor-EL (Cr-EL) and polysorbate-80 (PS-80) on the transepithelial permeability of digoxin (DIG) has been evaluated using the reciprocal permeability approach to delineate thermodynamic and transporter related events. Permeability data were corrected for solubilization using the micellar association constant (Ka) obtained from Papp data generated in the presence of the nonspecific ATPase inhibitor sodium orthovanadate. In the presence of mucosal Cr-EL, a concentration dependent decrease in serosal-mucosal (S-M) and increase in M-S transport was observed. Whilst serosal Cr-EL resulted in a reduction in S-M DIG transport, no impact on M-S transport was apparent. For PS-80, the presence of either serosal or mucosal surfactant led to a decrease in secretory (S-M) DIG transport, however no effect on absorptive transport was evident. The data confirm the potential P-gp inhibitory effects of Cr-EL, but suggest that in contrast to Cr-EL, PS-80 is not a potent inhibitor of P-gp and is incapable of increasing absorptive drug transport, at least in excised rat intestinal tissue and at the concentrations tested. The data are also consistent with the involvement of additional transporters (both apical and basolateral) in the intestinal permeability of DIG, although more definitive data is required to confirm this possibility.

  18. Acyl-homoserine lactones suppresses IEC-6 cell proliferation and increase permeability of isolated rat colon.

    PubMed

    Joe, Ga-Hyun; Andoh, Midori; Nomura, Mikako; Iwaya, Hitoshi; Lee, Jae-Sung; Shimizu, Hidehisa; Tsuji, Youhei; Maseda, Hideaki; Miyazaki, Hitoshi; Hara, Hiroshi; Ishizuka, Satoshi

    2014-01-01

    We investigated to determine whether a variety of acyl-homoserine lactones (AHLs) influences epithelial cell proliferation and mucosal permeability. 3-Oxo-C12-homoserine lactone (HSL) and 3-oxo-C14-HSL significantly suppressed IEC-6 cell proliferation. A significant increase in mucosal permeability was observed in isolated rat colon tissue exposed to C12-HSL, 3-oxo-C12-HSL, and 3-oxo-C14-HSL. These data indicate that AHLs suppress epithelial proliferation and disrupt barrier function in intestinal mucosa.

  19. Unsaturated fatty acids lactose esters: cytotoxicity, permeability enhancement and antimicrobial activity.

    PubMed

    Lucarini, Simone; Fagioli, Laura; Campana, Raffaella; Cole, Hannah; Duranti, Andrea; Baffone, Wally; Vllasaliu, Driton; Casettari, Luca

    2016-10-01

    Sugar based surfactants conjugated with fatty acid chains are an emerging broad group of highly biocompatible and biodegradable compounds with established and potential future applications in the pharmaceutical, cosmetic and food industries. In this work, we investigated absorption enhancing and antimicrobial properties of disaccharide lactose, monoesterified with unsaturated fatty acids through an enzymatic synthetic approach. After chemical and cytotoxicity characterizations, their permeability enhancing activity was demonstrated using intestinal Caco-2 monolayers through transepithelial electrical resistance (TEER) and permeability studies. The synthesized compounds, namely lactose palmitoleate (URB1076) and lactose nervonate (URB1077), were shown to exhibit antimicrobial activity versus eight pathogenic species belonging to Gram-positive, Gram-negative microorganisms and fungi.

  20. Turbulent drag reduction by permeable coatings

    NASA Astrophysics Data System (ADS)

    Garcia-Mayoral, Ricardo; Abderrahaman-Elena, Nabil

    2015-11-01

    We present an assessment of permeable coatings as a form of passive drag reduction, proposing a simplified model to quantify the effect of the coating thickness and permeability. To reduce skin friction, the porous layer must be preferentially permeable in the streamwise direction, so that a slip effect is produced. For small permeability, the controlling parameter is the difference between streamwise and spanwise permeability lengths, scaled in viscous units, √{Kx+}-√{Kz+}. In this regime, the reduction in drag is proportional to that difference. However, the proportional performance eventually breaks down for larger permeabilities. A degradation mechanism is investigated, common to other obstructed surfaces in general and permeable substrates in particular, which depends critically on the geometric mean of the streamwise and wall-normal permeabilities, √{Kx+ Ky+}. For a streamwise-to-cross-plane permeability ratio of order Kx+/Ky+ = Kx+/Kz+ 10 -100, the model predicts a maximum drag reduction of order 15-25%.

  1. Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine.

    PubMed

    Ruhr, Ilan M; Bodinier, Charlotte; Mager, Edward M; Esbaugh, Andrew J; Williams, Cameron; Takei, Yoshio; Grosell, Martin

    2014-11-01

    The physiological effects of guanylin (GN) and uroguanylin (UGN) on fluid and electrolyte transport in the teleost fish intestine have yet to be thoroughly investigated. In the present study, the effects of GN, UGN, and renoguanylin (RGN; a GN and UGN homolog) on short-circuit current (Isc) and the transport of Cl-, Na+, bicarbonate (HCO3-), and fluid in the Gulf toadfish (Opsanus beta) intestine were determined using Ussing chambers, pH-stat titration, and intestinal sac experiments. GN, UGN, and RGN reversed the Isc of the posterior intestine (absorptive-to-secretory), but not of the anterior intestine. RGN decreased baseline HCO3- secretion, but increased Cl- and fluid secretion in the posterior intestine. The secretory response of the posterior intestine coincides with the presence of basolateral NKCC1 and apical cystic fibrosis transmembrane conductance regulator (CFTR), the latter of which is lacking in the anterior intestine and is not permeable to HCO3- in the posterior intestine. However, the response to RGN by the posterior intestine is counterintuitive given the known role of the marine teleost intestine as a salt- and water-absorbing organ. These data demonstrate that marine teleosts possess a tissue-specific secretory response, apparently associated with seawater adaptation, the exact role of which remains to be determined.

  2. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  3. Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility–Permeability Interplay

    PubMed Central

    Beig, Avital; Lindley, David; Miller, Jonathan M.; Agbaria, Riad; Dahan, Arik

    2016-01-01

    Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs’ permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility–permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility–permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ∼30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (∼17-fold for nicotinamide and ∼9-fold for urea), revealing a solubility–permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility–permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility–permeability balance may promote the overall goal of the formulation to maximize oral drug exposure. PMID:27826241

  4. Intestinal lymphangiectasia in children

    PubMed Central

    Isa, Hasan M.; Al-Arayedh, Ghadeer G.; Mohamed, Afaf M.

    2016-01-01

    Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation of intestinal lymphatics. It can be classified as primary or secondary according to the underlying etiology. The clinical presentations of IL are pitting edema, chylous ascites, pleural effusion, acute appendicitis, diarrhea, lymphocytopenia, malabsorption, and intestinal obstruction. The diagnosis is made by intestinal endoscopy and biopsies. Dietary modification is the mainstay in the management of IL with a variable response. Here we report 2 patients with IL in Bahrain who showed positive response to dietary modification. PMID:26837404

  5. Intestinal transplantation: a review.

    PubMed

    Desai, Chirag Sureshchandra; Khan, Khalid Mahmood; Girlanda, Raffaele; Fishbein, Thomas M

    2012-09-01

    Parenteral nutrition is a life-saving therapy for patients with intestinal failure. Intestinal transplantation is now recognized as a treatment for patients who develop complications of parenteral nutrition and in whom attempts at intestinal rehabilitation have failed. Patients with parenteral nutrition related liver disease will require a liver graft typically part of a multivisceral transplant. Isolated intestinal transplants are more commonly performed in adults while multivisceral transplants are most commonly performed in infants. Isolated intestinal transplants have the best short-term outcome, with over 80 % survival at 1 year. Patients requiring multivisceral transplants have a high rate of attrition with a 1 year survival less than 70 %. Prognostic factors for a poor outcome include patient hospitalization at the time of transplant and donor age greater than 40 years while systemic sepsis and acute rejection are the major determinant of early postoperative outcome. For patients surviving the first year the outcome of transplantation of the liver in addition to intestine affords some survival advantage though long-term outcome does not yet match other abdominal organs. Outcomes for intestinal retransplantation are poor as a result of immunology and patient debility. Overall intestinal transplantation continues to develop and is a clear indication with cost and quality of life advantages in patients with intestinal failure that do not remain stable on parenteral nutrition.

  6. Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract.

    PubMed

    Masaoka, Yoshie; Tanaka, Yusuke; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

    2006-11-01

    This study was conducted to assess the site of drug absorption in the gastrointestinal (GI) tract after oral administration. Drug permeability to different regions of rat intestine, jejunum, ileum and colon, was measured by in situ single-pass perfusion method. It was revealed that the epithelial surface area should not be a determinant of the regional difference in the intestinal permeability of highly permeable drugs. Effects of the mucus layer at the surface of the epithelium and the fluidity of the epithelial cell membrane on the drug permeability were investigated. These factors are demonstrated to contribute to the regional differences in intestinal drug permeability. The luminal drug concentration in each segment of the GI tract after oral administration was measured directly in fasted rats. Water ingested orally was absorbed quickly in the jejunum and the luminal fluid volume was diminished in the middle to lower part of the small intestine. According to the absorption of water luminal concentration of atenolol, a drug with low permeability, was elevated and exceeded the initial dose concentration. In contrast, the concentration of highly permeable drugs, antipyrine and metoprolol, decreased quickly in the upper part of the intestine and a significant amount of drugs was not detected in the lower jejunum and the ileum. From the time-profiles of luminal drug concentration, fraction of dose absorbed from each segment of the GI tract was calculated. Both antipyrine and metoprolol were found to be absorbed quickly at the upper part of the small intestine. In addition, the possible contribution of gastric absorption was demonstrated for these drugs. The pattern of site-dependent absorption of atenolol showed the higher absorbability in the middle and lower portion of the jejunum. These informations on site-dependent absorption of drugs are considered to be important for effective oral delivery systems.

  7. Rigid gas permeable extended wear.

    PubMed

    Maehara, J R; Kastl, P R

    1994-04-01

    We have reviewed the pertinent literature on rigid gas permeable (RGP) extended wear contact lenses, and we discuss the benefits and adverse reactions of this contact lens modality, drawing conclusions from reviewed studies. We suggest parameters for success with these lenses and guidelines for the prevention of adverse reactions.

  8. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  9. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  10. The protective effect of supplemental calcium on colonic permeability depends on a calcium phosphate-induced increase in luminal buffering capacity.

    PubMed

    Schepens, Marloes A A; ten Bruggencate, Sandra J M; Schonewille, Arjan J; Brummer, Robert-Jan M; van der Meer, Roelof; Bovee-Oudenhoven, Ingeborg M J

    2012-04-01

    An increased intestinal permeability is associated with several diseases. Previously, we have shown that dietary Ca decreases colonic permeability in rats. This might be explained by a calcium-phosphate-induced increase in luminal buffering capacity, which protects against an acidic pH due to microbial fermentation. Therefore, we investigated whether dietary phosphate is a co-player in the effect of Ca on permeability. Rats were fed a humanised low-Ca diet, or a similar diet supplemented with Ca and containing either high, medium or low phosphate concentrations. Chromium-EDTA was added as an inert dietary intestinal permeability marker. After dietary adaptation, short-chain fructo-oligosaccharides (scFOS) were added to all diets to stimulate fermentation, acidify the colonic contents and induce an increase in permeability. Dietary Ca prevented the scFOS-induced increase in intestinal permeability in rats fed medium- and high-phosphate diets but not in those fed the low-phosphate diet. This was associated with higher faecal water cytotoxicity and higher caecal lactate levels in the latter group. Moreover, food intake and body weight during scFOS supplementation were adversely affected by the low-phosphate diet. Importantly, luminal buffering capacity was higher in rats fed the medium- and high-phosphate diets compared with those fed the low-phosphate diet. The protective effect of dietary Ca on intestinal permeability is impaired if dietary phosphate is low. This is associated with a calcium phosphate-induced increase in luminal buffering capacity. Dragging phosphate into the colon and thereby increasing the colonic phosphate concentration is at least part of the mechanism behind the protective effect of Ca on intestinal permeability.

  11. High membrane permeability for melatonin

    PubMed Central

    Yu, Haijie; Dickson, Eamonn J.; Jung, Seung-Ryoung; Koh, Duk-Su

    2016-01-01

    The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were designed to compare the cell membrane permeability to three indoleamines: melatonin and its precursors N-acetylserotonin (NAS) and serotonin (5-HT). The three experimental approaches were (1) to measure the concentration of effluxing indoleamines amperometrically in the bath while cells were being dialyzed internally by a patch pipette, (2) to measure the rise of intracellular indoleamine fluorescence as the compound was perfused in the bath, and (3) to measure the rate of quenching of intracellular fura-2 dye fluorescence as indoleamines were perfused in the bath. These measures showed that permeabilities of melatonin and NAS are high (both are uncharged molecules), whereas that for 5-HT (mostly charged) is much lower. Comparisons were made with predictions of solubility-diffusion theory and compounds of known permeability, and a diffusion model was made to simulate all of the measurements. In short, extracellular melatonin equilibrates with the cytoplasm in 3.5 s, has a membrane permeability of ∼1.7 µm/s, and could not be retained in secretory vesicles. Thus, it and NAS will be “secreted” from pineal cells by membrane diffusion. Circumstances are suggested when 5-HT and possibly catecholamines may also appear in the extracellular space passively by membrane diffusion. PMID:26712850

  12. Can lipid nanoparticles improve intestinal absorption?

    PubMed

    Mendes, M; Soares, H T; Arnaut, L G; Sousa, J J; Pais, A A C C; Vitorino, C

    2016-12-30

    Lipid nanoparticles and their multiple designs have been considered appealing nanocarrier systems. Bringing the benefits of these nanosystems together with conventional coating technology clearly results in product differentiation. This work aimed at developing an innovative solid dosage form for oral administration based on tableting nanostructured lipid carriers (NLC), coated with conventional polymer agents. NLC dispersions co-encapsulating olanzapine and simvastatin (Combo-NLC) were produced by high pressure homogenization, and evaluated in terms of scalability, drying procedure, tableting and performance from in vitro release, cytotoxicity and intestinal permeability stand points. Factorial design indicated that the scaling-up of the NLC production is clearly feasible. Spray-drying was the method selected to obtain dry particles, not only because it consists of a single step procedure, but also because it facilitates the coating process of NLC with different polymers. Modified NLC formulations with the polymers allowed obtaining distinct release mechanisms, comprising immediate, delayed and prolonged release. Sureteric:Combo-NLC provided a low cytotoxicity profile, along with a ca. 12-fold OL/3-fold SV higher intestinal permeability, compared to those obtained with commercial tablets. Such findings can be ascribed to drug protection and control over release promoted by NLC, supporting them as a versatile platform able to be modified according to the intended needs.

  13. Intestinal or bowel obstruction - discharge

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000150.htm Intestinal or bowel obstruction - discharge To use the sharing features on this ... your bowel (intestine). This condition is called an intestinal obstruction . The blockage may be partial or total (complete). ...

  14. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  15. Intestinal obstruction repair - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100116.htm Intestinal obstruction repair - series—Normal anatomy To use the sharing ... M. Editorial team. Related MedlinePlus Health Topics Adhesions Intestinal Obstruction A.D.A.M., Inc. is accredited by ...

  16. Intestinal obstruction (pediatric) - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100165.htm Intestinal obstruction (pediatric) - series—Normal anatomy To use the sharing ... A.M. Editorial team. Related MedlinePlus Health Topics Intestinal Obstruction A.D.A.M., Inc. is accredited by ...

  17. Quantifying Evaporation in a Permeable Pavement System

    EPA Science Inventory

    Studies quantifying evaporation from permeable pavement systems are limited to a few laboratory studies and one field application. This research quantifies evaporation for a larger-scale field application by measuring the water balance from lined permeable pavement sections. Th...

  18. Drug permeability prediction using PMF method.

    PubMed

    Meng, Fancui; Xu, Weiren

    2013-03-01

    Drug permeability determines the oral availability of drugs via cellular membranes. Poor permeability makes a drug unsuitable for further development. The permeability may be estimated as the free energy change that the drug should overcome through crossing membrane. In this paper the drug permeability was simulated using molecular dynamics method and the potential energy profile was calculated with potential of mean force (PMF) method. The membrane was simulated using DPPC bilayer and three drugs with different permeability were tested. PMF studies on these three drugs show that doxorubicin (low permeability) should pass higher free energy barrier from water to DPPC bilayer center while ibuprofen (high permeability) has a lower energy barrier. Our calculation indicates that the simulation model we built is suitable to predict drug permeability.

  19. Permeable Pavement Research - Edison, New Jersey

    EPA Science Inventory

    This presentation provides the background and summary of results collected at the permeable pavement parking lot monitored at the EPA facility in Edison, NJ. This parking lot is surfaced with permeable interlocking concrete pavers (PICP), pervious concrete, and porous asphalt. ...

  20. The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests.

    PubMed

    Kim, Jae-Seung; Mitchell, Stefanie; Kijek, Paul; Tsume, Yasuhiro; Hilfinger, John; Amidon, Gordon L

    2006-01-01

    The FDA has published recommendations for sponsors who wish to request a waiver of in vivo bioavailability (BA) or bioequivalence (BE) studies for immediate release (IR) solid oral dosage forms based on the Biopharmaceutics Classification System (BCS). Biowaivers can be requested for IR formulations in which the active ingredient is shown to be a BCS class I drug: that is, a drug showing high permeability and high solubility over a pH range of 1-7.5. For permeability determinations, a variety of experimental methods can be used, such as the rat in situ single pass perfusion or Caco-2 cell culture models, once the suitability of the particular method is established. Following the recommended procedure for assessing the suitability of permeability determinations, we determined the permeability of 20 test drugs using the in situ single pass perfusion model in rats. The test compounds were coperfused through jejunal intestinal segments with an internal permeability reference standard (metoprolol) over a 90 min time period. Sample analysis was performed by HPLC, and the ratio of the effective permeability, Peff (cm/s), of test compound to that of metoprolol was determined. To address the question of test drug permeabilities that approach that of the internal standard, we propose that a statistical analysis such as the "0.8-1.25 rule" used for in vivo or in vitro bioequivalence studies provide guidance for permeability classification using the in situ single pass perfusion model. We developed a method using the 90% confidence interval of the permeability ratio of the test to internal reference standard in order to differentiate between high and low permeability compounds. This analysis allowed for the proper permeability classification of all of the test compounds and suggests a robust means for assessing drug permeability classification.

  1. The Intestinal Microbiota and Irritable Bowel Syndrome.

    PubMed

    Ringel, Yehuda; Ringel-Kulka, Tamar

    2015-01-01

    Irritable bowel syndrome (IBS) is the most prevalent and the best studied functional gastrointestinal disorder. The etiology and the pathogenesis of IBS are still not clear; however, recent studies have implicated a role for alterations in the intestinal microbiota (dysbiosis) in the pathophysiology of the disorder. Epidemiological observations have demonstrated that the development of IBS symptoms is often preceded by a disruption of the individual's normal intestinal microbiota, and microbiological studies have demonstrated compositional differences in the intestinal microbiota between patients with IBS patients and healthy controls. In addition, animal studies and a few recent human clinical studies have demonstrated that compositional changes in the intestinal microbiota in IBS are associated with relevant abnormal gastrointestinal and brain-gut axis functions that are often observed in patients with IBS. This article discusses points of interest from the current research on the microbiota-gut-brain interactions in IBS and highlights the relevance of the emerging data to our understanding of the disorder and the clinical implications for patients' care.

  2. Novel additives to retard permeable flow

    SciTech Connect

    Golombok, Michael; Crane, Carel; Ineke, Erik; Welling, Marco; Harris, Jon

    2008-09-15

    Low concentrations of surfactant and cosolute in water, can selectively retard permeable flow in high permeability rocks compared to low permeability ones. This represents a way forward for more efficient areal sweep efficiency when water flooding a reservoir during improved oil recovery. (author)

  3. Review of Hydrogen Isotope Permeability Through Materials

    SciTech Connect

    Steward, S. A.

    1983-08-15

    This report is the first part of a comprehensive summary of the literature on hydrogen isotope permeability through materials that do not readily form hydrides. While we mainly focus on pure metals with low permeabilities because of their importance to tritium containment, we also give data on higher-permeability materials such as iron, nickel, steels, and glasses.

  4. Structure/Permeability Relationships Of Polyimide Membranes

    NASA Technical Reports Server (NTRS)

    St. Clair, A. K.; Yamamoto, H.; Mi, Y.; Stern, S. A.

    1995-01-01

    Report describes experimental study of permeabilities, by each of five gases, of membranes made of four different polyimides. Conducted to gain understanding of effects of molecular structures of membranes on permeabilities and to assess potential for exploitation of selective permeability in gas-separation processes. Gases used: H2, O2, N2, CO2, and CH4.

  5. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability

    PubMed Central

    Cani, P D; Possemiers, S; Van de Wiele, T; Guiot, Y; Everard, A; Rottier, O; Geurts, L; Naslain, D; Neyrinck, A; Lambert, D M; Muccioli, G G; Delzenne, N M

    2009-01-01

    Background and aims: Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Methods: Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Results: Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. Conclusion: We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism

  6. Nexal membrane permeability to anions

    PubMed Central

    1978-01-01

    The permeability of the septa of the earthworm in the median axon has been calculated for the anions fluorescein and its halogen derivatives. The values ranged from 5.4 X 10(-5) to 4 X 10(-6) cm/s. Previously, the septa had been shown to contain nexuses. By using freeze-fracture material, the surface area of nexus on the septal membranes was determined to be 4.5%, very similar to the percentage of nexus in the intercalated disk of mammalian myocardium. Plasma membrane permeability to these dyes was also calculated and shown to be much less than that of the septal membranes. In addition, an estimate of cytoplasmic binding for each dye was made, and most dyes showed little or no binding with the exception of aminofluorescein. PMID:702107

  7. THE GRADIENT OF VASCULAR PERMEABILITY

    PubMed Central

    Smith, Frederick; Rous, Peyton

    1931-01-01

    A mounting gradient of permeability exists along the capillaries of frog muscle. In chicken muscle on the other hand none has been demonstrated; but the close-knit vascularization is arranged in duplicate in such manner that the blood runs in opposite directions through the capillaries of nearly adjacent fibres. In a flight muscle of the pigeon there exists in addition to this artifice what appears to be a special collecting system of venous capillaries. In the mammalian diaphragm indications of such a system are also to be found, and a gradient of capillary permeability like that in the other skeletal muscles is probably present. These vascular conditions are briefly considered in terms of function. PMID:19869836

  8. Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays.

    PubMed

    Lee, Jong Bong; Zgair, Atheer; Taha, Dhiaa A; Zang, Xiaowei; Kagan, Leonid; Kim, Tae Hwan; Kim, Min Gi; Yun, Hwi-Yeol; Fischer, Peter M; Gershkovich, Pavel

    2017-01-12

    In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The differences were assessed by determining the root mean square error (RMSE) values between the datasets, which reached levels as high as 0.581 for the training set compounds, i.e. ten compounds with known effective human permeability (Peff). The consequences of these differences in Papp for prediction of oral drug absorption were demonstrated by introducing the Papp into the absorption and pharmacokinetics simulation software application GastroPlus™ for prediction of the fraction absorbed (Fa) in humans using calibrated "user-defined permeability models". The RMSE were calculated to assess the differences between the simulated Fa and experimental values reported in the literature. The RMSE for Fa simulated with the permeability model calibrated using experimental Papp from our laboratory was 0.128. When the calibration was performed using Papp from literature datasets, the RMSE values for Fa were higher in all cases except one. This study shows quantitative lab-to-lab variability of Caco-2 permeability results and the potential consequences this can have in the use of these results for predicting intestinal absorption of drugs.

  9. Skeletal abnormalities in homocystinuria.

    PubMed Central

    Brenton, D. P.

    1977-01-01

    The skeletal changes of thirty-four patients with the biochemical and clinical features of cystathionine synthase deficiency are described. It is emphasized that there is clinical evidence of excessive bone growth and the formation for bone which is structurally weaker than normal. The similarities and differences between this condition and Marfan's syndrome are stressed and the possible nature of the connective tissue defect leading to the skeletal changes discussed. The most characteristic skeletal changes in homocystinuria are the skeletal disproportion (pubis-heel length greater than crown-pubis length), the abnormal vertebrae, sternal deformities, genu valgum and large metaphyses and epiphyses. Images Fig. 2 Fig. 3 Fig. 4 Fig. 8 Fig. 9 Fig. 10 PMID:917963

  10. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem.

  11. Experimental Volcanology: Fragmentation and Permeability

    NASA Astrophysics Data System (ADS)

    Spieler, O.

    2005-12-01

    An increasing number of scientists design new experiments to analyse processes that control the dynamics of explosive eruptions. There research is mostly coupled to numerical models and aims toward its controlling parameters. The fragmentation process, its threshold and the speed of the fragmentation wave as well as the energy consumed by the fragmentation are some hot spots of the experimental volcanology. Analysing the fragmentation behaviour of volcaniclastics as close to the natural system as possible, we found a number of physical constrains. Identifying the porosity as determining factor of the threshold, we realised that neither threshold nor the speed of the fragmentation process are solely controlled by the rock density. The later results of the shock tube type apparatus lead to the analysis of the specific surface area and permeability as direct links to textural features. Permeability analysis performed in a modified shock tube type apparatus, show two clear, distinct trends for dome rock and pyroclastic samples. The specific surface determined by Argon sorbtion (BET) as well as textural features of pumices from Campi Flegrei, Montserrat and Krakatoa (1883) give in contrary evidence of a more complex story. Large spherical, or ellipsoidal bubbles around fractured crystals prove that the high permeability of the pumice has partially developed after the fixing of the bubble size distribution. This puts up the question, if permeability measurements on pyroclastic samples reveal relevant numbers! The surface tension controlled 'self sealing' behaviour of surfaces from foaming obsidian hinders in situ measurements. Close textural investigations will have to clarify how the 'post process' samples deviate from the syneruptive conduit filling.

  12. Models to predict intestinal absorption of therapeutic peptides and proteins.

    PubMed

    Antunes, Filipa; Andrade, Fernanda; Ferreira, Domingos; Nielsen, Hanne Morck; Sarmento, Bruno

    2013-01-01

    Prediction of human intestinal absorption is a major goal in the design, optimization, and selection of drugs intended for oral delivery, in particular proteins, which possess intrinsic poor transport across intestinal epithelium. There are various techniques currently employed to evaluate the extension of protein absorption in the different phases of drug discovery and development. Screening protocols to evaluate protein absorption include a range of preclinical methodologies like in silico, in vitro, in situ, ex vivo and in vivo. It is the careful and critical use of these techniques that can help to identify drug candidates, which most probably will be well absorbed from the human intestinal tract. It is well recognized that the human intestinal permeability cannot be accurately predicted based on a single preclinical method. However, the present social and scientific concerns about the animal well care as well as the pharmaceutical industries need for rapid, cheap and reliable models predicting bioavailability give reasons for using methods providing an appropriate correlation between results of in vivo and in vitro drug absorption. The aim of this review is to describe and compare in silico, in vitro, in situ, ex vivo and in vivo methods used to predict human intestinal absorption, giving a special attention to the intestinal absorption of therapeutic peptides and proteins.

  13. Mucositis and non-invasive markers of small intestinal function.

    PubMed

    Tooley, Katie L; Howarth, Gordon S; Butler, Ross N

    2009-05-01

    Mucositis is a common and debilitating side effect of chemotherapy that manifests due to the inability of chemotherapy agents to discriminate between normal and neoplastic cells. This results in ulcerating lesions lining the gastrointestinal tract. Moreover, the development of efficacious treatments for small intestinal mucositis has been hindered as the pathobiology of mucositis is still not fully understood. The small intestine is an extensive organ which is largely inaccessible by conventional means. Non-invasive biomarkers such as small intestinal permeability, H(2) breath tests, serum citrulline tests and the (13)C-sucrose breath test (SBT) have emerged as potential markers of small intestinal function. The SBT is emerging as the more appropriate biomarker to assess chemotherapy-induced mucositis in cancer patients and animal models, where it measures the decrease in sucrase activity associated with villus blunting and crypt disruption. The SBT has been successfully applied to detect mucositis induced by different classes of chemotherapy agents and has been used successfully to monitor small intestinal function with a range of candidate anti-mucositis treatments. We propose the SBT a superior biomarker of small intestinal function that could be successfully applied in clinical practice for monitoring the development of mucositis in cancer patients undergoing chemotherapy.

  14. From gut microflora imbalance to mycobacteria infection: is there a relationship with chronic intestinal inflammatory diseases?

    PubMed

    Tomasello, Giovanni; Bellavia, Maurizio; Palumbo, Vincenzo Davide; Gioviale, Maria Concetta; Damiani, Provvidenza; Lo Monte, Attilio Ignazio

    2011-01-01

    The gut of a healthy adult harbours a myriad of different microbial species. It is estimated that approximately 10 14 are present in total bacterial colony forming units (CFU). Each colony colonizes a specific intestinal tract. In healthy adult, the main control of intestinal bacterial colonization occurs through gastric acidity but also other factors can influence the intestinal microenvironment such as pH, temperature, competition among different bacterial strains, peristalsis, drugs, radiotherapy and much more. Impaired microbial homeostasis leads to an alteration of the permeability of tissue, together with the activation of the intestinal immune system MALT (mucosal associated lymphoid tissue). In this regard we discuss the increasing experimental evidences of the role of commensal microbiota in the activation of specific intestinal immunocompetent cells. The aforementioned micro-environmental changes provide the substrate for the etiopathogenetic outbreak of numerous pathologies of gastro-intestinal tract, such as intestinal chronic inflammation (Crohn's disease and Ulcerative Colitis), together with a miscellany of extra intestinal disorders. This article is an overview of the latest scientific findings about the close causal relationship between intestinal microbial flora and inflammatory bowel diseases or other extra-intestinal diseases; it is also mentioned the possible relationship between mycobacteria and Chron's disease. Finally we analyse the beneficial role of probiotics.

  15. Epidermal Vascular Endothelial Growth Factor Production Is Required for Permeability Barrier Homeostasis, Dermal Angiogenesis, and the Development of Epidermal Hyperplasia

    PubMed Central

    Elias, Peter M.; Arbiser, Jack; Brown, Barbara E.; Rossiter, Heidemarie; Man, Mao-Qiang; Cerimele, Francesca; Crumrine, Debra; Gunathilake, Roshan; Choi, Eung Ho; Uchida, Yoshikazu; Tschachler, Erwin; Feingold, Kenneth R.

    2008-01-01

    Primary abnormalities in permeability barrier function appear to underlie atopic dermatitis and epidermal trauma; a concomitant barrier dysfunction could also drive other inflammatory dermatoses, including psoriasis. Central to this outside-inside view of disease pathogenesis is the epidermal generation of cytokines/growth factors, which in turn signal downstream epidermal repair mechanisms. Yet, this cascade, if sustained, signals downstream epidermal hyperplasia and inflammation. We found here that acute barrier disruption rapidly stimulates mRNA and protein expression of epidermal vascular endothelial growth factor-A (VEGF-A) in normal hairless mice, a specific response to permeability barrier requirements because up-regulation is blocked by application of a vapor-impermeable membrane. Moreover, epidermal vegf−/− mice display abnormal permeability barrier homeostasis, attributable to decreased VEGF signaling of epidermal lamellar body production; a paucity of dermal capillaries with reduced vascular permeability; and neither angiogenesis nor epidermal hyperplasia in response to repeated tape stripping (a model of psoriasiform hyperplasia). These results support a central role for epidermal VEGF in the maintenance of epidermal permeability barrier homeostasis and a link between epidermal VEGF production and both dermal angiogenesis and the development of epidermal hyperplasia. Because psoriasis is commonly induced by external trauma [isomorphic (Koebner) phenomenon] and is associated with a prominent permeability barrier abnormality, excess VEGF production, prominent angiogenesis, and epidermal hyperplasia, these results could provide a potential outside-inside mechanistic basis for the development of psoriasis. PMID:18688025

  16. Stress modulates intestinal secretory immunoglobulin A

    PubMed Central

    Campos-Rodríguez, Rafael; Godínez-Victoria, Marycarmen; Abarca-Rojano, Edgar; Pacheco-Yépez, Judith; Reyna-Garfias, Humberto; Barbosa-Cabrera, Reyna Elizabeth; Drago-Serrano, Maria Elisa

    2013-01-01

    Stress is a response of the central nervous system to environmental stimuli perceived as a threat to homeostasis. The stress response triggers the generation of neurotransmitters and hormones from the hypothalamus pituitary adrenal axis, sympathetic axis and brain gut axis, and in this way modulates the intestinal immune system. The effects of psychological stress on intestinal immunity have been investigated mostly with the restraint/immobilization rodent model, resulting in an up or down modulation of SIgA levels depending on the intensity and time of exposure to stress. SIgA is a protein complex formed by dimeric (dIgA) or polymeric IgA (pIgA) and the secretory component (SC), a peptide derived from the polymeric immunoglobulin receptor (pIgR). The latter receptor is a transmembrane protein expressed on the basolateral side of gut epithelial cells, where it uptakes dIgA or pIgA released by plasma cells in the lamina propria. As a result, the IgA-pIgR complex is formed and transported by vesicles to the apical side of epithelial cells. pIgR is then cleaved to release SIgA into the luminal secretions of gut. Down modulation of SIgA associated with stress can have negative repercussions on intestinal function and integrity. This can take the form of increased adhesion of pathogenic agents to the intestinal epithelium and/or an altered balance of inflammation leading to greater intestinal permeability. Most studies on the molecular and biochemical mechanisms involved in the stress response have focused on systemic immunity. The present review analyzes the impact of stress (mostly by restraint/immobilization, but also with mention of other models) on the generation of SIgA, pIgR and other humoral and cellular components involved in the intestinal immune response. Insights into these mechanisms could lead to better therapies for protecting against pathogenic agents and avoiding epithelial tissue damage by modulating intestinal inflammation. PMID:24348350

  17. Oleic acid-induced mucosal injury in developing piglet intestine.

    PubMed

    Velasquez, O R; Henninger, K; Fowler, M; Tso, P; Crissinger, K D

    1993-03-01

    A role for luminal nutrients, in particular products of lipid digestion, in the pathogenesis of mucosal injury to developing intestine has been postulated. We evaluated changes in mucosal permeability and light and electron microscopic histology induced by luminal perfusion with the long-chain fatty acid oleate in developing piglet intestine as a function of age and concentration of the fatty acid. 51Cr-labeled EDTA plasma-to-lumen clearance was measured in jejunum and ileum of 1-day-, 3-day-, 2-wk-, and 1-mo-old piglets during sequential perfusion with saline control (20 min); 0, 1, 5, and 10 mM oleic acid/10 mM taurocholate in saline (20 min); and normal saline (60 min). The jejunum of piglets < or = 2 wk showed significantly greater increases in mucosal permeability compared with 1-mo-old animals after perfusion with oleic acid. This effect was dependent on the luminal concentration of the fatty acid and was associated with mucosal injury evident under light and electron microscopy. In contrast, the overall response in ileum was more attenuated compared with jejunum. Thus oleic acid, a common dietary fatty acid, induces dose- and age-dependent injury in developing piglet intestine. Investigation of the mechanisms of this injury may provide the basis for dietary modifications directed at decreasing the risk of mucosal injury during enteral feeding in neonatal intestine.

  18. Unraveling the ties between irritable bowel syndrome and intestinal microbiota

    PubMed Central

    Hong, Sung Noh; Rhee, Poong-Lyul

    2014-01-01

    Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorder. It is a multifactorial disorder. Intestinal microbiota may cause the pathogenesis of IBS by contributing to abnormal gastrointestinal motility, low-grade inflammation, visceral hypersensitivity, communication in the gut-brain axis, and so on. Previous attempts to identify the intestinal microbiota composition in IBS patients have yielded inconsistent and occasionally contradictory results. This inconsistency may be due to the differences in the molecular techniques employed, the sample collection and handling methods, use of single samples that are not linked to fluctuating symptoms, or other factors such as patients’ diets and phenotypic characterizations. Despite these difficulties, previous studies found that the intestinal microbiota in some IBS patients was completely different from that in healthy controls, and there does appear to be a consistent theme of Firmicutes enrichment and reduced abundance of Bacteroides. Based on the differences in intestinal microbiota composition, many studies have addressed the roles of microbiota-targeted treatments, such as antibiotics and probiotics, in alleviating certain symptoms of IBS. This review summarizes the current knowledge of the associations between intestinal microbiota and IBS as well as the possible modes of action of intestinal microbiota in the pathogenesis of IBS. Improving the current level of understanding of host-microbiota interactions in IBS is important not only for determining the role of intestinal microbiota in IBS pathogenesis but also for therapeutic modulation of the microbiota. PMID:24627584

  19. Microencapsulation of self-microemulsifying system: improving solubility and permeability of furosemide.

    PubMed

    Zvonar, A; Berginc, K; Kristl, A; Gasperlin, M

    2010-03-30

    The primary goal of this study was to formulate Ca-pectinate microcapsules with self-microemulsifying core to enhance the solubility and permeability of BCS class IV drug furosemide. An Inotech IE-50R encapsulator equipped with a concentric nozzle was utilized to transform liquid self-microemulsifying system (SMES) to solid microcapsules. Self-microemulsifying core was optimized with respect to drug loading capacity and encapsulation efficiency and evaluated for its impact on furosemide permeability through rat small intestine and Caco-2 cell monolayers. Retention of the core phase was considerably improved (up to 70-80%) by optimization of the SMES and microcapsules' drying process. Incorporation of furosemide in self-microemulsifying core of microcapsules resulted in improved permeability and drug release characteristics in comparison to microspheres (without SMES in the core). The obtained results illustrate the prospective use of microcapsules with self-microemulsifying core for the delivery of compounds with poor biopharmaceutical properties via the oral route.

  20. The effect of hyperosmosis on paracellular permeability in Caco-2 cell monolayers.

    PubMed

    Inokuchi, Hitoshi; Takei, Takuto; Aikawa, Katsuyoshi; Shimizu, Makoto

    2009-02-01

    The intestinal epithelium is a significant barrier to oral absorption of hydrophilic compounds, and their passage through the intercellular space is restricted by the tight junctions. In this study we found that hyperosmosis is a significant factor altering paracellular transport in Caco-2 cell monolayers. Osmotic regulators, such as sodium chloride, mannitol, and raffinose, decreased transepithelial electrical resistance and enhanced lucifer yellow permeability. The effect of these osmotic regulators on Caco-2 cell monolayers was not likely to be caused by gross cytotoxicity. Although certain amino acids and oligosaccharides have been reported to have specific tight junction-modulating activity, we found that the increased paracellular permeability of Caco-2 monolayers induced by these compounds was at least partly due to the increased osmotic pressure of the test solutions. These findings provide a new potential precaution in the evaluation of paracellular permeability-modulating substances using the Caco-2 cell monolayer system.

  1. Synthesis and Characterization of a New Peptide Prodrug of Glucosamine with Enhanced Gut Permeability

    PubMed Central

    Gilzad Kohan, Hamed; Kaur, Kamaljit; Jamali, Fakhreddin

    2015-01-01

    The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a quick cleavage to GlcN after exposure to the liver homogenate. In conclusion, a novel prodrug of glucosamine with superior gut permeability compared to GlcN was developed and successfully tested in vitro. PMID:25978315

  2. Potential benefits of pro- and prebiotics on intestinal mucosal immunity and intestinal barrier in short bowel syndrome.

    PubMed

    Stoidis, Christos N; Misiakos, Evangelos P; Patapis, Paul; Fotiadis, Constantine I; Spyropoulos, Basileios G

    2011-06-01

    The mechanism of impaired gut barrier function in patients with short bowel syndrome (SBS) is poorly understood and includes decreased intestinal motility leading to bacterial overgrowth, a reduction in gut-associated lymphoid tissue following the loss of intestinal length, inhibition of mucosal immunity of the small intestine by intravenous total parental nutrition, and changes in intestinal permeability to macromolecules. Novel therapeutic strategies (i.e. nutritive and surgical) have been introduced in order to prevent the establishment or improve the outcome of this prevalent disease. Pre- and probiotics as a nutritive supplement are already known to be very active in the intestinal tract (mainly in the colon) by maintaining a healthy gut microflora and influencing metabolic, trophic and protective mechanisms, such as the production of SCFA which influence epithelial cell metabolism, turnover and apoptosis. Probiotics have been recommended for patients suffering from SBS in order to decrease bacterial overgrowth and prevent bacterial translocation, two major mechanisms in the pathogenesis of SBS. The present review discusses the research available in the international literature, clinical and experimental, regarding probiotic supplementation for this complicated group of patients based on the clinical spectrum and pathophysiological aspects of the syndrome. The clinical data that were collected for the purposes of the present review suggest that it is difficult to correctly characterise probiotics as a preventive or therapeutic measure. It is very challenging after all to examine the relationship of the bacterial flora, the intestinal barrier and the probiotics as, according to the latest knowledge, demonstrate an interesting interaction.

  3. Current industrial practices of assessing permeability and P-glycoprotein interaction.

    PubMed

    Balimane, Praveen V; Han, Yong-Hae; Chong, Saeho

    2006-01-13

    Combination of the in vitro models that are high throughput but less predictive and the in vivo models that are low throughput but more predictive is used effectively to evaluate the intestinal permeability and transport characteristics of a large number of drug candidates during lead selection and lead optimization processes. Parallel artificial membrane permeability assay and Caco-2 cells are the most frequently used in vitro models to assess intestinal permeability. The popularity of these models stems from their potential for high throughput, cost effectiveness, and adequate predictability of absorption potential in humans. However, several caveats associated with these models (eg, poor predictability for transporter-mediated and paracellularly absorbed compounds, significant nonspecific binding to cells/devices leading to poor recovery, variability associated with experimental factors) need to be considered carefully to realize their full potential. P-glycoprotein, among other pharmaceutically relevant transporters, has been well demonstrated to be the major determinant of drug disposition. The review article presents an objective analysis of the permeability and transporter models currently being used in the pharmaceutical industry and could help guide the discovery scientists in implementing these models in an optimal fashion.

  4. Biochemistry of intestinal development.

    PubMed Central

    Henning, S J

    1979-01-01

    In biochemical terms, the rat small intestine is relatively immature at birth and for the first two postnatal weeks. Then during the third week a dramatic array of enzymic changes begins, and by the end of the fourth week the intestine has the digestive and absorptive properties of the adult. Selective examples of these changes are discussed with emphasis on their implications for toxicological studies. The review also includes a detailed consideration of the roles of the dietary change of weaning and of glucocorticoid and thyroid hormones in the regulation of intestinal development. PMID:575507

  5. Pulmonary epithelial permeability in hyaline-membrane disease

    SciTech Connect

    Jefferies, A.L.; Coates, G.; O'Brodovich, H.

    1984-10-25

    Neonatal hyaline-membrane disease is complicated by pulmonary edema, yet left atrial pressures are normal. Alveolar-capillary-membrane permeability may therefore be increased. To assess pulmonary epithelial permeability, we measured the pulmonary clearance and half-life of aerosolized /sup 99m/Tc-diethylenetriamine pentacetate (/sup 99m/Tc-DTPA) on 31 occasions in 15 intubated premature infants with hyaline-membrane disease. Three infants with respiratory failure due to other diseases were studied on four occasions. All studies of infants with hyaline-membrane disease that were performed in the first 72 hours of life demonstrated a biphasic clearance curve with a rapid-phase half-life of 1.6 +/- 0.6 minutes (mean +/- S.D.). As these infants recovered, the curve became monophasic with a half-life of 56.0 +/- 32.1 minutes. Two infants remained dependent on oxygen and ventilator support and had persistent biphasic curves with a rapid-phase half-life of 1.5 +/- 0.7 minutes. All infants without hyaline-membrane disease had monophasic curves with a half-life of 65.4 +/- 33.6 minutes. Using a similar technique, we observed that newborn lambs and piglets have a monophasic pulmonary clearance of /sup 99m/Tc-DTPA (114 +/- 59 minutes in lambs and 52.5 +/- 16.3 minutes in piglets). We conclude that the lungs of neonates with hyaline-membrane disease are abnormally permeable to small solutes and that this abnormality persists in infants with subsequent chronic lung disease.

  6. Permeability evolution of shale during spontaneous imbibition

    DOE PAGES

    Chakraborty, N.; Karpyn, Z. T.; Liu, S.; ...

    2017-01-05

    Shales have small pore and throat sizes ranging from nano to micron scales, low porosity and limited permeability. The poor permeability and complex pore connectivity of shales pose technical challenges to (a) understanding flow and transport mechanisms in such systems and, (b) in predicting permeability changes under dynamic saturation conditions. This paper presents quantitative experimental evidence of the migration of water through a generic shale core plug using micro CT imaging. In addition, in-situ measurements of gas permeability were performed during counter-current spontaneous imbibition of water in nano-darcy permeability Marcellus and Haynesville core plugs. It was seen that water blocksmore » severely reduced the effective permeability of the core plugs, leading to losses of up to 99.5% of the initial permeability in experiments lasting 30 days. There was also evidence of clay swelling which further hindered gas flow. When results from this study were compared with similar counter-current gas permeability experiments reported in the literature, the initial (base) permeability of the rock was found to be a key factor in determining the time evolution of effective gas permeability during spontaneous imbibition. With time, a recovery of effective permeability was seen in the higher permeability rocks, while becoming progressively detrimental and irreversible in tighter rocks. Finally, these results suggest that matrix permeability of ultra-tight rocks is susceptible to water damage following hydraulic fracturing stimulation and, while shut-in/soaking time helps clearing-up fractures from resident fluid, its effect on the adjacent matrix permeability could be detrimental.« less

  7. Bifidobacterium lactis 420 and fish oil enhance intestinal epithelial integrity in Caco-2 cells.

    PubMed

    Mokkala, Kati; Laitinen, Kirsi; Röytiö, Henna

    2016-03-01

    Increased intestinal permeability is a predisposing factor for low-grade inflammation-associated conditions, including obesity and type 2 diabetes. Dietary components may influence intestinal barrier integrity. We hypothesized that the dietary supplements Bifidobacterium lactis 420, Lactobacillus rhamnosus HN001, and fish oil have beneficial impacts on intestinal barrier integrity. In addition, we hypothesized that the coadministration of these components results in synergistic benefits to the integrity of the intestinal barrier. To study this, we investigated the impact of cell-free culture supernatant from dietary supplements B lactis 420 and L rhamnosus HN001, and fish oil, separately and in combination, on intestinal permeability in a CaCo-2 cell model. Administered separately, both B lactis 420 supernatant and fish oil significantly increased the integrity of the intestinal epithelial barrier, as determined by an increase in transepithelial electrical resistance (TEER), whereas L rhamnosus did not. The TEER increase with B lactis 420 was dose dependent. Interestingly, a combination of B lactis 420 supernatant and fish oil negated the increase in TEER of the single components. mRNA expression of tight junction proteins, measured by real-time quantitative polymerase chain reaction, was not altered, but the mRNA expression of myosin light chain kinase increased after fish oil treatment. To conclude, single dietary components, namely, B lactis 420 and fish oil, induced beneficial effects on intestinal barrier integrity in vitro, whereas a combination of 2 beneficial test compounds resulted in a null effect.

  8. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo.

    PubMed

    Sommansson, Anna; Saudi, Wan Salman Wan; Nylander, Olof; Sjöblom, Markus

    2013-07-01

    Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a ~30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of ⁵¹Cr-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol- and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol- and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions.

  9. Oral Administration of Surface-Deacetylated Chitin Nanofibers and Chitosan Inhibit 5-Fluorouracil-Induced Intestinal Mucositis in Mice

    PubMed Central

    Koizumi, Ryo; Azuma, Kazuo; Izawa, Hironori; Morimoto, Minoru; Ochi, Kosuke; Tsuka, Takeshi; Imagawa, Tomohiro; Osaki, Tomohiro; Ito, Norihiko; Okamoto, Yoshiharu; Saimoto, Hiroyuki; Ifuku, Shinsuke

    2017-01-01

    This study investigated the prophylactic effects of orally administered surface-deacetylated chitin nanofibers (SDACNFs) and chitosan against 5-fluorouracil (5-FU)-induced intestinal mucositis, which is a common side effect of 5-FU chemotherapy. SDACNFs and chitosan abolished histological abnormalities associated with intestinal mucositis and suppressed hypoproliferation and apoptosis of intestinal crypt cells. These results indicate that SDACNF and chitosan are useful agents for preventing mucositis induced by anti-cancer drugs. PMID:28134832

  10. Intestinal Complications of IBD

    MedlinePlus

    ... that only affects the colon). LOCAL COMPLICATIONS OF CROHN’S DISEASE INTESTINAL OBSTRUCTION The most common complication of Crohn’s disease, obstruction may arise from swelling and the formation ...

  11. Intestinal pseudo-obstruction

    MedlinePlus

    ... Taking drugs that slow intestinal movements. These include narcotic (pain) medicines and drugs used when you are ... that may have caused the problem (such as narcotic drugs) may help. In severe cases, surgery may ...

  12. Does the Intestinal Microbiota Explain Differences in the Epidemiology of Liver Disease between East and West?

    PubMed

    Nakamoto, Nobuhiro; Schnabl, Bernd

    2016-04-01

    Changes in bacterial communities are associated with the pathogenesis of many diseases including inflammatory bowel disease and liver disease. Dysbiosis can induce intestinal inflammation resulting in increased intestinal permeability and bacterial translocation. The majority of chronic liver diseases are associated with bacterial translocation resulting in or enhancing an inflammatory response in the liver. Intestinal inflammation and a dysfunctional intestinal barrier are not sufficient to cause liver disease in the absence of an additional liver insult. In this article, the authors summarize differences in intestinal microbiota composition between Eastern and Western countries. The authors specifically discuss whether differences in microbiota composition could explain the epidemiological differences in liver disease found in Asia and Europe/the USA.

  13. Does the Intestinal Microbiota Explain Differences in the Epidemiology of Liver Disease between East and West?

    PubMed Central

    Nakamoto, Nobuhiro; Schnabl, Bernd

    2016-01-01

    Changes in bacterial communities are associated with the pathogenesis of many diseases including inflammatory bowel disease and liver disease. Dysbiosis can induce intestinal inflammation resulting in increased intestinal permeability and bacterial translocation. The majority of chronic liver diseases are associated with bacterial translocation resulting in or enhancing an inflammatory response in the liver. Intestinal inflammation and a dysfunctional intestinal barrier are not sufficient to cause liver disease in the absence of an additional liver insult. In this article, the authors summarize differences in intestinal microbiota composition between Eastern and Western countries. The authors specifically discuss whether differences in microbiota composition could explain the epidemiological differences in liver disease found in Asia and Europe/the USA. PMID:27243019

  14. Increased Gut Permeability and Bacterial Translocation after Chronic Chlorpyrifos Exposure in Rats

    PubMed Central

    Joly Condette, Claire; Khorsi-Cauet, Hafida; Morlière, Patrice; Zabijak, Luciane; Reygner, Julie; Bach, Véronique; Gay-Quéheillard, Jérôme

    2014-01-01

    The epithelium's barrier function is crucial for maintaining homeostasis and preventing the passage of food antigens and luminal bacteria. This function is essentially subserved by tight junctions (TJs), multiprotein complexes located in the most apical part of the lateral membrane. Some gastrointestinal disease states are associated with elevated intestinal permeability to macromolecules. In a study on rats, we determined the influence of chronic, daily ingestion of chlorpyrifos (CPF, a pesticide that crosses the placental barrier) during pre- and postnatal periods on intestinal permeability and TJ characteristics in the pups. Fluorescein isothiocyanate (FITC)-dextran was used as a marker of paracellular transport and mucosal barrier dysfunction. Pups were gavaged with FITC-dextran solution and blood samples were collected every 30 min for 400 min and analyzed spectrofluorimetrically. At sacrifice, different intestinal segments were resected and prepared for analysis of the transcripts (qPCR) and localization (using immunofluorescence) of ZO-1, occludin and claudins (scaffolding proteins that have a role in the constitution of TJs). In rats that had been exposed to CPF in utero and after birth, we observed a progressive increase in FITC-dextran passage across the epithelial barrier from 210 to 325 min at day 21 after birth (weaning) but not at day 60 (adulthood). At both ages, there were significant changes in intestinal TJ gene expression, with downregulation of ZO-1 and occludin and upregulation of claudins 1 and 4. In some intestinal segments, there were changes in the cellular localization of ZO-1 and claudin 4 immunostaining. Lastly, bacterial translocation to the spleen was also observed. The presence of CPF residues in food may disturb epithelial homeostasis in rats. Changes in TJ protein expression and localization may be involved in gut barrier dysfunction in this model. Uncontrolled passage of macromolecules and bacteria across the intestinal epithelium

  15. Intestinal lymphangiectasia and thymic hypoplasia.

    PubMed Central

    Sorensen, R U; Halpin, T C; Abramowsky, C R; Hornick, D L; Miller, K M; Naylor, P; Incefy, G S

    1985-01-01

    We have evaluated the immunological abnormalities present in a 6 year old patient with primary intestinal and generalized lymphangiectasia confirmed by intestinal, lung and lymph node biopsies. Lymphocyte loss through the gut was confirmed by the detection of lymphocytes in her stool. An increased enteric protein loss was suggested by hypoproteinaemia, peripheral oedema, and a very short half-life for i.v. immune serum globulin (3 days). Lymphocyte subpopulation analysis revealed a selective loss of T lymphocytes, with a proportionally increased loss of the OKT4 positive helper/inducer subpopulation. Functionally, there was a decrease in proliferative responses to some mitogens and to allogeneic cells, and a lack of T cell help for in vitro B lymphocyte differentiation into immunoglobulin secreting cells. Natural killer function was normal. In this patient, a concomitant thymic deficiency was documented by failure to identify thymic tissue on a thymus biopsy and by an absence or decrease of the serum thymic factor (thymulin) and thymosin alpha 1. No compensatory lymphopoiesis was detected in the bone marrow. In an attempt to increase T lymphocyte development, the patient was treated with thymosin fraction 5. Daily treatment with this preparation resulted in a transient clinical improvement which could not be sustained on a weekly thymosin treatment schedule. However, lymphocyte numbers did not increase during this treatment. The findings in this patient support the notion that T lymphocytes are needed to stimulate thymic epithelium. In situations of excessive loss of long lived T lymphocytes a secondary thymic atrophy may occur and further contribute to the development of a deficiency in cell-mediated immunity. Images Fig. 1 Fig. 2 PMID:3971596

  16. Intestinal parasitic infection.

    PubMed

    Park, Mi-Suk; Kim, Ki Whang; Ha, Hyun Kwon; Lee, Dong Ho

    2008-01-01

    In general, gastrointestinal tract is the primary involvement site of parasites during their life cycle. In this article, we will describe amebiasis, ascariasis, and anisakiasis among the many common intestinal parasitic diseases. We will review the epidemiology, life cycles, clinical manifestations and complications, and illustrate detailed imaging findings of intestinal parasites. Recognizing features of parasitic infection is important to establish an early diagnosis that leads to prompt treatment and helps avoid unnecessary surgery.

  17. Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo.

    PubMed

    Yang, Qi Joy; Fan, Jianghong; Chen, Shu; Liu, Lutan; Sun, Huadong; Pang, K Sandy

    2016-07-01

    We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism.

  18. Structural determinants of glomerular permeability.

    PubMed

    Deen, W M; Lazzara, M J; Myers, B D

    2001-10-01

    Recent progress in relating the functional properties of the glomerular capillary wall to its unique structure is reviewed. The fenestrated endothelium, glomerular basement membrane (GBM), and epithelial filtration slits form a series arrangement in which the flow diverges as it enters the GBM from the fenestrae and converges again at the filtration slits. A hydrodynamic model that combines morphometric findings with water flow data in isolated GBM has predicted overall hydraulic permeabilities that are consistent with measurements in vivo. The resistance of the GBM to water flow, which accounts for roughly half that of the capillary wall, is strongly dependent on the extent to which the GBM surfaces are blocked by cells. The spatial frequency of filtration slits is predicted to be a very important determinant of the overall hydraulic permeability, in keeping with observations in several glomerular diseases in humans. Whereas the hydraulic resistances of the cell layers and GBM are additive, the overall sieving coefficient for a macromolecule (its concentration in Bowman's space divided by that in plasma) is the product of the sieving coefficients for the individual layers. Models for macromolecule filtration reveal that the individual sieving coefficients are influenced by one another and by the filtrate velocity, requiring great care in extrapolating in vitro observations to the living animal. The size selectivity of the glomerular capillary has been shown to be determined largely by the cellular layers, rather than the GBM. Controversial findings concerning glomerular charge selectivity are reviewed, and it is concluded that there is good evidence for a role of charge in restricting the transmural movement of albumin. Also discussed is an effect of albumin that has received little attention, namely, its tendency to increase the sieving coefficients of test macromolecules via steric interactions. Among the unresolved issues are the specific contributions of the

  19. The Membrane Permeability Outcome study.

    PubMed

    Locatelli, Francesco; Cavalli, Andrea; Manzoni, Celestina; Pontoriero, Giuseppe

    2011-01-01

    Many observational studies have consistently shown that high-flux hemodialysis has positive effects on the survival and morbidity of uremic patients when compared with low-flux hemodialysis. However, the HEMO study, a randomized trial designed to evaluate the effect of membrane permeability on patient survival, showed only an 8% non-statistically significant reduction of mortality, albeit a secondary analysis suggested an advantage for high-flux membranes in certain patient subgroups. The prospective, randomized Membrane Permeability Outcome (MPO) study investigated the impact of membrane permeability on survival in incident hemodialysis patients who had low albumin (≤4 g/dl) and normal albumin ( >4 g/dl) as separate randomization groups. Patients with serum albumin ≤4 g/dl had significantly better survival rates in the high-flux group compared with the low-flux group (p = 0.032). Moreover, a post-hoc secondary analysis showed that high-flux membranes may significantly improve survival in diabetic patients. No difference was found in patients with normal albumin levels. Considering the increasing number of dialysis patients with low serum albumin levels and with diabetes, the relevance of the MPO study led to the publication of a position statement by the European Renal Best Practice Advisory Board. This board strongly recommended that high-flux hemodialysis should be used for high-risk patients and, with a lower degree of evidence, even also for low-risk subjects due to the substantial reduction in β(2)-microglobulin levels observed in the high-flux group.

  20. Intestinal adaptation following resection.

    PubMed

    Tappenden, Kelly A

    2014-05-01

    Intestinal adaptation is a natural compensatory process that occurs following extensive intestinal resection, whereby structural and functional changes in the intestine improve nutrient and fluid absorption in the remnant bowel. In animal studies, postresection structural adaptations include bowel lengthening and thickening and increases in villus height and crypt depth. Functional changes include increased nutrient transporter expression, accelerated crypt cell differentiation, and slowed transit time. In adult humans, data regarding adaptive changes are sparse, and the mechanisms underlying intestinal adaptation remain to be fully elucidated. Several factors influence the degree of intestinal adaptation that occurs post resection, including site and extent of resection, luminal stimulation with enteral nutrients, and intestinotrophic factors. Two intestinotrophic growth factors, the glucagon-like peptide 2 analog teduglutide and recombinant growth hormone (somatropin), are now approved for clinical use in patients with short bowel syndrome (SBS). Both agents enhance fluid absorption and decrease requirements for parenteral nutrition (PN) and/or intravenous fluid. Intestinal adaptation has been thought to be limited to the first 1-2 years following resection in humans. However, recent data suggest that a significant proportion of adult patients with SBS can achieve enteral autonomy, even after many years of PN dependence, particularly with trophic stimulation.

  1. Permeability of normal versus carious dentin.

    PubMed

    Pashley, E L; Talman, R; Horner, J A; Pashley, D H

    1991-10-01

    Although a number of reports have been published demonstrating that carious dentin is less permeable than normal dentin, these reports have been qualitative rather than quantitative. The purpose of this in vitro study was to apply a quantitative technique to the study of the permeability of carious human teeth before and after excavation, before and after removal of the smear layer and before and after preparation of a control cavity of similar size and depth in normal dentin subjected to the same measurements, for comparative purposes. Dentin permeability was measured as a hydraulic conductance. The permeability values measured at each step in the protocol were expressed as a percent of the maximum permeability of both cavities, permitting each tooth the serve as its own control. Carious lesions exhibited a slight degree of permeability (2.3 +/- 0.6% of controls) which remained unchanged after excavation of the lesions. Removal of the smear layer in the excavated carious lesions increased the permeability significantly to 6.9 +/- 3.2%. Preparation of a control cavity of the same area and depth increased the permeability slightly. Removal of its smear layer increased the permeability of the dentin 91%. These results confirm previous qualitative studies that carious dentin, even after excavation and removal of the smear layer has a very low permeability.

  2. Anisotropic hydraulic permeability in compressed articular cartilage.

    PubMed

    Reynaud, Boris; Quinn, Thomas M

    2006-01-01

    The extent to which articular cartilage hydraulic permeability is anisotropic is largely unknown, despite its importance for understanding mechanisms of joint lubrication, load bearing, transport phenomena, and mechanotransduction. We developed and applied new techniques for the direct measurement of hydraulic permeability within statically compressed adult bovine cartilage explant disks, dissected such that disk axes were perpendicular to the articular surface. Applied pressure gradients were kept small to minimize flow-induced matrix compaction, and fluid outflows were measured by observation of a meniscus in a glass capillary under a microscope. Explant disk geometry under radially unconfined axial compression was measured by direct microscopic observation. Pressure, flow, and geometry data were input to a finite element model where hydraulic permeabilities in the disk axial and radial directions were determined. At less than 10% static compression, near free-swelling conditions, hydraulic permeability was nearly isotropic, with values corresponding to those of previous studies. With increasing static compression, hydraulic permeability decreased, but the radially directed permeability decreased more dramatically than the axially directed permeability such that strong anisotropy (a 10-fold difference between axial and radial directions) in the hydraulic permeability tensor was evident for static compression of 20-40%. Results correspond well with predictions of a previous microstructurally-based model for effects of tissue mechanical deformations on glycosaminoglycan architecture and cartilage hydraulic permeability. Findings inform understanding of structure-function relationships in cartilage matrix, and suggest several biomechanical roles for compression-induced anisotropic hydraulic permeability in articular cartilage.

  3. Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats

    PubMed Central

    Decuypere, Jean-Paul; Farré, Ricard; De Hertogh, Gert; Lenaerts, Kaatje; Jochmans, Ina; Monbaliu, Diethard; Nevens, Frederik; Tack, Jan; Laleman, Wim; Pirenne, Jacques

    2017-01-01

    Introduction The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury. Material and Methods In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping), 3 conditions were tested (n = 16/group): laparotomy only (sham group); ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group); ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group). Vehicle or OCA (INT-747, 2*30mg/kg) was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP); histology (morphologic injury to villi/crypts and villus length); intestinal permeability (Ussing chamber); endotoxin translocation (Lipopolysaccharide assay); cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13); apoptosis (cleaved caspase-3); and autophagy (LC3, p62). Results It was found that intestinal IRI was associated with high mortality (90%); loss of intestinal integrity (structurally and functionally); increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition. Conclusion Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier

  4. A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

    PubMed Central

    Wu, Youping; Chung, Chun-Shiang; Chen, Yaping; Monaghan, Sean Farrell; Patel, Sima; Huang, Xin; Heffernan, Daithi Seamus; Ayala, Alfred

    2016-01-01

    Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, the co-inhibitory molecule programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it is not known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability and tissue cytokine levels were assessed. Subsequently, septic or nonseptic colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 in a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly upregulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability and tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared with WT after sepsis. Comparatively, while Caco2 cell monolayers also responded to inflammatory cytokine stimulation with elevated PD-L1 expression, increased monolayer permeability and altered/decreased monolayer tight junction protein morphology/expression, these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction. PMID:27782294

  5. Small Intestine Bacterial Overgrowth and Environmental Enteropathy in Bangladeshi Children

    PubMed Central

    Haque, Rashidul; Kirkpatrick, Beth D.; Alam, Masud; Lu, Miao; Kabir, Mamun; Kakon, Shahria Hafiz; Islam, Bushra Zarin; Afreen, Sajia; Musa, Abu; Khan, Shaila Sharmeen; Colgate, E. Ross; Carmolli, Marya P.; Ma, Jennie Z.

    2016-01-01

    ABSTRACT Recent studies suggest small intestine bacterial overgrowth (SIBO) is common among developing world children. SIBO’s pathogenesis and effect in the developing world are unclear. Our objective was to determine the prevalence of SIBO in Bangladeshi children and its association with malnutrition. Secondary objectives included determination of SIBO’s association with sanitation, diarrheal disease, and environmental enteropathy. We performed a cross-sectional analysis of 90 Bangladeshi 2-year-olds monitored since birth from an impoverished neighborhood. SIBO was diagnosed via glucose hydrogen breath testing, with a cutoff of a 12-ppm increase over baseline used for SIBO positivity. Multivariable logistic regression was performed to investigate SIBO predictors. Differences in concomitant inflammation and permeability between SIBO-positive and -negative children were compared with multiple comparison adjustment. A total of 16.7% (15/90) of the children had SIBO. The strongest predictors of SIBO were decreased length-for-age Z score since birth (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.03 to 0.60) and an open sewer outside the home (OR, 4.78; 95% CI, 1.06 to 21.62). Recent or frequent diarrheal disease did not predict SIBO. The markers of intestinal inflammation fecal Reg 1β (116.8 versus 65.6 µg/ml; P = 0.02) and fecal calprotectin (1,834.6 versus 766.7 µg/g; P = 0.004) were elevated in SIBO-positive children. Measures of intestinal permeability and systemic inflammation did not differ between the groups. These findings suggest linear growth faltering and poor sanitation are associated with SIBO independently of recent or frequent diarrheal disease. SIBO is associated with intestinal inflammation but not increased permeability or systemic inflammation. PMID:26758185

  6. An in vivo model of human small intestine using pluripotent stem cells.

    PubMed

    Watson, Carey L; Mahe, Maxime M; Múnera, Jorge; Howell, Jonathan C; Sundaram, Nambirajan; Poling, Holly M; Schweitzer, Jamie I; Vallance, Jefferson E; Mayhew, Christopher N; Sun, Ying; Grabowski, Gregory; Finkbeiner, Stacy R; Spence, Jason R; Shroyer, Noah F; Wells, James M; Helmrath, Michael A

    2014-11-01

    Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant. To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds. Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the crypt-villus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response. This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies.

  7. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome.

    PubMed

    Camilleri, Michael; Lasch, Karen; Zhou, Wen

    2012-10-01

    Irritable bowel syndrome (IBS) is one of the most common gastrointestinal ailments among those seeking health care for gastrointestinal disorders. Despite its prevalence, IBS pathophysiology is still not completely understood. Continued elucidation of IBS etiological mechanisms will lead to a greater appreciation of possible therapeutic targets. In the past decade, there has been increasing focus on the possible connection between increased intestinal mucosal permeability, inflammation, and visceral hypersensitivity. Increased permeability in subsets of IBS patients has been observed and the possible mechanisms underlying this defect are just beginning to be understood. The objectives of this review are to summarize the role of the healthy intestinal epithelium as a barrier between the lumen and the rest of the body with a focus on tight junctions; to examine the lines of evidence that suggest that different triggers lead to increased intestinal mucosal permeability and disruption of tight junctions in IBS patients; and to explore how this increased permeability may elicit immune responses that affect afferent nerves, resulting in the pain associated with IBS.

  8. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  9. Systemic abnormalities in liver disease

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases. PMID:19554648

  10. Saturated High Permeability Magnetic Shields

    NASA Astrophysics Data System (ADS)

    Trenkel, Christian

    2016-05-01

    High permeability magnetic shields can be used in space to mitigate the effect of magnetic sources by several orders of magnitude. Nevertheless, the presence of significant amounts of ferromagnetic material on-board a spacecraft carries, by itself, a certain risk in terms of meeting magnetic cleanliness requirements. One possibility is that the shield is accidentally magnetised irreversibly, either by a strong external field, or mechanical shock. A second possibility is that the shield will acquire an induced moment in the presence of external fields (DC or AC), and could potentially amplify them.Here, we propose the use of high permeability shields which are driven into their fully saturated state - by the source that is being shielded. This approach limits the shielding effect to perhaps one or two orders of magnitude, but is expected to mitigate the above risks substantially. We present extensive numerical simulations describing the design principle behind optimised, fully saturated shields, as well as some results to substantiate the above claims.

  11. Steam-water relative permeability

    SciTech Connect

    Ambusso, W.; Satik, C.; Home, R.N.

    1997-12-31

    A set of relative permeability relations for simultaneous flow of steam and water in porous media have been measured in steady state experiments conducted under the conditions that eliminate most errors associated with saturation and pressure measurements. These relations show that the relative permeabilities for steam-water flow in porous media vary approximately linearly with saturation. This departure from the nitrogen/water behavior indicates that there are fundamental differences between steam/water and nitrogen/water flows. The saturations in these experiments were measured by using a high resolution X-ray computer tomography (CT) scanner. In addition the pressure gradients were obtained from the measurements of liquid phase pressure over the portions with flat saturation profiles. These two aspects constitute a major improvement in the experimental method compared to those used in the past. Comparison of the saturation profiles measured by the X-ray CT scanner during the experiments shows a good agreement with those predicted by numerical simulations. To obtain results that are applicable to general flow of steam and water in porous media similar experiments will be conducted at higher temperature and with porous rocks of different wetting characteristics and porosity distribution.

  12. Brain permeability of inhaled corticosteroids.

    PubMed

    Arya, Vikram; Issar, Manish; Wang, Yaning; Talton, James D; Hochhaus, Guenther

    2005-09-01

    The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 microg kg-1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20-56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2-55.0%, n=14; 2; wild-type: 11.5+/-33.0%, n=14; 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.

  13. Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect.

    PubMed

    Russo, Michael A; Hogenauer, Christoph; Coates, Stephen W; Santa Ana, Carol A; Porter, Jack L; Rosenblatt, Randall L; Emmett, Michael; Fordtran, John S

    2003-07-01

    Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF.

  14. Vortex rings impinging on permeable boundaries

    NASA Astrophysics Data System (ADS)

    Mujal-Colilles, Anna; Dalziel, Stuart B.; Bateman, Allen

    2015-01-01

    Experiments with vortex rings impinging permeable and solid boundaries are presented in order to investigate the influence of permeability. Utilizing Particle Image Velocimetry, we compared the behaviour of a vortex ring impinging four different reticulated foams (with permeability k ˜ 26 - 85 × 10-8 m2) and a solid boundary. Results show how permeability affects the stretching phenomena of the vortex ring and the formation and evolution of the secondary vortex ring with opposite sign. Moreover, permeability also affects the macroscopic no-slip boundary condition found on the solid boundary, turning it into an apparent slip boundary condition for the most permeable boundary. The apparent slip-boundary condition and the flux exchange between the ambient fluid and the foam are jointly responsible for both the modified formation of the secondary vortex and changes on the vortex ring diameter increase.

  15. Clogging in permeable concrete: A review.

    PubMed

    Kia, Alalea; Wong, Hong S; Cheeseman, Christopher R

    2017-05-15

    Permeable concrete (or "pervious concrete" in North America) is used to reduce local flooding in urban areas and is an important sustainable urban drainage system. However, permeable concrete exhibits reduction in permeability due to clogging by particulates, which severely limits service life. This paper reviews the clogging mechanism and current mitigating strategies in order to inform future research needs. The pore structure of permeable concrete and characteristics of flowing particulates influence clogging, which occurs when particles build-up and block connected porosity. Permeable concrete requires regular maintenance by vacuum sweeping and pressure washing, but the effectiveness and viability of these methods is questionable. The potential for clogging is related to the tortuosity of the connected porosity, with greater tortuosity resulting in increased potential for clogging. Research is required to develop permeable concrete that can be poured on-site, which produces a pore structure with significantly reduced tortuosity.

  16. The intestine is a blender

    NASA Astrophysics Data System (ADS)

    Yang, Patricia; Lamarca, Morgan; Kravets, Victoria; Hu, David

    According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines Contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

  17. The intestine is a blender

    NASA Astrophysics Data System (ADS)

    Yang, Patricia; Lamarca, Morgan; Hu, David

    2015-11-01

    According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

  18. They Must Hold Tight: Junction Proteins, Microbiota And Immunity In Intestinal Mucosa.

    PubMed

    Castoldi, Angela; Favero de Aguiar, Cristhiane; Moraes-Vieira, Pedro Manoel; Olsen Saraiva Câmara, Niels

    2015-01-01

    Homeostasis of the immune system depends on several factors. The gastrointestinal tract plays an important role in maintaining our immune system. With this aim, the intestinal immune system interacts with epithelial barrier molecules, especially tight junction proteins, that are key molecules involved in controlling paracellular permeability to increase the protection barrier against external antigens or possibly to respond to commensal microorganisms. During intestinal inflammatory diseases, the expression of innate immune receptors in intestinal epithelial cells and infiltration of immune cells are related, but it is still unclear how the immune system induces modulation of paracellular permeability. In this review, we provide an overview of the understanding of how the immune system modulates the expression of tight junctions to maintain the mucosal immune system.

  19. Prenatal Intestinal Obstruction Affects the Myenteric Plexus and Causes Functional Bowel Impairment in Fetal Rat Experimental Model of Intestinal Atresia

    PubMed Central

    Khen-Dunlop, Naziha; Sarnacki, Sabine; Victor, Anais; Grosos, Celine; Menard, Sandrine; Soret, Rodolphe; Goudin, Nicolas; Pousset, Maud; Sauvat, Frederique; Revillon, Yann; Cerf-Bensussan, Nadine; Neunlist, Michel

    2013-01-01

    Background Intestinal atresia is a rare congenital disorder with an incidence of 3/10 000 birth. About one-third of patients have severe intestinal dysfunction after surgical repair. We examined whether prenatal gastrointestinal obstruction might effect on the myenteric plexus and account for subsequent functional disorders. Methodology/Principal Findings We studied a rat model of surgically induced antenatal atresia, comparing intestinal samples from both sides of the obstruction and with healthy rat pups controls. Whole-mount preparations of the myenteric plexus were stained for choline acetyltransferase (ChAT) and nitric oxide synthase (nNOS). Quantitative reverse transcription PCR was used to analyze mRNAs for inflammatory markers. Functional motility and permeability analyses were performed in vitro. Phenotypic studies were also performed in 8 newborns with intestinal atresia. In the experimental model, the proportion of nNOS-immunoreactive neurons was similar in proximal and distal segments (6.7±4.6% vs 5.6±4.2%, p = 0.25), but proximal segments contained a higher proportion of ChAT-immunoreactive neurons (13.2±6.2% vs 7.5±4.3%, p = 0.005). Phenotypic changes were associated with a 100-fold lower concentration-dependent contractile response to carbachol and a 1.6-fold higher EFS-induced contractile response in proximal compared to distal segments. Transcellular (p = 0.002) but not paracellular permeability was increased. Comparison with controls showed that modifications involved not only proximal but also distal segments. Phenotypic studies in human atresia confirmed the changes in ChAT expression. Conclusion Experimental atresia in fetal rat induces differential myenteric plexus phenotypical as well as functional changes (motility and permeability) between the two sides of the obstruction. Delineating these changes might help to identify markers predictive of motility dysfunction and to define guidelines for post-surgical care. PMID:23667464

  20. Transepithelial transport of PAMAM dendrimers across isolated intestinal tissue

    NASA Astrophysics Data System (ADS)

    Hubbard, Dallin A.

    Poly(amido amine) (PAMAM) dendrimers have shown potential to carry poorly absorbed drugs across the intestinal barrier and into systemic circulation, reducing the need for intravenous injections. Much of the in vitro transepithelial transport of PAMAM dendrimers to date has been investigated using Caco-2 monolayers which lack the microvilli morphology and enzymes present in isolated intestinal tissues. In addition, a challenge in predicting oral absorption is establishing a correlation between transport across rodent and human intestinal tissues. This dissertation focused on investigating the transepithelial transport of PAMAM dendrimers across rat and human isolated intestinal tissues. Permeability values in isolated tissues were compared with those across Caco-2 cell monolayers. Results indicate a difference in transport of PAMAM dendrimers, morphological changes and transepithelial electrical resistance between Caco-2 cell monolayers, rat and human intestinal tissue models. A relatively high transport rate across the tissues, given the macromolecular nature of PAMAM dendrimers, shows promise for use of these constructs for oral delivery in human.

  1. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.

    PubMed

    Hsiao, Elaine Y; McBride, Sara W; Hsien, Sophia; Sharon, Gil; Hyde, Embriette R; McCue, Tyler; Codelli, Julian A; Chow, Janet; Reisman, Sarah E; Petrosino, Joseph F; Patterson, Paul H; Mazmanian, Sarkis K

    2013-12-19

    Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.

  2. Vascular permeability in cerebral cavernous malformations.

    PubMed

    Mikati, Abdul G; Khanna, Omaditya; Zhang, Lingjiao; Girard, Romuald; Shenkar, Robert; Guo, Xiaodong; Shah, Akash; Larsson, Henrik B W; Tan, Huan; Li, Luying; Wishnoff, Matthew S; Shi, Changbin; Christoforidis, Gregory A; Awad, Issam A

    2015-10-01

    Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

  3. Vascular permeability in cerebral cavernous malformations

    PubMed Central

    Mikati, Abdul G; Khanna, Omaditya; Zhang, Lingjiao; Girard, Romuald; Shenkar, Robert; Guo, Xiaodong; Shah, Akash; Larsson, Henrik BW; Tan, Huan; Li, Luying; Wishnoff, Matthew S; Shi, Changbin; Christoforidis, Gregory A; Awad, Issam A

    2015-01-01

    Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy. PMID:25966944

  4. Radiation-induced recurrent intestinal pseudo-obstruction

    SciTech Connect

    Conklin, J.L.; Anuras, S.

    1981-06-01

    The syndrome of intestinal pseudo-obstruction is a complex of signs and symptoms of intestinal obstruction without evidence of mechanical obstruction of the intestinal lumen. A patient with radiation-induced intestinal pseudoobstruction is described. The patient is a 74-year old woman with a history of chronic diarrhea, recurrent episodes of crampy abdominal pain, nausea and vomiting since receiving a 13,000 rad radiation dose to the pelvis in 1954. She has been hospitalized on many occasions for symptoms and signs of bowel obstruction. Upper gastrointestinal contrast roentgenograms with small bowel follow-through done during these episodes revealed multiple dilated loops of small bowel with no obstructing lesion. Barium enemas revealed no obstructing lesion. Each episode resolved with conservative therapy. Other secondary causes for intestinal pseudo-obstruction were ruled out in our patient. She gave no history of familial gastrointestinal disorders. Although postirradiation motility abnormalities have been demonstrated experimentally this is the first report of radiation induced intestinal pseudo-obstruction.

  5. Tight junctions and IBS--the link between epithelial permeability, low-grade inflammation, and symptom generation?

    PubMed

    Piche, T

    2014-03-01

    In this issue of Neurogastroenterology and Motility, Dr Ewa Wilcz-Villega and colleagues report low expression of E-cadherin, a tight junction protein involved in the regulation of paracellular permeability, in the colonic mucosa of patients with the irritable bowel syndrome (IBS) with predominance of diarrhea (IBS-D) or alternating symptoms (IBS-A). These findings constitute an improvement in our knowledge of epithelial barrier disruption associated with IBS. There is mounting evidence to indicate that a compromised epithelial barrier is associated with low-grade immune activation and intestinal dysfunction in at least a proportion of IBS patients. During the last 10 years of research, much interest has focused on the increase in the number of different types of immune cells in the gut mucosa of IBS patients including: mast cells, T lymphocytes, and other local cells such as enteroendocrine cells. The inflammatory mediators released by these cells or other luminal factors could be at the origin of altered epithelial barrier functions and enteric nervous system signaling, which lead to gut hypersensitivity. A current conceptual framework states that clinical symptoms of IBS could be associated with structural and functional abnormalities of the mucosal barrier, highlighting the crucial importance of elucidating the contributory role of epithelial barrier defects in the pathogenesis of IBS. More importantly, disruption of the epithelial barrier could also participate in the generation of persistent abdominal pain and discomfort mimicking IBS in patients with inflammatory bowel diseases considered in remission. This mini review gives a brief summary of clinical and experimental evidence concerning the mechanisms underlying epithelial barrier defects in IBS.

  6. Intestinal and multivisceral transplantation

    PubMed Central

    Meira, Sérgio Paiva; Guardia, Bianca Della; Evangelista, Andréia Silva; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Epstein, Marina Gabrielle; Pedroso, Pamella Tung; Salvalaggio, Paolo; Meirelles, Roberto Ferreira; Rocco, Rodrigo Andrey; de Almeida, Samira Scalso; de Rezende, Marcelo Bruno

    2015-01-01

    Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run. PMID:25993080

  7. Regional susceptibility to stress-induced intestinal injury in the mouse.

    PubMed

    Novosad, Veronica L; Richards, Jennifer L; Phillips, Neil A; King, Michelle A; Clanton, Thomas L

    2013-09-15

    Injury to the intestinal mucosa is a life-threatening problem in a variety of clinical disorders, including hemorrhagic shock, trauma, burn, pancreatitis, and heat stroke. The susceptibility to injury of different regions of intestine in these disorders is not well understood. We compared histological injury across the small intestine in two in vivo mouse models of injury, hemorrhagic shock (30% loss of blood volume) and heat stroke (peak core temperature 42.4°C). In both injury models, areas near the duodenum showed significantly greater mucosal injury and reductions in villus height. To determine if these effects were dependent on circulating factors, experiments were performed on isolated intestinal segments to test for permeability to 4-kDa FITC-dextran. The segments were exposed to hyperthermia (42°C for 90 min), moderate simulated ischemia (Po2 ∼30 Torr, Pco2 ∼60 Torr, pH 7.1), severe ischemia (Po2 ∼20 Torr, Pco2 ∼80 Torr, pH 6.9), or severe hypoxia (Po2 ∼0 Torr, Pco2 ∼35 Torr) for 90 min, and each group was compared with sham controls. All treatments resulted in marked elevations in permeability within segments near the duodenum. In severe hypoxia or hyperthermia, permeability was also moderately elevated in the jejunum and ileum; in moderate or severe ischemia, permeability was unaffected in these regions. The results demonstrate increased susceptibility of proximal regions of the small intestine to acute stress-induced damage, irrespective of circulating factors. The predominant injury in the duodenum may impact the pattern of acute inflammatory responses arising from breach of the intestinal barrier, and such knowledge may be useful for designing therapeutic strategies.

  8. Chromosomal abnormalities and mental illness.

    PubMed

    MacIntyre, D J; Blackwood, D H R; Porteous, D J; Pickard, B S; Muir, W J

    2003-03-01

    Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

  9. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  10. Postinjury Vagal Nerve Stimulation Protects Against Intestinal Epithelial Barrier Breakdown

    PubMed Central

    Krzyzaniak, Michael; Peterson, Carrie; Loomis, William; Hageny, Ann-Marie; Wolf, Paul; Reys, Luiz; Putnam, James; Eliceiri, Brian; Baird, Andrew; Bansal, Vishal; Coimbra, Raul

    2014-01-01

    Background Vagal nerve stimulation (VNS) can have a marked anti-inflammatory effect. We have previously shown that preinjury VNS prevented intestinal barrier breakdown and preserved epithelial tight junction protein expression. However, a pretreatment model has little clinical relevance for the care of the trauma patient. Therefore, we postulated that VNS conducted postinjury would also have a similar protective effect on maintaining gut epithelial barrier integrity. Methods Male balb/c mice were subjected to a 30% total body surface area, full-thickness steam burn followed by right cervical VNS at 15, 30, 60, 90, 120, and 150 minutes postinjury. Intestinal barrier dysfunction was quantified by permeability to 4 kDa fluorescein isothiocyanate-Dextran, histologic evaluation, gut tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay, and expression of tight junction proteins (myosin light chain kinase, occludin, and ZO-1) using immunoblot and immunoflourescence. Results Histologic examination documented intestinal villi appearance similar to sham if cervical VNS was performed within 90 minutes of burn insult. VNS done after injury decreased intestinal permeability to fluorescein isothiocyanate-Dextran when VNS was ≤90 minutes after injury. Burn injury caused a marked increase in intestinal TNF-α levels. VNS-treated animals had TNF-α levels similar to sham when VNS was performed within 90 minutes of injury. Tight junction protein expression was maintained at near sham values if VNS was performed within 90 minutes of burn, whereas expression was significantly altered in burn. Conclusion Postinjury VNS prevents gut epithelial breakdown when performed within 90 minutes of thermal injury. This could represent a therapeutic window and clinically relevant strategy to prevent systemic inflammatory response distant organ injury after trauma. PMID:21610431

  11. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  12. The ethanol metabolite acetaldehyde increases paracellular drug permeability in vitro and oral bioavailability in vivo.

    PubMed

    Fisher, Scott J; Swaan, Peter W; Eddington, Natalie D

    2010-01-01

    Alcohol consumption leads to the production of the highly reactive ethanol metabolite, acetaldehyde, which may affect intestinal tight junctions and increase paracellular permeability. We examined the effects of elevated acetaldehyde within the gastrointestinal tract on the permeability and bioavailability of hydrophilic markers and drug molecules of variable molecular weight and geometry. In vitro permeability was measured unidirectionally in Caco-2 and MDCKII cell models in the presence of acetaldehyde, ethanol, or disulfiram, an aldehyde dehydrogenase inhibitor, which causes acetaldehyde formation when coadministered with ethanol in vivo. Acetaldehyde significantly lowered transepithelial resistance in cell monolayers and increased permeability of the low-molecular-weight markers, mannitol and sucrose; however, permeability of high-molecular-weight markers, polyethylene glycol and inulin, was not affected. In vivo permeability was assessed in male Sprague-Dawley rats treated for 6 days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, whereas that of paclitaxel was increased upon acetaldehyde exposure. Although disulfiram has been shown to inhibit multidrug resistance-1 P-glycoprotein (P-gp) in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by coadministration of disulfiram. In conclusion, we demonstrate that acetaldehyde significantly modulates tight junctions and paracellular permeability in vitro as well as the oral bioavailability of low-molecular-weight hydrophilic probes and therapeutic molecules in vivo even when these molecules are substrates for efflux transporters. These studies emphasize the significance of ethanol metabolism and drug interactions outside of the liver.

  13. The interaction of nifedipine with selected cyclodextrins and the subsequent solubility-permeability trade-off.

    PubMed

    Beig, Avital; Miller, Jonathan M; Dahan, Arik

    2013-11-01

    The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β-cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

  14. Electrical parameters and water permeability properties of monolayers formed by T84 cells cultured on permeable supports.

    PubMed

    Ozu, M; Toriano, R; Capurro, C; Parisi, M

    2005-01-01

    T84 is an established cell line expressing an enterocyte phenotype whose permeability properties have been widely explored. Osmotic permeability (POSM), hydraulic permeability (PHYDR) and transport-associated net water fluxes (JW-transp), as well as short-circuit current (ISC), transepithelial resistance (RT), and potential difference (deltaVT) were measured in T84 monolayers with the following results: POSM 1.3 +/- 0.1 cm.s-1 x 10-3; PHYDR 0.27 +/- 0.02 cm.s-1; RT 2426 +/- 109 omega.cm2, and deltaVT 1.31 +/- 0.38 mV. The effect of 50 microM 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DCEBIO), a "net Cl- secretory agent", on T84 cells was also studied. We confirm the reported important increase in ISC induced by DCEBIO which was associated here with a modest secretory deltaJW-transp. The present results were compared with those reported using the same experimental approach applied to established cell lines originating from intestinal and renal epithelial cells (Caco-2, LLC-PK1 and RCCD-1). No clear association between PHYDR and RT could be demonstrated and high PHYDR values were observed in an electrically tight epithelium, supporting the view that a "water leaky" barrier is not necessarily an "electrically leaky" one. Furthermore, the modest secretory deltaJW-transp was not consistent with previous results obtained with RCCD-1 cells stimulated with vasopressin (absorptive fluxes) or with T84 cells secreting water under the action of Escherichia coli heat stable enterotoxin. We conclude that, while the presence of aquaporins is necessary to dissipate an external osmotic gradient, coupling between water and ion transport cannot be explained by a simple and common underlying mechanism.

  15. Celiac disease in a patient with a congenital deficiency of intestinal enteropeptidase.

    PubMed

    Moroz, S P; Hadorn, B; Rossi, T M; Haworth, J C

    2001-07-01

    We report on a 40-yr-old man with both primary enteropeptidase deficiency and celiac disease. He suffered from severe intestinal malabsorption and growth failure as a child. Enteropeptidase deficiency was found and pancreatic enzyme replacement therapy resulted in a growth spurt. Enteropeptidase levels in his intestinal mucosa and intraluminal fluid remained very low throughout childhood and early adult life. Celiac disease was confirmed by characteristic abnormalities in tests of intestinal function and in mucosal biopsies, which recovered when he instituted a gluten-free diet. He remains clinically intolerant to gluten as an adult. Enteropeptidase levels have remained abnormally low whether or not his intestinal mucosa has been normal in response to gluten restriction. Enteropeptidase levels have previously been shown to be normal in untreated celiac patients. The relationship between the two disorders remains unclear.

  16. Using FLIM in the study of permeability barrier function of aged and young skin

    NASA Astrophysics Data System (ADS)

    Xu, P.; Choi, E. H.; Man, M. Q.; Crumrine, D.; Mauro, T.; Elias, P.

    2006-02-01

    Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that can be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. It has been previously described a permeability barrier defect in humans of advanced age (> 75 years), which in a murine analog >18 mos, could be attributed to reduced lipid synthesis synthesis. However, the functional abnormality in moderately aged mice is due not to decreased lipid synthesis, but rather to a specific defect in stratum corneum (SC) acidification causing impaired lipid processing processing. Endogenous Na +/H + antiporter (NHE1) level was found declined in moderately aged mouse epidermis. This acidification defect leads to perturbed permeability barrier homeostasis through more than one pathways, we addressed suboptimal activation of the essential, lipid-processing enzyme, β-glucocerebrosidase (BGC) is linked to elevated SC pH. Finally, the importance of the epidermis acidity is shown by the normalization of barrier function after exogenous acidification of moderately aged skin.

  17. Intestinal barrier integrity and function in infants with cholestasis

    PubMed Central

    Sherif, Tahra M. K.; Mohammed, Omnia A.; Nasif, Khalid A.; El Gezawy, Ebtesam M.

    2017-01-01

    Background/Aims The safety of the human body is maintained by effective monitoring of the mucosal surface integrity and protection against potentially harmful compounds. This function of the gut called intestinal barrier function can be affected by cholestasis and the absence of bile in the intestinal lumen. We aimed to determine whether the gut barrier integrity is impaired in infants with cholestasis by evaluation of the intestinal fatty acid binding proteins (I-FABP) and ileal bile acid binding protein (I-BABP) as markers of intestinal epithelial cell damage and plasma D-lactate level as a marker of gut wall permeability. Methods This case-control study included 53 infants with cholestasis and 29 controls. Serum levels of I-FABP, I-BABP, and D-lactate were measured in all subjects. Results Both groups of patients with neonatal hepatitis and biliary atresia showed significantly higher levels of I-FABP and I-BABP than the controls. There were no differences in the serum D-lactate level between the cases and controls. There was no difference between the two groups of patients (I and II) regarding any of the parameters studied. No significant correlations between serum levels of I-FABP, I-BABP, or D-lactate and total or direct bilirubin levels were found in the cholestatic infants. Conclusions The intestinal epithelial barrier integrity is breached nearly in all parts of the intestine in infants with cholestasis. Further research is recommended to determine the impact of this finding on the management of these infants. The relationship between physical intestinal barrier damage and its functional failure remains subject for further research. PMID:28239322

  18. Influence of fentanyl and morphine on intestinal circulation

    SciTech Connect

    Tverskoy, M.; Gelman, S.; Fowler, K.C.; Bradley, E.L.

    1985-06-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of /sup 86/Rb and 9-micron spheres labeled with /sup 141/Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O/sub 2/up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.

  19. Intestinal anisakidosis (anisakiosis).

    PubMed

    Takei, Hidehiro; Powell, Suzanne Z

    2007-10-01

    A case of intestinal anisakidosis in a 42-year-old man in Japan is presented. His chief complaint was an acute onset of severe abdominal pain. Approximately 12 hours before the onset of this symptom, he had eaten sliced raw mackerel ("sashimi"). Upper endoscopy was unremarkable. At exploratory laparotomy, an edematous, diffusely thickened segment of jejunum was observed, which was resected. The postoperative course was uneventful. The segment of small intestine showed a granular indurated area on the mucosal surface, and microscopically, a helminthic larva penetrating the intestinal wall, which was surrounded by a cuff of numerous neutrophils and eosinophils, as well as diffuse acute serositis. A cross section of the larva revealed the internal structures, pathognomonic of Anisakis simplex. Although anisakidosis is rare in the United States, with the increasing popularity of Japanese cuisine, the incidence is expected to increase, and pathologists should be familiar with this disease.

  20. A new in vitro system for evaluation of passive intestinal drug absorption: establishment of a double artificial membrane permeation assay.

    PubMed

    Kataoka, Makoto; Tsuneishi, Saki; Maeda, Yukako; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2014-11-01

    The aim of this present study was to establish a new in vitro assay, double artificial membrane permeation assay (DAMPA), to evaluate the human intestinal permeability of drugs. A double artificial membrane with an intracellular compartment was constructed in side-by-side chambers by sandwiching a filter containing buffer solution with impregnated lipophilic filters with dodecane containing 2w/v% phosphatidylcholine. Permeation data of ionic compounds clearly indicated that not only the pH value of the apical solution but also that of the intracellular compartment affected the permeability across the double artificial membrane. DAMPA was performed with 20 compounds at physiological pH (apical; 6.5, intracellular and basal; 7.4). Paracellular and transcellular permeabilities of compounds in human epithelium were estimated based on the characteristics of the paracellular pathway using physicochemical properties of compounds with the Renkin function and the area factor i.e. the difference in the effective surface area between human epithelium and the double artificial membrane, respectively. The human intestinal permeability of each compound was predicted by the sum of estimated transcellular and paracellular permeabilities. Predicted human intestinal permeability was significantly correlated with the fraction of absorbed dose in humans, indicating that DAMPA has the potential to predict oral absorption of drugs in humans.

  1. Investigation of coco-glucoside as a novel intestinal permeation enhancer in rat models.

    PubMed

    Aguirre, Tanira A S; Rosa, Mónica; Guterres, Sílvia S; Pohlmann, Adriana R; Coulter, Ivan; Brayden, David J

    2014-11-01

    Due to instability in the GI tract and low intestinal permeability, peptides invariably have oral bioavailabilities below 1% and this has prevented the development of oral formulations. A mild plant-derived naturalalkyl polyglycoside (APG), coco-glucoside (CG), was studied for its capacity to enable rat intestinal permeation of the paracellular sugar marker, fluorescein isothiocyanate-dextran 4000 (FD4), across isolated rat jejunal and colonic mucosae mounted in Ussing chambers, as well as the polypeptide, salmon calcitonin (sCT) following intra-intestinal instillations in rats. 0.1% (w/v) CG enabled a 2.9-fold increase in the apparent permeability coefficient (Papp) of FD4 over the basal Papp across colonic mucosae, but it was without effect in jejunal mucosae. In situ intestinal instillations revealed that although sCT was absorbed across rat colonic loops to a greater extent than jejunal, CG still improved sCT absolute bioavailability(F) from both segments. Histopathology of rat intestinal mucosae following exposure to CG indicated only minor perturbation with adequate maintenance of secretory function. High content analysis(HCA) on Caco-2 showed that acute and chronic exposure to a range of concentrations of CG did not cause sub-lethal damage at concentrations at which it was effective as an enhancer. Overall, CG increased bioavailability of sCT across rat jejunal and colonic loops without indication of tissue damage. Thus, CG has potential as a safe and effective intestinal enhancer for oral delivery of proteins and peptides.

  2. Adenosine A2B receptor modulates intestinal barrier function under hypoxic and ischemia/reperfusion conditions

    PubMed Central

    Yang, Yang; Qiu, Yuan; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Zhang, Chaojun; Yang, Hanwenbo; Teitelbaum, Daniel H; Sun, Li-Hua; Yang, Hua

    2014-01-01

    Background: Intestinal barrier function failure from ischemia/reperfusion (I/R) and acute hypoxia has been implicated as a critical determinant in the predisposition to intestinal inflammation and a number of inflammatory disorders. Here, we identified the role of Adenosine A2B receptor (A2BAR) in the regulation of intestinal barrier function under I/R and acute hypoxic conditions. Methods: C57BL/6J mice were used, and were randomized into three groups: Sham, I/R, IR+PSB1115 (a specific A2BAR antagonist) groups. After surgery, the small bowel was harvested for immunohistochemical staining, RNA and protein content, and intestinal permeability analyses. Using an epithelial cell culture model, we investigated the influence of hypoxia on the epithelial function, and the role of A2BAR in the expressions of tight junction and epithelial permeability. The expressions of Claudin-1, occludin and ZO-1 were detected by RT-PCR and Western-Blot. Epithelial barrier function was assessed with transepithelial resistance (TER). Results and conclusions: The A2BAR antagonist, PSB1115, significantly increased tight junction protein expression after intestinal I/R or acute hypoxia conditions. PSB1115 also attenuated the disrupted distribution of TJ proteins. Furthermore, inhibition of A2BAR attenuated the decrease in TER induced by I/R or acute hypoxic conditions, and maintained intestinal barrier function. Antagonism of A2BAR activity improves intestinal epithelial structure and barrier function in a mouse model of intestinal I/R and a cell model of acute hypoxia. These findings support a potentially destructive role for A2BAR under intestinal I/R and acute hypoxic conditions. PMID:24966910

  3. Intestinal transport of 3,6'-disinapoylsucrose, a major active component of Polygala tenuifolia, using Caco-2 cell monolayer and in situ rat intestinal perfusion models.

    PubMed

    Chen, Ying; Liu, Xinmin; Pan, Ruile; Zhu, Xiaoxin; Steinmetz, André; Liao, Yonghong; Wang, Ning; Peng, Bo; Chang, Qi

    2013-10-01

    3,6'-Disinapoylsucrose is a major active component of the herb Polygala tenuifolia which has long been used for relieving tranquilization, uneasiness of the mind, and improving learning and memory. Our previous study found that 3,6'-disinapoylsucrose had a very low oral bioavailability. Its mechanisms of absorption in the small intestine have so far been unclear. In the present study, the absorption mechanisms of 3,6'-disinapoylsucrose were investigated by using the Caco-2 cell monolayer and in situ rat intestinal perfusion models. The 3,6'-disinapoylsucrose concentration was determined by an LC/MS/MS method. In a Caco-2 cell transport study, the results showed that 3,6'-disinapoylsucrose had very limited intestinal permeability with average apparent permeability coefficient values around (1.11-1.34) × 10(-7) cm/s from the apical (A) to the basolateral (B) side and (1.37-1.42) × 10(-7) cm/s from B to A, at concentrations of 5, 20, and 33 µM. No concentration dependence in the 3,6'-disinapoylsucrose transport was observed. The apparent permeability coefficient value of 3,6'-disinapoylsucrose (5 µM) from A to B greatly increased to 4.49 × 10(-7) and 1.81 × 10(-7) cm/s, respectively, when the cells were preincubated with EDTA (17 mM) and sodium caprate (5.14 mM). No significant effect on the 3,6'-disinapoylsucrose transport by the inhibitors including verapamil, cyclosporine A, and sodium azide was observed. Similar results were found in the small intestinal perfusion study. The apparent permeability coefficient value of 3,6'-disinapoylsucrose greatly increased from 3.97 × 10(-6) to 23.4 × 10(-6) and 20.0 × 10(-6) cm/s in the presence of EDTA (17 mM) and sodium caprate (5.14 mM), respectively, in perfusion buffer. An in vitro stability evaluation of 3,6'-disinapoylsucrose in the gastrointestinal tract showed that it was relatively stable both in the stomach and small intestine contents, while it was found to be more instable in the colon contents. All of the

  4. Intestinal microbiota and ulcerative colitis.

    PubMed

    Ohkusa, Toshifumi; Koido, Shigeo

    2015-11-01

    There is a close relationship between the human host and the intestinal microbiota, which is an assortment of microorganisms, protecting the intestine against colonization by exogenous pathogens. Moreover, the intestinal microbiota play a critical role in providing nutrition and the modulation of host immune homeostasis. Recent reports indicate that some strains of intestinal bacteria are responsible for intestinal ulceration and chronic inflammation in inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). Understanding the interaction of the intestinal microbiota with pathogens and the human host might provide new strategies treating patients with IBD. This review focuses on the important role that the intestinal microbiota plays in maintaining innate immunity in the pathogenesis and etiology of UC and discusses new antibiotic therapies targeting the intestinal microbiota.

  5. Intestinal Failure (Short Bowel Syndrome)

    MedlinePlus

    ... N Vitamin deficiencies as a result of poor absorption in the intestine N Electrolyte and mineral deficiencies ... N Kidney stones or gallstones due to poor absorption of calcium or bile How is intestinal failure ...

  6. Small intestine aspirate and culture

    MedlinePlus

    ... ency/article/003731.htm Small intestine aspirate and culture To use the sharing features on this page, please enable JavaScript. Small intestine aspirate and culture is a lab test to check for infection ...

  7. Advantageous Solubility-Permeability Interplay When Using Amorphous Solid Dispersion (ASD) Formulation for the BCS Class IV P-gp Substrate Rifaximin: Simultaneous Increase of Both the Solubility and the Permeability.

    PubMed

    Beig, Avital; Fine-Shamir, Noa; Lindley, David; Miller, Jonathan M; Dahan, Arik

    2017-02-15

    Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20 h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (k a) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility k a was doubled, similar to the k a in the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs' P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.

  8. [Intestinal microbiocenosis in children with intestinal enzymopathy].

    PubMed

    Kamilova, A T; Akhmedov, N N; Pulatova, D B; Nurmatov, B A

    2001-01-01

    141 children with different kinds of intestinal enzymopathy were examined; of these, 33 had celiac disease, 39--the syndrome of celiac disease, 12--congenital lactase deficiency and 57--the syndrome of disaccharidase insufficiency. In these patients a significant decrease in the average characteristics of the main protective flora and the growth of hemolytic and lactose-negative enterobacteria were established. In all groups of patients increased amounts of Proteus were detected, which was indicative of profound dysbiosis. The content of bifidobacteria was found to be decreased in 89.5-97% of the patients and the content of lactic acid bacteria, in 15.8-33.3%. The decreased content of Escherichia coli with normal enzymatic activity (less than 10(7) colony-forming units) was noted in one-third of the patients with the syndrome of celiac disease and congenital lactase deficiency, in about a half of the patients with the syndrome of disaccharidase insufficiency and least of all in patients with celiac disease (9.1%). The association of opportunistic microbes was detected in 15.6% of the patients, more often in those with celiac disease, the syndrome of celiac disease and congenital lactase deficiency. The severity of disturbances in intestinal eubiosis was found to depend on the gravity of the patients' state.

  9. Exercise regulation of intestinal tight junction proteins.

    PubMed

    Zuhl, Micah; Schneider, Suzanne; Lanphere, Katherine; Conn, Carole; Dokladny, Karol; Moseley, Pope

    2014-06-01

    Gastrointestinal distress, such as diarrhoea, cramping, vomiting, nausea and gastric pain are common among athletes during training and competition. The mechanisms that cause these symptoms are not fully understood. The stress of heat and oxidative damage during exercise causes disruption to intestinal epithelial cell tight junction proteins resulting in increased permeability to luminal endotoxins. The endotoxin moves into the blood stream leading to a systemic immune response. Tight junction integrity is altered by the phosphoylation state of the proteins occludin and claudins, and may be regulated by the type of exercise performed. Prolonged exercise and high-intensity exercise lead to an increase in key phosphorylation enzymes that ultimately cause tight junction dysfunction, but the mechanisms are different. The purpose of this review is to (1) explain the function and physiology of tight junction regulation, (2) discuss the effects of prolonged and high-intensity exercise on tight junction permeability leading to gastrointestinal distress and (3) review agents that may increase or decrease tight junction integrity during exercise.

  10. Intestinal Microbiota and Its Relationship with Necrotizing Enterocolitis

    PubMed Central

    Patel, Ravi Mangal; Denning, Patricia W.

    2015-01-01

    Necrotizing enterocolitis is a leading cause of morbidity and mortality in infants born prematurely. After birth, the neonatal gut must acquire a healthy complement of commensal bacteria. Disruption or delay of this critical process, leading to deficient or abnormal microbial colonization of the gut, has been implicated as key risk factor in the pathogenesis of NEC. Conversely, a beneficial complement of commensal intestinal microbiota may protect the immature gut from inflammation and injury. Interventions aimed at providing or restoring a healthy complement of commensal bacteria, such as probiotic therapy, are currently the most promising treatment to prevent NEC. Shifting the balance of intestinal microbiota from a pathogenic to protective complement of bacteria can protect the gut from inflammation and subsequent injury that leads to NEC. Herein, we review the relationship of intestinal microbiota and NEC in preterm infants. PMID:25992911

  11. Late effects of abdominal radiation on intestinal uptake of nutrients

    SciTech Connect

    Thomson, A.B.; Cheeseman, C.I.; Walker, K.

    1986-09-01

    The late effects of variable doses of abdominal irradiation on in vitro jejunal uptake were examined. The uptake of glucose, galactose, cholic acid, medium-chain length fatty acids, and decanol was studied 6 and 33 weeks following 300, 600, or 900 cGy abdominal irradiation. The intestinal morphological characteristics were similar 6 and 33 weeks after radiation. The uptake of cholic acid was unaffected by abdominal irradiation, but for glucose, galactose, and four fatty acids the direction and magnitude of the changes in uptake were influenced by the dose of irradiation and by the interval following exposure. The greater uptake of decanol at 6 weeks but lower uptake of decanol at 33 weeks reflected changes in the resistance of the intestinal unstirred water layer. These absorption changes suggest that the intestine may not be capable of correcting the transport abnormalities arising from sublethal doses of abdominal irradiation.

  12. Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors

    PubMed Central

    Kawahara, Tomohiro; Makizaki, Yutaka; Oikawa, Yosuke; Tanaka, Yoshiki; Maeda, Ayako; Shimakawa, Masaki; Komoto, Satoshi; Moriguchi, Kyoko; Ohno, Hiroshi; Taniguchi, Koki

    2017-01-01

    Human rotavirus (RV) infection is a leading cause of dehydrating diarrhea in infants and young children worldwide. Since therapeutic approaches to RV gastroenteritis are limited to alleviation of dehydration with oral rehydration solutions, more direct approaches to palliate symptoms of RV gastroenteritis are required. Treatments with probiotics have been increasingly recognized as alternative safe and low cost treatments for moderate infectious diarrhea. In this study, Bifidobacterium bifidum G9-1 (BBG9-1), which has been used as an intestinal drug for several decades, was shown to have a remarkable protective effect against RV gastroenteritis in a suckling mice model. As well as prophylactic oral administration of BBG9-1 from 2 days before RV infection, therapeutic oral administration of BBG9-1 from 1 day after RV infection significantly alleviated RV-induced diarrhea. Therapeutic administration of BBG9-1 reduced various types of damage in the small intestine, such as epithelial vacuolization and villous shortening, and significantly diminished the infectious RV titer in mixtures of cecal contents and feces. It was also shown that therapeutic administration of BBG9-1 significantly increased the number of acidic mucin-positive goblet cells and the gene expression of mucosal protective factors including MUC2, MUC3, MUC4, TGFβ1 and TFF3 in the small intestine. This led to alleviation of low gut permeability shown as decreased gene expression levels of occludin, claudin-1 and villin-1 after RV infection. Furthermore, in the small intestine, therapeutic administration of BBG9-1 significantly palliated the decreased gene expression of SGLT-1, which plays an important role in water absorption. In the large intestine, administered BBG9-1 was shown to replicate to assimilate undigested nutrients, resulting in normalization of the abnormally high osmotic pressure. These results suggested that water malabsorption caused by RV infection was alleviated in mice administered

  13. Effect of Dead Algae on Soil Permeability

    SciTech Connect

    Harvey, R.S.

    2003-02-21

    Since existing basins support heavy growths of unicellular green algae which may be killed by temperature variation or by inadvertent pH changes in waste and then deposited on the basin floor, information on the effects of dead algae on soil permeability was needed. This study was designed to show the effects of successive algal kills on the permeability of laboratory soil columns.

  14. Influence of fiber packing structure on permeability

    NASA Technical Reports Server (NTRS)

    Cai, Zhong; Berdichevsky, Alexander L.

    1993-01-01

    The study on the permeability of an aligned fiber bundle is the key building block in modeling the permeability of advanced woven and braided preforms. Available results on the permeability of fiber bundles in the literature show that a substantial difference exists between numerical and analytical calculations on idealized fiber packing structures, such as square and hexagonal packing, and experimental measurements on practical fiber bundles. The present study focuses on the variation of the permeability of a fiber bundle under practical process conditions. Fiber bundles are considered as containing openings and fiber clusters within the bundle. Numerical simulations on the influence of various openings on the permeability were conducted. Idealized packing structures are used, but with introduced openings distributed in different patterns. Both longitudinal and transverse flow are considered. The results show that openings within the fiber bundle have substantial effect on the permeability. In the longitudinal flow case, the openings become the dominant flow path. In the transverse flow case, the fiber clusters reduce the gap sizes among fibers. Therefore the permeability is greatly influenced by these openings and clusters, respectively. In addition to the porosity or fiber volume fraction, which is commonly used in the permeability expression, another fiber bundle status parameter, the ultimate fiber volume fraction, is introduced to capture the disturbance within a fiber bundle.

  15. A method of determination of permeability

    SciTech Connect

    Kuznetsov, S.V.; Trofimov, V.A.

    2007-11-15

    A method is proposed for determining permeability of coals under conditions of steady-state deformation and stationary filtration mode by employing a reference core made of gas-non-sorbing material with a known permeability. The approach has been developed to assess the time of transition to the stable filtration.

  16. Congenital abnormalities and selective abortion.

    PubMed

    Seller, M J

    1976-09-01

    The technique of amniocentesis, by which an abnormal fetus can be detected in utero, has brought a technological advance in medical science but attendant medical and moral problems. Dr Seller describes those congenital disabilities which can be detected in the fetus before birth, for which the "remedy" is selective abortion. She then discusses the arguments for and against selective abortion, for the issue is not simple, even in the strictly genetic sense of attempting to ensure a population free of congenital abnormality.

  17. Characterization of tumor microvascular structure and permeability: comparison between magnetic resonance imaging and intravital confocal imaging

    NASA Astrophysics Data System (ADS)

    Reitan, Nina Kristine; Thuen, Marte; Goa, Pa˚L. Erik; de Lange Davies, Catharina

    2010-05-01

    Solid tumors are characterized by abnormal blood vessel organization, structure, and function. These abnormalities give rise to enhanced vascular permeability and may predict therapeutic responses. The permeability and architecture of the microvasculature in human osteosarcoma tumors growing in dorsal window chambers in athymic mice were measured by confocal laser scanning microscopy (CLSM) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Dextran (40 kDa) and Gadomer were used as molecular tracers for CLSM and DCE-MRI, respectively. A significant correlation was found between permeability indicators. The extravasation rate Ki as measured by CLSM correlated positively with DCE-MRI parameters, such as the volume transfer constant Ktrans and the initial slope of the contrast agent concentration-time curve. This demonstrates that these two techniques give complementary information. Extravasation was further related to microvascular structure and was found to correlate with the fractal dimension and vascular density. The structural parameter values that were obtained from CLSM images were higher for abnormal tumor vasculature than for normal vessels.

  18. Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir.

    PubMed

    Talluri, Ravi S; Samanta, Swapan K; Gaudana, Ripal; Mitra, Ashim K

    2008-09-01

    The objective of this study was to synthesize and evaluate novel enzymatically stable dipeptide prodrugs for improved absorption of acyclovir. l-Valine-l-valine-acyclovir (LLACV), l-valine-d-valine-acyclovir (LDACV), d-valine-l-valine-acyclovir (DLACV) and d-valine-d-valine-acyclovir (DDACV) were successfully synthesized. The uptake and transport studies were conducted on a Caco-2 cell line. Buffer stability and metabolism of the prodrugs in Caco-2, rat intestine and liver homogenates were studied. Structure and purity of the all compounds were confirmed with LC-MS/MS and NMR spectroscopy. Uptake and transport of [(3)H] glycylsarcosine was inhibited by all prodrugs except DDACV. DLACV and DDACV exhibited no measurable degradation in Caco-2 homogenate. Except DDACV other three prodrugs were hydrolyzed in rat intestine and liver homogenates. The order of permeability across Caco-2 was LDACV>LLACV>DDACV>DLACV. A linear correlation between the amount of prodrug transported and over all permeability of acyclovir was established. This study shows that the incorporation of one d-valine in a dipeptide did not abolish its affinity towards peptide transporters (PEPT). Moreover, it enhanced enzymatic stability of prodrug to a certain extent depending on the position in a dipeptide conjugate. This strategy improved both the cellular permeability and the amount of intact prodrug transported which would enable targeting the nutrient transporters at blood ocular barrier (BOB).

  19. Abnormal refraction of microwave in ferrite/wire metamaterials.

    PubMed

    Zhao, Hongjie; Li, Bo; Zhou, Ji; Kang, Lei; Zhao, Qian; Li, Weibin

    2011-08-15

    We report the experimentally observed abnormal refraction in metamaterials (MMs) consisting of ferrite rods and metallic wires with two kinds of configurations. Negative refraction (NR) and positive refraction (PR) are demonstrated in an MM constructed with parallel-arranged rods and wires. The frequencies of both NR and PR can be adjusted dynamically and together by an applied magnetic field and the PR occurs at frequencies slightly lower than that of the NR. The NR is attributed to simultaneously negative effective permittivity and permeability, and the PR is resulted from positive effective permittivity and permeability with the positive effective permittivity originating from electromagnetic coupling between the closest rod and wire. By making the rod cross the wire to reduce the coupling, we observed sole NR in an MM consisting of the cross-arranged rods and wires. Theoretical analysis explained qualitatively the abnormal refraction behaviors of microwave for the two kinds of MMs and it is supported by the retrieved effective parameters and field distributions.

  20. Beneficial Effect of Synbiotic Supplementation on Hepatic Steatosis and Anthropometric Parameters, But Not on Gut Permeability in a Population with Nonalcoholic Steatohepatitis

    PubMed Central

    Ferolla, Silvia M.; Couto, Cláudia A.; Costa-Silva, Luciana; Armiliato, Geyza N. A.; Pereira, Cristiano A. S.; Martins, Flaviano S.; Ferrari, Maria de Lourdes A.; Vilela, Eduardo G.; Torres, Henrique O. G.; Cunha, Aloísio S.; Ferrari, Teresa C. A.

    2016-01-01

    Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western countries; it can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma. The importance of gut-liver-adipose tissue axis has become evident and treatments targeting gut microbiota may improve inflammatory and metabolic parameters in NASH patients. In a randomized, controlled clinical trial, involving 50 biopsy-proven NASH patients, we investigated the effects of synbiotic supplementation on metabolic parameters, hepatic steatosis, intestinal permeability, small intestinal bacterial overgrowth (SIBO) and lipopolysaccharide (LPS) serum levels. Patients were separated into two groups receiving Lactobacillus reuteri with guar gum and inulin for three months and healthy balanced nutritional counseling versus nutritional counseling alone. Before and after the intervention we assessed steatosis by magnetic resonance imaging, intestinal permeability by lactulose/mannitol urinary excretion and SIBO by glucose breath testing. NASH patients presented high gut permeability, but low prevalence of SIBO. After the intervention, only the synbiotic group presented a reduction in steatosis, lost weight, diminished BMI and waist circumference measurement. Synbiotic did not improve intestinal permeability or LPS levels. We concluded that synbiotic supplementation associated with nutritional counseling seems superior to nutritional counseling alone for NASH treatment as it attenuates steatosis and may help to achieve weight loss. PMID:27367724

  1. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    PubMed Central

    Cui, Yun-Liang; Zhang, Sheng; Tian, Zhao-Tao; Lin, Zhao-Fen; Chen, De-Chang

    2016-01-01

    Background: Intact endothelial structure and function are critical for maintaining microcirculatory homeostasis. Dysfunction of the latter is an underlying cause of various organ pathologies. In a previous study, we showed that rhubarb, a traditional Chinese medicine, protected intestinal mucosal microvascular endothelial cells in rats with metastasizing septicemia. In this study, we investigated the effects and mechanisms of rhubarb on matrix metalloproteinase-9 (MMP9)-induced vascular endothelial (VE) permeability. Methods: Rhubarb monomers were extracted and purified by a series of chromatography approaches. The identity of these monomers was analyzed by hydrogen-1 nuclear magnetic resonance (NMR), carbon-13 NMR, and distortionless enhancement by polarization transfer magnetic resonance spectroscopy. We established a human umbilical vein endothelial cell (HUVEC) monolayer on a Transwell insert. We measured the HUVEC permeability, proliferation, and the secretion of VE-cadherin into culture medium using fluorescein isothiocyanate-dextran assay, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, and enzyme-linked immunosorbent assay, respectively, in response to treatment with MMP9 and/or rhubarb monomers. Results: A total of 21 rhubarb monomers were extracted and identified. MMP9 significantly increased the permeability of the HUVEC monolayer, which was significantly reduced by five individual rhubarb monomer (emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl)-β-D-glucose, daucosterol linoleate, and rhein) or a combination of all five monomers (1 μmol/L for each monomer). Mechanistically, the five-monomer mixture at 1 μmol/L promoted HUVEC proliferation. In addition, MMP9 stimulated the secretion of VE-cadherin into the culture medium, which was significantly inhibited by the five-monomer mixture. Conclusions: The rhubarb mixture of emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2

  2. Influence of aging on membrane permeability transition in brain mitochondria.

    PubMed

    Toman, Julia; Fiskum, Gary

    2011-02-01

    The mitochondrial inner membrane permeability transition (MPT) plays an important role in the pathophysiology of acute disorders of the central nervous systems, including ischemic and traumatic brain injury, and possibly in neurodegenerative diseases. Opening of the permeability transition pore (PTP) by a combination of abnormally elevated intramitochondrial Ca2+ and oxidative stress induces the collapse of transmembrane ion gradients, resulting in membrane depolarization and uncoupling of oxidative phosphorylation. This loss of ATP synthesis eventually results in cellular metabolic failure and necrotic cell death. Drugs, e.g., cyclosporin A, can inhibit the permeability transition through their interaction with the mitochondria-specific protein, cyclophilin D, and demonstrate neuroprotection in several animal models. These characteristics of the MPT were developed almost exclusively from experiments performed with young, mature rodents whereas the neuropathologies associated with the MPT are most prevalent in the elderly population. Some evidence indicates that the sensitivity of mitochondria to Ca2+-induced PTP opening is greater in the aged compared to the young mature brain; however, the basis for this difference is unknown. Based on knowledge of factors that regulate the MPT and on other comparisons between cells and mitochondria from young and old animals, several features may be important. These aging-related features include impaired neuronal Ca2+ homeostasis, increased oxidative stress, increased cyclophilin D protein levels, oxidative modification of the adenine nucleotide translocase and of cardiolipin, and changes in the levels of anti-death mitochondrial proteins, e.g., Bcl-2. The influence of aging on both the contribution of the MPT to neuropathology and the neuroprotective efficacy of MPT inhibitors is a substantial knowledge gap that requires extensive research at the subcellular, cellular, and animal model levels.

  3. Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen

    PubMed Central

    Nakano, Daisuke; Kobori, Hiroyuki; Burford, James L.; Gevorgyan, Haykanush; Seidel, Saskia; Hitomi, Hirofumi; Nishiyama, Akira

    2012-01-01

    Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration. PMID:22997258

  4. Multiphoton imaging of the glomerular permeability of angiotensinogen.

    PubMed

    Nakano, Daisuke; Kobori, Hiroyuki; Burford, James L; Gevorgyan, Haykanush; Seidel, Saskia; Hitomi, Hirofumi; Nishiyama, Akira; Peti-Peterdi, Janos

    2012-11-01

    Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration.

  5. [Diagnosticum of abnormalities of plant meiotic division].

    PubMed

    Shamina, N V

    2006-01-01

    Abnormalities of plant meiotic division leading to abnormal meiotic products are summarized schematically in the paper. Causes of formation of monads, abnormal diads, triads, pentads, polyads, etc. have been observed in meiosis with both successive and simultaneous cytokinesis.

  6. Imaging diagnosis--muscular hypertrophy of the small intestine and pseudodiverticula in a horse.

    PubMed

    Navas De Solís, Cristobal; Biscoe, Elisabeth W; Lund, Caleb M; Labbe, Karyn; Muñoz, Juan; Farnsworth, Kelly

    2015-01-01

    A 14-year-old Thoroughbred gelding was presented for chronic colic and weight loss. Transcutaneous and transrectal abdominal ultrasonography revealed distended, thickened small intestine with primary thickening of the muscularis and a focally more thickened loop with an echoic structure crossing the wall from the mucosa to the serosa. Visualization of diffuse thickening of the muscularis (muscular hypertrophy of the small intestine) and a focal lesion (pseudodiverticulum) helped clinicians make informed decisions. This case illustrates the importance of transabdominal and transrectal ultrasonography in horses with chronic colic and the relevance of considering the abnormalities in layering pattern of the intestinal wall.

  7. Geometric estimation of intestinal contraction for motion tracking of video capsule endoscope

    NASA Astrophysics Data System (ADS)

    Mi, Liang; Bao, Guanqun; Pahlavan, Kaveh

    2014-03-01

    Wireless video capsule endoscope (VCE) provides a noninvasive method to examine the entire gastrointestinal (GI) tract, especially small intestine, where other endoscopic instruments can barely reach. VCE is able to continuously provide clear pictures in short fixed intervals, and as such researchers have attempted to use image processing methods to track the video capsule in order to locate the abnormalities inside the GI tract. To correctly estimate the speed of the motion of the endoscope capsule, the radius of the intestinal track must be known a priori. Physiological factors such as intestinal contraction, however, dynamically change the radius of the small intestine, which could bring large errors in speed estimation. In this paper, we are aiming to estimate the radius of the contracted intestinal track. First a geometric model is presented for estimating the radius of small intestine based on the black hole on endoscopic images. To validate our proposed model, a 3-dimentional virtual testbed that emulates the intestinal contraction is then introduced in details. After measuring the size of the black holes on the test images, we used our model to esimate the radius of the contracted intestinal track. Comparision between analytical results and the emulation model parameters has verified that our proposed method could preciously estimate the radius of the contracted small intestine based on endoscopic images.

  8. Beneficial effect of a symbiotic preparation with S. boulardii lysate in mild stress-induced gut hyper-permeability.

    PubMed

    Takadanohara, Hiroshi; Catanzaro, Roberto; Chui, De Hua; He, Fengtian; Yadav, Hariom; Ganguli, Abhijit; Sakata, Yasuhiko; Solimene, Umberto; Minelli, Emilio; Kobayashi, Riyichi; Nagamachi, Yoko; Marotta, Francesco

    2012-12-01

    Increased intestinal permeability has been advocated as one of the likely causes of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Thus, the aim of the present study was to test a symbiotic preparation containing microbial lysates (KC-1317, Named, Italy) against stress-induced derangement of gut mucosa permeability. Sprague Dawley rats were allocated into control (n=20) and stress (n=20) group. Stress was implemented by 1h of water avoidance stress daily for 10 days. Body weight, food and water intake and passage of stool pellet during stress session were recorded throughout the experiment. On the 11th day, fluorescent iso-thiocyanate dextran solution was injected into small intestinal loops. One hour after the injection, rats were sacrificed. Jejunum and ileum were taken for histopathology. Blood was collected from the abdominal aorta to measure intestinal permeability. In stress group, stool pellets during stress session was significantly higher than control group (p < 0.01). Villus height (p < 0.01), crypt depth (p < 0.01), number of goblet cells in villus (p < 0.01) and crypt (p < 0.05) decreased significantly in jejunum as compared to control. These phenomena were significantly prevented by KC-1317 (p < 0.05). Ileum also showed atrophy but villus height and the number of goblet cells in the villi did not significantly differ. Plasma-concentration of brain-gut peptides (substance P, thyrotropin-releasing hormone, cholecystokinin and motilin) were affected by stress (p < 0.001) and this effect did not change during supplementation with KC-1317. Polymorphonuclear neutrophil counting was significantly higher in stress group as compared to control (p < 0.01) but this phenomenon was abolished in the ileum (p < 0.01) or partly but significantly reduced by KC-1317 supplementation (p < 0.05). Accordingly, intestinal permeability was significantly enhanced in stress group as compared to control (p < 0.01) and prevented by KC

  9. Ste20-related proline/alanine-rich kinase: A novel regulator of intestinal inflammation

    PubMed Central

    Yan, Yutao; Merlin, Didier

    2008-01-01

    Recently, inflammatory bowel disease (IBD) has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase (SPAK) is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases (such as p38, JNK, NKCC1, PKCtheta;, WNK and MLCK), and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-like kinases and downstream mitogen-activated protein kinases (MAPKs) pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation. PMID:18985800

  10. Enhanced ex vivo intestinal absorption of olmesartan medoxomil nanosuspension: Preparation by combinative technology.

    PubMed

    Attari, Zenab; Bhandari, Amita; Jagadish, P C; Lewis, Shaila

    2016-01-01

    The purpose of this study was to develop nanosuspension based on combinative technology to enhance the intestinal absorption of Olmesartan medoxomil (OLM), a potent antihypertensive agent with limited oral bioavailability. Two combinative approaches were employed and then characterized. In vitro intestinal absorption of OLM nanosuspension and plain OLM was studied using non-everted rat intestinal sac model. Optimal OLM nanosuspension was prepared by a combination of ball milling and probe sonication using stabilizer, Poloxamer 407. The formula exhibited particle size of 469.9 nm and zeta potential of -19.1 mV, which was subjected to ex vivo studies. The flux and apparent permeability coefficient in intestine from OLM nanosuspension was higher than the plain drug, thereby suggesting better drug delivery.

  11. Effect of fluoride on the intestinal epithelial cell brush border membrane

    SciTech Connect

    Rastogi, R.; Upreti, R.K.; Kidwai, A.M.

    1987-07-01

    Fluoride consumed by man and animals is chiefly absorbed in the intestine. Chronic fluoride exposure causes mottled teeth and osteosclerosis. Over-fluoridation (126 mM) of drinking water have been reported to cause nausea, vomiting and diarrhea. Furthermore, the effect of acute and low concentrations of fluoride on gastric secretion, ion transport and other disorders have also been studied. Fluoride also causes alterations in the permeability of membranes and membrane bound enzymes. The intestinal cell lining plays an important role in digestion and absorption. It automatically becomes the most exposed site of contact to fluoride following ingestion. Earlier study have shown significant alterations in the formation of lipid peroxides in rat intestine following oral administration of fluoride. The present study was undertaken to investigate the damage of rat intestinal epithelium in situ caused by relatively high and low fluoride concentrations.

  12. Predicting human intestinal absorption in the presence of bile salt with micellar liquid chromatography.

    PubMed

    Waters, Laura J; Shokry, Dina S; Parkes, Gareth M B

    2016-10-01

    Understanding intestinal absorption for pharmaceutical compounds is vital to estimate the bioavailability and therefore the in vivo potential of a drug. This study considers the application of micellar liquid chromatography (MLC) to predict passive intestinal absorption with a selection of model compounds. MLC is already known to aid prediction of absorption using simple surfactant systems; however, with this study the focus was on the presence of a more complex, bile salt surfactant, as would be encountered in the in vivo environment. As a result, MLC using a specific bile salt has been confirmed as an ideal in vitro system to predict the intestinal permeability for a wide range of drugs, through the development of a quantitative partition-absorption relationship. MLC offers many benefits including environmental, economic, time-saving and ethical advantages compared with the traditional techniques employed to obtain passive intestinal absorption values. Copyright © 2016 John Wiley & Sons, Ltd.

  13. The effect of nonsteroidal anti-inflammatory drugs on the equine intestine.

    PubMed

    Marshall, J F; Blikslager, A T

    2011-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management of pain and endotoxaemia associated with colic in the horse. While NSAIDs effectively treat the symptoms of colic, there is evidence to suggest that their administration is associated with adverse gastrointestinal effects including right dorsal colitis and inhibition of mucosal barrier healing. Several studies have examined the pathophysiology of NSAID associated effects on the large and small intestine in an effort to avoid these complications and identify effective alternative medications. Differences in the response of the large and small intestines to injury and NSAID treatment have been identified. Flunixin meglumine has been shown in the small intestine to inhibit barrier function recovery and increase permeability to lipopolysaccharide (LPS). A range of NSAIDs has been examined in the small intestine and experimental evidence suggests that those NSAIDs with cyclooxygenase independent anti-inflammatory effects or a COX-2 selective mode of action may offer significant advantages over traditional NSAIDs.

  14. Anisotropy of permeability in faulted porous sandstones

    NASA Astrophysics Data System (ADS)

    Farrell, N. J. C.; Healy, D.; Taylor, C. W.

    2014-06-01

    Studies of fault rock permeabilities advance the understanding of fluid migration patterns around faults and contribute to predictions of fault stability. In this study a new model is proposed combining brittle deformation structures formed during faulting, with fluid flow through pores. It assesses the impact of faulting on the permeability anisotropy of porous sandstone, hypothesising that the formation of fault related micro-scale deformation structures will alter the host rock porosity organisation and create new permeability pathways. Core plugs and thin sections were sampled around a normal fault and oriented with respect to the fault plane. Anisotropy of permeability was determined in three orientations to the fault plane at ambient and confining pressures. Results show that permeabilities measured parallel to fault dip were up to 10 times higher than along fault strike permeability. Analysis of corresponding thin sections shows elongate pores oriented at a low angle to the maximum principal palaeo-stress (σ1) and parallel to fault dip, indicating that permeability anisotropy is produced by grain scale deformation mechanisms associated with faulting. Using a soil mechanics 'void cell model' this study shows how elongate pores could be produced in faulted porous sandstone by compaction and reorganisation of grains through shearing and cataclasis.

  15. Fluid permeability of deformable fracture networks

    SciTech Connect

    Brown, S.R.; Bruhn, R.L.

    1997-04-01

    The authors consider the problem of defining the fracture permeability tensor for each grid lock in a rock mass from maps of natural fractures. For this purpose they implement a statistical model of cracked rock due to M. Oda [1985], where the permeability tensor is related to the crack geometry via a volume average of the contribution from each crack in the population. In this model tectonic stress is implicitly coupled to fluid flow through an assumed relationship between crack aperture and normal stress across the crack. The authors have included the following enhancements to the basic model: (1) a realistic model of crack closure under stress has been added along with the provision to apply tectonic stresses to the fracture system in any orientation, the application of stress results in fracture closure and consequently a reduction in permeability; (2) the fracture permeability can be superimposed onto an arbitrary anisotropic matrix permeability; (3) the fracture surfaces are allowed to slide under the application of shear stress, causing fractures to dilate and result in a permeability increase. Through an example, the authors demonstrate that significant changes in permeability magnitudes and orientations are possible when tectonic stress is applied to a fracture system.

  16. Permeable Gas Flow Influences Magma Fragmentation Speed.

    NASA Astrophysics Data System (ADS)

    Richard, D.; Scheu, B.; Spieler, O.; Dingwell, D.

    2008-12-01

    Highly viscous magmas undergo fragmentation in order to produce the pyroclastic deposits that we observe, but the mechanisms involved remain unclear. The overpressure required to initiate fragmentation depends on a number of physical parameters, such as the magma's vesicularity, permeability, tensile strength and textural properties. It is clear that these same parameters control also the speed at which a fragmentation front travels through magma when fragmentation occurs. Recent mathematical models of fragmentation processes consider most of these factors, but permeable gas flow has not yet been included in these models. However, it has been shown that permeable gas flow through a porous rock during a sudden decompression event increases the fragmentation threshold. Fragmentation experiments on natural samples from Bezymianny (Russia), Colima (Mexico), Krakatau (Indonesia) and Augustine (USA) volcanoes confirm these results and suggest in addition that high permeable flow rates may increase the speed of fragmentation. Permeability from the investigated samples ranges from as low as 5 x 10-14 to higher than 9 x 10- 12 m2 and open porosity ranges from 16 % to 48 %. Experiments were performed for each sample series at applied pressures up to 35 MPa. Our results indicate that the rate of increase of fragmentation speed is higher when the permeability is above 10-12 m2. We confirm that it is necessary to include the influence of permeable flow on fragmentation dynamics.

  17. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

    PubMed

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

  18. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice

    PubMed Central

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F.; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G.; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4+ lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4+ Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability. PMID:27199937

  19. Effect of Layer-by-Layer (LbL) Encapsulation of Nano-Emulsified Fish Oil on Their Digestibility Ex Vivo and Skin Permeability In Vitro

    PubMed Central

    Jung, Eun Young; Hong, Ki Bae; Son, Heung Soo; Suh, Hyung Joo; Park, Yooheon

    2016-01-01

    Omega-3 rich fish oils are extremely labile, thus requiring control of oxidation and off flavor development. A recently proposed emulsification method, layer-by-layer (LbL) deposition, was found to be a plausible method to enhance the characteristics of bioactive ingredients, especially lipids. The present work was designed to test the possibility of enhancing the uptake and utilization of omega-3 fatty acids present in fish oil. The bioavailability of nano-emulsified fish oil was monitored in terms of intestinal absorption as well as skin permeability by using the everted intestinal sac model and Franz cell model. The skin permeability and intestinal absorption characteristics was significantly improved by LbL emulsification with lecithin/chitosan/low methoxypectin. Multilayer encapsulation along with nano-emulsification can be a useful method to deliver biologically active lipids and related components, such as fish oil. The protective effect of this tool from lipid oxidation still needs to be verified. PMID:27390723

  20. Permeability Barrier Generation in the Martian Lithosphere

    NASA Astrophysics Data System (ADS)

    Schools, Joe; Montési, Laurent

    2015-11-01

    Permeability barriers develop when a magma produced in the interior of a planet rises into the cooler lithosphere and crystallizes more rapidly than the lithosphere can deform (Sparks and Parmentier, 1991). Crystallization products may then clog the porous network in which melt is propagating, reducing the permeability to almost zero, i.e., forming a permeability barrier. Subsequent melts cannot cross the barrier. Permeability barriers have been useful to explain variations in crustal thickness at mid-ocean ridges on Earth (Magde et al., 1997; Hebert and Montési, 2011; Montési et al., 2011). We explore here under what conditions permeability barriers may form on Mars.We use the MELTS thermodynamic calculator (Ghiorso and Sack, 1995; Ghiorso et al., 2002; Asimow et al., 2004) in conjunction with estimated Martian mantle compositions (Morgan and Anders, 1979; Wänke and Dreibus, 1994; Lodders and Fegley, 1997; Sanloup et al., 1999; Taylor 2013) to model the formation of permeability barriers in the lithosphere of Mars. In order to represent potential past and present conditions of Mars, we vary the lithospheric thickness, mantle potential temperature (heat flux), oxygen fugacity, and water content.Our results show that permeability layers can develop in the thermal boundary layer of the simulated Martian lithosphere if the mantle potential temperature is higher than ~1500°C. The various Martian mantle compositions yield barriers in the same locations, under matching variable conditions. There is no significant difference in barrier location over the range of accepted Martian oxygen fugacity values. Water content is the most significant influence on barrier development as it reduces the temperature of crystallization, allowing melt to rise further into the lithosphere. Our lower temperature and thicker lithosphere model runs, which are likely the most similar to modern Mars, show no permeability barrier generation. Losing the possibility of having a permeability

  1. Evidence for regulatory control of iron uptake from ferric maltol across the small intestine of the rat.

    PubMed Central

    Barrand, M. A.; Callingham, B. A.

    1991-01-01

    1. 59Fe absorption from the novel iron compound, ferric maltol, was studied in rats pretreated twice daily for two weeks with non-radioactive ferric maltol in oral doses containing 7 mg elemental iron. Tissue accumulation of 59Fe 2 h after administration of radioactive ferric maltol into the stomach was significantly lower in iron pretreated animals than in saline-treated controls. 2. 59Fe uptake from ferric maltol into isolated fragments of ileum and of duodenum was of similar magnitude in control animals but in iron-treated animals, duodenal uptake was significantly lower than that of the ileum. 3. Absorption of 59Fe was also investigated in anaesthetized rats after intestinal perfusion with saline (controls) or with 5 mM chenodeoxycholate to render the intestines more permeable. 4. Changes in permeability of the small intestine were monitored by estimating the amount of [14C]-mannitol absorbed and fluid secreted with reference to the non-absorbable [3H]-inulin in the perfusate effluents. 5. Despite the increased permeability of the intestines after bile salt treatment, there was little difference from control in the tissue accumulation of 59Fe from ferric maltol 2 h after intraduodenal administration. However 59Fe absorption from ferrous sulphate was significantly increased after bile salt treatment. 6. Gel filtration profiles of plasma made 5 and 60 min after intraduodenal administration of [59Fe]-ferric [3H]-maltol demonstrated that metal and ligand do not enter the circulation as the complex even when intestinal permeability is increased. 7. Uptake of 59Fe was investigated in isolated fragments of rat small intestine after saline or bile salt perfusion. Although 59Fe uptake from ferric maltol was somewhat greater in the bile salt-treated intestinal fragments, saturable kinetics were still observed.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 4 PMID:2015422

  2. Gas Permeable Chemochromic Compositions for Hydrogen Sensing

    NASA Technical Reports Server (NTRS)

    Bokerman, Gary (Inventor); Mohajeri, Nahid (Inventor); Muradov, Nazim (Inventor); Tabatabaie-Raissi, Ali (Inventor)

    2013-01-01

    A (H2) sensor composition includes a gas permeable matrix material intermixed and encapsulating at least one chemochromic pigment. The chemochromic pigment produces a detectable change in color of the overall sensor composition in the presence of H2 gas. The matrix material provides high H2 permeability, which permits fast permeation of H2 gas. In one embodiment, the chemochromic pigment comprises PdO/TiO2. The sensor can be embodied as a two layer structure with the gas permeable matrix material intermixed with the chemochromic pigment in one layer and a second layer which provides a support or overcoat layer.

  3. Abnormal insulin levels and vertigo.

    PubMed

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  4. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  5. Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability.

    PubMed

    Zhang, Xingwang; Zhang, Tianpeng; Lan, Yali; Wu, Baojian; Shi, Zhihai

    2016-04-01

    Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.

  6. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.

    PubMed

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle J; Frederiksen, Jette L; Larsson, Henrik B W

    2015-09-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of

  7. Permeability of the blood–brain barrier predicts conversion from optic neuritis to multiple sclerosis

    PubMed Central

    Modvig, Signe; Simonsen, Helle J.; Frederiksen, Jette L.; Larsson, Henrik B. W.

    2015-01-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood–brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood–brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood–brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood–brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a

  8. Bifidobacterium animalis ssp. lactis 420 Protects against Indomethacin-Induced Gastric Permeability in Rats

    PubMed Central

    Lyra, Anna; Saarinen, Markku; Putaala, Heli; Olli, Kaisa; Lahtinen, Sampo J.; Ouwehand, Arthur C.; Madetoja, Mari; Tiihonen, Kirsti

    2012-01-01

    Gastrointestinal (GI) adverse effects such as erosion and increased permeability are common during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Our objective was to assess whether Bifidobacterium animalis ssp. lactis 420 protects against NSAID-induced GI side effects in a rat model. A total of 120 male Wistar rats were allocated into groups designated as control, NSAID, and probiotic. The NSAID and probiotic groups were challenged with indomethacin (10 mg/kg−1; single dose). The probiotic group was also supplemented daily with 1010 CFU of B. lactis 420 for seven days prior to the indomethacin administration. The control group rats received no indomethacin or probiotic. The permeability of the rat intestine was analysed using carbohydrate probes and the visual damage of the rat stomach mucosa was graded according to severity. B. lactis 420 significantly reduced the indomethacin-induced increase in stomach permeability. However, the protective effect on the visual mucosal damage was not significant. The incidence of severe NSAID-induced lesions was, nevertheless, reduced from 50% to 33% with the probiotic treatment. To conclude, the B. lactis 420 supplementation protected the rats from an NSAID-induced increase in stomach permeability and may reduce the formation of more serious GI mucosal damage and/or enhance the recovery rate of the stomach mucosa. PMID:22848210

  9. Ectodermal dysplasia and abnormal thumbs.

    PubMed

    Lucky, A W; Esterly, N B; Tunnessen, W W

    1980-05-01

    Two unrelated children, a girl and a boy, with alopecia, anomalous cutaneous pigmentation, abnormal thumbs, and endocrine disorders, including short stature and delayed bone age in one patient and juvenile onset diabetes mellitus in the other, are described. In one instance, the mother and the maternal grandmother had similar abnormalities, although of a less severe nature. Both children had normal nails and no unusual susceptibility to infections. We believe these two patients represent a previously undescribed syndrome of ectodermal dysplasia that may be inherited as an autosomal-dominant trait.

  10. Unusual intestinal talcosis.

    PubMed

    Anani, P A; Ribaux, C; Gardiol, D

    1987-11-01

    A case of intestinal talcosis in a 46-year-old man is reported. At the age of 27, the patient was treated for pulmonary tuberculosis with tablets containing talc (183 g talc per 2,670 g total drug intake) over a period of 28 months. Eighteen years later, the patient was hospitalized for abdominal pain that remained refractory to antacids; he subsequently underwent a right hemicolectomy. Light-microscopic examination revealed a prominent fibrosis of the intestinal wall in which birefringent particles were demonstrated by polarized light. Using energy-dispersive spectroscopy, an analysis of these particles showed that they were predominantly composed of silicon and magnesium as well as small amounts of phosphorus, sulphur, calcium, and iron--the spectrum typically associated with talc. We believe that the source of this talc is the tablets ingested by the patient during prior antituberculosis therapy.

  11. Elenoside increases intestinal motility

    PubMed Central

    Navarro, E; Alonso, SJ; Navarro, R; Trujillo, J; Jorge, E

    2006-01-01

    AIM: To study the effects of elenoside, an arylnaph-thalene lignan from Justicia hyssopifolia, on gastro-intestinal motility in vivo and in vitro in rats. METHODS: Routine in vivo experimental assessments were catharsis index, water percentage of boluses, intestinal transit, and codeine antagonism. The groups included were vehicle control (propylene glycol-ethanol-plant oil-tween 80), elenoside (i.p. 25 and 50 mg/kg), cisapride (i.p. 10 mg/kg), and codeine phosphate (intragastric route, 50 mg/kg). In vitro approaches used isolated rat intestinal tissues (duodenum, jejunum, and ileum). The effects of elenoside at concentrations of 3.2 x 10-4, 6.4 x 10-4 and 1.2 x 10-3 mol/L, and cisapride at 10-6 mol/L were investigated. RESULTS: Elenoside in vivo produced an increase in the catharsis index and water percentage of boluses and in the percentage of distance traveled by a suspension of activated charcoal. Codeine phosphate antagonized the effect of 25 mg/kg of elenoside. In vitro, elenoside in duodenum, jejunum and ileum produced an initial decrease in the contraction force followed by an increase. Elenoside resulted in decreased intestinal frequency in duodenum, jejunum, and ileum. The in vitro and in vivo effects of elenoside were similar to those produced by cisapride. CONCLUSION: Elenoside is a lignan with an action similar to that of purgative and prokinetics drugs. Elenoside, could be an alternative to cisapride in treatment of gastrointestinal diseases as well as a preventive therapy for the undesirable gastrointestinal effects produced by opioids used for mild to moderate pain. PMID:17131476

  12. Application of fluorescent tracer agent technology to point-of-care gastrointestinal permeability measurement

    NASA Astrophysics Data System (ADS)

    Dorshow, Richard B.; Shieh, Jeng-Jong; Rogers, Thomas E.; Hall-Moore, Carla; Shaikh, Nurmohammad; Talcott, Michael; Tarr, Phillip I.

    2016-03-01

    Gut dysfunction, often accompanied by increased mucosal permeability to gut contents, frequently accompanies a variety of human intestinal inflammatory conditions. These disorders include inflammatory bowel diseases (e.g., Crohn's Disease) and environmental enteropathy and enteric dysfunction, a condition strongly associated with childhood malnutrition and stunting in resource poor areas of the world. The most widely used diagnostic assay for gastrointestinal permeability is the lactulose to mannitol ratio (L:M) measurement. These sugars are administered orally, differentially absorbed by the gut, and then cleared from the body by glomerular filtration in the kidney. The amount of each sugar excreted in the urine is measured. The larger sugar, lactulose, is minimally absorbed through a healthy gut. The smaller sugar, mannitol, in contrast, is readily absorbed through both a healthy and injured gut. Thus a higher ratio of lactulose to mannitol reflects increased intestinal permeability. However, several issues prevent widespread use of the L:M ratio in clinical practice. Urine needs to be collected over time intervals of several hours, the specimen then needs to be transported to an analytical laboratory, and sophisticated equipment is required to measure the concentration of each sugar in the urine. In this presentation we show that fluorescent tracer agents with molecular weights similar to those of the sugars, selected from our portfolio of biocompatible renally cleared fluorophores, mimic the L:M ratio test for gut permeability. This fluorescent tracer agent detection technology can be used to overcome the limitations of the L:M assay, and is amenable to point-of-care clinical use.

  13. Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier.

    PubMed

    Bowie, Rachel V; Donatello, Simona; Lyes, Clíona; Owens, Mark B; Babina, Irina S; Hudson, Lance; Walsh, Shaun V; O'Donoghue, Diarmuid P; Amu, Sylvie; Barry, Sean P; Fallon, Padraic G; Hopkins, Ann M

    2012-04-15

    Intestinal epithelial barrier disruption is a feature of inflammatory bowel disease (IBD), but whether barrier disruption precedes or merely accompanies inflammation remains controversial. Tight junction (TJ) adhesion complexes control epithelial barrier integrity. Since some TJ proteins reside in cholesterol-enriched regions of the cell membrane termed lipid rafts, we sought to elucidate the relationship between rafts and intestinal epithelial barrier function. Lipid rafts were isolated from Caco-2 intestinal epithelial cells primed with the proinflammatory cytokine interferon-γ (IFN-γ) or treated with methyl-β-cyclodextrin as a positive control for raft disruption. Rafts were also isolated from the ilea of mice in which colitis had been induced in conjunction with in vivo intestinal permeability measurements, and lastly from intestinal biopsies of ulcerative colitis (UC) patients with predominantly mild or quiescent disease. Raft distribution was analyzed by measuring activity of the raft-associated enzyme alkaline phosphatase and by performing Western blot analysis for flotillin-1. Epithelial barrier integrity was estimated by measuring transepithelial resistance in cytokine-treated cells or in vivo permeability to fluorescent dextran in colitic mice. Raft and nonraft fractions were analyzed by Western blotting for the TJ proteins occludin and zonula occludens-1 (ZO-1). Our results revealed that lipid rafts were disrupted in IFN-γ-treated cells, in the ilea of mice with subclinical colitis, and in UC patients with quiescent inflammation. This was not associated with a clear pattern of occludin or ZO-1 relocalization from raft to nonraft fractions. Significantly, a time-course study in colitic mice revealed that disruption of lipid rafts preceded the onset of increased intestinal permeability. Our data suggest for the first time that lipid raft disruption occurs early in the inflammatory cascade in murine and human colitis and, we speculate, may contribute to

  14. NASA In-step: Permeable Membrane Experiment

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Viewgraphs on the Permeable Membrane Experiment are presented. An experiment overview is given. The Membrane Phase Separation Experiment, Membrane Diffusion Interference Experiment, and Membrane Wetting Experiment are described. Finally, summary and conclusions are discussed.

  15. The Edison Environmental Center Permeable Pavement Site

    EPA Science Inventory

    This a presentation for a Community Outreach Event called "Chemistry Works and Celebration of International Year of Chemistry." It will review the permeable pavement research project at the Edison Environmental center.

  16. Permeability of rayon based polymer composites

    NASA Technical Reports Server (NTRS)

    Stokes, E. H.

    1992-01-01

    Several types of anomalous rayon based phenolic behavior have been observed in post-fired nozzles and exit cones. Many of these events have been shown to be related to the development of internal gas pressure within the material. The development of internal gas pressure is a function of the amount of gas produced within the material and the rate at which that gas is allowed to escape. The latter property of the material is referred to as the material's permeability. The permeability of two dimensional carbonized rayon based phenolic composites is a function of material direction, temperature, and stress/strain state. Recently significant differences in the permeability of these materials has been uncovered which may explain their inconsistent performance. This paper summarizes what is known about the permeability of these materials to date and gives possible implications of these finding to the performance of these materials in an ablative environment.

  17. Permeable Reactive Zones for Groundwater Remediation

    EPA Science Inventory

    The presentation will cover aspects of the application of permeable reactive zones to treat contaminated ground water. Specific field studies will be discussed covering both granular iron-based and organic carbon-based reactive barriers. Specific contaminants addressed include:...

  18. Permeability After Impact Testing of Composite Laminates

    NASA Technical Reports Server (NTRS)

    Nettles, A.T.; Munafo, Paul (Technical Monitor)

    2002-01-01

    Since composite laminates are beginning to be identified for use in reusable launch vehicle propulsion systems, an understanding of their permeance is needed. A foreign object impact event can cause a localized area of permeability (leakage) in a polymer matrix composite and it is the aim of this study to assess a method of quantifying permeability-after-impact results. A simple test apparatus is presented and variables that could affect the measured values of permeability-after-impact were assessed. Once it was determined that valid numbers were being measured, a fiber/resin system was impacted at various impact levels and the resulting permeability measured, first with a leak check solution (qualitative) then using the new apparatus (quantitative). The results showed that as the impact level increased, so did the measured leakage. As the pressure to the specimen was increased, the leak rate was seen to increase in a non-linear fashion for almost all of the specimens tested.

  19. Permeability After Impact Testing of Composite Laminates

    NASA Technical Reports Server (NTRS)

    Nettles, Alan T.

    2003-01-01

    Since composite laminates are beginning to be identified for use in reusable launch vehicle propulsion systems, an understanding of their permeance is needed. A foreign object impact event can cause a localized area of permeability (leakage) in a polymer matrix composite and it is the aim of this study to assess a method of quantifying permeability-after-impact results. A simple test apparatus is presented and variables that could affect the measured values of permeability-after-impact were assessed. Once it was determined that valid numbers were being measured, a fiber/resin system was impacted at various impact levels and the resulting permeability measured, first with a leak check solution (qualitative) then using the new apparatus (quantitative). The results showed that as the impact level increased, so did the measured leakage. As the pressure to the specimen was increased, the leak rate was seen to increase in a non-linear fashion for almost all of the specimens tested.

  20. Flexible Sandwich Diaphragms Are Less Permeable

    NASA Technical Reports Server (NTRS)

    Michalovic, John G.; Vassallo, Franklin A.

    1993-01-01

    Diaphragms for use in refrigerator compressors made as laminates of commercially available elastomers and metals. Diaphragms flexible, but less permeable by chlorofluorocarbon refrigerant fluids than diaphragms made of homogeneous mixtures of materials.

  1. PERMEABLE REACTIVE BARRIERS FOR GROUNDWATER REMEDIATION

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  2. PERMEABLE REACTIVE BARRIERS FOR GROUND WATER REMEDIATION

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  3. HP-41 Calculates Dykstra-Parsons permeability

    SciTech Connect

    Bixler, B.

    1983-07-01

    A new program for the HP-41 programmable calculator has been written which will calculate the often used Dykstra-Parsons permeability variation factor, V. No longer must numerous individual permeability values be plotted on log probability paper as a first step in determining V. Input is simply these same permeability values selected at equal spacing along the interval in question. For most core analysis this spacing will be 1 ft. This program is labeled ''KVAR'' (for permeability variation) and is listed here, along with its bar code for those with optical wands. It requires only nine registers for program storage (since it uses HP built-in statistical functions) and eight registers for data storage. Also, it can be stored on one track of the standard two-track magnetic card. Data entry is terminated by entering ''O''. Lastly, it will run with or without a printer.

  4. The allometry of rodent intestines.

    PubMed

    Lovegrove, Barry G

    2010-06-01

    This study examined the allometry of the small intestine, caecum, colon and large intestine of rodents (n = 51) using a phylogenetically informed approach. Strong phylogenetic signal was detected in the data for the caecum, colon and large intestine, but not for the small intestine. Most of the phylogenetic signal could be attributed to clade effects associated with herbivorous versus omnivorous rodents. The herbivorous rodents have longer caecums, colons and large intestines, but their small intestines, with the exception of the desert otomyine rodents, are no different to those of omnivorous rodents. Desert otomyine rodents have significantly shorter small intestines than all other rodents, reflecting a possible habitat effect and providing a partial explanation for the low basal metabolic rates of small desert mammals. However, the desert otomyines do not have shorter colons or large intestines, challenging claims for adaptation to water retention in arid environments. Data for the Arvicolidae revealed significantly larger caecums and colons, and hence longer large intestines, with no compensatory reduction in the length of the small intestine, which may explain how the smallest mammalian herbivores manage to meet the demands of a very high mass-specific metabolic rate. This study provides phylogenetically corrected allometries suitable for future prediction testing.

  5. Alcohol and the Intestine

    PubMed Central

    Patel, Sheena; Behara, Rama; Swanson, Garth R.; Forsyth, Christopher B.; Voigt, Robin M.; Keshavarzian, Ali

    2015-01-01

    Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol-induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol-induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. PMID:26501334

  6. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers.

    PubMed

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function.

  7. Deoxynivalenol affects in vitro intestinal epithelial cell barrier integrity through inhibition of protein synthesis

    SciTech Connect

    Van De Walle, Jacqueline; Sergent, Therese; Piront, Neil; Toussaint, Olivier; Schneider, Yves-Jacques; Larondelle, Yvan

    2010-06-15

    Deoxynivalenol (DON), one of the most common mycotoxin contaminants of raw and processed cereal food, adversely affects the gastrointestinal tract. Since DON acts as a protein synthesis inhibitor, the constantly renewing intestinal epithelium could be particularly sensitive to DON. We analyzed the toxicological effects of DON on intestinal epithelial protein synthesis and barrier integrity. Differentiated Caco-2 cells, as a widely used model of the human intestinal barrier, were exposed to realistic intestinal concentrations of DON (50, 500 and 5000 ng/ml) during 24 h. DON caused a concentration-dependent decrease in total protein content associated with a reduction in the incorporation of [{sup 3}H]-leucine, demonstrating its inhibitory effect on protein synthesis. DON simultaneously increased the paracellular permeability of the monolayer as reflected through a decreased transepithelial electrical resistance associated with an increased paracellular flux of the tracer [{sup 3}H]-mannitol. A concentration-dependent reduction in the expression level of the tight junction constituent claudin-4 was demonstrated by Western blot, which was not due to diminished transcription, increased degradation, or NF-{kappa}B, ERK or JNK activation, and was also observed for a tight junction independent protein, i.e. intestinal alkaline phosphatase. These results demonstrate a dual toxicological effect of DON on differentiated Caco-2 cells consisting in an inhibition of protein synthesis as well as an increase in monolayer permeability, and moreover suggest a possible link between them through diminished synthesis of the tight junction constituent claudin-4.

  8. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

    PubMed Central

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function. PMID:26550018

  9. A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine.

    PubMed

    Gupta, Vivek; Hwang, Byeong Hee; Doshi, Nishit; Mitragotri, Samir

    2013-12-10

    Delivery of therapeutic macromolecules is limited by the physiological limitations of the gastrointestinal tract including poor intestinal permeability, low pH and enzymatic activity. Several permeation enhancers have been proposed to enhance intestinal permeability of macromolecules; however their utility is often hindered by toxicity and limited potency. Here, we report on a novel permeation enhancer, Dimethyl palmitoyl ammonio propanesulfonate (PPS), with excellent enhancement potential and minimal toxicity. PPS was tested for dose- and time-dependent cytotoxicity, delivery of two model fluorescent molecules, sulforhodamine-B and FITC-insulin in vitro, and absorption enhancement of salmon calcitonin (sCT) in vivo. Caco-2 studies revealed that PPS is an effective enhancer of macromolecular transport while being minimally toxic. TEER measurements in Caco-2 monolayers confirmed the reversibility of the effect of PPS. Confocal microscopy studies revealed that molecules permeate via both paracellular and transcellular pathways in the presence of PPS. In vivo studies in rats showed that PPS enhanced relative bioavailability of sCT by 45-fold after intestinal administration. Histological studies showed that PPS does not induce damage to the intestine. PPS is an excellent permeation enhancer which provides new opportunities for developing efficacious oral/intestinal delivery systems for therapeutic macromolecules.

  10. Vascular permeability, vascular hyperpermeability and angiogenesis

    PubMed Central

    Nagy, Janice A.; Benjamin, Laura; Zeng, Huiya