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Sample records for intestinal barrier permeability

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

    PubMed

    Pinton, Philippe; Nougayrède, 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.

  2. 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.

  3. 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

  4. Effects of Soybean Agglutinin on Intestinal Barrier Permeability and Tight Junction Protein Expression in Weaned Piglets

    PubMed Central

    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. PMID:22272087

  5. 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

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

    PubMed

    Guan, Guiping; Wang, Hongbing; 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

  7. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2013-09-01

    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.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

  9. The permeability of the plasma-lymph barrier of the small intestine of various species to macromolecules.

    PubMed

    Vogel, G; Martensen, I

    1982-03-01

    The filtration coefficients of polyvinylpyrrolidone (PVP) of molecular weight 10,000-110,000 were measured at the plasma-lymph barrier of the upper small intestine of rabbits, rats and cats. For this purpose the animals were given intravenous injections or infusions of PVP in such a way as to produce a constant blood level; PVP concentrations were measured in lymph obtained by cannulating the mesenteric duct and also in the plasma. In these species low molecular weight PVP had a filtration coefficient of 0.85-0.64, while high molecular weight PVP (MW 110,000) either had a very low filtration coefficient - 0.22 - or was not detectable in the intestinal lymph. The three species, representing herbivores, omnivores and carnivores, showed no differences in the penetration behavior of PVP, i.e., in the permeability of the plasma-lymph barrier to macromolecules.

  10. The feed contaminant deoxynivalenol affects the intestinal barrier permeability through inhibition of protein synthesis.

    PubMed

    Awad, Wageha A; Zentek, Jürgen

    2015-06-01

    Deoxynivalenol (DON) has critical health effects if the contaminated grains consumed by humans or animals. DON can have negative effects on the active transport of glucose and amino acids in the small intestine of chickens. As the underlying mechanisms are not fully elucidated, the present study was performed to delineate more precisely the effects of cycloheximide (protein synthesis inhibitor, CHX) and DON on the intestinal absorption of nutrients. This was to confirm whether DON effects on nutrient absorption are due to an inhibition of protein synthesis. Changes in ion transport and barrier function were assessed by short-circuit current (Isc) and transepithelial ion conductance (Gt) in Ussing chambers. Addition of D-glucose or L-glutamine to the luminal side of the isolated mucosa of the jejunum increased (P < 0.001) the Isc compared with basal conditions in the control tissues. However, the Isc was not increased by the glucose or glutamine addition after pre-incubation of tissues with DON or CHX. Furthermore, both DON and CHX reduced Gt, indicating that the intestinal barrier is compromised and consequently induced a greater impairment of the barrier function. The remarkable similarity between the activity of CHX and DON on nutrient uptake is consistent with their common ability to inhibit protein synthesis. It can be concluded that the decreases in transport activity by CHX was evident in this study using the chicken as experimental model. Similarly, DON has negative effects on the active transport of some nutrients, and these can be explained by its influence on protein synthesis. PMID:24888376

  11. The feed contaminant deoxynivalenol affects the intestinal barrier permeability through inhibition of protein synthesis.

    PubMed

    Awad, Wageha A; Zentek, Jürgen

    2015-06-01

    Deoxynivalenol (DON) has critical health effects if the contaminated grains consumed by humans or animals. DON can have negative effects on the active transport of glucose and amino acids in the small intestine of chickens. As the underlying mechanisms are not fully elucidated, the present study was performed to delineate more precisely the effects of cycloheximide (protein synthesis inhibitor, CHX) and DON on the intestinal absorption of nutrients. This was to confirm whether DON effects on nutrient absorption are due to an inhibition of protein synthesis. Changes in ion transport and barrier function were assessed by short-circuit current (Isc) and transepithelial ion conductance (Gt) in Ussing chambers. Addition of D-glucose or L-glutamine to the luminal side of the isolated mucosa of the jejunum increased (P < 0.001) the Isc compared with basal conditions in the control tissues. However, the Isc was not increased by the glucose or glutamine addition after pre-incubation of tissues with DON or CHX. Furthermore, both DON and CHX reduced Gt, indicating that the intestinal barrier is compromised and consequently induced a greater impairment of the barrier function. The remarkable similarity between the activity of CHX and DON on nutrient uptake is consistent with their common ability to inhibit protein synthesis. It can be concluded that the decreases in transport activity by CHX was evident in this study using the chicken as experimental model. Similarly, DON has negative effects on the active transport of some nutrients, and these can be explained by its influence on protein synthesis.

  12. 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...

  13. 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. PMID:23075554

  14. Bacterial translocation and in vivo assessment of intestinal barrier permeability in rainbow trout (Oncorhynchus mykiss) with and without soyabean meal-induced inflammation.

    PubMed

    Mosberian-Tanha, Peyman; Øverland, Margareth; Landsverk, Thor; Reveco, Felipe E; Schrama, Johan W; Roem, Andries J; Agger, Jane W; Mydland, Liv T

    2016-01-01

    The primary aim of this experiment was to evaluate the intestinal barrier permeability in vivo in rainbow trout (Oncorhynchus mykiss) fed increasing levels of soyabean meal (SBM). The relationship between SBM-induced enteritis (SBMIE) and the permeability markers was also investigated. Our results showed that the mean score of morphological parameters was significantly higher as a result of 37·5 % SBM inclusion in the diet, while the scores of fish fed 25 % SBM or lower were not different from those of the fish meal-fed controls (P < 0·05). SBMIE was found in the distal intestine (DI) in 18 % of the fish (eleven of sixty): ten in the 37·5 % SBM-fed group and one in the 25 % SBM-fed group. Sugar markers in plasma showed large variation among individuals probably due to variation in feed intake. We found, however, a significant linear increase in the level of plasma d-lactate with increasing SBM inclusion level (P < 0·0001). Plasma concentration of endotoxin was not significantly different in groups with or without SBMIE. Some individual fish showed high values of endotoxin in blood, but the same individuals did not show any bacterial translocation. Plasma bacterial DNA was detected in 28 % of the fish with SBMIE, and 8 % of non-SBMIE fish (P = 0·07). Plasma concentration of d-lactate was significantly higher in fish with SBMIE (P < 0·0001). To conclude, SBMIE in the DI of rainbow trout was associated with an increase in bacterial translocation and plasma d-lactate concentration, suggesting that these permeability markers can be used to evaluate intestinal permeability in vivo.

  15. Bacterial translocation and in vivo assessment of intestinal barrier permeability in rainbow trout (Oncorhynchus mykiss) with and without soyabean meal-induced inflammation.

    PubMed

    Mosberian-Tanha, Peyman; Øverland, Margareth; Landsverk, Thor; Reveco, Felipe E; Schrama, Johan W; Roem, Andries J; Agger, Jane W; Mydland, Liv T

    2016-01-01

    The primary aim of this experiment was to evaluate the intestinal barrier permeability in vivo in rainbow trout (Oncorhynchus mykiss) fed increasing levels of soyabean meal (SBM). The relationship between SBM-induced enteritis (SBMIE) and the permeability markers was also investigated. Our results showed that the mean score of morphological parameters was significantly higher as a result of 37·5 % SBM inclusion in the diet, while the scores of fish fed 25 % SBM or lower were not different from those of the fish meal-fed controls (P < 0·05). SBMIE was found in the distal intestine (DI) in 18 % of the fish (eleven of sixty): ten in the 37·5 % SBM-fed group and one in the 25 % SBM-fed group. Sugar markers in plasma showed large variation among individuals probably due to variation in feed intake. We found, however, a significant linear increase in the level of plasma d-lactate with increasing SBM inclusion level (P < 0·0001). Plasma concentration of endotoxin was not significantly different in groups with or without SBMIE. Some individual fish showed high values of endotoxin in blood, but the same individuals did not show any bacterial translocation. Plasma bacterial DNA was detected in 28 % of the fish with SBMIE, and 8 % of non-SBMIE fish (P = 0·07). Plasma concentration of d-lactate was significantly higher in fish with SBMIE (P < 0·0001). To conclude, SBMIE in the DI of rainbow trout was associated with an increase in bacterial translocation and plasma d-lactate concentration, suggesting that these permeability markers can be used to evaluate intestinal permeability in vivo. PMID:27547389

  16. 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

  17. 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

  18. 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.

  19. 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. PMID:15669640

  20. Validation of UHPLC-MS/MS methods for the determination of kaempferol and its metabolite 4-hydroxyphenyl acetic acid, and application to in vitro blood-brain barrier and intestinal drug permeability studies.

    PubMed

    Moradi-Afrapoli, Fahimeh; Oufir, Mouhssin; Walter, Fruzsina R; Deli, Maria A; Smiesko, Martin; Zabela, Volha; Butterweck, Veronika; Hamburger, Matthias

    2016-09-01

    Sedative and anxiolytic-like properties of flavonoids such as kaempferol and quercetin, and of some of their intestinal metabolites, have been demonstrated in pharmacological studies. However, routes of administration were shown to be critical for observing in vivo activity. Therefore, the ability to cross intestinal and blood-brain barriers was assessed in cell-based models for kaempferol (KMF), and for the major intestinal metabolite of KMF, 4-hydroxyphenylacetic acid (4-HPAA). Intestinal transport studies were performed with Caco-2 cells, and blood-brain barrier transport studies with an immortalized monoculture human model and a primary triple-co-culture rat model. UHPLC-MS/MS methods for KMF and 4-HPAA in Ringer-HEPES buffer and in Hank's balanced salt solution were validated according to industry guidelines. For all methods, calibration curves were fitted by least-squares quadratic regression with 1/X(2) as weighing factor, and mean coefficients of determination (R(2)) were >0.99. Data obtained with all barrier models showed high intestinal and blood-brain barrier permeation of KMF, and no permeability of 4-HPAA, when compared to barrier integrity markers.

  1. Validation of UHPLC-MS/MS methods for the determination of kaempferol and its metabolite 4-hydroxyphenyl acetic acid, and application to in vitro blood-brain barrier and intestinal drug permeability studies.

    PubMed

    Moradi-Afrapoli, Fahimeh; Oufir, Mouhssin; Walter, Fruzsina R; Deli, Maria A; Smiesko, Martin; Zabela, Volha; Butterweck, Veronika; Hamburger, Matthias

    2016-09-01

    Sedative and anxiolytic-like properties of flavonoids such as kaempferol and quercetin, and of some of their intestinal metabolites, have been demonstrated in pharmacological studies. However, routes of administration were shown to be critical for observing in vivo activity. Therefore, the ability to cross intestinal and blood-brain barriers was assessed in cell-based models for kaempferol (KMF), and for the major intestinal metabolite of KMF, 4-hydroxyphenylacetic acid (4-HPAA). Intestinal transport studies were performed with Caco-2 cells, and blood-brain barrier transport studies with an immortalized monoculture human model and a primary triple-co-culture rat model. UHPLC-MS/MS methods for KMF and 4-HPAA in Ringer-HEPES buffer and in Hank's balanced salt solution were validated according to industry guidelines. For all methods, calibration curves were fitted by least-squares quadratic regression with 1/X(2) as weighing factor, and mean coefficients of determination (R(2)) were >0.99. Data obtained with all barrier models showed high intestinal and blood-brain barrier permeation of KMF, and no permeability of 4-HPAA, when compared to barrier integrity markers. PMID:27281582

  2. Virtual screening of intestinal drug permeability.

    PubMed

    Stenberg, P; Luthman, K; Artursson, P

    2000-03-01

    Lead compounds generated in high throughput drug discovery programmes often have unfavorable biopharmaceutical properties, resulting in a low success rate of such drug candidates in clinical development. Drug companies and researchers would thus like to have methods of predicting biopharmaceutical properties accurately. The intestinal permeability to a lead compound is one such property which is particularly important. Therefore, access to methods to accurately predict biopharmaceutical properties, such as the intestinal permeability of a large series of compounds, is of particular importance. This review deals with new theoretical methods used to predict intestinal drug permeability. There are several possible transport routes across the intestine, but theoretical methods generally deal with only one of them, the passive transcellular route. Therefore, this review will also discuss the relative importance of passive and active drug transport and efflux routes using recent data generated in cell cultures, animal models and human subjects.

  3. 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

  4. Mechanisms of Intestinal Barrier Dysfunction in Sepsis.

    PubMed

    Yoseph, Benyam P; Klingensmith, Nathan J; Liang, Zhe; Breed, Elise R; Burd, Eileen M; Mittal, Rohit; Dominguez, Jessica A; Petrie, Benjamin; Ford, Mandy L; Coopersmith, Craig M

    2016-07-01

    Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis

  5. Intestinal permeability--a new target for disease prevention and therapy.

    PubMed

    Bischoff, Stephan C; Barbara, Giovanni; Buurman, Wim; Ockhuizen, Theo; Schulzke, Jörg-Dieter; Serino, Matteo; Tilg, Herbert; Watson, Alastair; Wells, Jerry M

    2014-11-18

    Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and--more recently recognized

  6. Sodium butyrate protects the intestinal barrier function in peritonitic mice

    PubMed Central

    Han, Xiaofeng; Song, Huimin; Wang, Yunlei; Sheng, Yingmo; Chen, Jie

    2015-01-01

    Objective: Peritonitis is a commonly seen disease with high morbidity and mortality. It is prevalently considered that the impaired intestinal barrier during peritonitis is the access point of gut microbes into the blood system, and acts as the engine of the following systemic infection. In our previous study, we found that Sodium Butyrate (NaB) was protective on intestinal barrier function. In this study, we aim to evaluate the effects of NaB on overwhelming infection animal models of peritonitis. Methods: Mouse cecal ligation and puncture (CLP) model was used to study the effects of NaB on the intestinal barrier. Experimental animals were fed of NaB by gavage. Post-CLP mortality, gut permeability and intestinal histological alterations were studied. Results: Gastrointestinal NaB pharmacodynamics profiles after medication were studied. Measurements of NaB concentration in chyme showed significantly higher intestinal concentration of NaB in the NaB treated group than that of the control group. CLP-induced mortality was significantly decreased by oral NaB treatments. Gut permeability was largely increased after CLP, which was partially prevented by NaB feeding. Histological study showed that intestinal, especially ileal injury following peritonitis was substantially alleviated by NaB treatments. Moreover, tissue regeneration was also prompted by NaB. Conclusion: NaB has a potential protective effect on intestinal barrier function in peritonitis. PMID:26064302

  7. Intestinal permeability in patients with acute myeloid leukemia.

    PubMed

    Sundström, G M; Wahlin, A; Nordin-Andersson, I; Suhr, O B

    1998-10-01

    Intestinal permeability was studied in patients with acute myeloid leukemia (AML) before, during and after chemotherapy. Intestinal permeability was determined by the lactulose (La)/mannitol (Ma) absorption test in 16 adult patients with de novo AML. The hydrogen breath test was used to disclose bacterial fermentation of the test substances in the small intestine. The permeability was found significantly increased (p<0.02) in the patients before induction chemotherapy treatment. During induction treatment and throughout the cytopenic period the intestinal permeability was constantly and significantly increased, compared with controls. In patients with abnormally increased permeability, no increase in hydrogen breath test result was noted. From our results it can be concluded that increased intestinal permeability is present in AML patients before commencing chemotherapy. Factors other than chemotherapy would seem to be more important regarding the occurrence of intestinal disturbances in these patients.

  8. Hydrogeologic modeling for permeable reactive barriers.

    PubMed

    Gupta, N; Fox, T C

    1999-08-12

    The permeable reactive barrier technology for in situ treatment of chlorinated solvents and other groundwater contaminants is becoming increasingly popular. Field scale implementation of this and other in situ technologies requires careful design based on the site-specific hydrogeology and contaminant plume characteristics. Groundwater flow modeling is an important tool in understanding the hydraulic behavior of the site and optimizing the reactive barrier design. A combination of groundwater flow modeling and particle tracking techniques was used to illustrate the effect of hydraulic conductivity of the aquifer and reactive media on key permeable barrier design parameters, such as the capture zone width, residence time, flow velocity, and discharge. Similar techniques were used to illustrate the modeling approach for design of different configurations of reactive barriers in homogeneous and heterogeneous settings.

  9. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

    PubMed Central

    Luther, Jay; Garber, John J.; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L.; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R.; Yarmush, Martin L.; Chung, Raymond T.; Patel, Suraj J.

    2015-01-01

    BACKGROUND & AIMS Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. METHODS A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. RESULTS Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. CONCLUSIONS Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNF

  10. Large intestine permeability is increased in patients with compensated liver cirrhosis.

    PubMed

    Pijls, Kirsten E; Koek, Ger H; Elamin, Elhaseen E; de Vries, Hanne; Masclee, Ad A M; Jonkers, Daisy M A E

    2014-01-01

    Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Increased intestinal permeability has been found in patients with liver cirrhosis, but data on small and large intestine permeability and tight junctions (TJs) in patients with compensated cirrhosis are scarce. We aimed to investigate both small and large intestine permeability in patients with stable compensated cirrhosis compared with healthy controls and evaluated the expression of TJ proteins in mucosal biopsies at duodenal and sigmoid level. Intestinal permeability was assessed in 26 patients with compensated cirrhosis and 27 matched controls using a multisugar test. Duodenal and sigmoid biopsies were available from a subgroup for analyses of gene transcription and expression of key TJ proteins by qRT-PCR and ELISA, respectively. Median 0-5-h urinary sucrose excretion and lactulose/rhamnose ratio were comparable between patients with compensated cirrhosis and controls, whereas 5-24-h urinary sucralose/erythritol ratio was increased in these patients. Downregulation of gene transcription was found for claudin-3 in duodenal biopsies and claudin-4 in sigmoid biopsies, and at the protein level occludin expression was significantly increased in both duodenal and sigmoid biopsies. This study shows that gastroduodenal and small intestine permeability are not altered, whereas large intestine permeability is increased in patients with stable compensated cirrhosis. Only limited alterations were found regarding the expression of TJ proteins in both the small and large intestine.

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

    PubMed Central

    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. PMID:26582965

  12. 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.

  13. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  14. Regulation of the Intestinal Barrier Function by Host Defense Peptides.

    PubMed

    Robinson, Kelsy; Deng, Zhuo; Hou, Yongqing; Zhang, Guolong

    2015-01-01

    Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity. PMID:26664984

  15. Regulation of the Intestinal Barrier Function by Host Defense Peptides

    PubMed Central

    Robinson, Kelsy; Deng, Zhuo; Hou, Yongqing; Zhang, Guolong

    2015-01-01

    Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity. PMID:26664984

  16. "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...

  17. Epidermal Growth Factor and Intestinal Barrier Function.

    PubMed

    Tang, Xiaopeng; Liu, Hu; Yang, Shufen; Li, Zuohua; Zhong, Jinfeng; Fang, Rejun

    2016-01-01

    Epidermal growth factor (EGF) is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health. PMID:27524860

  18. Epidermal Growth Factor and Intestinal Barrier Function

    PubMed Central

    Liu, Hu; Yang, Shufen; Li, Zuohua; Zhong, Jinfeng

    2016-01-01

    Epidermal growth factor (EGF) is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health. PMID:27524860

  19. Intestinal Membrane Permeability and Hypersensitivity In the Irritable Bowel Syndrome

    PubMed Central

    Zhou, QiQi; Zhang, Buyi; Verne, G. Nicholas

    2009-01-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the underlying pathophysiology is poorly understood; however, increased intestinal permeability in diarrhea-predominant IBS patients has been reported. Here we demonstrate diarrhea-predominant IBS patients (D-IBS) that display increased intestinal permeability. We have also found that increased intestinal membrane permeability is associated with visceral and thermal hypersensitivity in this subset of D-IBS patients. We evaluated 54 D-IBS patients and 22 controls for intestinal membrane permeability using the lactulose / mannitol method. All subjects ingested 5 g laclulose and 2 g mannitol in 100 ml of water after which their urine was collected. We also evaluated the mean mechanical visual analogue (MVAS) pain rating to nociceptive thermal and visceral stimulation in all subjects. All study participants also completed the FBDSI scale. Approximately 39% of diarrhea-predominant IBS patients have increased intestinal membrane permeability as measured by the lactulose / mannitol ratio. These IBS patients also demonstrated higher M-VAS pain intensity reading scale. Interestingly, the IBS patients with hypersensitivity and increased intestinal permeability had a higher FBDSI score (100.8±5.4) compared to IBS patients with normal membrane permeability and sensitivity (51.6±12.7) and controls (6.1 ± 5.6) (p<0.001). A subset of D-IBS patients have increased intestinal membrane permeability that is associated with an increased FBDSI score and increased hypersensitivity to visceral and thermal nociceptive pain stimuli. Thus, increased intestinal membrane permeability in D-IBS patients may lead to more severe IBS symptoms and hypersensitivity to somatic and visceral stimuli. PMID:19595511

  20. 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

  1. [THE INTESTINAL BARRIER, THE MICROBIOTA, MICROBIOME].

    PubMed

    Mar'yanovich, A T

    2016-01-01

    The review examined modern condition of development directions physiology of digestion, like structure and function of the intestinal barrier, the microbiota of the digestive tract in its relations with the microorganism.

  2. Chronic Kidney Disease Induced Intestinal Mucosal Barrier Damage Associated with Intestinal Oxidative Stress Injury

    PubMed Central

    Yu, Chao; Wang, Qiang; Zhou, Chunyu; Kang, Xin; Zhao, Shuang; Liu, Shuai; Fu, Huijun; Yu, Zhen; Peng, Ai

    2016-01-01

    Background. To investigate whether intestinal mucosal barrier was damaged or not in chronic kidney disease progression and the status of oxidative stress. Methods. Rats were randomized into two groups: a control group and a uremia group. The uremia rat model was induced by 5/6 kidney resection. In postoperative weeks (POW) 4, 6, 8, and 10, eight rats were randomly selected from each group to prepare samples for assessing systemic inflammation, intestinal mucosal barrier changes, and the status of intestinal oxidative stress. Results. The uremia group presented an increase trend over time in the serum tumor necrosis factor-alpha, interleukin-6 (IL-6) and IL-10, serum D-lactate and diamine oxidase, and intestinal permeability, and these biomarkers were significantly higher than those in control group in POW 8 and/or 10. Chiu's scores in uremia group were also increased over time, especially in POW 8 and 10. Furthermore, the intestinal malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were significantly higher in uremia group when compared with those in control group in POW 8 and/or 10. Conclusions. The advanced chronic kidney disease could induce intestinal mucosal barrier damage and further lead to systemic inflammation. The underlying mechanism may be associated with the intestinal oxidative stress injury. PMID:27493661

  3. 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

  4. 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

  5. Bovine Colostrum Supplementation During Running Training Increases Intestinal Permeability

    PubMed Central

    Buckley, Jonathan D.; Butler, Ross N.; Southcott, Emma; Brinkworth, Grant D.

    2009-01-01

    Endurance exercise training can increase intestinal permeability which may contribute to the development of gastrointestinal symptoms in some athletes. Bovine colostrum (BC) supplementation reduces intestinal permeability induced by non-steroidal anti-inflammatory drugs. This study aimed to determine whether BC could also reduce intestinal permeability induced by endurance exercise. Thirty healthy adult males (25.0 ± 4.7 yr; mean ± SD) completed eight weeks of running three times per week for 45 minutes at their lactate threshold while consuming 60 g/day of BC, whey protein (WP) or control (CON). Intestinal permeability was assessed at baseline and after eight weeks by measuring the ratio of urinary lactulose (L) and rhamnose (R) excretion. After eight weeks the L/R ratio increased significantly more in volunteers consuming BC (251 ± 140%) compared with WP (21 ± 35%, P < 0.05) and CON (−7 ± 13%, P < 0.02). The increase in intestinal permeability with BC may have been due to BC inducing greater leakiness of tight junctions between enterocytes or by increasing macromolecular transport as it does in neonatal gut. Further research should investigate the potential for BC to increase intestinal macromolecular transport in adults. PMID:22253980

  6. Stobadine attenuates impairment of an intestinal barrier model caused by 4-hydroxynonenal.

    PubMed

    Cindric, Marina; Cipak, Ana; Zapletal, Emilija; Jaganjac, Morana; Milkovic, Lidija; Waeg, Georg; Stolc, Svorad; Zarkovic, Neven; Suzana Borovic, Sunjic

    2013-02-01

    Alterations in the intestinal barrier permeability occur in a broad spectrum of abdominally related pathologies, mostly due to disturbed oxidative homeostasis and increased lipid peroxidation. 4-Hydroxynonenal (HNE), a major lipid peroxidation product, is physiologically present in healthy gastric mucosa, but is increased in early stages of colon cancer and patients with duodenal peptic ulcer. Nevertheless, such supraphysiological levels of HNE have not yet been associated with increased intestinal permeability, even though, as we have described in this paper, they could play important role. In vitro model of intestinal barrier was established by growing Caco-2 cell line on cell culture permeable inserts. The pyridoindole derivative stobadine in hydrophilic and lipophilic form was used for barrier model protection. Both forms of stobadine were able to prevent damaging HNE effects, and reduce generation of reactive oxygen species and permeability of the intestinal barrier. Immunocytochemical analysis has confirmed beneficial effect of stobadine in reducing the formation of HNE-protein conjugates in the cells. Lipophilic form of stobadine proved to be more efficient than hydrophilic, implying importance of lipids in maintaining barrier function. The results obtained indicate that HNE might be important factor affecting intestinal barrier integrity, while stobadine could efficiently protect intestinal cells against harmful HNE effects.

  7. Ground rubber: Reactive permeable barrier sorption media

    SciTech Connect

    Kershaw, D.S.; Pamukcu, S.

    1997-12-31

    The objective of this research was to examine the feasibility of using ground tire rubber as a sorbent media in reactive permeable barrier systems. Previous research by the current authors has demonstrated that tire rubber can sorb significant quantities of benzene, toluene, ethylbenzene and O-xylene from aqueous solutions. The current research was run to examine the usage rate of ground rubber in a packed bed reactor under specific contact times. In addition, desorption and repetitive sorption tests were run to determine the reversibility of the sorption process for ground tire rubber. These tests were run to determine the regeneration capacity of ground tire rubber. Results of the study show that the usage rates are greater than 50% with an empty bed contact times of 37 minutes, and minimal amounts of energy are needed to regenerate the tire rubber after use.

  8. Age-associated modifications of intestinal permeability and innate immunity in human small intestine.

    PubMed

    Man, Angela L; Bertelli, Eugenio; Rentini, Silvia; Regoli, Mari; Briars, Graham; Marini, Mario; Watson, Alastair J M; Nicoletti, Claudio

    2015-10-01

    The physical and immunological properties of the human intestinal epithelial barrier in aging are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40 years) and aging (67-77 years) individuals not showing symptoms of gastrointestinal (GI) pathologies were used to assess levels of inflammatory cytokines, barrier integrity and cytokine production in response to microbial challenges. Increased expression of interleukin (IL)-6, but not interferon (IFN)γ, tumour necrosis factor (TNF)-α and IL-1β was observed during aging; further analysis showed that cluster of differentiation (CD)11c(+) dendritic cells (DCs) are one of the major sources of IL-6 in the aging gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of zonula occludens-1 (ZO-1), occludin and junctional-adhesion molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production in response to different microbial stimuli was assessed in a polarized in vitro organ culture (IVOC). IL-8 production in response to flagellin declined progressively with age although the expression and distribution of toll-like receptor (TLR)-5 on intestinal epithelial cells (IECs) remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in aging individuals. In contrast, TNF-α production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL-6 and expression of claudin-2. These data suggested that aging affects properties of the intestinal barrier likely to impact on age-associated disturbances, both locally and systemically. PMID:25948052

  9. Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

    PubMed Central

    Forsyth, Christopher B.; Shannon, Kathleen M.; Kordower, Jeffrey H.; Voigt, Robin M.; Shaikh, Maliha; Jaglin, Jean A.; Estes, Jacob D.; Dodiya, Hemraj B.; Keshavarzian, Ali

    2011-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and

  10. Intestinal barrier homeostasis in inflammatory bowel disease.

    PubMed

    Goll, Rasmus; van Beelen Granlund, Atle

    2015-01-01

    The single-cell thick intestinal epithelial cell (IEC) lining with its protective layer of mucus is the primary barrier protecting the organism from the harsh environment of the intestinal lumen. Today it is clear that the balancing act necessary to maintain intestinal homeostasis is dependent on the coordinated action of all cell types of the IEC, and that there are no passive bystanders to gut immunity solely acting as absorptive or regenerative cells: Mucin and antimicrobial peptides on the epithelial surface are continually being replenished by goblet and Paneth's cells. Luminal antigens are being sensed by pattern recognition receptors on the enterocytes. The enteroendocrine cells sense the environment and coordinate the intestinal function by releasing neuropeptides acting both on IEC and inflammatory cells. All this while cells are continuously and rapidly being regenerated from a limited number of stem cells close to the intestinal crypt base. This review seeks to describe the cell types and structures of the intestinal epithelial barrier supporting intestinal homeostasis, and how disturbance in these systems might relate to inflammatory bowel disease.

  11. The role of immunomodulators on intestinal barrier homeostasis in experimental models.

    PubMed

    Andrade, Maria Emília Rabelo; Araújo, Raquel Silva; de Barros, Patrícia Aparecida Vieira; Soares, Anne Danieli Nascimento; Abrantes, Fernanda Alves; Generoso, Simone de Vasconcelos; Fernandes, Simone Odília Antunes; Cardoso, Valbert Nascimento

    2015-12-01

    The intestinal epithelium is composed of specialized epithelial cells that form a physical and biochemical barrier to commensal and pathogenic microorganisms. However, dysregulation of the epithelial barrier function can lead to increased intestinal permeability and bacterial translocation across the intestinal mucosa, which contributes to local and systemic immune activation. The increase in these parameters is associated with inflammatory bowel disease, physical exercise under heat stress, intestinal obstruction, ischemia, and mucositis, among other conditions. Lately, there has been growing interest in immunomodulatory nutrients and probiotics that can regulate host immune and inflammatory responses and possibly restore the intestinal barrier. Immunomodulators such as amino acids (glutamine, arginine, tryptophan, and citrulline), fatty acids (short-chain and omega-3 fatty acids and conjugated linoleic acids), and probiotics (Bifidobacterium, Saccharomyces, and Lactobacillus) have been reported in the literature. Here, we review the critical roles of immunomodulatory nutrients in supporting gut barrier integrity and function. PMID:25660317

  12. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?

    PubMed Central

    Buhner, S; Buning, C; Genschel, J; Kling, K; Herrmann, D; Dignass, A; Kuechler, I; Krueger, S; Schmidt, H H‐J; Lochs, H

    2006-01-01

    Background and aim A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods We studied 128 patients with quiescent CD, 129 first degree relatives (CD‐R), 66 non‐related household members (CD‐NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. Results Intestinal permeability was significantly increased in CD and CD‐R groups compared with CD‐NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD‐R but only in 6% of CD‐NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD‐R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild‐types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD. PMID:16000642

  13. Vasoactive Intestinal Polypeptide Promotes Intestinal Barrier Homeostasis and Protection Against Colitis in Mice

    PubMed Central

    Wu, Xiujuan; Conlin, Victoria S.; Morampudi, Vijay; Ryz, Natasha R.; Nasser, Yasmin; Bhinder, Ganive; Bergstrom, Kirk S.; Yu, Hong B.; Waterhouse, Chris C. M.; Buchan, Allison M. J.; Popescu, Oana E.; Gibson, William T.; Waschek, James A.; Vallance, Bruce A.; Jacobson, Kevan

    2015-01-01

    Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP’s role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP’s role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis. PMID:25932952

  14. The diffusion-active permeable reactive barrier.

    PubMed

    Schwarz, Alex O; Rittmann, Bruce E

    2010-03-01

    Using the biogeochemical model CCBATCH, which we expanded to include transport processes, we study a novel approach for the treatment of aquifers contaminated with toxic concentrations of metals, the diffusion-active permeable reactive barrier (DAPRB), which is based on generation of sulfide by Sulfate Reducing Bacteria (SRB) as the groundwater moves through a layered treatment zone. In the DAPRB, layers of low conductivity (low-K) containing reactive materials are intercalated between layers of high conductivity (high-K) that transport the groundwater across the barrier. Because diffusion dominates transport in the reactive layers, microbial communities can take advantage there of the chemical-gradient mechanism for protection from toxicants. The ideal sulfidic DAPRB design includes particulate organic matter (POM) and solid sulfate mineral inside the reactive (low-K) layer. This leads to sulfate reduction and the formation of sulfide ligands that complex with toxic metals, such as Zn(2+) in the high-K layer. We perform a theoretical biogeochemical analysis of the ideal configuration of a DAPRB for treatment of Zn-contaminated groundwater. Our analysis using the expanded CCBATCH confirms the gradient-resistance mechanism for bio-protection, with the ZnS bio-sink forming at the intersection of the Zn and sulfide plumes inside the high-K layers of the DAPRB. The detailed DAPRB analysis also shows that total alkalinity and pH distributions are representative footprints of the two key biogeochemical processes taking place, sulfidogenesis and Zn immobilization as sulfide mineral. This is so because these two reactions consume or produce acidic hydrogen and alkalinity. Additionally, because Zn immobilization is due to ZnS mineral precipitation, the ZnS mineral distribution is a good indicator for the bio-sink. Bio-sinks are located for the most part within the high-K layers, and their exact position depends on the relative magnitude of metal and sulfide fluxes. Finally

  15. TREATMENT OF INORGANIC CONTAMINANTS USING PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers are an emerging alternative to traditional pump and treat systems for groundwater remediation. This technique has progressed rapidly over the past decade from laboratory bench-scale studies to full-scale implementation. Laboratory studies indicate the ...

  16. Intestinal permeability in patients with coeliac disease and dermatitis herpetiformis.

    PubMed Central

    Bjarnason, I; Marsh, M N; Price, A; Levi, A J; Peters, T J

    1985-01-01

    Intestinal permeability was investigated in patients with coeliac disease and dermatitis herpetiformis by a 51Chromium-labelled ethylenediaminetetraacetate (51Cr-EDTA) absorption test and the results correlated with histomorphometric analysis and intraepithelial lymphocyte counts of jejunal biopsies. The mean (+/- SD) 24 hour urine excretion of 51Cr-EDTA in 34 healthy volunteers was 1.9 +/- 0.5% of the orally administered test dose. Patients with untreated coeliac disease (19) or untreated dermatitis herpetiformis (five) excreted significantly more 51Cr-EDTA than controls (5.9 +/- 2.7% and 4.6 +/- 2.1%, respectively, p less than 0.001) and all were outside the normal range of 1.0-2.6%. Patients with coeliac disease (42) treated for 6 months-23 years (mean 5 years) and patients with dermatitis herpetiformis (11) treated for 6 months-8 years (mean 3 years) excreted significantly more 51Cr-EDTA than controls, 4.2 +/- 2.4% p less than 0.0001 and 3.0 +/- 0.9% p less than 0.003 respectively. Eleven of 14 (79%) treated patients with coeliac disease with an entirely normal jejunal mucosae demonstrated abnormal intestinal permeability. Intestinal permeability did not correlate significantly with either the mucosal height/crypt depth ratio or intraepithelial lymphocyte counts in jejunal biopsies from patients with untreated or treated coeliac disease. The demonstration of a persistent increase in intestinal permeability in patients with both coeliac disease and dermatitis herpetiformis may suggest a common pathogenetic mechanism in both disorders. It is postulated that altered permeability may facilitate the entry of gluten or a fraction thereof into the lamina propria where it causes a cascade of immunological events. PMID:3934051

  17. PERMEABLE REACTIVE BARRIER TECHNOLOGIES FOR CONTAMINANT REMEDIATION

    EPA Science Inventory

    Environmental scientists are generally familiar with the concept of barriers for restricting the movement of contaminant plumes in ground water. Such barriers are typically constructed of highly impermeable emplacements of materials such as grouts, slurries, or sheet pilings to ...

  18. 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

  19. Review of potential subsurface permeable barrier emplacement and monitoring technologies

    SciTech Connect

    Riggsbee, W.H.; Treat, R.L.; Stansfield, H.J.; Schwarz, R.M.; Cantrell, K.J.; Phillips, S.J.

    1994-02-01

    This report focuses on subsurface permeable barrier technologies potentially applicable to existing waste disposal sites. This report describes candidate subsurface permeable barriers, methods for emplacing these barriers, and methods used to monitor the barrier performance. Two types of subsurface barrier systems are described: those that apply to contamination.in the unsaturated zone, and those that apply to groundwater and to mobile contamination near the groundwater table. These barriers may be emplaced either horizontally or vertically depending on waste and site characteristics. Materials for creating permeable subsurface barriers are emplaced using one of three basic methods: injection, in situ mechanical mixing, or excavation-insertion. Injection is the emplacement of dissolved reagents or colloidal suspensions into the soil at elevated pressures. In situ mechanical mixing is the physical blending of the soil and the barrier material underground. Excavation-insertion is the removal of a soil volume and adding barrier materials to the space created. Major vertical barrier emplacement technologies include trenching-backfilling; slurry trenching; and vertical drilling and injection, including boring (earth augering), cable tool drilling, rotary drilling, sonic drilling, jetting methods, injection-mixing in drilled holes, and deep soil mixing. Major horizontal barrier emplacement technologies include horizontal drilling, microtunneling, compaction boring, horizontal emplacement, longwall mining, hydraulic fracturing, and jetting methods.

  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. Lactobacillus gasseri SBT2055 inhibits adipose tissue inflammation and intestinal permeability in mice fed a high-fat diet.

    PubMed

    Kawano, Michio; Miyoshi, Masaya; Ogawa, Akihiro; Sakai, Fumihiko; Kadooka, Yukio

    2016-01-01

    The probiotic Lactobacillus gasseri SBT2055 (LG2055) has anti-obesity effects. Obesity is closely correlated with inflammation in adipose tissue, and maintaining adipose tissue in a less-inflamed state requires intestinal integrity or a barrier function to protect the intestine from the disruption that can be caused by a high-fat diet (HFD). Here, we examined the anti-inflammatory and intestinal barrier-protecting effects of LG2055 in C57BL/6 mice fed a normal-fat diet (NFD), HFD, or the HFD containing LG2055 (HFD-LG) for 21 weeks. HFD-LG intake significantly prevented HFD-induced increases in body weight, visceral fat mass, and the ratio of inflammatory-type macrophages to anti-inflammatory ones in adipose tissue. Mice fed the HFD showed higher intestinal permeability to a fluorescent dextran administered by oral administration and an elevated concentration of antibodies specific to lipopolysaccharides (LPS) in the blood compared with those fed the NFD, suggesting an increased penetration of the gut contents into the systemic circulation. These elevations of intestinal permeability and anti-LPS antibody levels were significantly suppressed in mice fed the HFD-LG. Moreover, treatment with LG2055 cells suppressed an increase in the cytokine-induced permeability of Caco-2 cell monolayers. These results suggest that LG2055 improves the intestinal integrity, reducing the entry of inflammatory substances like LPS from the intestine, which may lead to decreased inflammation in adipose tissue.

  2. Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?

    PubMed Central

    Soderholm, J; Olaison, G; Lindberg, E; Hannestad, U; Vindels, A; Tysk, C; Jarnerot, G; Sjodahl, R

    1999-01-01

    Background—A familial defect in intestinal barrier function has been found in Crohn's disease. 
Aim—To investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn's disease. 
Subjects—The study included 39 patients with Crohn's disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls. 
Methods—Intestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal. 
Results—Baseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls. 
Conclusion—The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn's disease. 

 Keywords: acetylsalicylic acid; environment; genetics; inflammatory bowel disease; lactulose; mannitol PMID:9862833

  3. Controlling ferrofluid permeability across the blood-brain barrier model

    NASA Astrophysics Data System (ADS)

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J.

    2014-02-01

    In the present study, an in vitro blood-brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood-brain barrier model was completed by examining the permeability of FITC-Dextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood-brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood-brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood-brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood-brain barrier (e.g. CPB).

  4. Controlling ferrofluid permeability across the blood–brain barrier model.

    PubMed

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2014-02-21

    In the present study, an in vitro blood–brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood–brain barrier model was completed by examining the permeability of FITCDextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood–brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood–brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood–brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood–brain barrier (e.g. CPB). PMID:24457539

  5. 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

  6. 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.

  7. Test device for measuring permeability of a barrier material

    SciTech Connect

    Reese, Matthew; Dameron, Arrelaine; Kempe, Michael

    2014-03-04

    A test device for measuring permeability of a barrier material. An exemplary device comprises a test card having a thin-film conductor-pattern formed thereon and an edge seal which seals the test card to the barrier material. Another exemplary embodiment is an electrical calcium test device comprising: a test card an impermeable spacer, an edge seal which seals the test card to the spacer and an edge seal which seals the spacer to the barrier material.

  8. Ginsenoside Rb1 protects the intestinal mucosal barrier following peritoneal air exposure

    PubMed Central

    Zhou, Feng; Zhang, Peichen; Chen, Xiaoxi; Yan, Jingyi; Yao, Jiangao; Yu, Zhen; Chen, Xiaolei

    2016-01-01

    Ginsenoside Rb1 (GRb1), which is one of the main ingredients derived from Panax ginseng, has been widely used to treat various gastrointestinal disorders. The present study aimed to determine whether GRb1 was able to prevent intestinal mucosal barrier damage in rats following peritoneal air exposure for 3 h. GRb1 (5, 10, and 20 mg/kg) was orally administrated via gavage four times prior to and following surgery. Blood and terminal ileum were sampled 24 h following surgery. Levels of serum D-lactate (D-LA) were detected using an enzyme-linked immunosorbent assay kit. Intestinal permeability was assessed by determining the intestinal clearance of fluorescein isothiocyanate-dextran (FD4). Activity of intestinal myeloperoxidase was measured to assess intestinal inflammation, and intestinal histopathology was assessed by light microscopy. The results showed that GRb1 reduced the level of serum D-LA, intestinal clearance of FD4, and the activity of intestinal myeloperoxidase. Intestinal edema and inflammation were also ameliorated by GRb1, and the Chiu's scores employed for assessing intestinal mucosal damage were also reduced in the GRb1-treated peritoneal air exposure group. In addition, GRb1 induced a significant difference at 10 and 20 mg/kg, indicating a dose-dependent effect. The results of the present study suggest that GRb1 may be able to protect the intestinal mucosal barrier against damage induced by peritoneal air exposure, which may be associated with its anti-inflammatory action. PMID:27703510

  9. Dietary inulin alters the intestinal absorptive and barrier function of piglet intestine after weaning.

    PubMed

    Awad, Wageha A; Ghareeb, Khaled; Paßlack, Nadine; Zentek, Jürgen

    2013-08-01

    An experiment was conducted to study the effects of dietary inulin supplementation on the electrophysiological properties of small intestine of suckling and weaned piglets as indicators for glucose absorption and barrier function. Ten sows were divided into two groups, receiving either a control diet, or a diet with 3% inulin. The diets were fed from 3 weeks ante partum to 6 weeks post partum. In the first 2 weeks of life, piglets received only sow's milk. Irrespective to sex and without castration of males, four piglets (one piglet of each litter) from each group were selected and sacrificed on day 10 of age. The gastrointestinal tract of each piglet was removed and segments were immediately taken from the mid-jejunum and mounted in Ussing chambers. Furthermore, at weaning (6 weeks old) 8 piglets were randomly selected irrespective to sex and males were un-castrated (4 animals from sows received control diet and 4 animals from sows received 3% inulin supplemented diet) and fed for 2 weeks either control weaning diet or inulin supplemented diet. Thereafter segments of the mid-jejunum were used to investigate the effect of inulin on the gut electrophysiology of weaned piglets. The increase in short-circuit current (Isc) after the addition of glucose is an indicator of higher glucose absorption and the higher tissue conductance (Gt) of the epithelium suggested a higher intestinal permeability to paracellular Na(+). In suckling piglets, the addition of d-glucose on the luminal side of the isolated jejunal mucosa increased (P<0.001) the Isc in the inulin-supplemented and control groups compared to basal values. Electrogenic glucose transport (ΔIsc) was similar in suckling piglets from sows fed inulin or control diet, suggesting that feeding of inulin to the mother sows had no effect on glucose absorption across the jejunal mucosa of suckling piglets. However, the dietary inulin supplementation after weaning increased the ΔIsc (P<0.001) compared with the controls

  10. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14.

    PubMed

    Guo, Shuhong; Al-Sadi, Rana; Said, Hamid M; Ma, Thomas Y

    2013-02-01

    Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4-dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4-dependent up-regulation of CD14 membrane expression.

  11. 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.

  12. 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

  13. 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. PMID:26550018

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

    PubMed

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

    2015-12-15

    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.

  15. Groundwater protection from cadmium contamination by permeable reactive barriers.

    PubMed

    Di Natale, F; Di Natale, M; Greco, R; Lancia, A; Laudante, C; Musmarra, D

    2008-12-30

    This work studies the reliability of an activated carbon permeable reactive barrier in removing cadmium from a contaminated shallow aquifer. Laboratory tests have been performed to characterize the equilibrium and kinetic adsorption properties of the activated carbon in cadmium-containing aqueous solutions. A 2D numerical model has been used to describe pollutant transport within a groundwater and the pollutant adsorption on the permeable adsorbing barrier (PRB). In particular, it has been considered the case of a permeable adsorbing barrier (PAB) used to protect a river from a Cd(II) contaminated groundwater. Numerical results show that the PAB can achieve a long-term efficiency by preventing river pollution for several months.

  16. 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

  17. MRI of Blood–Brain Barrier Permeability in Cerebral Ischemia

    PubMed Central

    Ewing, James R.; Chopp, Michael

    2013-01-01

    Quantitative measurement of blood–brain barrier (BBB) permeability using MRI and its application to cerebral ischemia are reviewed. Measurement of BBB permeability using MRI has been employed to evaluate ischemic damage during acute and subacute phases of stroke and to predict hemorrhagic transformation. There is also an emerging interest on the development and use of MRI to monitor vascular structural changes and angiogenesis during stroke recovery. In this review, we describe MRI BBB permeability and susceptibility-weighted MRI measurements and its applications to evaluate ischemic damage during the acute and subacute phases of stroke and vascular remodeling during stroke recovery. PMID:23997835

  18. Intestinal permeability of metformin using single-pass intestinal perfusion in rats

    PubMed Central

    Song, Nai-Ning; Li, Quan-Sheng; Liu, Chang-Xiao

    2006-01-01

    AIM: To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein (P-gp). METHODS: The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion (SPIP) technique in male Waster rats. SPIP was performed in three isolated intestinal segments (duodenum, jejunum and ileum) at the same concentration of metformin (50 μg/mL) to test if the intestinal transport of metformin exhibited site-dependent changes, and in a same isolated intestinal segment (duodenal segment) at three different concentrations of metformin (10, 50, 200 μg/mL) to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil (400 μg/mL) was co-perfused with metformin (50 μg/mL) in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS: The effective permeability values (Peff) of metformin in the jejunum and ileum at 50 μg/mL were significantly lower than those in the duodenum at the same concentration. Besides, Peff values in the duodenum at high concentration (200 μg/mL) were found to be significantly lower than those at low and medium concentrations (10 and 50 μg/mL). Moreover the co-perfusion with verapamil did not increase the Peff value of metformin at 50 μg/mL in the duodenum. CONCLUSION: Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The Peff value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported

  19. 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

  20. Inflammatory mediators and modulation of blood-brain barrier permeability.

    PubMed

    Abbott, N J

    2000-04-01

    1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with

  1. 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.

  2. 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.

  3. 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

  4. PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF INORGANIC CONTAMINANTS

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology is an in-situ approach for groundwater remediation that couples subsurface flow management with a passive chemical or biochemical treatment zone. The development and application of the PRB technology has progressed over the last de...

  5. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: LESSONS LEARNED

    EPA Science Inventory

    This presentation will provide an overview of research efforts at EPA on the application, monitoring, and performance of Permeable Reactive Barriers (PRBs) for groundwater restoration. Over the past 10 years, research projects conducted by research staff at EPA's National Risk M...

  6. Permeable Reactive Barriers for Treatment of Cr6

    EPA Science Inventory

    Several options are available for treatment of hexavalent chromium (Cr(VI)) in groundwater using the permeable reactive barrier (PRB) approach. They include conventional trench-and-fill systems, chemical redox curtains, and organic carbon redox curtains. Each of these PRB syste...

  7. MICROBIAL CHARACTERIZATION OF MANURE BASED PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    The implementation of permeable reactive barriers (PRB) provides a viable option for the remediation of contaminants of environmental significance such as dissolved metals (i.e., chromium), chlorinated solvents, and nitrate/ammonia. The designs of PRBs are usually based on the a...

  8. COLLECTION OF DESIGN DATA: SITE CHARACTERIZATION FOR PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers (PRBs) for the restoration of contaminated ground water are no longer innovative. PRBs have evolved from innovative to accepted, standard practice, for the containment and treatment of a variety of contaminants in ground water. Like any remedial tech...

  9. 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.

  10. Progression of Intestinal Permeability Changes and Alpha-Synuclein Expression in a Mouse Model of Parkinson’s Disease

    PubMed Central

    Kelly, Leo P.; Carvey, Paul M.; Keshavarzian, Ali; Shannon, Kathleen M.; Shaikh, Maliha; Bakay, Roy A. E.; Kordower, Jeffrey H.

    2014-01-01

    large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity. PMID:24898698

  11. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.

    PubMed

    Kelly, Leo P; Carvey, Paul M; Keshavarzian, Ali; Shannon, Kathleen M; Shaikh, Maliha; Bakay, Roy A E; Kordower, Jeffrey H

    2014-07-01

    large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity. PMID:24898698

  12. Design and construction techniques for permeable reactive barriers.

    PubMed

    Gavaskar, A R

    1999-08-12

    Adequate site characterization, bench-scale column testing, and hydrogeologic modeling formed the basis for the design and construction of permeable reactive barriers for groundwater remediation at various sites, such as Dover Air Force Base, DE and Naval Air Station, Moffett Field, CA. Dissolved chlorinated solvents, such as perchloroethylene (PCE) and trichloroethylene (TCE), have been the focus at many sites because the passive nature of the reactive barrier operation makes such barriers particularly useful for treating groundwater contaminants that can persist in the aquifer for several years. A combination of conventional and innovative site characterization, design, and construction techniques were used at these sites to increase the potential cost effectiveness of field application.

  13. Simulation of solute transport across low-permeability barrier walls

    USGS Publications Warehouse

    Harte, P.T.; Konikow, L.F.; Hornberger, G.Z.

    2006-01-01

    Low-permeability, non-reactive barrier walls are often used to contain contaminants in an aquifer. Rates of solute transport through such barriers are typically many orders of magnitude slower than rates through the aquifer. Nevertheless, the success of remedial actions may be sensitive to these low rates of transport. Two numerical simulation methods for representing low-permeability barriers in a finite-difference groundwater-flow and transport model were tested. In the first method, the hydraulic properties of the barrier were represented directly on grid cells and in the second method, the intercell hydraulic-conductance values were adjusted to approximate the reduction in horizontal flow, allowing use of a coarser and computationally efficient grid. The alternative methods were tested and evaluated on the basis of hypothetical test problems and a field case involving tetrachloroethylene (PCE) contamination at a Superfund site in New Hampshire. For all cases, advective transport across the barrier was negligible, but preexisting numerical approaches to calculate dispersion yielded dispersive fluxes that were greater than expected. A transport model (MODFLOW-GWT) was modified to (1) allow different dispersive and diffusive properties to be assigned to the barrier than the adjacent aquifer and (2) more accurately calculate dispersion from concentration gradients and solute fluxes near barriers. The new approach yields reasonable and accurate concentrations for the test cases. ?? 2006.

  14. Simulation of solute transport across low-permeability barrier walls.

    PubMed

    Harte, Philip T; Konikow, Leonard F; Hornberger, George Z

    2006-05-30

    Low-permeability, non-reactive barrier walls are often used to contain contaminants in an aquifer. Rates of solute transport through such barriers are typically many orders of magnitude slower than rates through the aquifer. Nevertheless, the success of remedial actions may be sensitive to these low rates of transport. Two numerical simulation methods for representing low-permeability barriers in a finite-difference groundwater-flow and transport model were tested. In the first method, the hydraulic properties of the barrier were represented directly on grid cells and in the second method, the intercell hydraulic-conductance values were adjusted to approximate the reduction in horizontal flow, allowing use of a coarser and computationally efficient grid. The alternative methods were tested and evaluated on the basis of hypothetical test problems and a field case involving tetrachloroethylene (PCE) contamination at a Superfund site in New Hampshire. For all cases, advective transport across the barrier was negligible, but preexisting numerical approaches to calculate dispersion yielded dispersive fluxes that were greater than expected. A transport model (MODFLOW-GWT) was modified to (1) allow different dispersive and diffusive properties to be assigned to the barrier than the adjacent aquifer and (2) more accurately calculate dispersion from concentration gradients and solute fluxes near barriers. The new approach yields reasonable and accurate concentrations for the test cases.

  15. In vivo analysis of intestinal permeability following hemorrhagic shock

    PubMed Central

    Alsaigh, Tom; Chang, Marisol; Richter, Michael; Mazor, Rafi; Kistler, Erik B

    2015-01-01

    AIM: To determine the time course of intestinal permeability changes to proteolytically-derived bowel peptides in experimental hemorrhagic shock. METHODS: We injected fluorescently-conjugated casein protein into the small bowel of anesthetized Wistar rats prior to induction of experimental hemorrhagic shock. These molecules, which fluoresce when proteolytically cleaved, were used as markers for the ability of proteolytically cleaved intestinal products to access the central circulation. Blood was serially sampled to quantify the relative change in concentration of proteolytically-cleaved particles in the systemic circulation. To provide spatial resolution of their location, particles in the mesenteric microvasculature were imaged using in vivo intravital fluorescent microscopy. The experiments were then repeated using an alternate measurement technique, fluorescein isothiocyanate (FITC)-labeled dextrans 20, to semi-quantitatively verify the ability of bowel-derived low-molecular weight molecules (< 20 kD) to access the central circulation. RESULTS: Results demonstrate a significant increase in systemic permeability to gut-derived peptides within 20 min after induction of hemorrhage (1.11 ± 0.19 vs 0.86 ± 0.07, P < 0.05) compared to control animals. Reperfusion resulted in a second, sustained increase in systemic permeability to gut-derived peptides in hemorrhaged animals compared to controls (1.2 ± 0.18 vs 0.97 ± 0.1, P < 0.05). Intravital microscopy of the mesentery also showed marked accumulation of fluorescent particles in the microcirculation of hemorrhaged animals compared to controls. These results were replicated using FITC dextrans 20 [10.85 ± 6.52 vs 3.38 ± 1.11 fluorescent intensity units (× 105, P < 0.05, hemorrhagic shock vs controls)], confirming that small bowel ischemia in response to experimental hemorrhagic shock results in marked and early increases in gut membrane permeability. CONCLUSION: Increased small bowel permeability in hemorrhagic

  16. 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

  17. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

    PubMed

    Nighot, Prashant K; Hu, Chien-An Andy; Ma, Thomas Y

    2015-03-13

    Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.

  18. Autophagy Enhances Intestinal Epithelial Tight Junction Barrier Function by Targeting Claudin-2 Protein Degradation*

    PubMed Central

    Nighot, Prashant K.; Hu, Chien-An Andy; Ma, Thomas Y.

    2015-01-01

    Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2. PMID:25616664

  19. Increased intestinal barrier function in the small intestine of formula-fed neonatal piglets.

    PubMed

    Huygelen, V; De Vos, M; Willemen, S; Tambuyzer, B; Casteleyn, C; Knapen, D; Van Cruchten, S; Van Ginneken, C

    2012-12-01

    Within-litter birth weight variation is adversely correlated to piglet survival and postnatal growth. A less efficient epithelial barrier function in light piglets may partly explain this inverse relationship between birth weight and zootechnical performance. A compromised epithelial barrier increases paracellular permeability; consequently, toxins, allergenic compounds, or bacteria may enter systemic circulation and induce inflammatory responses. Dietary effects on function of gut epithelium of piglet are largely unknown. This study investigated epithelial barrier function of the small intestine of normal birth weight (NBW) piglets (1.46 ± 0.10 kg) and low birth weight (LBW) piglets (<1 kg at birth) in relation to their diet. Sixteen pairs of 3-d-old LBW and NBW piglets were randomly assigned to 3 groups: a sow-fed control group euthanized at day 3 of age (SOW3), piglets sow fed until day 10 (SOW10), and formula-fed piglets fed formula from day 3 until day 10 (FOR10). To measure gut permeability, piglets were dosed intragastrically with 0.75 g lactulose/kg BW and 0.3 g mannitol/kg BW 4 h before euthanasia. Urinary sugar excretion was measured using enzymatic spectrophotometry. Irrespective of birth weight, lactulose levels of FOR10 (4.4 ± 2.3 mmol/L) tended to be lower (P = 0.07) than SOW10 (26.4 ± 10.2 mmol/L) indicating a reduced paracellular intestinal permeability in FOR10. This reduction was associated with a 6-fold elevated (P < 0.01) protein expression of occludin, an important tight junction protein, in FOR10 compared to SOW10. Mannitol levels in FOR10 (31.0 ± 18.2 mmol/L) did not differ (P = 0.28) from SOW10 (61.1 ± 10.2 mmol/L). However, shorter villi (P < 0.01) in FOR10 indicated a reduced absorptive capacity. In conclusion, formula feeding caused minor symptoms of gastrointestinal dysfunction compared to sow-fed piglets irrespective of their birth weight.

  20. Epidermal Permeability Barrier Defects and Barrier Repair Therapy in Atopic Dermatitis

    PubMed Central

    Lee, Hae-Jin

    2014-01-01

    Atopic dermatitis (AD) is a multifactorial inflammatory skin disease perpetuated by gene-environmental interactions and which is characterized by genetic barrier defects and allergic inflammation. Recent studies demonstrate an important role for the epidermal permeability barrier in AD that is closely related to chronic immune activation in the skin during systemic allergic reactions. Moreover, acquired stressors (e.g., Staphylococcus aureus infection) to the skin barrier may also initiate inflammation in AD. Many studies involving patients with AD revealed that defective skin barriers combined with abnormal immune responses might contribute to the pathophysiology of AD, supporting the outside-inside hypothesis. In this review, we discuss the recent advances in human and animal models, focusing on the defects of the epidermal permeability barrier, its immunologic role and barrier repair therapy in AD. PMID:24991450

  1. Integrity of the permeability barrier regulates epidermal Langerhans cell density.

    PubMed

    Proksch, E; Brasch, J; Sterry, W

    1996-04-01

    Previous studies have shown that barrier requirements regulate epidermal liquid and DNA synthesis. In the present study, we examined the possibility that the integrity of the permeability barrier influences epidermal Langerhans cells involved with the immune response. Barrier disruption was achieved by treatment of human skin with acetone, sodium dodecylsulphate (SDS), or tape stripping, until a 10-20-fold increase in transepidermal water loss was achieved. Serial biopsies were performed 6-168 h after treatment, and Langerhans cells were complexed with anti-CD1a (Leu6) or S-100 antibodies, and visualized with an immunoperoxidase technique. Acetone treatment resulted in an increase in epidermal Langerhans cell density, reaching a maximum of 94% over control (P < 0.01) by 24 and 48 h post-treatment. Following SDS treatment or tape stripping, epidermal Langerhans cell density was increased by 100 and 175% (P < 0.01), respectively. There was a linear correlation between the degree of barrier disruption and the increase in epidermal Langerhans cell density. Studies with the Ki-S3 proliferation-associated nuclear antigen revealed a two- to threefold increase in epidermal proliferation after barrier disruption. The time curves of the increase in Langerhans cell density and the increase in epidermal proliferation were similar, suggesting that there was a coordinate regulation. In contrast with our previous studies employing patch test reactions to allergens or irritants, disruption of barrier function neither resulted in an increased dermal Langerhans cell density, nor influenced T lymphocytes (CD3+, Leu4+), macrophages (KiM8+), ICAM-1 or ELAM-1 expression in the skin. In addition, barrier disruption did not result in either dermal inflammation or epidermal spongiosis. In summary, these findings support our hypothesis that the permeability barrier influences epidermal Langerhans cell density, which is involved in maintaining an immunological barrier.

  2. 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.

  3. A novel dual-flow bioreactor simulates increased fluorescein permeability in epithelial tissue barriers.

    PubMed

    Giusti, Serena; Sbrana, Tommaso; La Marca, Margherita; Di Patria, Valentina; Martinucci, Valentina; Tirella, Annalisa; Domenici, Claudio; Ahluwalia, Arti

    2014-09-01

    Permeability studies across epithelial barriers are of primary importance in drug delivery as well as in toxicology. However, traditional in vitro models do not adequately mimic the dynamic environment of physiological barriers. Here, we describe a novel two-chamber modular bioreactor for dynamic in vitro studies of epithelial cells. The fluid dynamic environment of the bioreactor was characterized using computational fluid dynamic models and measurements of pressure gradients for different combinations of flow rates in the apical and basal chambers. Cell culture experiments were then performed with fully differentiated Caco-2 cells as a model of the intestinal epithelium, comparing the effect of media flow applied in the bioreactor with traditional static transwells. The flow increases barrier integrity and tight junction expression of Caco-2 cells with respect to the static controls. Fluorescein permeability increased threefold in the dynamic system, indicating that the stimulus induced by flow increases transport across the barrier, closely mimicking the in vivo situation. The results are of interest for studying the influence of mechanical stimuli on cells, and underline the importance of developing more physiologically relevant in vitro tissue models. The bioreactor can be used to study drug delivery, chemical, or nanomaterial toxicity and to engineer barrier tissues.

  4. Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation.

    PubMed

    Summa, Keith C; Voigt, Robin M; Forsyth, Christopher B; Shaikh, Maliha; Cavanaugh, Kate; Tang, Yueming; Vitaterna, Martha Hotz; Song, Shiwen; Turek, Fred W; Keshavarzian, Ali

    2013-01-01

    The circadian clock orchestrates temporal patterns of physiology and behavior relative to the environmental light:dark cycle by generating and organizing transcriptional and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate the physiology and function of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation; a process that has been linked to pathologic inflammatory states associated with metabolic, hepatic, cardiovascular and neurodegenerative diseases - many of which are commonly reported in shift workers. Here we report, for the first time, that circadian disorganization, using independent genetic and environmental strategies, increases permeability of the intestinal epithelial barrier (i.e., gut leakiness) in mice. Utilizing chronic alcohol consumption as a well-established model of induced intestinal hyperpermeability, we also found that both genetic and environmental circadian disruption promote alcohol-induced gut leakiness, endotoxemia and steatohepatitis, possibly through a mechanism involving the tight junction protein occludin. Circadian organization thus appears critical for the maintenance of intestinal barrier integrity, especially in the context of injurious agents, such as alcohol. Circadian disruption may therefore represent a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease, as well as other conditions associated with intestinal hyperpermeability and an endotoxin-triggered inflammatory state. PMID:23825629

  5. Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation

    PubMed Central

    Forsyth, Christopher B.; Shaikh, Maliha; Cavanaugh, Kate; Tang, Yueming; Vitaterna, Martha Hotz; Song, Shiwen

    2013-01-01

    The circadian clock orchestrates temporal patterns of physiology and behavior relative to the environmental light:dark cycle by generating and organizing transcriptional and biochemical rhythms in cells and tissues throughout the body. Circadian clock genes have been shown to regulate the physiology and function of the gastrointestinal tract. Disruption of the intestinal epithelial barrier enables the translocation of proinflammatory bacterial products, such as endotoxin, across the intestinal wall and into systemic circulation; a process that has been linked to pathologic inflammatory states associated with metabolic, hepatic, cardiovascular and neurodegenerative diseases – many of which are commonly reported in shift workers. Here we report, for the first time, that circadian disorganization, using independent genetic and environmental strategies, increases permeability of the intestinal epithelial barrier (i.e., gut leakiness) in mice. Utilizing chronic alcohol consumption as a well-established model of induced intestinal hyperpermeability, we also found that both genetic and environmental circadian disruption promote alcohol-induced gut leakiness, endotoxemia and steatohepatitis, possibly through a mechanism involving the tight junction protein occludin. Circadian organization thus appears critical for the maintenance of intestinal barrier integrity, especially in the context of injurious agents, such as alcohol. Circadian disruption may therefore represent a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease, as well as other conditions associated with intestinal hyperpermeability and an endotoxin-triggered inflammatory state. PMID:23825629

  6. Co-Regulation and Interdependence of the Mammalian Epidermal Permeability and Antimicrobial Barriers

    PubMed Central

    Aberg, Karin M.; Man, Mao-Qiang; Gallo, Richard L.; Ganz, Tomas; Crumrine, Debra; Brown, Barbara E.; Choi, Eung-Ho; Kim, Dong-Kun; Schröder, Jens M.; Feingold, Kenneth R.; Elias, Peter M.

    2009-01-01

    Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), β-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1–8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP−/− mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis. PMID:17943185

  7. Intestinal permeability study of minoxidil: assessment of minoxidil as a high permeability reference drug for biopharmaceutics classification.

    PubMed

    Ozawa, Makoto; Tsume, Yasuhiro; Zur, Moran; Dahan, Arik; Amidon, Gordon L

    2015-01-01

    The purpose of this study was to evaluate minoxidil as a high permeability reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil was determined in in situ intestinal perfusion studies in rodents and permeability studies across Caco-2 cell monolayers. The permeability of minoxidil was compared with that of metoprolol, an FDA reference drug for BCS classification. In rat perfusion studies, the permeability of minoxidil was somewhat higher than that of metoprolol in the jejunum, while minoxidil showed lower permeability than metoprolol in the ileum. The permeability of minoxidil was independent of intestinal segment, while the permeability of metoprolol was region-dependent. Similarly, in mouse perfusion study, the jejunal permeability of minoxidil was 2.5-fold higher than that of metoprolol. Minoxidil and metoprolol showed similar permeability in Caco-2 study at apical pH of 6.5 and basolateral pH of 7.4. The permeability of minoxidil was independent of pH, while metoprolol showed pH-dependent transport in Caco-2 study. Minoxidil exhibited similar permeability in the absorptive direction (AP-BL) in comparison with secretory direction (BL-AP), while metoprolol had higher efflux ratio (ER > 2) at apical pH of 6.5 and basolateral pH of 7.4. No concentration-dependent transport was observed for either minoxidil or metoprolol transport in Caco-2 study. Verapamil did not alter the transport of either compounds across Caco-2 cell monolayers. The permeability of minoxidil was independent of both pH and intestinal segment in intestinal perfusion studies and Caco-2 studies. Caco-2 studies also showed no involvement of carrier mediated transport in the absorption process of minoxidil. These results suggest that minoxidil may be an acceptable reference drug for BCS high permeability classification. However, minoxidil exhibited higher jejunal permeability than metoprolol and thus to use minoxidil as a reference drug would raise the

  8. IBD Candidate Genes and Intestinal Barrier Regulation

    PubMed Central

    McCole, Declan F.

    2015-01-01

    Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn’s disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with disease, individual gene associations only affect a subset of patients, and the functional contribution(s) of these risk variants to the onset of IBD is largely undetermined. Although studies in twins have demonstrated that the development of IBD is not mediated solely by genetic risk, it is nevertheless important to elucidate the functional consequences of risk variants for gene function in relevant cell types known to regulate key physiological processes that are compromised in IBD. This article will discuss IBD candidate genes that are known to be, or are suspected of being, involved in regulating the intestinal epithelial barrier and several of the physiological processes presided over by this dynamic and versatile layer of cells. This will include assembly and regulation of tight junctions, cell adhesion and polarity, mucus and glycoprotein regulation, bacterial sensing, membrane transport, epithelial differentiation, and restitution. PMID:25215613

  9. Role of Snail Activation in Alcohol-induced iNOS-mediated Disruption of Intestinal Epithelial Cell Permeability

    PubMed Central

    Forsyth, Christopher B.; Tang, Yueming; Shaikh, Maliha; Zhang, Lijuan; Keshavarzian, Ali

    2013-01-01

    Background Chronic alcohol use results in many pathological effects including alcoholic liver disease (ALD). ALD pathogenesis requires endotoxemia. Our previous studies showed that increased intestinal permeability is the major cause of endotoxemia and that this gut leakiness is dependent on alcohol stimulation of inducible nitric oxide synthase (iNOS) in both alcoholic subjects and rodent models of alcoholic steatohepatitis (ASH). The mechanism of the alcohol-induced, iNOS-mediated disruption of the intestinal barrier function is not known. We have recently shown that alcohol stimulates activation of the transcription factor Snail and biomarkers of epithelial mesenchymal transition. Since activated Snail disrupts tight junctional proteins , we hypothesized that activation of Snail by iNOS might be one of the key signaling pathways mediating alcohol stimulated intestinal epithelial cell hyperpermeability. Methods We measured intestinal permeability in alcohol-fed C57BL/6 control and iNOS KO mice and measured Snail protein expression in the intestines of these mice. We then examined intestinal epithelial permeability using the Caco-2 cell model of the intestinal barrier ± siRNA inhibition of Snail. We assessed Snail activation by alcohol in Caco-2 cells ± inhibition of iNOS with L-NIL or siRNA. Finally, we assessed Snail activation by alcohol ± inhibition with siRNA for p21-activated kinase (PAK1). Results Our data show that chronic alcohol feeding promotes intestinal hyperpermeability in wild type BL/6 but not in iNOS KO mice. Snail protein expression was increased in the intestines of alcohol-treated wild type mice but not in iNOS KO mice. SiRNA inhibition of Snail significantly inhibited alcohol-induced hyperpermeability in Caco-2 cell monolayers. Alcohol stimulation of SnailpS246 activation was blocked by inhibition of iNOS with L-NIL or with siRNA. SiRNA inhibition of PAK1 significantly inhibited alcohol-mediated activation of Snail in Caco-2 cells

  10. IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis.

    PubMed

    Gerlach, Katharina; McKenzie, Andrew N; Neurath, Markus F; Weigmann, Benno

    2015-01-01

    As previous studies suggested that IL-9 may control intestinal barrier function, we tested the role of IL-9 in experimental T cell-mediated colitis induced by the hapten reagent 2,4,6-trinitrobenzenesulfonic acid (TNBS). The deficiency of IL-9 suppressed TNBS-induced colitis and led to lower numbers of PU.1 expressing T cells in the lamia propria, suggesting a regulatory role for Th9 cells in the experimental TNBS colitis model. Since IL-9 is known to functionally alter intestinal barrier function in colonic inflammation, we assessed the expression of tight junction molecules in intestinal epithelial cells of TNBS-inflamed mice. Therefore we made real-time PCR analyses for tight junction molecules in the inflamed colon from wild-type and IL-9 KO mice, immunofluorescent stainings and investigated the expression of junctional proteins directly in intestinal epithelial cells of TNBS-inflamed mice by Western blot studies. The results demonstrated that sealing proteins like occludin were up regulated in the colon of inflamed IL-9 KO mice. In contrast, the tight junction protein Claudin1 showed lower expression levels when IL-9 is absent. Surprisingly, the pore-forming molecule Claudin2 revealed equal expression in TNBS-treated wild-type and IL-9-deficient animals. These results illustrate the pleiotropic functions of IL-9 in changing intestinal permeability in experimental colitis. Thus, modulation of IL-9 function emerges as a new approach for regulating barrier function in intestinal inflammation.

  11. 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.

  12. Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis.

    PubMed

    Terc, Joshua; Hansen, Ashleigh; Alston, Laurie; Hirota, Simon A

    2014-05-13

    The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response. To this end considerable study has been undertaken to identify signaling pathways that may accelerate intestinal epithelial wound healing and normalize the barrier dysfunction observed in IBD. In the current study we examined the role of the pregnane X receptor (PXR) in modulating the intestinal epithelial wound healing response. Mutations and reduced mucosal expression of the PXR are associated with IBD, and others have reported that PXR agonists can dampen intestinal inflammation. Furthermore, stimulation of the PXR has been associated with increased cell migration and proliferation, two of the key processes involved in wound healing. We hypothesized that PXR agonists would enhance intestinal epithelial repair. Stimulation of Caco-2 intestinal epithelial cells with rifaximin, rifampicin and SR12813, all potent agonists of the PXR, significantly increased wound closure. This effect was driven by p38 MAP kinase-dependent cell migration, and occurred in the absence of cell proliferation. Treating mice with a rodent specific PXR agonist, pregnenolone 16α-carbonitrile (PCN), attenuated the intestinal barrier dysfunction observed in the dextran sulphate sodium (DSS) model of experimental colitis, an effect that occurred independent of the known anti-inflammatory effects of PCN. Taken together our data indicate that the activation of the PXR can enhance intestinal epithelial repair and suggest that targeting the PXR may help to normalize intestinal barrier dysfunction observed in patients with IBD

  13. The role of sphingolipid metabolism in cutaneous permeability barrier formation.

    PubMed

    Breiden, Bernadette; Sandhoff, Konrad

    2014-03-01

    The epidermal permeability barrier of mammalian skin is localized in the stratum corneum. Corneocytes are embedded in an extracellular, highly ordered lipid matrix of hydrophobic lipids consisting of about 50% ceramides, 25% cholesterol and 15% long and very long chain fatty acids. The most important lipids for the epidermal barrier are ceramides. The scaffold of the lipid matrix is built of acylceramides, containing ω-hydroxylated very long chain fatty acids, acylated at the ω-position with linoleic acid. After glucosylation of the acylceramides at Golgi membranes and secretion, the linoleic acid residues are replaced by glutamate residues originating from proteins exposed on the surface of corneocytes. Removal of their glucosyl residues generates a hydrophobic surface on the corneocytes used as a template for the formation of extracellular lipid layers of the water permeability barrier. Misregulation or defects in the formation of extracellular ceramide structures disturb barrier function. Important anabolic steps are the synthesis of ultra long chain fatty acids, their ω-hydroxylation, and formation of ultra long chain ceramides and glucosylceramides. The main probarrier precursor lipids, glucosylceramides and sphingomyelins, are packed in lamellar bodies together with hydrolytic enzymes such as glucosylceramide-β-glucosidase and acid sphingomyelinase and secreted into the intercelullar space between the stratum corneum and stratum granulosum. Inherited defects in the extracellular hydrolytic processing of the probarrier acylglucosylceramides impair epidermal barrier formation and cause fatal diseases: such as prosaposin deficiency resulting in lack of lysosomal lipid binding and transfer proteins, or the symptomatic clinical picture of the "collodion baby" in the absence of glucocerebrosidase. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous

  14. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis.

    PubMed

    Carlsson, Anders H; Yakymenko, Olena; Olivier, Isabelle; Håkansson, Fathima; Postma, Emily; Keita, Asa V; Söderholm, Johan D

    2013-10-01

    OBJECTIVE. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. MATERIAL AND METHODS. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with (51)Cr-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. RESULTS. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in (51)Cr-EDTA-passage compared to controls. (51)Cr-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. CONCLUSIONS. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.

  15. 13-Desmethyl spirolide-c and 13,19-didesmethyl spirolide-c trans-epithelial permeabilities: human intestinal permeability modelling.

    PubMed

    Espiña, Begoña; Otero, Paz; Louzao, M Carmen; Alfonso, Amparo; Botana, Luis M

    2011-09-01

    Human intestinal permeability prediction is an increasingly important field that helps to explain how efficient the absorption of drugs is. Spirolides, cyclic imines produced by dinoflagellates from the genera Alexandrium, can be accumulated in mollusks usually consumed by humans. These compounds exert neurological symptoms when injected intra-peritoneally in mice, although they seem to be less toxic by oral administration. In this study, we evaluate two of the most abundant analogues, 13-desmethyl spirolide C and 13,19-didesmethyl spirolide C and their ability to cross the human intestinal epithelium by the use of Caco-2 trans-epithelial permeability assays as a model. Toxin quantifications were carried out by using the liquid chromatography-tandem mass spectrometry analytical technique. We found that both compounds cross the Caco-2 epithelial barrier without altering the trans-epithelial electric resistance of the monolayer. The apparent permeability (P(app)) coefficient calculated was 18.65±1.2×10(-6)cm/s for 13-desmethyl spirolide C while a little lesser, 12.32±3.18×10(-6)cm/s, for 13,19-didesmethyl spirolide C. P(app) coefficients allow us to predict a human intestinal permeability ≥80% and ≥50%, respectively for each compound. Those results demonstrate that spirolides would be highly absorbed in the human intestine, thus being able to enter the circulatory system and to reach different organs where they could be accumulated or exert an unpredictable effect. Thus, it is necessary to carry out new studies about their pharmacokinetics and evaluate their potential acute and/or chronic effect on the human body.

  16. Permeability of exendin-4-loaded chitosan nanoparticles across MDCK cell monolayers and rat small intestine.

    PubMed

    Wang, Mengshu; Zhang, Yong; Sun, Bingxue; Sun, Yanan; Gong, Xin; Wu, Yongge; Zhang, Xizhen; Kong, Wei; Chen, Yan

    2014-01-01

    The purpose of this study was to investigate the permeability of exendin-4-loaded chitosan nanoparticles using the Madin Darby canine kidney (MDCK) cell monolayer as an in vitro model and the rat intestine as an ex vivo model of the human intestinal barrier. A series of formulations of sodium tripolyphosphate (TPP) and chitosan with different molecular weights and degrees of deacetylation was evaluated. The formulation consisting of 0.1% TPP and 0.2% chitosan (400 kDa, 95% degree of deacetylation), which gave optimized monodispersed particle size (303.1±10.36 nm), zeta potential (18.37±1.15 mV) and encapsulation efficiency (38.0±2.6%), was used for further analysis. After determining their biocompatibility, the transport potential of drug-loaded chitosan nanoparticles was evaluated and compared with free exendin-4 using both MDCK cell monolayers and different rat intestinal segments. Mechanisms underlying enhanced transport of exendin-4 in the cell model were also explored. Compared with free exendin-4, the absorption of optimized chitosan nanoparticles was enhanced by 4.7-fold in MDCK cell monolayers and by 2.0-2.78-fold in different rat intestinal segments, with no significant difference between the duodenum, jejunum and ileum. As supported by confocal laser scanning microscopic analysis, the lower enhancement of absorption in the intestine compared to the cell monolayer likely resulted from the chitosan nanoparticle-mediated opening of cellular tight junctions and not through intracellular transport. These findings suggest that the potential application of chitosan nanoparticles as delivery carriers of exendin-4 is limited and may need further modifications.

  17. Hydroxyethyl Starch (HES 130/0.4) Impairs Intestinal Barrier Integrity and Metabolic Function: Findings from a Mouse Model of the Isolated Perfused Small Intestine

    PubMed Central

    Dombrowsky, Heike; Zitta, Karina; Bein, Berthold; Krause, Thorsten; Goldmann, Torsten; Frerichs, Inez; Steinfath, Markus; Weiler, Norbert; Albrecht, Martin

    2015-01-01

    Background The application of hydroxyethyl starch (HES) for volume resuscitation is controversially discussed and clinical studies have suggested adverse effects of HES substitution, leading to increased patient mortality. Although, the intestine is of high clinical relevance and plays a crucial role in sepsis and inflammation, information about the effects of HES on intestinal function and barrier integrity is very scarce. We therefore evaluated the effects of clinically relevant concentrations of HES on intestinal function and barrier integrity employing an isolated perfused model of the mouse small intestine. Methods An isolated perfused model of the mouse small intestine was established and intestines were vascularly perfused with a modified Krebs-Henseleit buffer containing 3% Albumin (N=7) or 3% HES (130/0.4; N=7). Intestinal metabolic function (galactose uptake, lactate-to-pyruvate ratio), edema formation (wet-to-dry weight ratio), morphology (histological and electron microscopical analysis), fluid shifts within the vascular, lymphatic and luminal compartments, as well as endothelial and epithelial barrier permeability (FITC-dextran translocation) were evaluated in both groups. Results Compared to the Albumin group, HES perfusion did not significantly change the wet-to-dry weight ratio and lactate-to-pyruvate ratio. However, perfusing the small intestine with 3% HES resulted in a significant loss of vascular fluid (p<0.01), an increased fluid accumulation in the intestinal lumen (p<0.001), an enhanced translocation of FITC-dextran from the vascular to the luminal compartment (p<0.001) and a significantly impaired intestinal galactose uptake (p<0.001). Morphologically, these findings were associated with an aggregation of intracellular vacuoles within the intestinal epithelial cells and enlarged intercellular spaces. Conclusion A vascular perfusion with 3% HES impairs the endothelial and epithelial barrier integrity as well as metabolic function of the small

  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. 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. PMID:27199937

  20. Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair.

    PubMed

    Luissint, Anny-Claude; Parkos, Charles A; Nusrat, Asma

    2016-10-01

    The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte-epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation. PMID:27436072

  1. Zinc-fortified oral rehydration solution improved intestinal permeability and small intestinal mucosal recovery.

    PubMed

    Tran, Cuong D; Hawkes, Joanna; Graham, Robin D; Kitchen, Julie L; Symonds, Erin L; Davidson, Geoffrey P; Butler, Ross N

    2015-06-01

    A randomized double-blind placebo-controlled study was conducted in children admitted to hospital with gastroenteritis (≥3 loose stools per day). All were treated for 5 days following admission with either zinc (Zn, 3 mg) or without Zn-fortified rice-based oral rehydration solution (ORS). (13)C-sucrose breath test (SBT) and intestinal permeability (lactulose/rhamnose or L/R ratio) were performed concurrently prior to commencement of ORS with or without Zn and at day 5 post-admission. There was a significant improvement in the SBT results in both the Zn-fortified group, median (5th-95th percentile) 2.1% (0.4% to 8.3%) versus 4.4% (0.4% to 10.4%), P < .05, and control group, 1.4% (0.1% to 5.4%) versus 4.3% (0.4% to 11.4%), P < .05, between the day of admission and day 5 post-admission. In the Zn-fortified group, there was also a significant improvement in L/R ratio between the day of admission and day 5 post-admission, 53.0 (19.5-90.6) versus 17.7 (13.4-83.2), P < .05. Low levels of Zn improved intestinal permeability but did not enhance short-term recovery following diarrheal illness.

  2. Electroacupuncture at Bilateral Zusanli Points (ST36) Protects Intestinal Mucosal Immune Barrier in Sepsis

    PubMed Central

    Zhu, Mei-fei; Xing, Xi; Lei, Shu; Wu, Jian-nong; Wang, Ling-cong; Huang, Li-quan; Jiang, Rong-lin

    2015-01-01

    Sepsis results in high morbidity and mortality. Immunomodulation strategies could be an adjunctive therapy to treat sepsis. Acupuncture has also been used widely for many years in China to treat sepsis. However, the underlying mechanisms are not well-defined. We demonstrated here that EA preconditioning at ST36 obviously ameliorated CLP-induced intestinal injury and high permeability and reduced the mortality of CLP-induced sepsis rats. Moreover, electroacupuncture (EA) pretreatment exerted protective effects on intestinal mucosal immune barrier by increasing the concentration of sIgA and the percentage of CD3+, γ/δ, and CD4+ T cells and the ratio of CD4+/CD8+ T cells. Although EA at ST36 treatments immediately after closing the abdomen in the CLP procedure with low-frequency or high-frequency could not reduce the mortality of CLP-induced sepsis in rats, these EA treatments could also significantly improve intestinal injury index in rats with sepsis and obviously protected intestinal mucosal immune barrier. In conclusion, our findings demonstrated that EA at ST36 could improve intestinal mucosal immune barrier in sepsis induced by CLP, while the precise mechanism underlying the effects needs to be further elucidated. PMID:26346309

  3. Does fluid loading influence measurements of intestinal permeability?

    PubMed Central

    Parviainen, Ilkka; Takala, Jukka; Jakob, Stephan M

    2005-01-01

    Introduction Urinary recovery of enterally administered probes is used as a clinical test of intestinal mucosal permeability. Recently, evidence has been provided that the recovery of some but not all sugar probes is dependent on the amount of diuresis and renal function. The aim of this study was to assess the effect of fluid loading on the urinary recovery of sugar probes in healthy volunteers. Methods In a cross-over study, 10 healthy volunteers ingested 100 ml of a solution containing 0.2 g of 3-O-methyl-D-glucose (3-OMG), 0.5 g of D-xylose, 1.0 g of L-rhamnose, and 5.0 g of lactulose on two different days. The volunteers were randomized to receive either 2 litres of Ringer acetate or no fluid during the following 3 hours. The sugar concentrations were measured in 5-hour urine samples period. Results Fluid loading increased urine production and urinary recovery of xylose. Fluid loading did not influence the urinary recovery of 3-OMG, L-rhamnose, or lactulose. Neither the lactulose/rhamnose ratio nor the 3-OMG/rhamnose ratio changed. Conclusion Fluid loading increases mediated carbohydrate transport but not the lactulose/rhamnose ratio, after oral sugar administration in healthy volunteers. It remains to be determined whether sugar probes are handled differently in response to fluids in patients with organ dysfunctions. PMID:15987395

  4. The Relationship between Small-Intestinal Bacterial Overgrowth and Intestinal Permeability in Patients with Irritable Bowel Syndrome

    PubMed Central

    Park, Dong Il; Kim, Hong Joo; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik; Won, Kyoung Hee; Park, Soon Min

    2009-01-01

    Background/Aims Small-intestinal bacterial overgrowth (SIBO) is a frequent finding in patients with irritable bowel syndrome (IBS). Many patients with IBS also have abnormal intestinal permeability, which is probably due to low-grade inflammation in the intestinal mucosa. Our aim was to verify the relationship between SIBO and small-intestinal permeability in IBS patients. Methods A cohort of 38 IBS patients (20 women and 18 men; age range 16-70 years; mean age 40.2 years) with symptoms that fulfilled Rome-II criteria, and 12 healthy controls (5 women and 7 men; age range 25-52 years; mean age: 37.8 years) were recruited. All subjects underwent lactulose breath tests (LBTs) and intestinal permeability tests using the polyethylene glycol (PEG) 3350/400 retrieval ratio. Results A positive LBT was found in 18.4% (7/38) of patients with IBS and 8.3% (1/12) of control subjects. Intestinal permeability was significantly increased in patients with IBS compared with the normal controls (0.82±0.09 vs 0.41±0.05 [mean±SD], respectively; p<0.05). However, the intestinal permeability did not differ significantly between IBS patients with a positive LBT and those with a negative LBT (0.90±0.13 and 0.80±0.11, respectively; p>0.05). Conclusions Intestinal permeability was increased in patients with IBS, but this finding did not correlated with the occurrence of SIBO. PMID:20431742

  5. Impaired function of the intestinal barrier in a novel sub-health rat model

    PubMed Central

    FENG, SISI; LIU, WEIDONG; ZUO, SHENGNAN; XIE, TINGYAN; DENG, HUI; ZHANG, QIUHUAN; ZHONG, BAIYUN

    2016-01-01

    Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub-health model, the rats were subjected to a high-fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D-lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti-apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription-quantitative polymerase chain reaction analyses In the present study, the sub-health rat model was successfully established, and sub-health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub-health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub-health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub-health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms. PMID:26957295

  6. Impaired function of the intestinal barrier in a novel sub-health rat model.

    PubMed

    Feng, Sisi; Liu, Weidong; Zuo, Shengnan; Xie, Tingyan; Deng, Hui; Zhang, Qiuhuan; Zhong, Baiyun

    2016-04-01

    Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub‑health model, the rats were subjected to a high‑fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D‑lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti‑apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription‑quantitative polymerase chain reaction analyses In the present study, the sub‑health rat model was successfully established, and sub‑health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub‑health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub‑health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub‑health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms. PMID:26957295

  7. Automated Impedance Tomography for Monitoring Permeable Reactive Barrier Health

    SciTech Connect

    LaBrecque, D J; Adkins, P L

    2009-07-02

    The objective of this research was the development of an autonomous, automated electrical geophysical monitoring system which allows for near real-time assessment of Permeable Reactive Barrier (PRB) health and aging and which provides this assessment through a web-based interface to site operators, owners and regulatory agencies. Field studies were performed at four existing PRB sites; (1) a uranium tailing site near Monticello, Utah, (2) the DOE complex at Kansas City, Missouri, (3) the Denver Federal Center in Denver, Colorado and (4) the Asarco Smelter site in East Helena, Montana. Preliminary surface data over the PRB sites were collected (in December, 2005). After the initial round of data collection, the plan was modified to include studies inside the barriers in order to better understand barrier aging processes. In September 2006 an autonomous data collection system was designed and installed at the EPA PRB and the electrode setups in the barrier were revised and three new vertical electrode arrays were placed in dedicated boreholes which were in direct contact with the PRB material. Final data were collected at the Kansas City, Denver and Monticello, Utah PRB sites in the fall of 2007. At the Asarco Smelter site in East Helena, Montana, nearly continuous data was collected by the autonomous monitoring system from June 2006 to November 2007. This data provided us with a picture of the evolution of the barrier, enabling us to examine barrier changes more precisely and determine whether these changes are due to installation issues or are normal barrier aging. Two rounds of laboratory experiments were carried out during the project. We conducted column experiments to investigate the effect of mineralogy on the electrical signatures resulting from iron corrosion and mineral precipitation in zero valent iron (ZVI) columns. In the second round of laboratory experiments we observed the electrical response from simulation of actual field PRBs at two sites: the

  8. Oral supplementation of butyrate reduces mucositis and intestinal permeability associated with 5-Fluorouracil administration.

    PubMed

    Ferreira, Talita Mayra; Leonel, Alda Jusceline; Melo, Marco Antônio; Santos, Rosana R G; Cara, Denise Carmona; Cardoso, Valbert N; Correia, Maria I T D; Alvarez-Leite, Jacqueline I

    2012-07-01

    Mucositis affects about 40 % of patients undergoing chemotherapy. Short chain fatty acids (SCFA), mainly butyrate, are claimed to improve mucosal integrity, reduce intestinal permeability and act as anti-inflammatory agents for the colon mucosa. We evaluated the effects of oral administration of SCFA or butyrate in the 5FU-induced mucositis. Mice received water, SCFA or butyrate during all experiment (10 days) and a single dose of 5FU (200 mg/kg) 3 days before euthanasia. We evaluated inflammatory and histological score by morphometry, and by activity of enzymes specific to neutrophil, eosinophil and macrophage and TLR-4, TNF-alpha and IL6 expressions. Intestinal permeability and tight junction protein ZO-1 expression were evaluated. Mice from the 5FU (5-Fluorouracil) group presented weight loss, ulcerations and inflammatory infiltration of neutrophils and eosinophils, increased expression of IL6 and TNF-alpha and increased intestinal permeability. SCFA minimized intestinal damage, reduced ulcerations without affecting intestinal permeability. Butyrate alone was more efficient at improving those parameters than in SCFA solution and also reduced intestinal permeability. The expression of pro-inflammatory cytokines and ZO-1 tended to be higher in the SCFA supplemented but not in the butyrate supplemented group. We showed the beneficial effects of butyrate on intestinal mucositis and its promising function as an adjuvant in the treatment of diseases not only of the colon, but also of the small intestine.

  9. Evidence of multiple permeability barriers in sarcolemmal (SL) aortic vesicles

    SciTech Connect

    Kaufman, L.J.; Kahn, A.M.; Allen, J.C.

    1986-03-05

    SL vesicles from canine aorta were prepared using Mg aggregation and differential centrifugation. Na/sup +/, K/sup +/-ATPase (NKA) and K/sup +/-Phosphatase (K-Pase) were determined in native and SDS treated SL with either 0.4 mM ouabain (OB) or the lipophilic inhibitor, digitoxigenin (DG). Native SL: OB inhibited NKA=0, DG inhibited NKA=7.7 ..mu..m/mg/hr; SDS treated SL: OB inhibited NKA=4.6, DG inhibited NKA=9.5; Native SL: OB inhibited K-Pase = 177nm/mg/hr, DG inhibited K-Pase = 285, SDS treated SL: OB inhibited K-Pase = 217, DG inhibited K- Pase = 283. Thus, native SL, primarily unbroken and both right side- and inside-out, may be impermeable to ATP and OB. Specific /sup 3/H-OB binding (Mg, P/sub i/) to SL was 5.0 pm/mg in native and 9.6 pm/mg in SL treated with the Mg chelator, CDTA. Altered binding was due to increased B/sub max/, not K/sub m/. Thus, in addition to the permeability barrier of SL, the Mg-bound basement membrane may present another barrier by obscuring OB binding sites. Gel filtration revealed that only the higher molecular weight fractions demonstrated specific OB binding which decreased with decreasing molecular weight, a finding consistent with varying vesicular size. These data indicate that SL prepared by Mg aggregation contain vesicles of differing size with at least two permeability barriers, SL and basement membrane.

  10. 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…

  11. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats.

    PubMed

    Lauffer, Adriana; Vanuytsel, Tim; Vanormelingen, Christophe; Vanheel, Hanne; Salim Rasoel, Shadea; Tóth, Joran; Tack, Jan; Fornari, Fernando; Farré, Ricard

    2016-01-01

    Psychological stress increases intestinal permeability, potentially leading to low-grade inflammation and symptoms in functional gastrointestinal disorders. We assessed the effect of subacute, chronic and combined stress on intestinal barrier function and mast cell density. Male Wistar rats were allocated to four experimental groups (n = 8/group): 1/sham; 2/subacute stress (isolation and limited movement for 24 h); 3/chronic crowding stress for 14 days and 4/combined subacute and chronic stress. Jejunum and colon were collected to measure: transepithelial electrical resistance (TEER; a measure of epithelial barrier function); gene expression of tight junction molecules; mast cell density. Plasma corticosterone concentration was increased in all three stress conditions versus sham, with highest concentrations in the combined stress condition. TEER in the jejunum was decreased in all stress conditions, but was significantly lower in the combined stress condition than in the other groups. TEER in the jejunum correlated negatively with corticosterone concentration. Increased expression of claudin 1, 5 and 8, occludin and zonula occludens 1 mRNAs was detected after subacute stress in the jejunum. In contrast, colonic TEER was decreased only after combined stress, and the expression of tight junction molecules was unaltered. Increased mast cell density was observed in the chronic and combined stress condition in the colon only. In conclusion, our data show that chronic stress sensitizes the gastrointestinal tract to the effects of subacute stress on intestinal barrier function; different underlying cellular and molecular alterations are indicated in the small intestine versus the colon.

  12. Live Faecalibacterium prausnitzii in an apical anaerobic model of the intestinal epithelial barrier.

    PubMed

    Ulluwishewa, Dulantha; Anderson, Rachel C; Young, Wayne; McNabb, Warren C; van Baarlen, Peter; Moughan, Paul J; Wells, Jerry M; Roy, Nicole C

    2015-02-01

    Faecalibacterium prausnitzii, an abundant member of the human commensal microbiota, has been proposed to have a protective role in the intestine. However, it is an obligate anaerobe, difficult to co-culture in viable form with oxygen-requiring intestinal cells. To overcome this limitation, a unique apical anaerobic model of the intestinal barrier, which enabled co-culture of live obligate anaerobes with the human intestinal cell line Caco-2, was developed. Caco-2 cells remained viable and maintained an intact barrier for at least 12 h, consistent with gene expression data, which suggested Caco-2 cells had adapted to survive in an oxygen-reduced atmosphere. Live F. prausnitzii cells, but not ultraviolet (UV)-killed F. prausnitzii, increased the permeability of mannitol across the epithelial barrier. Gene expression analysis showed inflammatory mediators to be expressed at lower amounts in Caco-2 cells exposed to live F. prausnitzii than UV-killed F. prausnitzii, This, consistent with previous reports, implies that live F. prausnitzii produces an anti-inflammatory compound in the culture supernatant, demonstrating the value of a physiologically relevant co-culture system that allows obligate anaerobic bacteria to remain viable.

  13. Characterisation of the passive permeability barrier of nuclear pore complexes

    PubMed Central

    Mohr, Dagmar; Frey, Steffen; Fischer, Torsten; Güttler, Thomas; Görlich, Dirk

    2009-01-01

    Nuclear pore complexes (NPCs) restrict uncontrolled nucleocytoplasmic fluxes of inert macromolecules but permit facilitated translocation of nuclear transport receptors and their cargo complexes. We probed the passive barrier of NPCs and observed sieve-like properties with a dominating mesh or channel radius of 2.6 nm, which is narrower than proposed earlier. A small fraction of diffusion channels has a wider opening, explaining the very slow passage of larger molecules. The observed dominant passive diameter approximates the distance of adjacent hydrophobic clusters of FG repeats, supporting the model that the barrier is made of FG repeat domains cross-linked with a spacing of an FG repeat unit length. Wheat germ agglutinin and the dominant-negative importin β45-462 fragment were previously regarded as selective inhibitors of facilitated NPC passage. We now observed that they do not distinguish between the passive and the facilitated mode. Instead, their inhibitory effect correlates with the size of the NPC-passing molecule. They have little effect on small species, inhibit the passage of green fluorescent protein-sized objects >10-fold and virtually block the translocation of larger ones. This suggests that passive and facilitated NPC passage proceed through one and the same permeability barrier. PMID:19680228

  14. Cellular uptake and transcytosis of lipid-based nanoparticles across the intestinal barrier: Relevance for oral drug delivery.

    PubMed

    Neves, Ana Rute; Queiroz, Joana Fontes; Costa Lima, Sofia A; Figueiredo, Francisco; Fernandes, Rui; Reis, Salette

    2016-02-01

    Oral administration is the preferred route for drug delivery and nanosystems represent a promising tool for protection and transport of hardly soluble, chemically unstable and poorly permeable drugs through the intestinal barrier. In the present work, we have studied lipid nanoparticles cellular uptake, internalization pathways and transcytosis routes through Caco-2 cell monolayers. Both lipid nanosystems presented similar size (∼180nm) and surface charge (-30mV). Nanostructured lipid carriers showed a higher cellular uptake and permeability across the barrier, but solid lipid nanoparticles could enter cells faster than the former. The internalization of lipid nanoparticles occurs mainly through a clathrin-mediated endocytosis mechanism, although caveolae-mediated endocytosis is also involved in the uptake. Both lipid nanoparticles were able to cross the intestinal barrier by a preferential transcellular route. This work contributed to a better knowledge of the developed nanosystems for the oral delivery of a wide spectrum of drugs.

  15. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease.

    PubMed

    Williams, Benjamin B; Tebbutt, Niall C; Buchert, Michael; Putoczki, Tracy L; Doggett, Karen; Bao, Shisan; Johnstone, Cameron N; Masson, Frederick; Hollande, Frederic; Burgess, Antony W; Scott, Andrew M; Ernst, Matthias; Heath, Joan K

    2015-08-01

    The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33(-/-) mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33(-/-) mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33(-/-) mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33(-/-) mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33(-/-) mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33(-/-) mice provide a valuable model to study the mechanisms linking intestinal

  16. Flow Characteristics in Permeable Reactive Barrier Affected by Biological Clogging

    NASA Astrophysics Data System (ADS)

    Seki, K.; Hanada, J.; Miyazaki, T.

    2004-12-01

    Permeable reactive barriers (PRB) are becoming popular for the in situ remediation of contaminated groundwater. The efficiency of the PRB is affected by permeability of the reactive zone, because when permeability decreases contaminants can bypass the reactive zone without degraded. One of the factors affecting permeability of the permeable reactive zone is biological clogging of soil pore, i.e., biomass buildup and resultant decrease in hydraulic conductivity. So far biological clogging in laboratory was mostly observed in one-dimensional flow field, but the actual flow field in PRB is better simulated in two-dimensional flow field. The objective of this study is to observe the flow characteristics in PRB by using simulated flow cells in laboratory, by comparing one-dimensional and two-dimensional flow field. One-dimensional flow field was simulated by 20 cm length and 1 cm width flow cell, and two-dimensional flow field was simulated by 20 cm length and 10 cm width flow cell. Each flow cell was operated under water-saturated conditions, in horizontal position, and at a constant temperature of 20 degree centigrade. Glass beads of 0.1 mm mean diameter was packed uniformly in the flow cells and inoculum was injected into the nutrient injection ports at the middle of the flow cells. After 24 h incubation time continuous flow was started. Background flow of de-ionized water was supplied to the inlet ports, and the mineral medium was supplied from the nutrient injection ports. The flux was measured every day and local hydraulic head distribution was measured by water manometer, and hydraulic conductivity was calculated. The flow cell experiments were continued for 9 days. In one-dimensional flow cell, hydraulic conductivity of the nutrient supplied part decreased to about half of the initial value in 9 days flow period, where the hydraulic conductivity of the part where nutrient was not supplied remained constant. Bacterial and fungal number in the moderately clogged

  17. Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis.

    PubMed

    Naydenov, Nayden G; Feygin, Alex; Wang, Dongdong; Kuemmerle, John F; Harris, Gianni; Conti, Mary Anne; Adelstein, Robert S; Ivanov, Andrei I

    2016-01-01

    The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo. PMID:27063635

  18. Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis

    PubMed Central

    Naydenov, Nayden G.; Feygin, Alex; Wang, Dongdong; Kuemmerle, John F.; Harris, Gianni; Conti, Mary Anne; Adelstein, Robert S.; Ivanov, Andrei I.

    2016-01-01

    The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo. PMID:27063635

  19. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function.

    PubMed

    Yue, Yuan; Wu, Shuangchan; Li, Zhike; Li, Jian; Li, Xiaofei; Xiang, Jin; Ding, Hong

    2015-08-01

    Dietary polysaccharides provide various beneficial effects for our health. We investigated the protective effects of wild jujube (Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou) sarcocarp polysaccharides (WJPs) against experimental inflammatory bowel disease (IBD) by enabling enhanced intestinal barrier function. Colitis was induced in rats by the intrarectal administration of TNBS. We found that WJPs markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage in colitis rats. Moreover, WJPs suppressed the inflammatory response via attenuation of TNF-α, IL-1β, IL-6 and MPO activity in colitis rats. And then, to determine the effect of WJPs on the intestinal barrier, we measured the effect of WJPs on the transepithelial electrical resistance (TER) and FITC-conjugated dextran permeability in Caco-2 cell stimulation with TNF-α. We further demonstrated that the alleviation of WJPs to colon injury was associated with barrier function by assembly of tight junction proteins. Moreover, the effect of WJPs on TER was eliminated by the specific inhibitor of AMPK. AMPK activity was also up-regulated by WJPs in Caco-2 cell stimulation with TNF-α and in colitis rats. This study demonstrates that WJPs protect against IBD by enabling enhanced intestinal barrier function involving the activation of AMPK.

  20. Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data.

    PubMed

    Sjögren, Erik; Dahlgren, David; Roos, Carl; Lennernäs, Hans

    2015-06-01

    Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.

  1. The complexity of intestinal permeability: Assigning the correct BCS classification through careful data interpretation.

    PubMed

    Zur, Moran; Hanson, Allison S; Dahan, Arik

    2014-09-30

    While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower LogP compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-Fabs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation.

  2. 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.

  3. Directed site exploration for permeable reactive barrier design

    USGS Publications Warehouse

    Lee, J.; Graettinger, A.J.; Moylan, J.; Reeves, H.W.

    2009-01-01

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations. ?? 2008 Elsevier B.V.

  4. Wave scattering by a permeable barrier over undulating bed topography

    NASA Astrophysics Data System (ADS)

    Choudhary, A.; Martha, S. C.

    2016-06-01

    The scattering of surface water waves by bottom undulation in the presence of a permeable vertical barrier is investigated for its solution. A mixed boundary value problem (BVP) arises here in a natural way while examining this physical problem. Regular perturbation analysis is employed to determine the solution of the BVP. By utilizing this analysis the given BVP reduces to two different BVPs up to first order. The solution of the zeroth order BVP is obtained with the aid of eigenfunction expansion method in conjunction with least-squares approximation. The first order BVP is solved with the help of the Green's integral theorem and the physical quantities, namely the reflection and transmission coefficients, are obtained in the form of integrals which involve the bottom undulation and the solution of the zeroth order BVP. A particular form of the bottom undulation which closely resembles to some obstacles made by nature due to sedimentation and ripple growth of sand, is considered to evaluate these integrals. The variation of these coefficients is examined for different values of the porous effect parameter, barrier length, number of ripples and ripple amplitude.

  5. Directed site exploration for permeable reactive barrier design.

    PubMed

    Lee, Jejung; Graettinger, Andrew J; Moylan, John; Reeves, Howard W

    2009-02-15

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations. PMID:18573602

  6. Directed site exploration for permeable reactive barrier design.

    PubMed

    Lee, Jejung; Graettinger, Andrew J; Moylan, John; Reeves, Howard W

    2009-02-15

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations.

  7. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage

    PubMed Central

    Catanzaro, Daniela; Rancan, Serena; Orso, Genny; Dall’Acqua, Stefano; Brun, Paola; Giron, Maria Cecilia; Carrara, Maria; Castagliuolo, Ignazio; Ragazzi, Eugenio; Caparrotta, Laura; Montopoli, Monica

    2015-01-01

    Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the

  8. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage.

    PubMed

    Catanzaro, Daniela; Rancan, Serena; Orso, Genny; Dall'Acqua, Stefano; Brun, Paola; Giron, Maria Cecilia; Carrara, Maria; Castagliuolo, Ignazio; Ragazzi, Eugenio; Caparrotta, Laura; Montopoli, Monica

    2015-01-01

    Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027 μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the

  9. ECONOMICS ANALYSIS OF THE IMPLEMENTATION OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF CONTAMINATED GROUND WATER

    EPA Science Inventory

    This report presents an analysis of the cost of using permeable reactive barriers to remediate contaminated ground water. When possible, these costs are compared with the cost of pump-and-treat technology for similar situations. Permeable reactive barriers are no longer perceiv...

  10. SURFACE-ALTERED ZEOLITES AS PERMEABLE BARRIERS FOR IN SITU TREATMENT OF CONTAMINATED GROUNDWATER

    SciTech Connect

    Robert S. Bowman; Zhaohui Li; Stephen J. Roy; Todd Burt; Timothy L. Johnson; Richard L. Johnson

    1999-08-30

    The overall objective of this effort is to develop and test a zeolite-based permeable barrier system for containing and remediating contaminated groundwater. The projected product is an engineered and tested permeable barrier system that can be adopted by the commercial sector.

  11. Raltegravir permeability across blood-tissue barriers and the potential role of drug efflux transporters.

    PubMed

    Hoque, M Tozammel; Kis, Olena; De Rosa, María F; Bendayan, Reina

    2015-05-01

    The objectives of this study were to investigate raltegravir transport across several blood-tissue barrier models and the potential interactions with drug efflux transporters. Raltegravir uptake, accumulation, and permeability were evaluated in vitro in (i) P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1), or MRP4-overexpressing MDA-MDR1 (P-gp), HEK-ABCG2, HeLa-MRP1, or HEK-MRP4 cells, respectively; (ii) cell culture systems of the human blood-brain (hCMEC/D3), mouse blood-testicular (TM4), and human blood-intestinal (Caco-2) barriers; and (iii) rat jejunum and ileum segments using an in situ single-pass intestinal perfusion model. [(3)H]Raltegravir accumulation by MDA-MDR1 (P-gp) and HEK-ABCG2-overexpressing cells was significantly enhanced in the presence of PSC833 {6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporine}, a P-gp inhibitor, or Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], a BCRP inhibitor, suggesting the inhibition of a P-gp- or BCRP-mediated efflux process, respectively. Furthermore, [(3)H]raltegravir accumulation by human cerebral microvessel endothelial hCMEC/D3 and mouse Sertoli TM4 cells was significantly increased by PSC833 and Ko143. In human intestinal Caco-2 cells grown on Transwell filters, PSC833, but not Ko143, significantly decreased the [(3)H]raltegravir efflux ratios. In rat intestinal segments, [(3)H]raltegravir in situ permeability was significantly enhanced by the concurrent administration of PSC833 and Ko143. In contrast, in the transporter inhibition assays, raltegravir (10 to 500 μM) did not increase the accumulation of substrate for P-gp (rhodamine-6G), BCRP ([(3)H]mitoxantrone), or MRP1 [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)] by MDA-MDR1 (P-gp)-, HEK-ABCG2-, or HeLa-MRP1-overexpressing

  12. Protective Effects of Bifidobacterium on Intestinal Barrier Function in LPS-Induced Enterocyte Barrier Injury of Caco-2 Monolayers and in a Rat NEC Model

    PubMed Central

    Weixia, Du; Hong, Wei

    2016-01-01

    Zonulin protein is a newly discovered modulator which modulates the permeability of the intestinal epithelial barrier by disassembling intercellular tight junctions (TJ). Disruption of TJ is associated with neonatal necrotizing enterocolitis (NEC). It has been shown bifidobacterium could protect the intestinal barrier function and prophylactical administration of bifidobacterium has beneficial effects in NEC patients and animals. However, it is still unknown whether the zonulin is involved in the gut barrier dysfunction of NEC, and the protective mechanisms of bifidobacterium on intestinal barrier function are also not well understood. The present study aims to investigate the effects of bifidobacterium on intestinal barrier function, zonulin regulation, and TJ integrity both in LPS-induced enterocyte barrier injury of Caco-2 monolayers and in a rat NEC model. Our results showed bifidobacterium markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS (P < 0.01). Compared with the LPS group, bifidobacterium significantly decreased the production of IL-6 and TNF-α (P < 0.01) and suppressed zonulin release (P < 0.05). In addition, bifidobacterium pretreatment up-regulated occludin, claudin-3 and ZO-1 expression (P < 0.01) and also preserved these proteins localization at TJ compared with the LPS group. In the in vivo study, bifidobacterium decreased the incidence of NEC from 88 to 47% (P < 0.05) and reduced the severity in the NEC model. Increased levels of IL-6 and TNF-α in the ileum of NEC rats were normalized in bifidobacterium treated rats (P < 0.05). Moreover, administration of bifidobacterium attenuated the increase in intestinal permeability (P < 0.01), decreased the levels of serum zonulin (P < 0.05), normalized the expression and localization of TJ proteins in the ileum compared with animals with NEC. We concluded that bifidobacterium may protect against

  13. Protective Effects of Bifidobacterium on Intestinal Barrier Function in LPS-Induced Enterocyte Barrier Injury of Caco-2 Monolayers and in a Rat NEC Model.

    PubMed

    Ling, Xiang; Linglong, Peng; Weixia, Du; Hong, Wei

    2016-01-01

    Zonulin protein is a newly discovered modulator which modulates the permeability of the intestinal epithelial barrier by disassembling intercellular tight junctions (TJ). Disruption of TJ is associated with neonatal necrotizing enterocolitis (NEC). It has been shown bifidobacterium could protect the intestinal barrier function and prophylactical administration of bifidobacterium has beneficial effects in NEC patients and animals. However, it is still unknown whether the zonulin is involved in the gut barrier dysfunction of NEC, and the protective mechanisms of bifidobacterium on intestinal barrier function are also not well understood. The present study aims to investigate the effects of bifidobacterium on intestinal barrier function, zonulin regulation, and TJ integrity both in LPS-induced enterocyte barrier injury of Caco-2 monolayers and in a rat NEC model. Our results showed bifidobacterium markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS (P < 0.01). Compared with the LPS group, bifidobacterium significantly decreased the production of IL-6 and TNF-α (P < 0.01) and suppressed zonulin release (P < 0.05). In addition, bifidobacterium pretreatment up-regulated occludin, claudin-3 and ZO-1 expression (P < 0.01) and also preserved these proteins localization at TJ compared with the LPS group. In the in vivo study, bifidobacterium decreased the incidence of NEC from 88 to 47% (P < 0.05) and reduced the severity in the NEC model. Increased levels of IL-6 and TNF-α in the ileum of NEC rats were normalized in bifidobacterium treated rats (P < 0.05). Moreover, administration of bifidobacterium attenuated the increase in intestinal permeability (P < 0.01), decreased the levels of serum zonulin (P < 0.05), normalized the expression and localization of TJ proteins in the ileum compared with animals with NEC. We concluded that bifidobacterium may protect against

  14. THE ROLE OF MIR-212 AND INOS IN ALCOHOL-INDUCED INTESTINAL BARRIER DYSFUNCTION AND STEATOHEPATITIS

    PubMed Central

    Tang, Yueming; Zhang, Lijuan; Forsyth, Christopher B.; Shaikh, Maliha; Song, Shiwen; Keshavarzian, Ali

    2015-01-01

    Background Alcoholic liver disease (ALD) is commonly associated with intestinal barrier dysfunction. Alcohol-induced dysregulation of intestinal tight junction (TJ) proteins, such as Zonula Occludens-1 (ZO-1), plays an important role in alcohol-induced gut leakiness. However, the mechanism of alcohol-induced disruption of TJ proteins is not well established. The goal of this study was to elucidate this mechanism by studying the role of MicroRNA 212 (miR-212) and inducible nitric oxide synthase (iNOS) in alcohol-induced gut leakiness. Methods The permeability of the Caco-2 monolayer was assessed by transepithelial electrical resistance (TER) and flux of fluorescein sulfonic acid (FSA). miR-212 was measured by real time PCR. The wild type, iNOS knockout, and miR-212 knockdown mice were fed with alcohol diet (29% of total calories, 4.5% v/v) for 8 weeks. The LNA-anti-miR-212 was used to inhibit miR-212 expression in mice. The alcohol-induced intestinal permeability, miR-212 expression and liver injuries in mice were measured. Results Our in vitro monolayer and in vivo mice studies showed that: (1) alcohol-induced over-expression of the intestinal miR-212 and intestinal hyperpermeability is prevented by using miR-212 knock-down techniques; and (2). iNOS is upregulated in the intestine by alcohol and that iNOS signaling is required for alcohol-induced miR-212 over-expression, ZO-1 disruption, gut leakiness and steatohepatis. Conclusions These studies thus support a novel miR-212 mechanism for alcohol-induced gut leakiness and a potential target that could be exploited for therapeutic intervention to prevent leaky gut and liver injury in alcoholics. PMID:26207424

  15. Berberine ameliorates severe acute pancreatitis‑induced intestinal barrier dysfunction via a myosin light chain phosphorylation‑dependent pathway.

    PubMed

    Liang, Hong-Yin; Chen, Tao; Yan, Hong-Tao; Huang, Zhu; Tang, Li-Jun

    2014-05-01

    Berberine is a traditional drug used to treat gastrointestinal disorders in China and has been demonstrated to attenuate intestinal barrier dysfunction in certain animal models. However, the effects of berberine on pancreatitis-induced intestinal barrier dysfunction are yet to be fully elucidated. This study aimed to investigate the effect of berberine pretreatment on the attenuation of intestinal barrier dysfunction induced by severe acute pancreatitis (SAP). A total of 36 rats were randomly divided into Sham, SAP and SAP plus berberine groups. Pancreatitis was induced using retrograde injection of 3% Na-taurocholate into the pancreatic duct. Histological examinations of the pancreas were performed and intestinal barrier dysfunction was characterized by histological measurements and the assessment of serum diamine oxidase activity and endotoxin levels. Zonula occludens-1 and occludin mRNA and protein expression, as well as myosin light chain (MLC) phosphorylation, were assessed. SAP rat models were successfully established. Berberine treatment was found to have no significant effect on the histological changes in the pancreas, but was observed to ameliorate the intestinal mucosal barrier damage and membrane permeability associated with SAP. Although berberine exerted minimal effects on tight junction proteins in the ilea of SAP rats, it was observed to significantly inhibit SAP-induced MLC phosphorylation. To the best of our knowledge, this is the first study to demonstrate that berberine attenuates SAP‑induced intestinal barrier dysfunction in vivo. In addition, this study shows that the effect of berberine on intestinal barrier function may be associated with the inhibition of SAP‑induced upregulation of MLC phosphorylation.

  16. 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.

  17. Zeolite in horizontal permeable reactive barriers for artificial groundwater recharge

    NASA Astrophysics Data System (ADS)

    Leal, María; Martínez-Hernández, Virtudes; Lillo, Javier; Meffe, Raffaella; de Bustamante, Irene

    2013-04-01

    The Spanish Water Reuse Royal Decree 1620/2007 considers groundwater recharge as a feasible use of reclaimed water. To achieve the water quality established in the above-mentioned legislation, a tertiary wastewater treatment is required. In this context, the infiltration of effluents generated by secondary wastewater treatments through a Horizontal Permeable Reactive Barrier (HPRB) may represent a suitable regeneration technology. Some nutrients (phosphate and ammonium) and some Pharmaceutical and Personal Care Products (PPCPs) are not fully removed in conventional wastewater treatment plants. To avoid groundwater contamination when effluents of wastewater treatments plants are used in artificial recharge activities, these contaminants have to be removed. Due to its sorption capacities, zeolite is among the most used reactive materials in Permeable Reactive Barrier (PRB). Therefore, the main goal of this study is to evaluate the zeolite retention effectiveness of nutrients and PPCPs occurring in treated wastewater. Batch sorption experiments using synthetic wastewater (SWW) and zeolite were performed. A 1:4 zeolite/SWW ratio was selected due to the high sorption capacity of the reactive material.The assays were carried out by triplicate. All the bottles containing the SWW-zeolite mixture were placed on a mechanical shaker during 24 hours at 140 rpm and 25 °C. Ammonium and phosphate, as main nutrients, and a group of PPCPs were selected as compounds to be tested during the experiments. Nutrients were analyzed by ion chromatography. For PPCPs determination, Solid Phase Extraction (SPE) was applied before their analysis by liquid chromatography-mass spectrometry time of flight (LC-MS/ TOF). The experimental data were fitted to linearized Langmuir and Freundlich isotherm equations to obtain sorption parameters. In general, Freundlich model shows a greater capability of reproducing experimental data. To our knowledge, sorption of the investigated compounds on zeolite

  18. 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.

  19. Application of controlled nutrient release to permeable reactive barriers.

    PubMed

    Freidman, Benjamin L; Gras, Sally L; Snape, Ian; Stevens, Geoff W; Mumford, Kathryn A

    2016-03-15

    The application of controlled release nutrient (CRN) materials to permeable reactive barriers to promote biodegradation of petroleum hydrocarbons in groundwater was investigated. The longevity of release, influence of flow velocity and petroleum hydrocarbon concentration on nutrient release was assessed using soluble and ion exchange CRN materials; namely Polyon™ and Zeopro™. Both CRN materials, assessed at 4 °C and 23 °C, demonstrated continuing release of nitrogen, phosphorus and potassium (N-P-K) at 3500 bed volumes passing, with longer timeframes of N-P-K release at 4 °C. Zeopro™-activated carbon mixtures demonstrated depletion of N-P-K prior to 3500 bed volumes passing. Increased flow velocity was shown to lower nutrient concentrations in Polyon™ flow cells while nutrient release from Zeopro™ was largely unchanged. The presence of petroleum hydrocarbons, at 1.08 mmol/L and 3.25 mmol/L toluene, were not shown to alter nutrient release from Polyon™ and Zeopro™ across 14 days. These findings suggest that Polyon™ and Zeopro™ may be suitable CRN materials for application to PRBs in low nutrient environments.

  20. Simplified, noninvasive PET measurement of blood-brain barrier permeability

    SciTech Connect

    Iannotti, F.; Fieschi, C.; Alfano, B.; Picozzi, P.; Mansi, L.; Pozzilli, C.; Punzo, A.; Del Vecchio, G.; Lenzi, G.L.; Salvatore, M.

    1987-05-01

    Blood-brain barrier (BBB) permeability to (/sup 68/Ga)EDTA was measured by positron emission tomography (PET) in four normal volunteers and in 11 patients with brain tumors. A unidirectional transfer constant, Ki, was calculated applying multiple-time graphical analysis (MTGA). This method allows the detection of backflux from brain to blood and, by generalization, the measurement of the constant Kb (brain to blood). Furthermore, the need for an independent measurement of the intravascular tracer is obviated: MTGA itself provides an estimate of the cerebral plasma volume (Vp). In the four normal volunteers the Ki was 3.0 +/- 0.8 X 10(-4) ml g-1 min-1 (mean +/- SD) and the Vp 0.034 +/- 0.007 ml g-1. A net increase in Ki up to a maximum of 121.0 X 10(-4) ml g-1 min-1 (correspondent value of Kb = 0.025 min-1) as well as an increase of Vp was observed in malignant tumors. The input function was calculated using both the (/sup 68/Ga)EDTA concentration in sequential arterial blood samples and, noninvasively, the activity derived from the superior sagittal sinus image. The values of Ki and Vp from these two calculations were in good agreement. The application of MTGA to PET permits the evaluation of passage of substances across the BBB without making assumptions about the compartments in which the tracer distributes.

  1. [Removal of nitrate from groundwater using permeable reactive barrier].

    PubMed

    Li, Xiu-Li; Yang, Jun-Jun; Lu, Xiao-Xia; Zhang, Shu; Hou, Zhen

    2013-03-01

    To provide a cost-effective method for the remediation of nitrate-polluted groundwater, column experiments were performed to study the removal of nitrate by permeable reactive barrier filled with fermented mulch and sand (biowall), and the mechanisms and influence factors were explored. The experimental results showed that the environmental condition in the simulated biowall became highly reduced after three days of operation (oxidation-reduction potential was below - 100 mV), which was favorable for the reduction of nitrate. During the 15 days of operation, the removal rate of nitrate nitrogen (NO3(-) -N) by the simulated biowall was 80%-90% (NO3(-)-N was reduced from 20 mg x L(-1) in the inlet water to 1.6 mg x L(-1) in the outlet water); the concentration of nitrite nitrogen (NO2(-) -N) in the outlet water was below 2.5 mg x L(-1); the concentration of ammonium nitrogen (NH4(+) -N) was low in the first two days but increased to about 12 mg x L(-1) since day three. The major mechanisms involved in the removal of nitrate nitrogen were adsorption and biodegradation. When increasing the water flow velocity in the simulated biowall, the removal rate of NO3(-) -N was reduced and the concentration of NH4(+) -N in the outlet water was significantly reduced. A simulated zeolite wall was set up following the simulated biowall and 98% of the NH4(+) -N could be removed from the water.

  2. A coculture model mimicking the intestinal mucosa reveals a regulatory role for myofibroblasts in immune-mediated barrier disruption.

    PubMed

    Willemsen, L E M; Schreurs, C C H M; Kroes, H; Spillenaar Bilgen, E J; Van Deventer, S J H; Van Tol, E A F

    2002-10-01

    The pathogenesis of Crohn's disease involves a mucosal inflammatory response affecting the barrier function of the gut. Myofibroblasts directly underlining the intestinal epithelium may have a regulatory role in immune-mediated barrier disruption. A coculture system of T84 epithelial and CCD-18Co myofibroblasts was established in order to mimic the in situ spatial interactions between these cell types and to evaluate their role in barrier: integrity. Lamina propria mononuclear cells (LPMC) were introduced in co- and monocultures. Effects of immune cells on barrier integrity was determined by measuring resistance and permeability for macromolecules. Introduction of LPMC in both culture systems caused a time-dependent decrease in barrier integrity. This was found to be less pronounced in cocultures indicating a regulatory role for mesenchymal cells. The effects were also found to depend on the route of LPMC stimulation. Additional analyses suggested that the regulatory role of myofibroblasts in barrier integrity involves production of growth factors. PMID:12395905

  3. CXCR4 Antagonist AMD3100 Modulates Claudin Expression and Intestinal Barrier Function in Experimental Colitis

    PubMed Central

    Xia, Xian-Ming; Wang, Fang-Yu; Zhou, Ju; Hu, Kai-Feng; Li, Su-Wen; Zou, Bing-Bing

    2011-01-01

    Ulcerative colitis is a gastrointestinal disorder characterized by local inflammation and impaired epithelial barrier. Previous studies demonstrated that CXC chemokine receptor 4 (CXCR4) antagonists could reduce colonic inflammation and mucosal damage in dextran sulfate sodium (DSS)-induced colitis. Whether CXCR4 antagonist has action on intestinal barrier and the possible mechanism, is largely undefined. In the present study, the experimental colitis was induced by administration of 5% DSS for 7 days, and CXCR4 antagonist AMD3100 was administered intraperitoneally once daily during the study period. For in vitro study, HT-29/B6 colonic cells were treated with cytokines or AMD3100 for 24 h until assay. DSS-induced colitis was characterized by morphologic changes in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced, and the disease activity index was also significantly decreased. Increased intestinal permeability in DSS-induced colitis was also significantly reduced by AMD3100. The expressions of colonic claudin-1, claudin-3, claudin-5, claudin-7 and claudin-8 were markedly decreased after DSS administration, whereas colonic claudin-2 expression was significantly decreased. Treatment with AMD3100 prevented all these changes. However, AMD3100 had no influence on claudin-3, claudin-5, claudin-7 and claudin-8 expression in HT-29/B6 cells. Cytokines as TNF-α, IL-6, and IFN-γ increased apoptosis and monolayer permeability, inhibited the wound-healing and the claudin-3, claudin-7 and claudin-8 expression in HT-29/B6 cells. We suggest that AMD3100 acted on colonic claudin expression and intestinal barrier function, at least partly, in a cytokine-dependent pathway. PMID:22073304

  4. Clathrin inhibitor Pitstop-2 disrupts the nuclear pore complex permeability barrier

    PubMed Central

    Liashkovich, Ivan; Pasrednik, Dzmitry; Prystopiuk, Valeria; Rosso, Gonzalo; Oberleithner, Hans; Shahin, Victor

    2015-01-01

    Existence of a selective nucleocytoplasmic permeability barrier is attributed to Phenylalanine-Glycine rich proteins (FG-nups) within the central channel of the nuclear pore complex (NPC). Limited understanding of the FG-nup structural arrangement hinders development of strategies directed at disrupting the NPC permeability barrier. In this report we explore an alternative approach to enhancing the NPC permeability for exogenous macromolecules. We demonstrate that the recently discovered inhibitor of clathrin coat assembly Pitstop-2 compromises the NPC permeability barrier in a rapid and effective manner. Treatment with Pitstop-2 causes a collapse of the NPC permeability barrier and a reduction of Importin β binding accompanied by alteration of the NPC ultrastructure. Interestingly, the effects are induced by the same chemical agent that is capable of inhibiting clathrin-mediated endocytosis. To our knowledge, this is the first functional indication of the previously postulated evolutionary relation between clathrin and NPC scaffold proteins. PMID:25944393

  5. Ascorbate Reverses High Glucose- and RAGE-induced Leak of the Endothelial Permeability Barrier

    PubMed Central

    Meredith, M. Elizabeth; Qu, Zhi-chao; May, James M.

    2014-01-01

    High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose-induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5 mM glucose. Acute loading of the cells for 30–60 min with ascorbate before the permeability assay prevented the high glucose-induced increase in permeability and decreased basal permeability at 5 mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose-induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant. PMID:24472555

  6. Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms.

    PubMed

    Dahlgren, David; Roos, Carl; Johansson, Pernilla; Lundqvist, Anders; Tannergren, Christer; Abrahamsson, Bertil; Sjögren, Erik; Lennernäs, Hans

    2016-09-01

    The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process. PMID:27500599

  7. Stress does not increase blood-brain barrier permeability in mice.

    PubMed

    Roszkowski, Martin; Bohacek, Johannes

    2016-07-01

    Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood-brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood-brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood-brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood-brain barrier permeability. To additionally assess if stress could change blood-brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood-brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood-brain barrier permeability. PMID:27146513

  8. Hot spices influence permeability of human intestinal epithelial monolayers.

    PubMed

    Jensen-Jarolim, E; Gajdzik, L; Haberl, I; Kraft, D; Scheiner, O; Graf, J

    1998-03-01

    Indirect evidence suggests that hot spices may interact with epithelial cells of the gastrointestinal tract to modulate their transport properties. Using HCT-8 cells, a cell line from a human ileocoecal carcinoma, we studied the effects of spices on transepithelial electrical resistance (TER), permeability for fluorescein isothiocyanate (FITC)-labeled dextrans with graded molecular weight, and morphological alterations of tight junctions by immunofluorescence using an anti-ZO-1 antibody, a marker for tight junction integrity. Two different reactivity patterns were observed: paprika and cayenne pepper significantly decreased the TER and increased permeability for 10-, 20- and 40-kDa dextrans but not for -70 kDa dextrans. Simultaneously, tight junctions exhibited a discontinuous pattern. Applying extracts from black or green pepper, bay leaf or nutmeg increased the TER and macromolecular permeability remained low. Immunofluorescence ZO-1 staining was preserved. In accordance with the above findings, capsaicin transiently reduced resistance and piperine increased resistance, making them candidates for causing the effects seen with crude spice extracts. The observation that Solanaceae spices (paprika, cayenne pepper) increase permeability for ions and macromolecules might be of pathophysiological importance, particularly with respect to food allergy and intolerance.

  9. Regional Intestinal Permeability of Three Model Drugs in Human.

    PubMed

    Dahlgren, David; Roos, Carl; Lundqvist, Anders; Abrahamsson, Bertil; Tannergren, Christer; Hellström, Per M; Sjögren, Erik; Lennernäs, Hans

    2016-09-01

    Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools. PMID:27504798

  10. 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.

  11. Direct In Vivo Human Intestinal Permeability (Peff ) Determined with Different Clinical Perfusion and Intubation Methods.

    PubMed

    Dahlgren, David; Roos, Carl; Sjögren, Erik; Lennernäs, Hans

    2015-09-01

    Regional in vivo human intestinal effective permeability (Peff ) is calculated by measuring the disappearance rate of substances during intestinal perfusion. Peff is the most relevant parameter in the prediction of rate and extent of drug absorption from all parts of the intestine. Today, human intestinal perfusions are not performed on a routine basis in drug development. Therefore, it would be beneficial to increase the accuracy of the in vitro and in silico tools used to evaluate the intestinal Peff of novel drugs. This review compiles historical Peff data from 273 individual measurements of 80 substances from 61 studies performed in all parts of the human intestinal tract. These substances include: drugs, monosaccharaides, amino acids, dipeptides, vitamins, steroids, bile acids, ions, fatty acids, and water. The review also discusses the determination and prediction of Peff using in vitro and in silico methods such as quantitative structure-activity relationship, Caco-2, Ussing chamber, animal intestinal perfusion, and physiologically based pharmacokinetic (PBPK) modeling. Finally, we briefly outline how to acquire accurate human intestinal Peff data by deconvolution of plasma concentration-time profiles following regional intestinal bolus dosing. PMID:25410736

  12. In Vitro Intestinal Permeability Studies and Pharmacokinetic Evaluation of Famotidine Microemulsion for Oral Delivery

    PubMed Central

    Jha, Sajal Kumar; Karki, Roopa; Puttegowda, Venkatesh Dinnekere; Harinarayana, D.

    2014-01-01

    The absolute bioavailability of famotidine after oral administration is about 40–45% and absorbance only in the initial part of small intestine may be due to low intestinal permeability. Hence, an olive oil based microemulsion formulation with Tween-80 as surfactant and PEG-400 as cosurfactant was developed by using water titration method with the aim of enhancing the intestinal permeability as well as oral bioavailability. In vitro drug permeation in intestine after 8 h for all formulations varied from 30.42% to 78.39% and most of the formulations showed enhanced permeation compared to pure drug (48.92%). Famotidine microemulsion exhibited the higher absorption and Cmax⁡ achieved from the optimized famotidine formulation (456.20 ng·h/ml) was higher than the standard (126.80 ng·h/mL). It was found that AUC0–24 h obtained from the optimized famotidine test formulation (3023.5 ng·h/mL) was significantly higher than the standard famotidine (1663.3 ng·h/mL). F-1 demonstrated a longer (6 h) Tmax⁡ compared with standard drug (2 h) and sustained the release of drug over 24 h. The bioavailability of F-1 formulation was about 1.8-fold higher than that of standard drug. This enhanced bioavailability of famotidine loaded in microemulsion system might be due to increased intestinal permeability. PMID:27379272

  13. Effect of polyethylene glycol 400 on the intestinal permeability of carbamazepine in the rabbit

    SciTech Connect

    Riad, L.E.; Sawchuk, R.J. )

    1991-04-01

    Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous solutions in rabbit intestinal permeability of carbamazepine in the duodenojejunum and the ascending colon using an in situ perfusion technique. In both segments the intestinal permeability varied inversely with the percentage of PEG-400, when the concentration of carbamazepine in the perfusing solution was maintained constant. The decreased permeability may be explained by a reduction in the thermodynamic activity of carbamazepine with increased concentrations of PEG-400, as well as by reverse solvent drag because of the hyperosmolarity of the perfusing solutions.

  14. Topical apigenin improves epidermal permeability barrier homoeostasis in normal murine skin by divergent mechanisms.

    PubMed

    Hou, Maihua; Sun, Richard; Hupe, Melanie; Kim, Peggy L; Park, Kyungho; Crumrine, Debra; Lin, Tzu-Kai; Santiago, Juan Luis; Mauro, Theodora M; Elias, Peter M; Man, Mao-Qiang

    2013-03-01

    The beneficial effects of certain herbal medicines on cutaneous function have been appreciated for centuries. Among these agents, chrysanthemum extract, apigenin, has been used for skin care, particularly in China, for millennia. However, the underlying mechanisms by which apigenin benefits the skin are not known. In this study, we first determined whether topical apigenin positively influences permeability barrier homoeostasis, and then the basis thereof. Hairless mice were treated topically with either 0.1% apigenin or vehicle alone twice daily for 9 days. At the end of the treatments, permeability barrier function was assessed with either an electrolytic water analyzer or a Tewameter. Our results show that topical apigenin significantly enhanced permeability barrier homoeostasis after tape stripping, although basal permeability barrier function remained unchanged. Improved barrier function correlated with enhanced filaggrin expression and lamellar body production, which was paralleled by elevated mRNA levels for the epidermal ABCA12. The mRNA levels for key lipid synthetic enzymes also were upregulated by apigenin. Finally, both cathelicidin-related peptide and mouse beta-defensin 3 immunostaining were increased by apigenin. We conclude that topical apigenin improves epidermal permeability barrier function by stimulating epidermal differentiation, lipid synthesis and secretion, as well as cutaneous antimicrobial peptide production. Apigenin could be useful for the prevention and treatment of skin disorders characterized by permeability barrier dysfunction, associated with reduced filaggrin levels and impaired antimicrobial defenses, such as atopic dermatitis.

  15. Heavy Cigarette Smokers in a Chinese Population Display a Compromised Permeability Barrier

    PubMed Central

    Xin, Shujun; Ye, Li; Lv, Chengzhi; Elias, Peter M.

    2016-01-01

    Cigarette smoking is associated with various cutaneous disorders with defective permeability. Yet, whether cigarette smoking influences epidermal permeability barrier function is largely unknown. Here, we measured skin biophysical properties, including permeability barrier homeostasis, stratum corneum (SC) integrity, SC hydration, skin surface pH, and skin melanin/erythema index, in cigarette smokers. A total of 99 male volunteers were enrolled in this study. Smokers were categorized as light-to-moderate (<20 cigarettes/day) or heavy smokers (≥20 cigarettes/day). An MPA5 was used to measure SC hydration and skin melanin/erythema index on the dorsal hand, forehead, and cheek. Basal transepidermal water loss (TEWL) and barrier recovery rates were assessed on the forearm. A Skin-pH-Meter pH900 was used to measure skin surface pH. Our results showed that heavy cigarette smokers exhibited delayed barrier recovery after acute abrogation (1.02% ± 13.06 versus 16.48% ± 6.07), and barrier recovery rates correlated negatively with the number of daily cigarettes consumption (p = 0.0087). Changes in biophysical parameters in cigarette smokers varied with body sites. In conclusion, heavy cigarette smokers display compromised permeability barrier homeostasis, which could contribute, in part, to the increased prevalence of certain cutaneous disorders characterized by defective permeability. Thus, improving epidermal permeability barrier should be considered for heavy cigarette smokers. PMID:27437403

  16. Metabolic regulation of intestinal epithelial barrier during inflammation

    PubMed Central

    Colgan, Sean P; Curtis, Valerie F; Lanis, Jordi M; Glover, Louise E

    2014-01-01

    The gastrointestinal mucosa has proven to be an interesting tissue for which to investigate disease-related metabolism. In this review, we outline some evidence that implicates metabolic signaling as important features of barrier in the healthy and disease. Studies from cultured cell systems, animal models and human patients have revealed that metabolites generated within the inflammatory microenvironment are central to barrier regulation. These studies have revealed a prominent role for hypoxia and hypoxia-inducible factor (HIF) at key steps in adenine nucleotide metabolism and within the creatine kinase pathway. Results from animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes and barrier function. Studies underway to elucidate the contribution of immune responses will provide additional insight into how metabolic changes contribute to the complexity of the gastrointestinal tract and how such information might be harnessed for therapeutic benefit. PMID:25838978

  17. Bile enhances glucose uptake, reduces permeability, and modulates effects of lectins, trypsin inhibitors and saponins on intestinal tissue.

    PubMed

    Bakke, Anne Marie; Chikwati, Elvis M; Venold, Fredrik F; Sahlmann, Christian; Holm, Halvor; Penn, Michael H; Oropeza-Moe, Marianne; Krogdahl, Åshild

    2014-02-01

    Antinutritional factors (ANFs) can disrupt digestive and other intestinal functions. ANFs in soybean meal (SBM) are implicated in proliferative and inflammatory responses in the intestine of various (functionally) monogastric animals, including Atlantic salmon (Salmo salar L.). The goal of the current study was to investigate the effect of ex vivo exposure of mid and distal intestinal tissue of salmon to soybean saponins (SAP), lectin (LEC) and Kunitz' trypsin inhibitor (KTI), singly and in combination, on epithelial function, as assessed by measuring in vitro glucose uptake pathways along a glucose concentration gradient. As solubilization of SAP in the calcium-containing Ringer's solution was problematic but resolved with the addition of a physiological concentration of bile collected from the gall bladder of salmon, an evaluation of bile effects became an added element. Results indicated that bile increased baseline glucose absorption and possibly transport, and also had a protective effect on the epithelial barrier, at least partially due to taurocholate. Compared to controls, tissues exposed to LEC+bile, KTI+bile and LEC+KTI+bile exhibited increased glucose uptake at the higher glucose concentrations, apparently due to markedly increased tissue permeability. Addition of SAP, however, attenuated the response, possibly by binding bile components. SAP+bile, also in combination with LEC and/or KTI, as well as LEC, KTI and LEC+KTI without bile often reduced transcellular glucose uptake pathways, while maintaining low tissue permeability. SAP+LEC+KTI+bile, LEC and KTI caused the most marked reductions. The distal intestine was more affected, reflecting the restriction of in vivo SBM-induced inflammatory changes to this region. PMID:24291392

  18. Simultaneous gas-chromatographic urinary measurement of sugar probes to assess intestinal permeability: use of time course analysis to optimize its use to assess regional gut permeability

    PubMed Central

    Shaikh, Maliha; Rajan, Kumar; Forsyth, Christopher B.; Voigt, Robin M.; Keshavarzian, Ali

    2015-01-01

    Background Measurement of intestinal permeability is important in several diseases but currently several methods are employed. We sought to: (1) develop a new GC based method to measure urinary mannitol, lactulose and sucralose to assess regional and total gut permeability; (2) analyze the kinetics of these sugars in the urine to determine which ratio is useful to represent intestinal permeability; and (3) determine whether age, gender, race and BMI impact these values. Methods Subjects drank a cocktail of sucrose, lactulose, mannitol and sucralose and these sugars were measured in the urine at 5, 12 and 24 h with gas chromatography. Results Urinary mannitol exhibited significantly different kinetics than lactulose and sucralose which were similar to each other and varied little over the 24 h. No permeability differences were observed for renal function, age, race, sex, or BMI. Conclusions Our data do not support the use of the widely used L/M ratio as an accurate estimate of intestinal permeability. Our data support the use of: The sucralose/lactulose (S/M) ratio to measure: small intestine permeability (first 5 h); small and large intestine (first 12 hours), and total gut permeability (24 h). This was also found to be true in a Parkinson’s disease model. PMID:25591964

  19. 'You shall not pass!': quantifying barrier permeability and proximity avoidance by animals.

    PubMed

    Beyer, Hawthorne L; Gurarie, Eliezer; Börger, Luca; Panzacchi, Manuela; Basille, Mathieu; Herfindal, Ivar; Van Moorter, Bram; R Lele, Subhash; Matthiopoulos, Jason

    2016-01-01

    Impediments to animal movement are ubiquitous and vary widely in both scale and permeability. It is essential to understand how impediments alter ecological dynamics via their influence on animal behavioural strategies governing space use and, for anthropogenic features such as roads and fences, how to mitigate these effects to effectively manage species and landscapes. Here, we focused primarily on barriers to movement, which we define as features that cannot be circumnavigated but may be crossed. Responses to barriers will be influenced by the movement capabilities of the animal, its proximity to the barriers, and habitat preference. We developed a mechanistic modelling framework for simultaneously quantifying the permeability and proximity effects of barriers on habitat preference and movement. We used simulations based on our model to demonstrate how parameters on movement, habitat preference and barrier permeability can be estimated statistically. We then applied the model to a case study of road effects on wild mountain reindeer summer movements. This framework provided unbiased and precise parameter estimates across a range of strengths of preferences and barrier permeabilities. The quality of permeability estimates, however, was correlated with the number of times the barrier is crossed and the number of locations in proximity to barriers. In the case study we found that reindeer avoided areas near roads and that roads are semi-permeable barriers to movement. There was strong avoidance of roads extending up to c. 1 km for four of five animals, and having to cross roads reduced the probability of movement by 68·6% (range 3·5-99·5%). Human infrastructure has embedded within it the idea of networks: nodes connected by linear features such as roads, rail tracks, pipelines, fences and cables, many of which divide the landscape and limit animal movement. The unintended but potentially profound consequences of infrastructure on animals remain poorly understood

  20. 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.

  1. 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

  2. Heat stress reduces intestinal barrier integrity and favors intestinal glucose transport in growing pigs.

    PubMed

    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.

  3. BIFUNCTIONAL ALUMINUN: A PERMEABLE BARRIER MATERIAL FOR THE DEGRADATION OF MTBE

    EPA Science Inventory

    Bifunctional aluminum is an innovative remedial material for the treatment of gasoline oxygenates in permeable reactive barriers (PRBs). PRBs represent a promising environmental technology for remediation of groundwater contamination. Although zero-valent metals (ZVM) have been...

  4. COST ANALYSIS OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF GROUND WATER

    EPA Science Inventory

    ABSTRACT

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating contaminated groundwater that combine subsurface fluid flow management with a passive chemical treatment zone. PRB's are a potentially more cost effective treatment...

  5. LONG-TERM PERFORMANCE ASSESSMENT OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRBs) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. The few pilot and commercial installations which have been implemented ...

  6. Iron Hydroxy Carbonate Formation in Zerovalent Iron Permeable Reactive Barriers: Characterization and Evaluation of Phase Stability

    EPA Science Inventory

    Predicting the long-term potential of permeable reactive barriers for treating contaminated groundwater relies on understanding the endpoints of biogeochemical reactions between influent groundwater and the reactive medium. Iron hydroxy carbonate (chukanovite) is frequently obs...

  7. Performance Assessment of a Permeable Reactive Barrier for Ground Water Remediation Fifteen Years After Installation

    EPA Science Inventory

    The fifteen-year performance of a granular iron, permeable reactive barrier (PRB; Elizabeth City, North Carolina) is reviewed with respect to contaminanttreatment (hexavalent chromium and trichloroethylene) and hydraulic performance. Due to in-situ treatment of the chromium sourc...

  8. PERMEABLE REACTIVE BARRIERS FOR IN-SITU TREATMENT OF ARSENIC-CONTAMINATED GROUNDWATER

    EPA Science Inventory

    Laboratory and field research has shown that permeable reactive barriers (PRBs) containing a variety of materials can treat arsenic (As) contaminated groundwater. Sites where these PRBs are located include a mine tailings facility, fertilizer and chemical manufacturing sites, a...

  9. Corticosterone mediates stress-related increased intestinal permeability in a region-specific manner

    PubMed Central

    Zheng, Gen; Wu, Shu-Pei; Hu, Yongjun; Smith, David E; Wiley, John W.; Hong, Shuangsong

    2012-01-01

    Background Chronic psychological stress (CPS) is associated with increased intestinal epithelial permeability and visceral hyperalgesia. It is unknown whether corticosterone (CORT) plays a role in mediating alterations of epithelial permeability in response to CPS. Methods Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous CORT injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486. The visceromotor response (VMR) to colorectal distension (CRD) was measured. The in situ single-pass intestinal perfusion was used to measure intestinal permeability in jejunum and colon simultaneously. Key Results We observed significant decreases in the levels of glucocorticoid receptor (GR) and tight junction proteins in the colon but not the jejunum in stressed rats. These changes were largely reproduced by serial CORT injections in control rats and were significantly reversed by RU-486. Stressed and CORT-injected rats demonstrated a 3-fold increase in permeability for PEG-400 (MW) in colon but not jejunum and significant increase in VMR to CRD, which was significantly reversed by RU-486. In addition, no differences in permeability to PEG-4,000 and PEG-35,000 were detected between control and WA groups. Conclusions & Inferences Our findings indicate that CPS was associated with region-specific decrease in epithelial tight junction protein levels in the colon, increased colon epithelial permeability to low-molecular weight macromolecules which were largely reproduced by CORT treatment in control rats and prevented by RU-486. These observations implicate a novel, region-specific role for CORT as a mediator of CPS-induced increased permeability to macromolecules across the colon epithelium. PMID:23336591

  10. Changes in intestinal permeability and nutritional status after cytotoxic therapy in patients with cancer.

    PubMed

    Souza, Nilian C S; Simões, Belinda P; Júnior, Alceu A J; Chiarello, Paula G

    2014-01-01

    Damage to intestinal mucosa may impair nutritional status and increase the demand for nutrients involved in intestinal cell proliferation (retinol and folate). It is still unclear if cytotoxic therapy affects serum concentrations of these nutrients in patients with cancer and if this would be associated with disturbances of intestinal mucosa. Intestinal permeability, serum folate, and retinol and nutritional status of 22 patients with hematologic malignancies and 17 healthy volunteers [control group (CG)] were assessed before (T0) and after cytotoxic therapy (T1). Ingestion of lactulose and mannitol was used to assess intestinal permeability. Anthropometric, body composition, phase angle (PA), and biochemical analysis (albumin, retinol, and folate) were also performed. Lactulose/mannitol ratio (0.026 ± 0.014 vs. 0.052 ± 0.037) and lactulose excretion (0.27 ± 0.18% vs. 0.53 ± 0.6%) increased at T1. PA decreased (7.2 ± 1.9° vs. 6.2 ± 0.9°). Serum folate and albumin (20.7 ± 9.5 nmol/L, 37.7 ± 5.5 g/L) were lower than CG (39.2 ± 16.4 nmol/L, 42.9 ± 5.2 g/L) but did not change at T1 (17.5 ± 7.0 nmol/L, 35.9 ± 4.5 g/L). Serum retinol did not differ from CG and did not change at T1 (1.83 ± 0.30 μmol/L vs. 1.69 ± 0.3 μmol/L; CG: 1.86 ± 0.20 μmol/L). Abnormal intestinal permeability, low serum folate levels, and its possible relationship with intestinal alterations, and reduced PA, may be associated with poor nutritional status in cancer patients.

  11. Campylobacter infection in chickens modulates the intestinal epithelial barrier function.

    PubMed

    Awad, Wageha A; Molnár, Andor; Aschenbach, Jörg R; Ghareeb, Khaled; Khayal, Basel; Hess, Claudia; Liebhart, Dieter; Dublecz, Károly; Hess, Michael

    2015-02-01

    Asymptomatic carriage of Campylobacter jejuni is highly prevalent in chicken flocks. Thus, we investigated whether chronic Campylobacter carriage affects chicken intestinal functions despite the absence of clinical symptoms. An experiment was carried out in which commercial chickens were orally infected with C. jejuni (1 × 10(8) CFU/bird) at 14 days of life. Changes in ion transport and barrier function were assessed by short-circuit current (I(sc)) and transepithelial ion conductance (G(t)) in Ussing chambers. G(t) increased in cecum and colon of Campylobacter-infected chicken 7 d post-infection (DPI), whereas G t initially decreased in the jejunum at 7 DPI and increased thereafter at 14 DPI. The net charge transfer across the epithelium was reduced or tended to be reduced in all segments, as evidenced by a decreased I sc. Furthermore, the infection induced intestinal histomorphological changes, most prominently including a decrease in villus height, crypt depth and villus surface area in the jejunum at 7 DPI. Furthermore, body mass gain was decreased by Campylobacter carriage. This study demonstrates, for the first time, changes in the intestinal barrier function in Campylobacter-infected chickens and these changes were associated with a decrease in growth performance in otherwise healthy-appearing birds.

  12. Delivery of berberine using chitosan/fucoidan-taurine conjugate nanoparticles for treatment of defective intestinal epithelial tight junction barrier.

    PubMed

    Wu, Shao-Jung; Don, Trong-Ming; Lin, Cheng-Wei; Mi, Fwu-Long

    2014-11-01

    Bacterial-derived lipopolysaccharides (LPS) can cause defective intestinal barrier function and play an important role in the development of inflammatory bowel disease. In this study, a nanocarrier based on chitosan and fucoidan was developed for oral delivery of berberine (Ber). A sulfonated fucoidan, fucoidan-taurine (FD-Tau) conjugate, was synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy. The FD-Tau conjugate was self-assembled with berberine and chitosan (CS) to form Ber-loaded CS/FD-Tau complex nanoparticles with high drug loading efficiency. Berberine release from the nanoparticles had fast release in simulated intestinal fluid (SIF, pH 7.4), while the release was slow in simulated gastric fluid (SGF, pH 2.0). The effect of the berberine-loaded nanoparticles in protecting intestinal tight-junction barrier function against nitric oxide and inflammatory cytokines released from LPS-stimulated macrophage was evaluated by determining the transepithelial electrical resistance (TEER) and paracellular permeability of a model macromolecule fluorescein isothiocyanate-dextran (FITC-dextran) in a Caco-2 cells/RAW264.7 cells co-culture system. Inhibition of redistribution of tight junction ZO-1 protein by the nanoparticles was visualized using confocal laser scanning microscopy (CLSM). The results suggest that the nanoparticles may be useful for local delivery of berberine to ameliorate LPS-induced intestinal epithelia tight junction disruption, and that the released berberine can restore barrier function in inflammatory and injured intestinal epithelial. PMID:25421323

  13. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    PubMed

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications. PMID:23426527

  14. DHA protects against experimental colitis in IL-10-deficient mice associated with the modulation of intestinal epithelial barrier function.

    PubMed

    Zhao, Jie; Shi, Peiliang; Sun, Ye; Sun, Jing; Dong, Jian-Ning; Wang, Hong-Gang; Zuo, Lu-Gen; Gong, Jian-Feng; Li, Yi; Gu, Li-Li; Li, Ning; Li, Jie-Shou; Zhu, Wei-Ming

    2015-07-01

    A defect in the intestinal barrier is one of the characteristics of Crohn's disease (CD). The tight junction (TJ) changes and death of epithelial cells caused by intestinal inflammation play an important role in the development of CD. DHA, a long-chain PUFA, has been shown to be helpful in treating inflammatory bowel disease in experimental models by inhibiting the NF-κB pathway. The present study aimed at investigating the specific effect of DHA on the intestinal barrier function in IL-10-deficient mice. IL-10-deficient mice (IL-10(-/-)) at 16 weeks of age with established colitis were treated with DHA (i.g. 35.5 mg/kg per d) for 2 weeks. The severity of their colitis, levels of pro-inflammatory cytokines, epithelial gene expression, the distributions of TJ proteins (occludin and zona occludens (ZO)-1), and epithelial apoptosis in the proximal colon were measured at the end of the experiment. DHA treatment attenuated the established colitis and was associated with reduced infiltration of inflammatory cells in the colonic mucosa, lower mean histological scores and decreased levels of pro-inflammatory cytokines (IL-17, TNF-α and interferon-γ). Moreover, enhanced barrier function was observed in the DHA-treated mice that resulted from attenuated colonic permeability, rescued expression and corrected distributions of occludin and ZO-1. The results of the present study indicate that DHA therapy may ameliorate experimental colitis in IL-10(-/-) mice by improving the intestinal epithelial barrier function.

  15. The role of intestinal epithelial barrier function in the development of NEC

    PubMed Central

    Halpern, Melissa D; Denning, Patricia W

    2015-01-01

    The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC. PMID:25927016

  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. Food Derived Bioactive Peptides and Intestinal Barrier Function

    PubMed Central

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-01-01

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action. PMID:25501338

  18. Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

    PubMed Central

    Maharshak, Nitsan; Huh, Eun Young; Paiboonrungruang, Chorlada; Shanahan, Michael; Thurlow, Lance; Herzog, Jeremy; Djukic, Zorka; Orlando, Roy; Pawlinski, Rafal; Ellermann, Melissa; Borst, Luke; Patel, Siten; Dotan, Iris; Sartor, Ryan B.

    2015-01-01

    Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2−/−) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2−/− mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2−/− mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2−/− mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2. PMID:25916983

  19. Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2.

    PubMed

    Maharshak, Nitsan; Huh, Eun Young; Paiboonrungruang, Chorlada; Shanahan, Michael; Thurlow, Lance; Herzog, Jeremy; Djukic, Zorka; Orlando, Roy; Pawlinski, Rafal; Ellermann, Melissa; Borst, Luke; Patel, Siten; Dotan, Iris; Sartor, Ryan B; Carroll, Ian M

    2015-07-01

    Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2(-/-)) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2(-/-) mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2(-/-) mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2(-/-) mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2. PMID:25916983

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

    PubMed

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

    2015-06-15

    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

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

    PubMed

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

    2015-06-15

    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.

  2. 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

  3. 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

  4. 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.

  5. Protective Effects of Ferulic Acid against Heat Stress-Induced Intestinal Epithelial Barrier Dysfunction In Vitro and In Vivo

    PubMed Central

    He, Shasha; Liu, Fenghua; Xu, Lei; Yin, Peng; Li, Deyin; Mei, Chen; Jiang, Linshu; Ma, Yunfei; Xu, Jianqin

    2016-01-01

    Heat stress is important in the pathogenesis of intestinal epithelial barrier dysfunction. Ferulic acid (FA), a phenolic acid widely found in fruits and vegetables, can scavenge free radicals and activate cell stress responses. This study is aimed at investigating protective effects of FA on heat stress-induced dysfunction of the intestinal epithelial barrier in vitro and in vivo. Intestinal epithelial (IEC-6) cells were pretreated with FA for 4 h and then exposed to heat stress. Heat stress caused decreased transepithelial electrical resistance (TER) and increased permeability to 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4). Both effects were inhibited by FA in a dose-dependent manner. FA significantly attenuated the decrease in occludin, ZO-1 and E-cadherin expression observed with heat stress. The distortion and redistribution of occludin, ZO-1 and E-cadherin proteins were also effectively prevented by FA pretreatment. Moreover, heat stress diminished electron-dense material detected in tight junctions (TJs), an effect also alleviated by FA in a dose-dependent manner. In an in vivo heat stress model, FA (50 mg/kg) was administered to male Sprague–Dawley rats for 7 consecutive days prior to exposure to heat stress. FA pretreatment significantly attenuated the effects of heat stress on the small intestine, including the increased FD4 permeability, disrupted tight junctions and microvilli structure, and reduced occludin, ZO-1 and E-cadherin expression. Taken together, our results demonstrate that FA pretreatment is potentially protective against heat stress-induced intestinal epithelial barrier dysfunction. PMID:26894689

  6. Protective Effects of Ferulic Acid against Heat Stress-Induced Intestinal Epithelial Barrier Dysfunction In Vitro and In Vivo.

    PubMed

    He, Shasha; Liu, Fenghua; Xu, Lei; Yin, Peng; Li, Deyin; Mei, Chen; Jiang, Linshu; Ma, Yunfei; Xu, Jianqin

    2016-01-01

    Heat stress is important in the pathogenesis of intestinal epithelial barrier dysfunction. Ferulic acid (FA), a phenolic acid widely found in fruits and vegetables, can scavenge free radicals and activate cell stress responses. This study is aimed at investigating protective effects of FA on heat stress-induced dysfunction of the intestinal epithelial barrier in vitro and in vivo. Intestinal epithelial (IEC-6) cells were pretreated with FA for 4 h and then exposed to heat stress. Heat stress caused decreased transepithelial electrical resistance (TER) and increased permeability to 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4). Both effects were inhibited by FA in a dose-dependent manner. FA significantly attenuated the decrease in occludin, ZO-1 and E-cadherin expression observed with heat stress. The distortion and redistribution of occludin, ZO-1 and E-cadherin proteins were also effectively prevented by FA pretreatment. Moreover, heat stress diminished electron-dense material detected in tight junctions (TJs), an effect also alleviated by FA in a dose-dependent manner. In an in vivo heat stress model, FA (50 mg/kg) was administered to male Sprague-Dawley rats for 7 consecutive days prior to exposure to heat stress. FA pretreatment significantly attenuated the effects of heat stress on the small intestine, including the increased FD4 permeability, disrupted tight junctions and microvilli structure, and reduced occludin, ZO-1 and E-cadherin expression. Taken together, our results demonstrate that FA pretreatment is potentially protective against heat stress-induced intestinal epithelial barrier dysfunction. PMID:26894689

  7. A permeability barrier surrounds taste buds in lingual epithelia

    PubMed Central

    Dando, Robin; Pereira, Elizabeth; Kurian, Mani; Barro-Soria, Rene; Chaudhari, Nirupa

    2014-01-01

    Epithelial tissues are characterized by specialized cell-cell junctions, typically localized to the apical regions of cells. These junctions are formed by interacting membrane proteins and by cytoskeletal and extracellular matrix components. Within the lingual epithelium, tight junctions join the apical tips of the gustatory sensory cells in taste buds. These junctions constitute a selective barrier that limits penetration of chemosensory stimuli into taste buds (Michlig et al. J Comp Neurol 502: 1003–1011, 2007). We tested the ability of chemical compounds to permeate into sensory end organs in the lingual epithelium. Our findings reveal a robust barrier that surrounds the entire body of taste buds, not limited to the apical tight junctions. This barrier prevents penetration of many, but not all, compounds, whether they are applied topically, injected into the parenchyma of the tongue, or circulating in the blood supply, into taste buds. Enzymatic treatments indicate that this barrier likely includes glycosaminoglycans, as it was disrupted by chondroitinase but, less effectively, by proteases. The barrier surrounding taste buds could also be disrupted by brief treatment of lingual tissue samples with DMSO. Brief exposure of lingual slices to DMSO did not affect the ability of taste buds within the slice to respond to chemical stimulation. The existence of a highly impermeable barrier surrounding taste buds and methods to break through this barrier may be relevant to basic research and to clinical treatments of taste. PMID:25209263

  8. A permeability barrier surrounds taste buds in lingual epithelia.

    PubMed

    Dando, Robin; Pereira, Elizabeth; Kurian, Mani; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

    2015-01-01

    Epithelial tissues are characterized by specialized cell-cell junctions, typically localized to the apical regions of cells. These junctions are formed by interacting membrane proteins and by cytoskeletal and extracellular matrix components. Within the lingual epithelium, tight junctions join the apical tips of the gustatory sensory cells in taste buds. These junctions constitute a selective barrier that limits penetration of chemosensory stimuli into taste buds (Michlig et al. J Comp Neurol 502: 1003-1011, 2007). We tested the ability of chemical compounds to permeate into sensory end organs in the lingual epithelium. Our findings reveal a robust barrier that surrounds the entire body of taste buds, not limited to the apical tight junctions. This barrier prevents penetration of many, but not all, compounds, whether they are applied topically, injected into the parenchyma of the tongue, or circulating in the blood supply, into taste buds. Enzymatic treatments indicate that this barrier likely includes glycosaminoglycans, as it was disrupted by chondroitinase but, less effectively, by proteases. The barrier surrounding taste buds could also be disrupted by brief treatment of lingual tissue samples with DMSO. Brief exposure of lingual slices to DMSO did not affect the ability of taste buds within the slice to respond to chemical stimulation. The existence of a highly impermeable barrier surrounding taste buds and methods to break through this barrier may be relevant to basic research and to clinical treatments of taste.

  9. Protective Effect of Huoxiang Zhengqi Oral Liquid on Intestinal Mucosal Mechanical Barrier of Rats with Postinfectious Irritable Bowel Syndrome Induced by Acetic Acid

    PubMed Central

    Liu, Yao; Liu, Wei; Peng, Qiu-Xian; Peng, Jiang-Li; Yu, Lin-Zhong; Hu, Jian-Lan

    2014-01-01

    In this study, a rat model with acetic acid-induced PI-IBS was used to study the role of HXZQ oral liquid in repairing the colonic epithelial barrier and reducing intestinal permeability. Pathomorphism of colonic tissue, epithelial ultrastructure, DAO activity in serum, and the protein expression of ZO-1 and occludin were examined to investigate protective effect mechanisms of HXZQ on intestinal mucosa barrier and then present experimental support for its use for prevention and cure of PI-IBS. PMID:25254052

  10. Permeability reduction of self-affine fractures explained by means of the critical barrier concept

    NASA Astrophysics Data System (ADS)

    Talon, Laurent; Auradou, Harold; Hansen, Alex

    2011-11-01

    In many low permeability geological formations, flow occurs primarily through fracture networks. There is therfore a need for reliable modeling of the hydromechanical behavior of fracture. We consider here fracture with self-affine correlation. Most of the models fails to predict the effective permeability of such fracture as soon as some contact area are present. We introduce a model based on the generalization of the concept of the bottle neck which allows the prediction of the permeability of self-affine rough channels (one-dimensional fracture) and two-dimensional fractures over the entire range of possible apertures. In one-dimensional rough fracture, when the two wall are brought to contact, the permeability is increasingly controlled by the region of minimum aperture. This is the bottle neck concept. In two-dimensionnal fracture, the position of the minimum aperture is not so crucial since the flow can easily by-pass regions of low permeability. To generalize this concept, we introduce the most restrictive barrier path defined as being the barrier that has the smallest average permeability. Using numerical simulation, we identify three permeability scaling regime that will be explained by the introduction of other critical barrier ordered by its criticality.

  11. Changes of the immunological barrier of intestinal mucosa in rats with sepsis

    PubMed Central

    Jiang, Long-yuan; Zhang, Meng; Zhou, Tian-en; Yang, Zheng-fei; Wen, Li-qiang; Chang, Jian-xing

    2010-01-01

    BACKGROUND: Sepsis has become the greatest threat to in-patients, with a mortality of over 25%. The dysfunction of gut barrier, especially the immunological barrier, plays an important role in the development of sepsis. This dysfunction occurs after surgery, but the magnitude of change does not differentiate patients with sepsis from those without sepsis. Increased intestinal permeability before surgery is of no value in predicating sepsis. The present study aimed to observe the changes of intestinal mucosal immunologic barrier in rat models of sepsis induced by cecal ligation and puncture. METHODS: Sixty Sprague-Dawley rats were randomly divided into a sepsis group (n=45) and a control group (n=15). The rats in the sepsis group were subjected to cecal ligation and puncture (CLP), whereas the rats in the control group underwent a sham operation. The ileac mucosa and segments were harvested 3, 6 and 12 hours after CLP, and blood samples were collected. Pathological changes, protein levels of defensin-5 (RD-5) and trefoil factor-3 (TFF3) mRNA, and lymphocytes apoptosis in the intestinal mucosa were determined. In an additional experiment, the gut-origin bacterial DNA in blood was detected. RESULTS: The intestinal mucosa showed marked injury with loss of ileal villi, desquamation of epithelium, detachment of lamina propria, hemorrhage and ulceration in the sepsis group. The expression of TFF3 mRNA and level of RD-5 protein were decreased and the apoptosis of mucosal lymphocyte increased (P<0.05) in the sepsis group compared with the control group. Significant differences were observed in RD-5 and TFF3 mRNA 3 hours after CLP and they were progressively increased 6 and 12 hours after CLP in the sepsis group compared with the control group (P<0.05, RD-5 F=11.76, TFF3 F=16.86 and apoptosis F=122.52). In addition, the gut-origin bacterial DNA detected in plasma was positive in the sepsis group. CONCLUSION: The immunological function of the intestinal mucosa was impaired in

  12. Protective Capacity of Resveratrol, a Natural Polyphenolic Compound, against Deoxynivalenol-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.

    PubMed

    Ling, Ka-Ho; Wan, Murphy Lam Yim; El-Nezami, Hani; Wang, Mingfu

    2016-05-16

    Contamination of food/feedstuffs by mycotoxins is a serious problem worldwide, causing severe economic losses and serious health problems in animals/humans. Deoxynivalenol (DON) is a major mycotoxin contaminant and is known to impair intestinal barrier function. Grapes and red wine are rich in polyphenols, such as resveratrol (RES), which has striking antioxidant and anti-inflammatory activities. RES is a food-derived component; therefore, it may be simultaneously present with DON in the gastrointestinal tract. The aim of this study was to explore in vitro protective effects of RES against DON-induced intestinal damage. The results showed that RES could protect DON-induced bacteria translocation because of enhanced of intestinal barrier function by restoring the DON-induced decrease in transepithelial electrical resistance and increase in paracellular permeability. Further mechanistic studies demonstrated that RES protects against DON-induced barrier dysfunction by promoting the assembly of claudin-4 in the tight junction complex. This is probably mediated through modulation of IL-6 and IL-8 secretion via mitogen-activated protein kinase-dependent pathways. Our results imply that RES can protect against DON-induced intestinal damage and that RES may be used as a novel dietary intervention strategy to reduce DON toxicity in animals/humans. PMID:27058607

  13. Protective Capacity of Resveratrol, a Natural Polyphenolic Compound, against Deoxynivalenol-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.

    PubMed

    Ling, Ka-Ho; Wan, Murphy Lam Yim; El-Nezami, Hani; Wang, Mingfu

    2016-05-16

    Contamination of food/feedstuffs by mycotoxins is a serious problem worldwide, causing severe economic losses and serious health problems in animals/humans. Deoxynivalenol (DON) is a major mycotoxin contaminant and is known to impair intestinal barrier function. Grapes and red wine are rich in polyphenols, such as resveratrol (RES), which has striking antioxidant and anti-inflammatory activities. RES is a food-derived component; therefore, it may be simultaneously present with DON in the gastrointestinal tract. The aim of this study was to explore in vitro protective effects of RES against DON-induced intestinal damage. The results showed that RES could protect DON-induced bacteria translocation because of enhanced of intestinal barrier function by restoring the DON-induced decrease in transepithelial electrical resistance and increase in paracellular permeability. Further mechanistic studies demonstrated that RES protects against DON-induced barrier dysfunction by promoting the assembly of claudin-4 in the tight junction complex. This is probably mediated through modulation of IL-6 and IL-8 secretion via mitogen-activated protein kinase-dependent pathways. Our results imply that RES can protect against DON-induced intestinal damage and that RES may be used as a novel dietary intervention strategy to reduce DON toxicity in animals/humans.

  14. Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model.

    PubMed

    Noth, Rainer; Häsler, Robert; Stüber, Eckhard; Ellrichmann, Mark; Schäfer, Heiner; Geismann, Claudia; Hampe, Jochen; Bewig, Burkhard; Wedel, Thilo; Böttner, Martina; Schreiber, Stefan; Rosenstiel, Philip; Arlt, Alexander

    2013-04-01

    Although a profound barrier dysfunction has been reported, little is known about the pathophysiological mechanism evoking gastrointestinal graft-vs.-host disease (GI-GvHD) and apparent therapeutic options. The aim of this study was to evaluate the influence of oral glutamine on the course of GI-GvHD in an acute semiallogenic graft-vs.-host disease (GvHD) in irradiated B6D2F1 mice. An acute semiallogenic GvHD was induced by intraperitoneal injection of lymphocytes from C57BL/6 mice to irradiated B6D2F1 mice. Half of the GvHD animals received oral glutamine supplementation for 6 days started at the time of lymphocyte transfer. Six days after induction of the semiallogenic GvHD, jejunum specimens were prepared. The expression of the proinflammatory cytokine TNF-α and the tight junction protein occludin was investigated by PCR. Histological changes along with the apoptotic response were evaluated and intestinal permeability was assessed. Animals with GvHD showed a strong increase in paracellular permeability as a sign of the disturbed barrier function. TNF-α expression was significantly increased and the expression of the tight junction protein occludin decreased. GvHD led to mucosal atrophy, crypt hyperplasia, crypt apoptosis, and a disintegration of the tight junctions. Glutamine-treated mice showed reduced expression of TNF-α, increased occludin expression, fewer histological changes in the jejunum, smaller number of apoptotic cells in the crypt, and reduced gastrointestinal permeability. In conclusion, oral glutamine seems to have beneficial effects on the severity of inflammatory changes in the course of GvHD and might be a therapeutic option.

  15. [Maintenance of intestinal barrier function in patients with chronic critical illness].

    PubMed

    Wu, Xiuwen; Ren, Jianan; Li, Jieshou

    2016-07-01

    The syndrome known as chronic critical illness (CCI) is defined as that critically ill patients survive their initial acute illness but go on to experience persistent organ failures necessitating prolonged intensive care. Intestinal barrier is the physical barrier that separates the internal and external environments and prevents the invasion of pathogenic antigens. Due to its pathogenesis, many CCI patients have injured intestinal barrier. Gut is the motor organ of stress responses, and gut-associated infections may initiate multiple organ dysfunction. In this way, it is important to maintain intestinal barrier of such patients. Apart from treatment for underlying diseases, resuscitation aiming at improving tissue perfusion, appropriate nutritional support, protection of normal intestinal flora, and provision of probiotics can maintain intestinal barrier of CCI patients. The maintenance and support of barrier function requires attention. PMID:27452748

  16. (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.

  17. The use of drug metabolism for prediction of intestinal permeability (dagger).

    PubMed

    Chen, Mei-Ling; Yu, Lawrence

    2009-01-01

    The Biopharmaceutics Classification System (BCS), based on the aqueous solubility and intestinal permeability of a drug substance, has been widely used to predict the extent of drug absorption during the course of pharmaceutical development. Combined with product dissolution data, this system has gained a prominent role in regulatory process to determine if a drug formulated in an immediate release solid oral dosage form qualifies for waiver of in vivo bioequivalence studies. In parallel, the Biopharmaceutics Drug Disposition Classification System (BDDCS), using aqueous solubility and drug metabolism, takes on another venue to predict overall drug disposition. It has been suggested that the matrix of drug metabolism in BDDCS can be used to substantiate the classification of permeability by BCS. A total of 51 drugs were compiled in this study to examine the use of drug metabolism for predicting permeability. All compounds were classified as high permeability based on BCS, but only 73% of the compounds were found to exhibit extensive metabolism. Lipophilicity accounts for significant metabolism of many highly permeable drugs. Fourteen (14) out of 51 drugs have poor metabolism, suggesting that high permeability as defined by BCS does not necessarily dictate extensive metabolism. The drugs that have high permeability but poor metabolism are generally hydrophilic molecules with low molecular weight and are likely to be absorbed by active transport mechanisms. Based on the present data and literature information, it seems logical to predict that the extent of absorption is mostly complete (or > or =90%) if the drug is subject to a high degree of metabolism (e.g., > or =90%). The extent of drug metabolism may be useful in supporting permeability classification under certain circumstances.

  18. Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro.

    PubMed

    Meir, Michael; Flemming, Sven; Burkard, Natalie; Bergauer, Lisa; Metzger, Marco; Germer, Christoph-Thomas; Schlegel, Nicolas

    2015-10-15

    Recent data suggest that neurotrophic factors from the enteric nervous system are involved in intestinal epithelial barrier regulation. In this context the glial cell line-derived neurotrophic factor (GDNF) was shown to affect gut barrier properties in vivo directly or indirectly by largely undefined processes in a model of inflammatory bowel disease (IBD). We further investigated the potential role and mechanisms of GDNF in the regulation of intestinal barrier functions. Immunostaining of human gut specimen showed positive GDNF staining in enteric neuronal plexus and in enterocytes. In Western blots of the intestinal epithelial cell lines Caco2 and HT29B6, significant amounts of GDNF were detected, suggesting that enterocytes represent an additional source of GDNF. Application of recombinant GDNF on Caco2 and HT29B6 cells for 24 h resulted in significant epithelial barrier stabilization in monolayers with immature barrier functions. Wound-healing assays showed a significantly faster closure of the wounded areas after GDNF application. GDNF augmented cAMP levels and led to significant inactivation of p38 MAPK in immature cells. Activation of p38 MAPK signaling by SB-202190 mimicked GDNF-induced barrier maturation, whereas the p38 MAPK activator anisomycin blocked GDNF-induced effects. Increasing cAMP levels had adverse effects on barrier maturation, as revealed by permeability measurements. However, increased cAMP augmented the proliferation rate in Caco2 cells, and GDNF-induced proliferation of epithelial cells was abrogated by the PKA inhibitor H89. Our data show that enterocytes represent an additional source of GDNF synthesis. GDNF contributes to wound healing in a cAMP/PKA-dependent manner and promotes barrier maturation in immature enterocytes cells by inactivation of p38 MAPK signaling.

  19. 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

  20. Effects of Soybean Agglutinin on Mechanical Barrier Function and Tight Junction Protein Expression in Intestinal Epithelial Cells from Piglets

    PubMed Central

    Pan, Li; Qin, Guixin; Zhao, Yuan; Wang, Jun; Liu, Feifei; Che, Dongsheng

    2013-01-01

    In this study, we sought to investigate the role of soybean agglutinin (SBA) in mediating membrane permeability and the mechanical barrier function of intestinal epithelial cells. The IPEC-J2 cells were cultured and treated with 0, 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 mg/mL SBA. Transepithelial electrical resistance (TEER) and alkaline phosphatase (AP) activity were measured to evaluate membrane permeability. The results showed a significant decrease in TEER values (p < 0.05) in a time- and dose-dependent manner, and a pronounced increase in AP activity (p < 0.05). Cell growth and cell morphology were used to evaluate the cell viability. A significant cell growth inhibition (p < 0.05) and alteration of morphology were observed when the concentration of SBA was increased. The results of western blotting showed that the expression levels of occludin and claudin-3 were decreased by 31% and 64% compared to those of the control, respectively (p < 0.05). In addition, immunofluorescence labeling indicated an obvious decrease in staining of these targets and changes in their localizations. In conclusion, SBA increased the membrane permeability, inhibited the cell viability and reduced the levels of tight junction proteins (occludin and claudin-3), leading to a decrease in mechanical barrier function in intestinal epithelial cells. PMID:24189218

  1. Effects of simulated weightlessness on the intestinal mucosal barrier of rats

    NASA Astrophysics Data System (ADS)

    Chen, Ying; Yang, Chun-min; Mao, Gao-ping; Liu, Qing-sen; Guo, Ming-zhou

    2011-07-01

    This study employed a rat tail-suspension model to investigate the effects of simulated weightlessness on the intestinal mucosal barrier. Twenty-four Wistar rats were randomly divided into control (CON), 14-day tail-suspension (SUS-14d), and 21-day tail-suspension (SUS-21d) groups ( n = 8 per group). Expression of occludin and zonula occludins-1 (ZO-1), proteins of the tight junction (TJ), in the intestinal mucosa was measured by immunohistochemical analysis, Western blotting, and mRNA fluorescent quantitation PCR. Plasma concentrations of diamine oxidase (DAO) and D-lactate were determined using an enzymatic spectrophotometric assay. Expression of occludin and ZO-1 was reduced in the SUS-14d and SUS-21d groups as compared to the CON group, with lowest expression observed in the SUS-21d group ( P < 0.01). Examination by transmission electron microscopy (TEM) of the jejunal epithelium revealed increased intercellular space, decreased TJ and desmosome densities, and destruction of microvilli in the SUS-14d and SUS-21d groups. Plasma DAO and D-lactate concentrations in the SUS-21d group were higher than those in SUS-14d group and significantly higher than those in the CON group ( P < 0.01). In all three groups, the expression of occludin and ZO-1 was found to correlate negatively with DAO ( P < 0.01) and D-lactate ( P < 0.01) concentrations. It is concluded that simulated weightless results in down-regulation of expression of TJ proteins in the rat intestinal mucosa. Simulated weightlessness is proposed to increase intestinal permeability through damage to the TJ.

  2. 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

  3. 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. PMID:23717570

  4. Bovine Colostrum Increases Pore-Forming Claudin-2 Protein Expression but Paradoxically Not Ion Permeability Possibly by a Change of the Intestinal Cytokine Milieu

    PubMed Central

    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. PMID:23717570

  5. Ethanol Impairs Intestinal Barrier Function in Humans through Mitogen Activated Protein Kinase Signaling: A Combined In Vivo and In Vitro Approach

    PubMed Central

    Elamin, Elhaseen; Masclee, Ad; Troost, Freddy; Pieters, Harm-Jan; Keszthelyi, Daniel; Aleksa, Katarina; Dekker, Jan; Jonkers, Daisy

    2014-01-01

    Background Ethanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders. Aim Since human data on effects of moderate ethanol consumption on intestinal barrier integrity and involved mechanisms are limited, the objectives of this study were to investigate effects of a single moderate ethanol dose on small and large intestinal permeability and to explore the role of mitogen activated protein kinase (MAPK) pathway as a primary signaling mechanism. Methods Intestinal permeability was assessed in 12 healthy volunteers after intraduodenal administration of either placebo or 20 g ethanol in a randomised cross-over trial. Localization of the tight junction (TJ) and gene expression, phosphorylation of the MAPK isoforms p38, ERK and JNK as indicative of activation were analyzed in duodenal biopsies. The role of MAPK was further examined in vitro using Caco-2 monolayers. Results Ethanol increased small and large intestinal permeability, paralleled by redistribution of ZO-1 and occludin, down-regulation of ZO-1 and up-regulation of myosin light chain kinase (MLCK) mRNA expression, and increased MAPK isoforms phosphorylation. In Caco-2 monolayers, ethanol increased permeability, induced redistribution of the junctional proteins and F-actin, and MAPK and MLCK activation, as indicated by phosphorylation of MAPK isoforms and myosin light chain (MLC), respectively, which could be reversed by pretreatment with either MAPK inhibitors or the anti-oxidant L-cysteine. Conclusions Administration of moderate ethanol dosage can increase both small and colon permeability. Furthermore, the data indicate a pivotal role for MAPK and its crosstalk with MLCK in ethanol-induced intestinal barrier disruption. Trial Registration ClinicalTrials.gov NCT00928733 PMID:25226407

  6. A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease.

    PubMed

    Rodríguez-Feo, Juan Antonio; Puerto, Marta; Fernández-Mena, Carolina; Verdejo, Cristina; Lara, José Manuel; Díaz-Sánchez, María; Álvarez, Emilio; Vaquero, Javier; Marín-Jiménez, Ignacio; Bañares, Rafael; Menchén, Luis

    2015-06-15

    Inflammatory bowel disease (IBD) is characterized by an impaired intestinal barrier function. We aimed to investigate the role of reticulon-4B (RTN-4B/NOGO-B), a structural protein of the endoplasmic reticulum, in intestinal barrier function and IBD. We used immunohistochemistry, confocal microscopy, real-time PCR, and Western blotting to study tissue distribution and expression levels of RTN-4B/NOGO-B in control and IBD samples from mouse and humans. We also targeted RTN-4B/NOGO-B using siRNAs in cultured human intestinal epithelial cell (IECs). Epithelial barrier permeability was assessed by transepithelial electrical resistance (TEER) measurement. RTN-4B/NOGO-B is expressed in the intestine mainly by IECs. Confocal microscopy revealed a colocalization of RTN-4B, E-cadherin, and polymerized actin fibers in tissue and cultured IECs. RTN-4B mRNA and protein expression were lower in the colon of IL-10(-/-) compared with wild-type mice. Colocalization of RTN-4B/E-cadherin/actin was reduced in the colon of IL-10(-/-) mice. Analysis of endoscopic biopsies from IBD patients showed a significant reduction of RTN-4B/NOGO-B expression in inflamed mucosa compared with control. Treatment of IECs with H2O2 reduced TEER values and triggered phosphorylation of RTN-4B in serine 107 residues as well as downregulation of RTN-4B expression. Acute RTN-4B/NOGO-B knockdown by siRNAs resulted in a decreased TEER values and reduction of E-cadherin and α-catenin expression and in the amount of F-actin-rich filaments in IECs. Epithelial RTN-4B/NOGO-B was downregulated in human and experimental IBD. RTN-4B participates in the intestinal epithelial barrier function, most likely via its involvement in E-cadherin, α-catenin expression, and actin cytoskeleton organization at sites of cell-to-cell contacts.

  7. The important role of epidermal triacylglycerol metabolism for maintenance of the skin permeability barrier function.

    PubMed

    Radner, Franz P W; Fischer, Judith

    2014-03-01

    Survival in a terrestrial, dry environment necessitates a permeability barrier for regulated permeation of water and electrolytes in the cornified layer of the skin (the stratum corneum) to minimize desiccation of the body. This barrier is formed during cornification and involves a cross-linking of corneocyte proteins as well as an extensive remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by various hydrolytic enzymes generates ceramides, cholesterol, and non-esterified fatty acids for the extracellular lipid lamellae in the stratum corneum. However, the important role of epidermal triacylglycerol (TAG) metabolism during formation of a functional permeability barrier in the skin was only recently discovered. Humans with mutations in the ABHD5/CGI-58 (α/β hydrolase domain containing protein 5, also known as comparative gene identification-58, CGI-58) gene suffer from a defect in TAG catabolism that causes neutral lipid storage disease with ichthyosis. In addition, mice with deficiencies in genes involved in TAG catabolism (Abhd5/Cgi-58 knock-out mice) or TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2, Dgat2 knock-out mice) also develop severe skin permeability barrier dysfunctions and die soon after birth due to increased dehydration. As a result of these defects in epidermal TAG metabolism, humans and mice lack ω-(O)-acylceramides, which leads to malformation of the cornified lipid envelope of the skin. In healthy skin, this epidermal structure provides an interface for the linkage of lamellar membranes with corneocyte proteins to maintain permeability barrier homeostasis. This review focuses on recent advances in the understanding of biochemical mechanisms involved in epidermal neutral lipid metabolism and the generation of a functional skin permeability barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous

  8. Gastrointestinal Symptoms and Altered Intestinal Permeability Induced by Combat Training Are Associated with Distinct Metabotypic Changes.

    PubMed

    Phua, Lee Cheng; Wilder-Smith, Clive H; Tan, Yee Min; Gopalakrishnan, Theebarina; Wong, Reuben K; Li, Xinhua; Kan, Mary E; Lu, Jia; Keshavarzian, Ali; Chan, Eric Chun Yong

    2015-11-01

    Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress-induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies. PMID:26506213

  9. 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.

  10. Effect of wild-type Shigella species and attenuated Shigella vaccine candidates on small intestinal barrier function, antigen trafficking, and cytokine release.

    PubMed

    Fiorentino, Maria; Levine, Myron M; Sztein, Marcelo B; Fasano, Alessio

    2014-01-01

    Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality worldwide. The pathogenesis of Shigella is based on the bacteria's ability to invade and replicate within the colonic epithelium, resulting in severe intestinal inflammatory response and epithelial destruction. Although the mechanisms of pathogenesis of Shigella in the colon have been extensively studied, little is known on the effect of wild-type Shigella on the small intestine and the role of the host response in the development of the disease. Moreover, to the best of our knowledge no studies have described the effects of apically administered Shigella flexneri 2a and S. dysenteriae 1 vaccine strains on human small intestinal enterocytes. The aim of this study was to assess the coordinated functional and immunological human epithelial responses evoked by strains of Shigella and candidate vaccines on small intestinal enterocytes. To model the interactions of Shigella with the intestinal mucosa, we apically exposed monolayers of human intestinal Caco2 cells to increasing bacterial inocula. We monitored changes in paracellular permeability, examined the organization of tight-junctions and the pro-inflammatory response of epithelial cells. Shigella infection of Caco2 monolayers caused severe mucosal damage, apparent as a drastic increase in paracellular permeability and disruption of tight junctions at the cell-cell boundary. Secretion of pro-inflammatory IL-8 was independent of epithelial barrier dysfunction. Shigella vaccine strains elicited a pro-inflammatory response without affecting the intestinal barrier integrity. Our data show that wild-type Shigella infection causes a severe alteration of the barrier function of a small intestinal cell monolayer (a proxy for mucosa) and might contribute (along with enterotoxins) to the induction of watery diarrhea. Diarrhea may be a mechanism by which the host attempts to eliminate harmful bacteria and transport them from the small to

  11. Protein tyrosine phosphatase σ targets apical junction complex proteins in the intestine and regulates epithelial permeability.

    PubMed

    Murchie, Ryan; Guo, Cong-Hui; Persaud, Avinash; Muise, Aleixo; Rotin, Daniela

    2014-01-14

    Protein tyrosine phosphatase (PTP)σ (PTPRS) was shown previously to be associated with susceptibility to inflammatory bowel disease (IBD). PTPσ(-/-) mice exhibit an IBD-like phenotype in the intestine and show increased susceptibility to acute models of murine colitis. However, the function of PTPσ in the intestine is uncharacterized. Here, we show an intestinal epithelial barrier defect in the PTPσ(-/-) mouse, demonstrated by a decrease in transepithelial resistance and a leaky intestinal epithelium that was determined by in vivo tracer analysis. Increased tyrosine phosphorylation was observed at the plasma membrane of epithelial cells lining the crypts of the small bowel and colon of the PTPσ(-/-) mouse, suggesting the presence of PTPσ substrates in these regions. Using mass spectrometry, we identified several putative PTPσ intestinal substrates that were hyper-tyrosine-phosphorylated in the PTPσ(-/-) mice relative to wild type. Among these were proteins that form or regulate the apical junction complex, including ezrin. We show that ezrin binds to and is dephosphorylated by PTPσ in vitro, suggesting it is a direct PTPσ substrate, and identified ezrin-Y353/Y145 as important sites targeted by PTPσ. Moreover, subcellular localization of the ezrin phosphomimetic Y353E or Y145 mutants were disrupted in colonic Caco-2 cells, similar to ezrin mislocalization in the colon of PTPσ(-/-) mice following induction of colitis. Our results suggest that PTPσ is a positive regulator of intestinal epithelial barrier, which mediates its effects by modulating epithelial cell adhesion through targeting of apical junction complex-associated proteins (including ezrin), a process impaired in IBD.

  12. Regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine.

    PubMed

    Fairstein, Moran; Swissa, Rotem; Dahan, Arik

    2013-04-01

    Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P(eff)) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F(abs)) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P(eff)-F(abs) correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine'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. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P(eff) and F(abs) is involved in its absorption. Rather, it reflects the complexity behind P(eff) when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P(eff) that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

  13. Phosphodiesterase inhibitors block the acceleration of skin permeability barrier repair by red light.

    PubMed

    Goto, Makiko; Ikeyama, Kazuyuki; Tsutsumi, Moe; Denda, Sumiko; Denda, Mitsuhiro

    2011-07-01

    We previously demonstrated that exposure to red light (550-670 nm) accelerates epidermal permeability barrier recovery after barrier disruption. Furthermore, we showed that photosensitive proteins, originally found in retina, are also expressed in epidermis. In retina, transducin and phosphodiesterase 6 play key roles in signal transmission. In this study, we evaluate the role of phosphodiesterese 6 in the acceleration by red light of epidermal permeability barrier recovery. Immunohistochemical study and reverse transcription-PCR assays confirmed the expression of both transducin and phosphodiesterase 6 in epidermal keratinocytes. Topical application of 3-isobutyl-1-methylxanthine, a non-specific phosphodiesterase inhibitor, blocked the acceleration of the barrier recovery by red light. Topical application of zaprinast, a specific inhibitor of phosphodiesterases 5 and 6, also blocked the acceleration, whereas T0156, a specific inhibitor of phosphodiesterase 5, had no effect. Red light exposure reduced the epidermal hyperplasia induced by barrier disruption under low humidity, and the effect was blocked by pretreatment with zaprinast. Our results indicate phosphodiesterase 6 is involved in the recovery-accelerating effect of red light on the disrupted epidermal permeability barrier.

  14. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

    PubMed Central

    Elias, Peter M.; Williams, Mary L.; Holleran, Walter M.; Jiang, Yan J.; Schmuth, Matthias

    2010-01-01

    Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality “drives” pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of nonpolar lipid metabolism, triglyceride accumulation in neutral lipid storage disease as a result of a lipase mutation provokes a barrier abnormality via lamellar/nonlamellar phase separation within the extracellular matrix of the stratum corneum (SC). Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate (CSO4) accumulation also produces a permeability barrier defect through lamellar/nonlamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of CSO4 as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (GD; from accumulation of glucosylceramides as a result of to β-glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies (LBs) accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis (HI). The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation. PMID:18245815

  15. Stability of multi-permeable reactive barriers for long term removal of mixed contaminants.

    PubMed

    Lee, Jai-Young; Lee, Kui-Jae; Youm, Sun Young; Lee, Mi-Ran; Kamala-Kannan, Seralathan; Oh, Byung-Taek

    2010-02-01

    The Permeable Reactive Barriers (PRBs) are relatively simple, promising technology for groundwater remediation. A PRBs consisting of two reactive barriers (zero valent iron-barrier and bio-barrier) were designed to evaluate the application and feasibility of the barriers for the removal of wide range of pollutants from synthetic water. After 470 days of Multi-PRBs column operation, the pH level in the water sample is increased from 4 to 7, whereas the oxidation reduction potential (ORP) is decreased to -180 mV. Trichloroethylene (TCE), heavy metals, and nitrate were completely removed in the zero valent iron-barrier. Ammonium produced during nitrate reduction is removed in the biologically reactive zone of the column. The results of the present study suggest that Multi-PRBs system is an effective alternate method to confine wide range of pollutants from contaminated groundwater.

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

    PubMed Central

    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

  17. Potential performance of pillared inorgano- organo bentonite for soil mix technology permeable reactive barrier (Invited)

    NASA Astrophysics Data System (ADS)

    Abunada, Z. M.; Al-Tabbaa, A.

    2013-12-01

    Modified bentonite has gained more interest for their effect in contaminant removal and environmental protection. This study is investigating the use of three different modified inorgano-organo bentonite (IOB) in soil mixing permeable reactive barrier. IOB were prepared using pillaring agents and quaternary ammonium cations (QAC) with different loading ratios. The permeabilities of compacted specimens containing IOB with two different soil types (sandy and gravelly soil) were measured for site contaminated groundwater, pure water and TEX compounds to study the potential of soil mix permeable reactive barrier (PRB). The soil permeability decreased by 1-2 order of magnitude once mixed with IOB. It also decreased by about 100 in case of TEX compound and site groundwater. The IOB was tested to remove Toluene, Ethyl-benzene, and o-Xylene (TEX) compound from model contaminated water in both batch and column test. Physical characteristics such as pore volume, porosity and specific structure in addition to level of surfactant loading were determined. Materials removal efficiency varied due to the surfactant loading, soil type and contaminant molecular weight. Sorption isotherm showed that the adsorbates preference increased in the order of T>E>X in all IOB types. Maximum TEX compound sorptive capacity varied also due to soil type with the highest was 86.89% 93.19% and 90.2% for T,E,X respectively on sandy soil. Key words: Inorgano-organo bentonite, permeability, reactive barrier, soil mix, sorption

  18. 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

  19. 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).

  20. Assessment of intestinal permeability: enzymatic determination of urinary mannitol, raffinose, sucrose and lactose on Hitachi analyzer.

    PubMed

    Hessels, Jan; Snoeyink, Ellen J M; Platenkamp, Antonius J; Voortman, Gerrit; Steggink, Jan; Eidhof, Harry H M

    2003-01-01

    The sugar absorption test is the usual test for measurement of intestinal permeability. After intestinal absorption of probe sugars the subsequently excreted sugars are measured in urine. We have developed four enzymatic methods for the measurement of the urinary concentration of the probe sugars mannitol, raffinose, lactose and sucrose. Mannitol, lactose and sucrose are directly measured on Hitachi 917 using mannitol dehydrogenase, beta-galactosidase and invertase, respectively, as enzyme reagents. Raffinose measurement needs a three hours preincubation with alpha-galactosidase, after which the liberated sucrose is measured. The analytical performances such as within- and between-run precision, linearity, lowest detection limit, interference of other sugars and comparison with a gas chromatographic method are described for the four methods. These methods are accurate an can easily be performed in any clinical laboratory.

  1. A framework for understanding semi-permeable barrier effects on migratory ungulates

    USGS Publications Warehouse

    Sawyer, Hall; Kauffman, Matthew J.; Middleton, Arthur D.; Morrison, Thomas A.; Nielson, Ryan M.; Wyckoff, Teal B.

    2013-01-01

    1. Impermeable barriers to migration can greatly constrain the set of possible routes and ranges used by migrating animals. For ungulates, however, many forms of development are semi-permeable, and making informed management decisions about their potential impacts to the persistence of migration routes is difficult because our knowledge of how semi-permeable barriers affect migratory behaviour and function is limited. 2. Here, we propose a general framework to advance the understanding of barrier effects on ungulate migration by emphasizing the need to (i) quantify potential barriers in terms that allow behavioural thresholds to be considered, (ii) identify and measure behavioural responses to semi-permeable barriers and (iii) consider the functional attributes of the migratory landscape (e.g. stopovers) and how the benefits of migration might be reduced by behavioural changes. 3. We used global position system (GPS) data collected from two subpopulations of mule deer Odocoileus hemionus to evaluate how different levels of gas development influenced migratory behaviour, including movement rates and stopover use at the individual level, and intensity of use and width of migration route at the population level. We then characterized the functional landscape of migration routes as either stopover habitat or movement corridors and examined how the observed behavioural changes affected the functionality of the migration route in terms of stopover use. 4. We found migratory behaviour to vary with development intensity. Our results suggest that mule deer can migrate through moderate levels of development without any noticeable effects on migratory behaviour. However, in areas with more intensive development, animals often detoured from established routes, increased their rate of movement and reduced stopover use, while the overall use and width of migration routes decreased. 5. Synthesis and applications. In contrast to impermeable barriers that impede animal movement

  2. Chitosan-modified porous silicon microparticles for enhanced permeability of insulin across intestinal cell monolayers.

    PubMed

    Shrestha, Neha; Shahbazi, Mohammad-Ali; Araújo, Francisca; Zhang, Hongbo; Mäkilä, Ermei M; Kauppila, Jussi; Sarmento, Bruno; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2014-08-01

    Porous silicon (PSi) based particulate systems are emerging as an important drug delivery system due to its advantageous properties such as biocompatibility, biodegradability and ability to tailor the particles' physicochemical properties. Here, annealed thermally hydrocarbonized PSi (AnnTHCPSi) and undecylenic acid modified AnnTHCPSi (AnnUnTHCPSi) microparticles were developed as a PSi-based platform for oral delivery of insulin. Chitosan (CS) was used to modify the AnnUnTHCPSi microparticles to enhance the intestinal permeation of insulin. Surface modification with CS led to significant increase in the interaction of PSi microparticles with Caco-2/HT-29 cell co-culture monolayers. Compared to pure insulin, the CS-conjugated microparticles significantly improved the permeation of insulin across the Caco-2/HT-29 cell monolayers, with ca. 20-fold increase in the amount of insulin permeated and ca. 7-fold increase in the apparent permeability (P(app)) value. Moreover, among all the investigated particles, the CS-conjugated microparticles also showed the highest amount of insulin associated with the mucus layer and the intestinal Caco-2 cells and mucus secreting HT-29 cells. Our results demonstrate that CS-conjugated AnnUnTHCPSi microparticles can efficiently enhance the insulin absorption across intestinal cells, and thus, they are promising microsystems for the oral delivery of proteins and peptides across the intestinal cell membrane.

  3. Dexou low pH plume baseline permeable reactive barrier options

    SciTech Connect

    Phifer, M.A.

    2000-06-20

    The current Environmental Restoration Department (ERD) Permeable Reactive Barrier (PRB) baseline configuration consists of a limestone trench and a granular cast iron trench in series. This report provides information relative to the use of PRB technology for the remediation of the D-Area low pH groundwater plumes.

  4. CHROMIUM REMOVAL PROCESSES DURING GROUNDWATER REMEDIATION BY A ZEROVALENT IRON PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    Solid-phase associations of chromium were examined in core materials collected from a full-scale, zerovalent iron, permeable reactive barrier (PRB) at the U.S. Coast Guard Support Center located near Elizabeth City (NC). The PRB was installed in 1996 to treat groundwater contami...

  5. Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

    ERIC Educational Resources Information Center

    Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

    2004-01-01

    Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

  6. A clay permeable reactive barrier to remove Cs-137 from groundwater: Column experiments.

    PubMed

    De Pourcq, K; Ayora, C; García-Gutiérrez, M; Missana, T; Carrera, J

    2015-11-01

    Clay minerals are reputed sorbents for Cs-137 and can be used as a low-permeability material to prevent groundwater flow. Therefore, clay barriers are employed to seal Cs-137 polluted areas and nuclear waste repositories. This work is motivated by cases where groundwater flow cannot be impeded. A permeable and reactive barrier to retain Cs-137 was tested. The trapping mechanism is based on the sorption of cesium on illite-containing clay. The permeability of the reactive material is provided by mixing clay on a matrix of wood shavings. Column tests combined with reactive transport modeling were performed to check both reactivity and permeability. Hydraulic conductivity of the mixture (10(-4) m/s) was sufficient to ensure an adequate hydraulic performance of an eventual barrier excavated in most aquifers. A number of column experiments confirmed Cs retention under different flow rates and inflow solutions. A 1D reactive transport model based on a cation-exchange mechanism was built. It was calibrated with batch experiments for high concentrations of NH4+ and K+ (the main competitors of Cs in the exchange positions). The model predicted satisfactorily the results of the column experiments. Once validated, it was used to investigate the performance and duration of a 2 m thick barrier under different scenarios (flow, clay content, Cs-137 and K concentration).

  7. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: LESSONS LEARNED, FUTURE DIRECTIONS

    EPA Science Inventory

    Recently, a synthesis of research findings by EPA has been prepared and presented in an EPA report titled Capstone Report on the Application, Monitoring, and Performance of Permeable Reactive Barriers for Ground-Water Remediation (EPA/600/R-03/045 a,b). Another report has also be...

  8. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    This research brief presents findings over the past four years at two sites where detailed investigations by the U.S. Environmental Protection Agency (U.S. EPA) have focused on the long-term performance of PRBs under a Tri-Agency Permeable Reactive Barrier Initiative (TRI). This ...

  9. A Tracer Test to Characterize Treatment of TCE in a Permeable Reactive Barrier

    EPA Science Inventory

    A tracer test was conducted to characterize the flow of ground water surrounding a permeable reactive barrier constructed with plant mulch (a biowall) at the OU-1 site on Altus Air Force Base, Oklahoma. This biowall is intended to intercept and treat ground water contaminated by ...

  10. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE: A TRI-AGENCY INITIATIVE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  11. A clay permeable reactive barrier to remove Cs-137 from groundwater: Column experiments.

    PubMed

    De Pourcq, K; Ayora, C; García-Gutiérrez, M; Missana, T; Carrera, J

    2015-11-01

    Clay minerals are reputed sorbents for Cs-137 and can be used as a low-permeability material to prevent groundwater flow. Therefore, clay barriers are employed to seal Cs-137 polluted areas and nuclear waste repositories. This work is motivated by cases where groundwater flow cannot be impeded. A permeable and reactive barrier to retain Cs-137 was tested. The trapping mechanism is based on the sorption of cesium on illite-containing clay. The permeability of the reactive material is provided by mixing clay on a matrix of wood shavings. Column tests combined with reactive transport modeling were performed to check both reactivity and permeability. Hydraulic conductivity of the mixture (10(-4) m/s) was sufficient to ensure an adequate hydraulic performance of an eventual barrier excavated in most aquifers. A number of column experiments confirmed Cs retention under different flow rates and inflow solutions. A 1D reactive transport model based on a cation-exchange mechanism was built. It was calibrated with batch experiments for high concentrations of NH4+ and K+ (the main competitors of Cs in the exchange positions). The model predicted satisfactorily the results of the column experiments. Once validated, it was used to investigate the performance and duration of a 2 m thick barrier under different scenarios (flow, clay content, Cs-137 and K concentration). PMID:26197347

  12. Nanosized iron based permeable reactive barriers for nitrate removal - Systematic review

    NASA Astrophysics Data System (ADS)

    Araújo, Rui; Castro, Ana C. Meira; Santos Baptista, João; Fiúza, António

    2016-08-01

    It is unquestionable that an effective decision concerning the usage of a certain environmental clean-up technology should be conveniently supported. Significant amount of scientific work focussing on the reduction of nitrate concentration in drinking water by both metallic iron and nanomaterials and their usage in permeable reactive barriers has been worldwide published over the last two decades. This work aims to present in a systematic review of the most relevant research done on the removal of nitrate from groundwater using nanosized iron based permeable reactive barriers. The research was based on scientific papers published between 2004 and June 2014. It was performed using 16 combinations of keywords in 34 databases, according to PRISMA statement guidelines. Independent reviewers validated the selection criteria. From the 4161 records filtered, 45 met the selection criteria and were selected to be included in this review. This study's outcomes show that the permeable reactive barriers are, indeed, a suitable technology for denitrification and with good performance record but the long-term impact of the use of nanosized zero valent iron in this remediation process, in both on the environment and on the human health, is far to be conveniently known. As a consequence, further work is required on this matter, so that nanosized iron based permeable reactive barriers for the removal of nitrate from drinking water can be genuinely considered an eco-efficient technology.

  13. GROUND WATER REMEDIATION RESEARCH: PERMEABLE REACTIVE BARRIERS AND SOURCE ZONE REMEDIATION

    EPA Science Inventory

    An overview of ground water remediation research conducted at the Subsurface Protection and Remediation Division is provided. The focus of the overview is on Permeable Reactive Barriers for treatment of organic and inorganic contaminants and remediation of DNAPL source zones.

  14. AMELIORATION OF ACID MINE DRAINAGE USING REACTIVE MIXTURES IN PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    The generation and release of acidic drainage from mine wastes is an environmental problem of international scale. The use of zero-valent iron and/or iron mixtures in subsurface Permeable Reactive Barriers (PRB) presents a possible passive alternative for remediating acidic grou...

  15. SPATIAL DISTRIBUTION OF CARBON AND SULFUR PRECIPITATING WITHIN PERMEABLE REACTIVE BARRIERS: DEVELOPMENT OF ANALYTICAL METHODS

    EPA Science Inventory

    A permeable reactive barrier (PRB) is a wall of porous reactive material placed in the path of a dissolved contaminant plume for the purpose of removing contaminants from ground water. Chemical processes within these reactive materials remove both inorganic and organic contamina...

  16. Intestinal permeability to 99mTc-diethylenetriaminopentaacetic acid in inflammatory bowel disease

    SciTech Connect

    Casellas, F.; Aguade, S.; Soriano, B.; Accarino, A.; Molero, J.; Guarner, L.

    1986-09-01

    Intestinal permeability in inflammatory bowel disease and its relation to periods of disease activity has been investigated by measuring the urinary excretion of DTPA labeled with 99mTc. Urine excretion in 10 control subjects was 2.7 +/- 1% of the test dose. Twelve patients with ulcerative colitis excreted 5.08 +/- 1.6% in remission, 10.61 +/- 2% during periods of mild activity, 19.41 +/- 0.9% during moderate activity, and 15.41 +/- 6.3% with severe activity. Sixteen patients with Crohn's disease excreted 5.7 +/- 1.9% in remission, 8.47 +/- 2.8% during mild activity of the disease, and 14.29 +/- 5.8% during moderate activity. No differences were observed between ulcerative colitis and Crohn's disease, or between ileal and colonic forms of Crohn's disease. Excretion in remission was significantly greater than in control subjects and there was a correlation between excretion and disease activity. In serial determinations done in seven patients we found that urine excretion of the test substance correlated with disease activity. We also studied DTPA excretion in 10 cases with gastric or duodenal ulcer (2.28 +/- 1.4%), six cases of acute gastroenteritis (4.87 +/- 3.1%) and nine cases with other intestinal diseases (3.6 +/- 1.1%). In all these cases, DTPA excretion was lower than in inflammatory bowel disease. Our results show that the urinary excretion of DTPA is a simple test that measures accurately the degree of activity of inflammatory bowel disease. The test is useful in Crohn's disease as well as in ulcerative colitis, and detects intestinal permeability abnormalities even in clinical remission. Significantly lower excretions are found in other intestinal diseases. The test may be recommended as a screening test for use in clinical practice.

  17. 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.

  18. Intestinal Diffusion Barrier: Unstirred Water Layer or Membrane Surface Mucous Coat?

    NASA Astrophysics Data System (ADS)

    Smithson, Kenneth W.; Millar, David B.; Jacobs, Lucien R.; Gray, Gary M.

    1981-12-01

    The dimensions of the small intestinal diffusion barrier interposed between luminal nutrients and their membrane receptors were determined from kinetic analysis of substrate hydrolysis by integral surface membrane enzymes. The calculated equivalent thickness of the unstirred water layer was too large to be compatible with the known dimensions of rat intestine. The discrepancy could be reconciled by consideration of the mucous coat overlying the intestinal surface membrane. Integral surface membrane proteins could not be labeled by an iodine-125 probe unless the surface coat was first removed. The mucoprotein surface coat appears to constitute an important diffusion barrier for nutrients seeking their digestive and transport sites on the outer intestinal membrane.

  19. Measurement of blood-brain barrier permeability with positron emission tomography and (68Ga)EDTA

    SciTech Connect

    Kessler, R.M.; Goble, J.C.; Bird, J.H.; Girton, M.E.; Doppman, J.L.; Rapoport, S.I.; Barranger, J.A.

    1984-09-01

    Positron emission tomography (PET) was employed to examine time-dependent changes in blood-brain barrier (BBB) permeability to (68Ga)ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product (PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to (68Ga)EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.

  20. Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis

    PubMed Central

    Li, Ming; Liang, Pin; Li, Zhenzhen; Wang, Ying; Zhang, Guobin; Gao, Hongwei; Wen, Shu; Tang, Li

    2015-01-01

    Fecal microbiota transplantation (FMT) is a promising therapy, despite some reports of adverse side effects. Bacterial consortia transplantation (BCT) for targeted restoration of the intestinal ecosystem is considered a relatively safe and simple procedure. However, no systematic research has assessed the effects of FMT and BCT on immune responses of intestinal mucosal barrier in patients. We conducted complementary studies in animal models on the effects of FMT and BCT, and provide recommendations for improving the clinical outcomes of these treatments. To establish the dysbiosis model, male BALB/c mice were treated with ceftriaxone intra-gastrically for 7 days. After that, FMT and BCT were performed on ceftriaxone-treated mice for 3 consecutive days to rebuild the intestinal ecosystem. Post-FMT and post-BCT changes of the intestinal microbial community and mucosal barrier functions were investigated and compared. Disruption of intestinal microbial homeostasis impacted the integrity of mucosal epithelial layer, resulting in increased intestinal permeability. These outcomes were accompanied by overexpression of Muc2, significant decrease of SIgA secretion, and overproduction of defensins and inflammatory cytokines. After FMT and BCT, the intestinal microbiota recovered quickly, this was associated with better reconstruction of mucosal barriers and re-establishment of immune networks compared with spontaneous recovery (SR). Although based on a short-term study, our results suggest that FMT and BCT promote the re-establishment of intestinal microbial communities in mice with antibiotic-induced dysbiosis, and contribute to the temporal and spatial interactions between microbiota and mucosal barriers. The effects of BCT are comparable to that of FMT, especially in normalizing the intestinal levels of Muc2, SIgA, and defensins. PMID:26217323

  1. Intestinal mucosa permeability following oral insulin delivery using core shell corona nanolipoparticles.

    PubMed

    Li, Xiuying; Guo, Shiyan; Zhu, Chunliu; Zhu, Quanlei; Gan, Yong; Rantanen, Jukka; Rahbek, Ulrik Lytt; Hovgaard, Lars; Yang, Mingshi

    2013-12-01

    Chitosan nanoparticles (NC) have excellent capacity for protein entrapment, favorable epithelial permeability, and are regarded as promising nanocarriers for oral protein delivery. Herein, we designed and evaluated a class of core shell corona nanolipoparticles (CSC) to further improve the absorption through enhanced intestinal mucus penetration. CSC contains chitosan nanoparticles as a core component and pluronic F127-lipid vesicles as a shell with hydrophilic chain and polyethylene oxide PEO as a corona. These particles were developed by hydration of a dry pluronic F127-lipid film with NC suspensions followed by extrusion. Insulin nested inside CSC was well protected from enzymatic degradation. Compared with NC, CSC exhibited significantly higher efficiency of mucosal penetration and, consequently, higher cellular internalization of insulin in mucus secreting E12 cells. The cellular level of insulin after CSC treatment was 36-fold higher compared to treatment with free insulin, and 10-fold higher compared to NC. CSC significantly facilitated the permeation of insulin across the ileum epithelia, as demonstrated in an ex vivo study and an in vivo absorption study. CSC pharmacological studies in diabetic rats showed that the hypoglycemic effects of orally administrated CSC were 2.5-fold higher compared to NC. In conclusion, CSC is a promising oral protein delivery system to enhance the stability, intestinal mucosal permeability, and oral absorption of insulin.

  2. 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...

  3. Effect of cryoprotectants for maintaining drug permeability barriers in porcine buccal mucosa.

    PubMed

    Marxen, Eva; Axelsen, Mary Carlos; Pedersen, Anne Marie Lynge; Jacobsen, Jette

    2016-09-10

    Ex vivo drug permeation studies are useful for early screening of drug candidates for buccal delivery. However, it is not always feasible to obtain fresh tissue for each experiment. Therefore, a method for storing excised tissue for later use is needed. The purpose of this study was to determine if permeability barriers for small molecules (nicotine and diazepam) were maintained after freezing porcine buccal mucosa with cryoprotectants to -80°C. Combinations of dimethyl sulfoxide, bovine serum albumin, glycerol and sucrose were used as cryoprotectants. The permeability of nicotine and diazepam across fresh or frozen/thawed tissue was determined using modified Ussing chambers. Haematoxylin-eosin stained tissue sections for histology were prepared. The permeability of nicotine across tissue frozen without cryoprotectants was significantly higher compared to tissue frozen with cryoprotectants or fresh tissue. Freezing with or without cryoprotectants did not significantly affect the flux of diazepam compared to fresh tissue. Only minor histological changes were seen in frozen/thawed porcine buccal mucosa compared to fresh tissue. In conclusion, permeability barriers for nicotine and diazepam were preserved after freezing with any of the combinations of cryoprotectants; however, the barrier may be damaged when freezing without cryoprotectants. PMID:27426107

  4. Use of jet grouting to create a low permeability horizontal barrier below an incinerator ash landfill

    SciTech Connect

    Furth, A.J.; Burke, G.K.; Deutsch, W.L. Jr.

    1997-12-31

    The City of Philadelphia`s Division of Aviation (DOA) has begun construction of a new commuter runway, designated as Runway 8-26, at the Philadelphia International Airport. A portion of this runway will be constructed over a former Superfund site known as the Enterprise Avenue Landfill, which for many years was used to dispose of solid waste incinerator ash and other hazardous materials. The site was clay capped in the 1980`s, but in order for the DOA to use the site, additional remediation was needed to meet US EPA final closure requirements. One component of the closure plan included installation of a low permeability horizontal barrier above a very thin (approximately 0.61 to 0.91 meters) natural clay stratum which underlies an approximately 1020 m{sup 2} area of the landfill footprint so as to insure that a minimum 1.52 meter thick low permeability barrier exists beneath the entire 150,000 m{sup 2} landfill. The new barrier was constructed using jet grouting techniques to achieve remote excavation and replacement of the bottom 0.91 meters of the waste mass with a low permeability grout. The grout was formulated to meet the low permeability, low elastic modulus and compressive strength requirements of the project design. This paper will discuss the advantages of using jet grouting for the work and details the development of the grout mixture, modeling of the grout zone under load, field construction techniques, performance monitoring and verification testing.

  5. Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model.

    PubMed

    Arseneault-Bréard, Jessica; Rondeau, Isabelle; Gilbert, Kim; Girard, Stéphanie-Anne; Tompkins, Thomas A; Godbout, Roger; Rousseau, Guy

    2012-06-01

    Myocardial infarction (MI) in rats is accompanied by apoptosis in the limbic system and a behavioural syndrome similar to models of depression. We have already shown that probiotics can reduce post-MI apoptosis and designed the present study to determine if probiotics can also prevent post-MI depressive behaviour. We also tested the hypothesis that probiotics achieve their central effects through changes in the intestinal barrier. MI was induced in anaesthetised rats via 40-min transient occlusion of the left anterior coronary artery. Sham rats underwent the same surgical procedure without actual coronary occlusion. For 7 d before MI and between the seventh post-MI day and euthanasia, half the MI and sham rats were given one billion live bacterial cells of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 per d dissolved in water, while the remaining animals received only the vehicle (maltodextrin). Depressive behaviour was evaluated 2 weeks post-MI in social interaction, forced swimming and passive avoidance step-down tests. Intestinal permeability was evaluated by oral administration with fluorescein isothiocyanate-dextran, 4 h before euthanasia. MI rats displayed less social interaction and impaired performance in the forced swimming and passive avoidance step-down tests compared to the sham controls (P < 0·05). Probiotics reversed the behavioural effects of MI (P < 0·05), but did not alter the behaviour of sham rats. Intestinal permeability was increased in MI rats and reversed by probiotics. In conclusion, L. helveticus R0052 and B. longum R0175 combination interferes with the development of post-MI depressive behaviour and restores intestinal barrier integrity in MI rats.

  6. Human in vivo regional intestinal permeability: importance for pharmaceutical drug development.

    PubMed

    Lennernäs, Hans

    2014-01-01

    Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silico methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration-time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silico biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (Peff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics models with improved predictive accuracy. The Peff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values.

  7. Research Advance in Intestinal Mucosal Barrier and Pathogenesis of Crohn's Disease.

    PubMed

    Wang, Kuan; Wu, Lu-Yi; Dou, Chuan-Zi; Guan, Xin; Wu, Huan-Gan; Liu, Hui-Rong

    2016-01-01

    To date, the etiology and pathogenesis of Crohn's disease (CD) have not been fully elucidated. It is widely accepted that genetic, immune, and environment factors are closely related to the development of CD. As an important defensive line for human body against the environment, intestinal mucosa is able to protect the homeostasis of gut bacteria and alleviate the intestinal inflammatory and immune response. It is evident that the dysfunction of intestinal mucosa barriers plays a crucial role in CD initiation and development. Yet researches are insufficient on intestinal mucosal barrier's action in the prevention of CD onset. This article summarizes the research advances about the correlations between the disorders of intestinal mucosal barriers and CD. PMID:27651792

  8. Research Advance in Intestinal Mucosal Barrier and Pathogenesis of Crohn's Disease

    PubMed Central

    Dou, Chuan-zi; Guan, Xin; Wu, Huan-gan

    2016-01-01

    To date, the etiology and pathogenesis of Crohn's disease (CD) have not been fully elucidated. It is widely accepted that genetic, immune, and environment factors are closely related to the development of CD. As an important defensive line for human body against the environment, intestinal mucosa is able to protect the homeostasis of gut bacteria and alleviate the intestinal inflammatory and immune response. It is evident that the dysfunction of intestinal mucosa barriers plays a crucial role in CD initiation and development. Yet researches are insufficient on intestinal mucosal barrier's action in the prevention of CD onset. This article summarizes the research advances about the correlations between the disorders of intestinal mucosal barriers and CD.

  9. Research Advance in Intestinal Mucosal Barrier and Pathogenesis of Crohn's Disease

    PubMed Central

    Dou, Chuan-zi; Guan, Xin; Wu, Huan-gan

    2016-01-01

    To date, the etiology and pathogenesis of Crohn's disease (CD) have not been fully elucidated. It is widely accepted that genetic, immune, and environment factors are closely related to the development of CD. As an important defensive line for human body against the environment, intestinal mucosa is able to protect the homeostasis of gut bacteria and alleviate the intestinal inflammatory and immune response. It is evident that the dysfunction of intestinal mucosa barriers plays a crucial role in CD initiation and development. Yet researches are insufficient on intestinal mucosal barrier's action in the prevention of CD onset. This article summarizes the research advances about the correlations between the disorders of intestinal mucosal barriers and CD. PMID:27651792

  10. Epidermal Permeability Barrier Recovery Is Delayed in Vitiligo-Involved Sites

    PubMed Central

    Liu, J.; Man, W.Y.; Lv, C.Z.; Song, S.P.; Shi, Y.J.; Elias, P.M.; Man, M.Q.

    2010-01-01

    Background/Objectives Prior studies have demonstrated that both the skin surface pH and epidermal permeability barrier function vary with skin pigmentation types. Although melanin deficiency is the main feature of vitiligo, alterations in cutaneous biophysical properties in vitiligo have not yet been well defined. In the present study, stratum corneum (SC) hydration, the skin surface pH and epidermal permeability barrier function in vitiligo were evaluated. Methods A total of 30 volunteers with vitiligo comprising 19 males and 11 females aged 13–51 years (mean age: 27.91 ± 2.06 years) were enrolled in this study. The skin surface pH, SC hydration, melanin/erythema index and transepidermal water loss (TEWL) were measured by respective probes connected to a Courage-Khazaka MPA5. SC integrity was determined by measuring the TEWL following each D-Squame application. The barrier recovery rate was assessed at 5 h following barrier disruption by repeated tape stripping. Results In addition to SC hydration, both melanin and erythema index were significantly lower in vitiligo lesions than in contralateral, nonlesional sites, while no difference in skin surface pH between vitiligo-involved and uninvolved areas was observed. In addition, neither the basal TEWL nor SC integrity in the involved areas differed significantly from that in the uninvolved areas. However, barrier recovery in vitiligo-involved sites was significantly delayed in comparison with uninvolved sites (40.83 ± 5.39% vs. 58.30 ± 4.71%; t = 2.441; p < 0.02). Conclusion Barrier recovery following tape stripping of the SC is delayed in vitiligo. Therefore, improvement in epidermal permeability barrier function may be an important unrecognized factor to be considered in treating patients with vitiligo. PMID:20185976

  11. Induced phytoextraction/soil washing of lead using biodegradable chelate and permeable barriers.

    PubMed

    Kos, Bostjan; Lestan, Domen

    2003-02-01

    Chelate-induced remediation has been proposed as an effective tool for the extraction of lead (Pb) from contaminated soils by plants. However, side-effects, mainly mobilization and leaching of Pb, raise environmental concerns. Biodegradable, synthetic organic chelate ethylenediaminedisuccinic acid (EDDS), and commonly used ethylenedimanetetraacetic acid (EDTA) were used for induced phytoextraction with a test plant Brassica rapa and in situ washing of soil contaminated with 1350 mg/kg of Pb. Horizontal permeable barriers were placed 20 cm deep in soil columns and tested for their ability to prevent leaching of Pb. The reactive materials in the barriers were nutrient enriched vermiculite, peat or agricultural hydrogel, and apatite. EDTA and EDDS addition increased Pb concentrations in the test plant by 158 and 89 times compared to the control, to 817 and 464 mg/kg, respectively. In EDTA treatments, approximately 25% or more of total initial soil Pb was leached in single cycle of chelate addition. In EDDS treatments, 20% of the initial Pb was leached from columns with no barrier, while barriers with vermiculite or hydrogel and apatite decreased leaching by more than 60 times, to 0.35%. 11.6% of total initial Pb was washed from the soil above the barrier with vermiculite and apatite, where almost all leached Pb was accumulated. Results indicate that use of biodegradable chelate EDDS and permeable barriers may lead to environmentally safe induced Pb phytoextraction and in situ washing of Pb.

  12. Permeable Adsorptive Barrier (PAB) for the remediation of groundwater simultaneously contaminated by some chlorinated organic compounds.

    PubMed

    Erto, A; Bortone, I; Di Nardo, A; Di Natale, M; Musmarra, D

    2014-07-01

    In this paper, a Permeable Reactive Barrier (PRB) made with activated carbon, namely a Permeable Adsorptive Barrier (PAB), is put forward as an effective technique for the remediation of aquifers simultaneously contaminated by some chlorinated organic compounds. A design procedure, based on a computer code and including different routines, is presented as a tool to accurately describe mass transport within the aquifer and adsorption/desorption phenomena occurring inside the barrier. The remediation of a contaminated aquifer near a solid waste landfill in the district of Napoli (Italy), where Tetrachloroethylene (PCE) and Trichloroethylene (TCE) are simultaneously present, is considered as a case study. A complete hydrological and geotechnical site characterization, as well as a number of dedicated adsorption laboratory tests for the determination of activated carbon PCE/TCE adsorption capacity in binary systems, are carried out to support the barrier design. By means of a series of numerical simulations it is possible to determine the optimal barrier location, orientation and dimensions. PABs appear to be an effective remediation tool for the in-situ treatment of an aquifer contaminated by PCE and TCE simultaneously, as the concentration of both compounds flowing out of the barrier is everywhere lower than the regulatory limits on groundwater quality.

  13. Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives.

    PubMed Central

    Munkholm, P; Langholz, E; Hollander, D; Thornberg, K; Orholm, M; Katz, K D; Binder, V

    1994-01-01

    Increased intestinal permeability in patients with Crohn's disease and their first degree relatives has been proposed as an aetiological factor. The nine hour overnight urinary excretion of polyethyleneglycol-400 (PEG-400) and three inert sugars (lactulose, l-rhamnose, and mannitol) was used to test the permeation in 47 patients with Crohn's disease of whom 18 had at least one first degree relative with inflammatory bowel disease (2BD) and 52 patients with ulcerative colitis of whom 16 had at least one first degree relative with IBD. A total of 17 first degree relatives with IBD and 56 healthy first degree relatives were included. Thirty one healthy subjects not related to patients with IBD served as controls. No significant differences in PEG-400 permeation were found between the groups of patients, relatives, and controls, or between diseased and healthy relatives. The permeability to lactulose, rhamnose, and mannitol similarly did not differ between the three groups. This study challenges the previously reported findings of increased PEG-400 permeation in patients with Crohn's disease and in their healthy and diseased first degree relatives. There was no increase in permeability in a similar group of ulcerative colitis patients and their families. PMID:8307453

  14. Ascorbic Acid may Exacerbate Aspirin-Induced Increase in Intestinal Permeability.

    PubMed

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

    2015-09-01

    Ascorbic acid in combination with aspirin has been used to prevent aspirin-induced oxidative GI damage. We aimed to determine whether ascorbic acid reduces or prevents aspirin-induced changes in intestinal permeability over a 6-hr period using saccharidic probes mannitol and lactulose. The effects of administration of 600 mg aspirin alone, 500 mg ascorbic acid alone and simultaneous dosage of both agents were compared in a cross-over study in 28 healthy female volunteers. These effects were also compared with that of a placebo. The ability of ascorbic acid to mitigate the effects of aspirin when administered either half an hour before or after dosage with aspirin was also assessed in 19 healthy female volunteers. The excretion of lactulose over the 6-hr period was augmented after consumption of either aspirin or ascorbic acid compared with that after consumption of placebo. Dosage with ascorbic acid alone augmented the excretion of lactulose more than did aspirin alone. Simultaneous dosage with both agents augmented the excretion of lactulose in an additive manner. The timing of dosage with ascorbic acid in relation to that with aspirin had no significant effect on the excretion of the two sugars. These findings indicate that ascorbic acid does not prevent aspirin-induced increase in gut permeability rather that both agents augment it to a similar extent. The additive effect on simultaneous dosage with both agents in augmenting the absorption of lactulose suggests that each influences paracellular permeability by different pathways.

  15. New treatments for restoring impaired epidermal barrier permeability: skin barrier repair creams.

    PubMed

    Draelos, Zoe Diana

    2012-01-01

    Skin health depends on an intact barrier composed of protein-rich corneocytes surrounded by the lamellar intercellular lipids. This barrier provides waterproof protection for the body, preventing infection, regulating electrolyte balance, maintaining body temperature, and providing a mechanism for sensation. Damage to the skin barrier results in skin disease that can be treated by a variety of externally applied substances, such as ceramides, hyaluronic acid, licorice extracts, dimethicone, petrolatum, and paraffin wax. These substances are found in moisturizers that are sold as cosmetics and in prescriptions as 510(k) devices. This contribution examines the formulation and effect of skin barrier creams.

  16. 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.

  17. Localization of epidermal sphingolipid synthesis and serine palmitoyl transferase activity: alterations imposed by permeability barrier requirements.

    PubMed

    Holleran, W M; Gao, W N; Feingold, K R; Elias, P M

    1995-01-01

    Sphingolipids, the predominant lipid species in mammalian stratum corneum play, a central role in permeability barrier homeostatis. Prior studies have shown that the epidermis synthesizes abundant sphingolipids, a process regulated by barrier requirements, and that inhibition of sphingolipid synthesis interferes with barrier homeostasis. To investigate further the relationship between epidermal sphingolipid metabolism and barrier function, we localized sphingolipid synthetic activity in murine epidermis under basal conditions, and following acute (acetone treatment) or chronic (essential fatty acid deficiency, EFAD) barrier perturbation, using dithiothreitol and/or the staphylococcal epidermolytic toxin to isolate the lower from the outer epidermis. Under basal conditions, both the activity of serine palmitoyl transferase (SPT), the rate-limiting enzyme of sphingolipid synthesis, and the rates of 3H-H2O incorporation into sphingolipids were nearly equivalent in the lower and the outer epidermis. Following acute barrier perturbation, SPT activity increased significantly in both the lower (35%; P < 0.05) and the outer epidermal layers (60%; P < 0.01). The rates of 3H-H2O incorporation into each major sphingolipid family, including ceramides, glucosylceramides and sphingomyelin, increased significantly in both the lower and the outer epidermis of treated flanks after acute barrier disruption. Finally, SPT activity was modestly elevated (20%; P < 0.01) in the lower but not in the outer epidermis of EFAD animals. These studies demonstrate the ability of both lower and outer epidermal cells to generate sphingolipids, and that permeability barrier homeostatic mechanisms appear to differentially regulate SPT activity and sphingolipid synthesis in the lower and the outer epidermis in response to acute and chronic barrier perturbation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7598529

  18. Topical application of TRPM8 agonists accelerates skin permeability barrier recovery and reduces epidermal proliferation induced by barrier insult: role of cold-sensitive TRP receptors in epidermal permeability barrier homoeostasis.

    PubMed

    Denda, Mitsuhiro; Tsutsumi, Moe; Denda, Sumiko

    2010-09-01

    TRPA1 and TRPM8 receptors are activated at low temperature (A1: below 17 degrees C and M8: below 22 degrees C). Recently, we observed that low temperature (below 22 degrees C) induced elevation of intracellular calcium in keratinocytes. Moreover, we demonstrated that topical application of TRPA1 agonists accelerated the recovery of epidermal permeability barrier function after disruption. In this study, we examined the effect of topical application of TRPM8 modulators on epidermal permeability barrier homoeostasis. Immunohistochemical study and RT-PCR confirmed the expression of TRPM8 or TRPM8-like protein in epidermal keratinocytes. Topical application of TRPM8 agonists, menthol and WS 12 accelerated barrier recovery after tape stripping. The effect of WS12 was blocked by a non-selective TRP antagonist, Ruthenium Red, and a TRPM8-specific antagonist, BTCT. Topical application of WS12 also reduced epidermal proliferation associated with barrier disruption under low humidity, and this effect was blocked by BTCT. Our results indicate that TRPM8 or a closely related protein in epidermal keratinocytes plays a role in epidermal permeability barrier homoeostasis and epidermal proliferation after barrier insult.

  19. Protective effect of 1,25-dihydroxyvitamin D3 on ethanol-induced intestinal barrier injury both in vitro and in vivo.

    PubMed

    Chen, Shan-Wen; Ma, Yuan-Yuan; Zhu, Jing; Zuo, Shuai; Zhang, Jun-Ling; Chen, Zi-Yi; Chen, Guo-Wei; Wang, Xin; Pan, Yi-Sheng; Liu, Yu-Cun; Wang, Peng-Yuan

    2015-09-01

    Studies have suggested the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in protecting intestinal barrier function from injuries induced by multiple reagents. Vitamin D deficiency was reported to be associated with poor prognosis in patients with alcoholic liver disease (ALD). This study is designed to investigate the effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms utilizing Caco-2 cell monolayers and a mouse model with acute ethanol injury. In Caco-2 monolayers, ethanol significantly increased monolayer permeability, disrupted TJ distribution, increased phosphorylation level of MLC, and induced generation of ROS compared with controls. However, pre-treatment with 1,25(OH)2D3 greatly ameliorated the ethanol-induced barrier dysfunction, TJ disruption, phosphorylation level of MLC, and generation of ROS compared with ethanol-exposed monolayers. Mice fed with vitamin d-sufficient diet had a higher plasma level of 25(OH)D3 and were more resistant to ethanol-induced acute intestinal barrier injury compared with the vitamin d-deficient group. These results suggest that the suppression of generation of ROS and increased phosphorylation level of MLC might be one of the mechanisms underlying the protective effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier injury and provide evidence for the application of vitamin D as therapeutic factors against ethanol-induced gut leakiness.

  20. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization

    PubMed Central

    McCall, Ingrid C.; Betanzos, Abigail; Weber, Dominique A.; Nava, Porfirio; Miller, Gary W.; Parkos, Charles A.

    2010-01-01

    Phenol contamination of soil and water has raised concerns among people living near phenol-producing factories and hazardous waste sites containing the chemical. Phenol, particularly in high concentrations, is an irritating and corrosive substance, making mucosal membranes targets of toxicity in humans. However, few data on the effects of phenol after oral exposure exist. We used an in vitro model employing human intestinal epithelial cells (SK-CO15) cultured on permeable supports to examine effects of phenol on epithelial barrier function. We hypothesized that phenol disrupts epithelial barrier by altering tight junction (TJ) protein expression. The dose-response effect of phenol on epithelial barrier function was determined using transepithelial electrical resistance (TER) and FITC-dextran permeability measurements. We studied phenol-induced changes in cell morphology and expression of several tight junction proteins by immunofluorescence and Western blot analysis. Effects on cell viability were assessed by MTT, Trypan blue, propidium iodide and TUNEL staining. Exposure to phenol resulted in decreased TER and increased paracellular flux of FITC-dextran in a dose-dependent manner. Delocalization of claudin-1 and ZO-1 from TJs to cytosol correlated with the observed increase in permeability after phenol treatment. Additionally, the decrease in TER correlated with changes in the distribution of a membrane raft marker, suggesting phenol-mediated effects on membrane fluidity. Such observations were independent of effects of phenol on cell viability as enhanced permeability occurred at doses of phenol that did not cause cell death. Overall, these findings suggest that phenol may affect transiently the lipid bilayer of the cell membrane, thus destabilizing TJ-containing microdomains. PMID:19679145

  1. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization.

    PubMed

    McCall, Ingrid C; Betanzos, Abigail; Weber, Dominique A; Nava, Porfirio; Miller, Gary W; Parkos, Charles A

    2009-11-15

    Phenol contamination of soil and water has raised concerns among people living near phenol-producing factories and hazardous waste sites containing the chemical. Phenol, particularly in high concentrations, is an irritating and corrosive substance, making mucosal membranes targets of toxicity in humans. However, few data on the effects of phenol after oral exposure exist. We used an in vitro model employing human intestinal epithelial cells (SK-CO15) cultured on permeable supports to examine effects of phenol on epithelial barrier function. We hypothesized that phenol disrupts epithelial barrier by altering tight junction (TJ) protein expression. The dose-response effect of phenol on epithelial barrier function was determined using transepithelial electrical resistance (TER) and FITC-dextran permeability measurements. We studied phenol-induced changes in cell morphology and expression of several tight junction proteins by immunofluorescence and Western blot analysis. Effects on cell viability were assessed by MTT, Trypan blue, propidium iodide and TUNEL staining. Exposure to phenol resulted in decreased TER and increased paracellular flux of FITC-dextran in a dose-dependent manner. Delocalization of claudin-1 and ZO-1 from TJs to cytosol correlated with the observed increase in permeability after phenol treatment. Additionally, the decrease in TER correlated with changes in the distribution of a membrane raft marker, suggesting phenol-mediated effects on membrane fluidity. Such observations were independent of effects of phenol on cell viability as enhanced permeability occurred at doses of phenol that did not cause cell death. Overall, these findings suggest that phenol may affect transiently the lipid bilayer of the cell membrane, thus destabilizing TJ-containing microdomains.

  2. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization

    SciTech Connect

    McCall, Ingrid C.; Betanzos, Abigail; Weber, Dominique A.; Nava, Porfirio; Miller, Gary W.; Parkos, Charles A.

    2009-11-15

    Phenol contamination of soil and water has raised concerns among people living near phenol-producing factories and hazardous waste sites containing the chemical. Phenol, particularly in high concentrations, is an irritating and corrosive substance, making mucosal membranes targets of toxicity in humans. However, few data on the effects of phenol after oral exposure exist. We used an in vitro model employing human intestinal epithelial cells (SK-CO15) cultured on permeable supports to examine effects of phenol on epithelial barrier function. We hypothesized that phenol disrupts epithelial barrier by altering tight junction (TJ) protein expression. The dose-response effect of phenol on epithelial barrier function was determined using transepithelial electrical resistance (TER) and FITC-dextran permeability measurements. We studied phenol-induced changes in cell morphology and expression of several tight junction proteins by immunofluorescence and Western blot analysis. Effects on cell viability were assessed by MTT, Trypan blue, propidium iodide and TUNEL staining. Exposure to phenol resulted in decreased TER and increased paracellular flux of FITC-dextran in a dose-dependent manner. Delocalization of claudin-1 and ZO-1 from TJs to cytosol correlated with the observed increase in permeability after phenol treatment. Additionally, the decrease in TER correlated with changes in the distribution of a membrane raft marker, suggesting phenol-mediated effects on membrane fluidity. Such observations were independent of effects of phenol on cell viability as enhanced permeability occurred at doses of phenol that did not cause cell death. Overall, these findings suggest that phenol may affect transiently the lipid bilayer of the cell membrane, thus destabilizing TJ-containing microdomains.

  3. Cellular zinc is required for intestinal epithelial barrier maintenance via the regulation of claudin-3 and occludin expression.

    PubMed

    Miyoshi, Yuka; Tanabe, Soichi; Suzuki, Takuya

    2016-07-01

    Intracellular zinc is required for a variety of cell functions, but its precise roles in the maintenance of the intestinal tight junction (TJ) barrier remain unclear. The present study investigated the essential roles of intracellular zinc in the preservation of intestinal TJ integrity and the underlying molecular mechanisms. Depletion of intracellular zinc in both intestinal Caco-2 cells and mouse colons through the application of a cell-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induced a disruption of the TJ barrier, as indicated by increased FITC-labeled dextran flux and decreased transepithelial electrical resistance. The TPEN-induced TJ disruption is associated with downregulation of two TJ proteins, occludin and claudin-3. Biotinylation of cell surface proteins revealed that the zinc depletion induced the proteolysis of occludin but not claudin-3. Occludin proteolysis was sensitive to the inhibition of calpain activity, and increased calpain activity was observed in the zinc-depleted cells. Although quantitative PCR analysis and promoter reporter assay have demonstrated that the zinc depletion-induced claudin-3 downregulation occurred at transcriptional levels, a site-directed mutation in the egr1 binding site in the claudin-3 promoter sequence induced loss of both the basal promoter activity and the TPEN-induced decreases. Reduced egr1 expression by a specific siRNA also inhibited claudin-3 expression and transepithelial electrical resistance maintenance in cells. This study shows that intracellular zinc has an essential role in the maintenance of the intestinal epithelial TJ barrier through regulation of occludin proteolysis and claudin-3 transcription. PMID:27151944

  4. Effect of a probiotic mixture on intestinal microflora, morphology, and barrier integrity of broilers subjected to heat stress.

    PubMed

    Song, J; Xiao, K; Ke, Y L; Jiao, L F; Hu, C H; Diao, Q Y; Shi, B; Zou, X T

    2014-03-01

    The current study investigated the efficacy of a probiotic mixture on ameliorating heat stress-induced impairment of intestinal microflora, morphology, and barrier integrity in broilers. The probiotic mixture contained Bacillus licheniformis, Bacillus subtilis, and Lactobacillus plantarum. Three hundred sixty 21-d-old Ross 308 male broilers were allocated in 4 experimental treatments, each of which was replicated 6 times with 15 broilers per replicate. A 2 × 2 factorial design was used in the study, and the main factors were composed of diet (basal diet or addition of 1.5 g/kg of probiotic mixture) and temperature (thermoneutral zone or heat stress). From d 22 to 42, birds were either raised in a thermoneutral zone (22°C) or subjected to cyclic heat stress by exposing them to 33°C for 10 h (from 0800 to 1800) and 22°C from 1800 to 0800. Compared with birds kept in the thermoneutral zone, birds subjected to heat stress had reduced ADG and ADFI; lower viable counts of Lactobacillus and Bifidobacterium and increased viable counts of coliforms and Clostridium in small intestinal contents; shorter jejunal villus height, deeper crypt depth, and lower ratio of villus height to crypt depth; decreased jejunal transepithelial electrical resistance and a higher level of jejunal paracellular permeability of fluorescein isothiocyanate dextran 4 kDa; and downregulated protein levels of occludin and zonula occludens-1 (P < 0.05). Supplemental probiotics increased (P < 0.05) small intestinal Lactobacillus and Bifidobacterium, jejunal villus height, protein level of occludin, and decreased (P < 0.05) feed to gain ratio and small intestinal coliforms. These results indicate that dietary addition of probiotic mixture was effective in partially ameliorating intestinal barrier function. But no temperature × diet interaction was observed in the present study, revealing that the supplemented probiotics had the same effect at both temperatures.

  5. Surfactant-modified zeolites as permeable barriers to organic and inorganic groundwater contaminants

    SciTech Connect

    Bowman, R.S.; Sullivan, E.J.

    1995-10-01

    We have shown in laboratory experiments that natural zeolites treated with hexadecyltrimethylammonium (HDTMA) are effective sorbents for nonpolar organics, inorganic cations, and inorganic anions. Due to their low cost ({approximately}$0.75/kg) and granular nature, HDTMA-zeolites appear ideal candidates for reactive, permeable subsurface barriers. The HDTMA-zeolites are stable over a wide range of pH (3-13), ionic strength (1 M Cs{sup +} or Ca{sup 2+}), and in organic solvents. Surfactant-modified zeolites sorb nonpolar organics (benzene, toluene, xylene, chlorinated aliphatics) via a partitioning mechanism, inorganic cations (Pb{sup 2+}) via ion exchange and surface complexation, and inorganic anions (CrO{sub 4}{sup 2-}, SeO{sub 4}{sup 2-}, SO{sub 4}{sup 2-}) via surface precipitation.The goal of this work is to demonstrate the use of surfactant-modified zeolite as a permeable barrier to ground water contaminants.

  6. Permeable membranes containing crystalline silicotitanate as model barriers for cesium ion.

    PubMed

    Warta, Andrew M; Arnold, William A; Cussler, Edward L

    2005-12-15

    In diaphragm cell experiments, a permeable model reactive barrier for the containment of cesium is tested. Primary targets for cesium containment are former plutonium processing sites (e.g., Hanford, WA and Savannah River, SC), which are currently contaminated with cesium-137. Adding up to 10 wt % crystalline silicotitanate, a sacrificial reagent, to poly(vinyl alcohol) films increases the time before cesium can cross the film by a factor of 30. The increased lag times are consistent with theories developed for this type of reactive membrane. Theory also correctly predicts the effects of cesium concentration and membrane thickness on membrane performance. Because the relative improvements of the model barrier are expected to be independent of the polymer used, these increased lags should hold for less permeable polymers that are more resistant to radiation, although these polymers have not been tested. PMID:16475361

  7. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it

    SciTech Connect

    Zgurskaya, Helen I.; López, Cesar A.; Gnanakaran, Sandrasegaram

    2015-09-18

    Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This article summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

  8. Spray-dried animal plasma prevents the effects of Staphylococcus aureus enterotoxin B on intestinal barrier function in weaned rats.

    PubMed

    Pérez-Bosque, Anna; Amat, Concepció; Polo, Javier; Campbell, Joy M; Crenshaw, Joe; Russell, Louis; Moretó, Miquel

    2006-11-01

    In this study, we investigated intestinal barrier function during inflammation as well as the effects of dietary supplementation with porcine spray-dried animal plasma (SDAP) proteins and porcine immunoglobulin concentrate (IC). Wistar Lewis rats were fed from d 21 (weaning) until d 34 or 35 either a control diet or a diet containing SDAP or IC. On d 30 and d 33, rats received an intraperitoneal dose of Staphylococcus aureus enterotoxin B (SEB; 0.5 mg/kg body wt; groups SEB, SEB-SDAP, and SEB-IC). SEB reduced the potential difference across the jejunum by 60%, the short-circuit current by 70%, and Na-K-ATPase activity in intestinal mucosa (all P < 0.05). The fluxes of dextran flux (4 kDa) and horseradish peroxidase (HRP, 40 kDa) across the intestinal wall also increased in SEB-treated rats (P < 0.01, P = 0.068, respectively). SEB also increased HRP flux across the paracellular space (P < 0.05). Moreover, SEB-treated rats had a reduced expression of tight junction proteins, such as ZO-1 (10% reduction; P < 0.05) and beta-catenin (20% reduction; P < 0.05). Dietary supplementation with SDAP or IC prevented dextran (P < 0.05) and HRP (P < 0.05) paracellular flux across the intestinal epithelium. SDAP supplementation also prevented SEB effects on Na-K-ATPase activity (P < 0.05). In our model of SEB-induced intestinal inflammation, the increased permeability across the intestinal mucosa was due to the lower expression of tight junction proteins, an effect that can be prevented by both SDAP and IC supplementation.

  9. The mechanisms and quantification of the selective permeability in transport across biological barriers: the example of kyotorphin.

    PubMed

    Serrano, Isa D; Freire, Joao M; Carvalho, Miguel V; Neves, Mafalda; Melo, Manuel N; Castanho, Miguel A R B

    2014-02-01

    This paper addresses the mechanisms behind selective endothelial permeability and their regulations. The singular properties of each of the seven blood-tissues barriers. Then, it further revisits the physical, quantitative meaning of permeability, and the way it should be measured based on sound physical chemistry reasoning and methodologies. Despite the relevance of permeability studies one often comes across inaccurate determinations, mostly from oversimplified data analyses. To worsen matters, the exact meaning of permeability is being lost along with this loss of accuracy. The importance of proper permeability calculation is illustrated with a family of derivatives of kyotorphin, an analgesic dipeptide. PMID:24456269

  10. Blood brain barrier is impermeable to solutes and permeable to water after experimental pediatric cardiac arrest.

    PubMed

    Tress, Erika E; Clark, Robert S B; Foley, Lesley M; Alexander, Henry; Hickey, Robert W; Drabek, Tomas; Kochanek, Patrick M; Manole, Mioara D

    2014-08-22

    Pediatric asphyxial cardiac arrest (CA) results in unfavorable neurological outcome in most survivors. Development of neuroprotective therapies is contingent upon understanding the permeability of intravenously delivered medications through the blood brain barrier (BBB). In a model of pediatric CA we sought to characterize BBB permeability to small and large molecular weight substances. Additionally, we measured the percent brain water after CA. Asphyxia of 9 min was induced in 16-18 day-old rats. The rats were resuscitated and the BBB permeability to small (sodium fluorescein and gadoteridol) and large (immunoglobulin G, IgG) molecules was assessed at 1, 4, and 24 h after asphyxial CA or sham surgery. Percent brain water was measured post-CA and in shams using wet-to-dry brain weight. Fluorescence, gadoteridol uptake, or IgG staining at 1, 4h and over the entire 24 h post-CA did not differ from shams, suggesting absence of BBB permeability to these solutes. Cerebral water content was increased at 3h post-CA vs. sham. In conclusion, after 9 min of asphyxial CA there is no BBB permeability over 24h to conventional small or large molecule tracers despite the fact that cerebral water content is increased early post-CA indicating the development of brain edema. Evaluation of novel therapies targeting neuronal death after pediatric CA should include their capacity to cross the BBB.

  11. Plasma From Patients With HELLP Syndrome Increases Blood–Brain Barrier Permeability

    PubMed Central

    Tremble, Sarah M.; Owens, Michelle Y.; Morris, Rachael; Cipolla, Marilyn J.

    2015-01-01

    Circulating inflammatory factors and endothelial dysfunction have been proposed to contribute to the pathophysiology of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. To date, the occurrence of neurological complications in these women has been reported, but few studies have examined whether impairment in blood–brain barrier (BBB) permeability or cerebrovascular reactivity is present in women having HELLP syndrome. We hypothesized that plasma from women with HELLP syndrome causes increased BBB permeability and cerebrovascular dysfunction. Posterior cerebral arteries from female nonpregnant rats were perfused with 20% serum from women with normal pregnancies (n = 5) or women with HELLP syndrome (n = 5), and BBB permeability and vascular reactivity were compared. Plasma from women with HELLP syndrome increased BBB permeability while not changing myogenic tone and reactivity to pressure. Addition of the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester caused constriction of arteries that was not different with the different plasmas nor was dilation to the NO donor sodium nitroprusside different between the 2 groups. However, dilation to the small- and intermediate-conductance, calcium-activated potassium channel activator NS309 was decreased in vessels exposed to HELLP plasma. Thus, increased BBB permeability in response to HELLP plasma was associated with selective endothelial dysfunction. PMID:25194151

  12. Iron Sulfide as a Sustainable Reactive Material for Permeable Reactive Barriers

    NASA Astrophysics Data System (ADS)

    Henderson, A. D.; Demond, A. H.

    2012-12-01

    Permeable reactive barriers (PRBs) are gaining acceptance for groundwater remediation, as they operate in situ and do not require continuous energy input. The majority of PRBs use zero-valent iron (ZVI). However, some ZVI PRBs have hydraulically failed [1,2], due to the fact that ZVI may reduce not only contaminants but also water and non-contaminant solutes. These reactions may form precipitates or gas phases that reduce permeability. Therefore, there is a need to assess the hydraulic suitability of possible alternatives, such as iron sulfide (FeS). The capability of FeS to remove both metals and halogenated organics from aqueous systems has been demonstrated previously [3,4], and FeS formed in situ within a ZVI PRB has been linked to contaminant removal [5]. These results suggest possible applications in groundwater remediation as a permeable reactive barrier (PRB) material. However, the propensity of FeS for permeability loss, due to solids and gas production, must be evaluated in order to address its suitability for PRBs. The reduction in permeability for FeS-coated sands under the anoxic conditions often encountered at contaminated groundwater sites was examined through column experiments and geochemical modeling under conditions of high calcium and nitrate, which have been previously shown to cause significant permeability reduction in zero-valent iron (ZVI) systems [6]. The column experiments showed negligible production of both solids and gases. The geochemical model was used to estimate solid and gas volumes generated under conditions of varying FeS concentration. Then, the Kozeny-Carman equation and a power-law relationship was used to predict permeability reduction, with a maximum reduction in permeability of 1% due to solids and about 30% due to gas formation under conditions for which a complete loss of permeability was predicted for ZVI systems. This difference in permeability reduction is driven by the differences in thermodynamic stability of ZVI

  13. Evaluating Blood-Brain Barrier Permeability in Delayed Cerebral Infarction after Aneurysmal Subarachnoid Hemorrhage

    PubMed Central

    Ivanidze, J.; Kesavabhotla, K.; Kallas, O.N.; Mir, D.; Baradaran, H.; Gupta, A.; Segal, A.Z.; Claassen, J.; Sanelli, P.C.

    2015-01-01

    BACKGROUND AND PURPOSE Patients with SAH are at increased risk of delayed infarction. Early detection and treatment of delayed infarction remain challenging. We assessed blood-brain barrier permeability, measured as permeability surface area product, by using CTP in patients with SAH with delayed infarction. MATERIALS AND METHODS We performed a retrospective study of patients with SAH with delayed infarction on follow-up NCCT. CTP was performed before the development of delayed infarction. CTP data were postprocessed into permeability surface area product, CBF, and MTT maps. Coregistration was performed to align the infarcted region on the follow-up NCCT with the corresponding location on the CTP maps obtained before infarction. Permeability surface area product, CBF, and MTT values were then obtained in the location of the subsequent infarction. The contralateral noninfarcted region was compared with the affected side in each patient. Wilcoxon signed rank tests were performed to determine statistical significance. Clinical data were collected at the time of CTP and at the time of follow-up NCCT. RESULTS Twenty-one patients with SAH were included in the study. There was a statistically significant increase in permeability surface area product in the regions of subsequent infarction compared with the contralateral control regions (P < .0001). However, CBF and MTT values were not significantly different in these 2 regions. Subsequent follow-up NCCT demonstrated new delayed infarction in all 21 patients, at which time 38% of patients had new focal neurologic deficits. CONCLUSIONS Our study reveals a statistically significant increase in permeability surface area product preceding delayed infarction in patients with SAH. Further investigation of early permeability changes in SAH may provide new insights into the prediction of delayed infarction. PMID:25572949

  14. Dietary glutamine prevents the loss of intestinal barrier function and attenuates the increase in core body temperature induced by acute heat exposure.

    PubMed

    Soares, Anne D N; Costa, Kátia A; Wanner, Samuel P; Santos, Rosana G C; Fernandes, Simone O A; Martins, Flaviano S; Nicoli, Jacques R; Coimbra, Cândido C; Cardoso, Valbert N

    2014-11-28

    Dietary glutamine (Gln) supplementation improves intestinal function in several stressful conditions. Therefore, in the present study, the effects of dietary Gln supplementation on the core body temperature (T core), bacterial translocation (BT) and intestinal permeability of mice subjected to acute heat stress were evaluated. Male Swiss mice (4 weeks old) were implanted with an abdominal temperature sensor and randomly assigned to one of the following groups fed isoenergetic and isoproteic diets for 7 d before the experimental trials: group fed the standard AIN-93G diet and exposed to a high ambient temperature (39°C) for 2 h (H-NS); group fed the AIN-93G diet supplemented with l-Gln and exposed to a high temperature (H-Gln); group fed the standard AIN-93G diet and not exposed to a high temperature (control, C-NS). Mice were orally administered diethylenetriaminepentaacetic acid radiolabelled with technetium (99mTc) for the assessment of intestinal permeability or 99mTc-Escherichia coli for the assessment of BT. Heat exposure increased T core (approximately 41°C during the experimental trial), intestinal permeability and BT to the blood and liver (3 h after the experimental trial) in mice from the H-NS group relative to those from the C-NS group. Dietary Gln supplementation attenuated hyperthermia and prevented the increases in intestinal permeability and BT induced by heat exposure. No correlations were observed between the improvements in gastrointestinal function and the attenuation of hyperthermia by Gln. Our findings indicate that dietary Gln supplementation preserved the integrity of the intestinal barrier and reduced the severity of hyperthermia during heat exposure. The findings also indicate that these Gln-mediated effects occurred through independent mechanisms.

  15. Supplementing formula-fed piglets with a low molecular weight fraction of bovine colostrum whey results in an improved intestinal barrier.

    PubMed

    De Vos, M; Huygelen, V; Van Raemdonck, G; Willemen, S; Fransen, E; Van Ostade, X; Casteleyn, C; Van Cruchten, S; Van Ginneken, C

    2014-08-01

    To test the hypothesis that a low molecular weight fraction of colostral whey could affect the morphology and barrier function of the small intestine, 30 3-d-old piglets (normal or low birth weight) were suckled (n = 5), artificially fed with milk formula (n = 5), or artificially fed with milk formula with a low molecular weight fraction of colostral whey (n = 5) until 10 d of age. The small intestine was sampled for histology (haematoxylin and eosin stain; anti-KI67 immunohistochemistry) and enzyme activities (aminopeptidase A, aminopeptidase N, dipeptidylpeptidase IV, lactase, maltase, and sucrase). In addition, intestinal permeability was evaluated via a dual sugar absorption test and via the measurement of occludin abundance. Artificially feeding of piglets reduced final BW (P < 0.001), villus height (P < 0.001), lactase (P < 0.001), and dipeptidylpeptidase IV activities (P < 0.07), whereas crypt depth (P < 0.001) was increased. No difference was observed with regard to the permeability measurements when comparing artificially fed with naturally suckling piglets. Supplementing piglets with the colostral whey fraction did not affect BW, enzyme activities, or the outcome of the dual sugar absorption test. On the contrary, the small intestines of supplemented piglets had even shorter villi (P = 0.001) than unsupplemented piglets and contained more occludin (P = 0.002). In conclusion, at 10 d of age, no differences regarding intestinal morphology and permeability measurements were observed between the 2 BW categories. In both weight categories, the colostral whey fraction affected the morphology of the small intestine but did not improve the growth performances or the in vivo permeability. These findings should be acknowledged when developing formulated milk for neonatal animals with the aim of improving the performance of low birth weight piglets. PMID:25012977

  16. Supplementing formula-fed piglets with a low molecular weight fraction of bovine colostrum whey results in an improved intestinal barrier.

    PubMed

    De Vos, M; Huygelen, V; Van Raemdonck, G; Willemen, S; Fransen, E; Van Ostade, X; Casteleyn, C; Van Cruchten, S; Van Ginneken, C

    2014-08-01

    To test the hypothesis that a low molecular weight fraction of colostral whey could affect the morphology and barrier function of the small intestine, 30 3-d-old piglets (normal or low birth weight) were suckled (n = 5), artificially fed with milk formula (n = 5), or artificially fed with milk formula with a low molecular weight fraction of colostral whey (n = 5) until 10 d of age. The small intestine was sampled for histology (haematoxylin and eosin stain; anti-KI67 immunohistochemistry) and enzyme activities (aminopeptidase A, aminopeptidase N, dipeptidylpeptidase IV, lactase, maltase, and sucrase). In addition, intestinal permeability was evaluated via a dual sugar absorption test and via the measurement of occludin abundance. Artificially feeding of piglets reduced final BW (P < 0.001), villus height (P < 0.001), lactase (P < 0.001), and dipeptidylpeptidase IV activities (P < 0.07), whereas crypt depth (P < 0.001) was increased. No difference was observed with regard to the permeability measurements when comparing artificially fed with naturally suckling piglets. Supplementing piglets with the colostral whey fraction did not affect BW, enzyme activities, or the outcome of the dual sugar absorption test. On the contrary, the small intestines of supplemented piglets had even shorter villi (P = 0.001) than unsupplemented piglets and contained more occludin (P = 0.002). In conclusion, at 10 d of age, no differences regarding intestinal morphology and permeability measurements were observed between the 2 BW categories. In both weight categories, the colostral whey fraction affected the morphology of the small intestine but did not improve the growth performances or the in vivo permeability. These findings should be acknowledged when developing formulated milk for neonatal animals with the aim of improving the performance of low birth weight piglets.

  17. Randomized Clinical Trial of Pre-operative Feeding to Evaluate Intestinal Barrier Function in Neonates Requiring Cardiac Surgery

    PubMed Central

    Zyblewski, Sinai C.; Nietert, Paul J.; Graham, Eric M.; Taylor, Sarah N.; Atz, Andrew M.; Wagner, Carol L.

    2015-01-01

    Objective To evaluate intestinal barrier function in neonates undergoing cardiac surgery using lactulose/mannitol (L/M) ratio measurements and to determine correlations with early breast milk feeding. Study design This was a single-center, prospective, randomized pilot study of 27 term neonates (≥37 weeks gestation) requiring cardiac surgery who were randomized to one of two pre-operative feeding groups: 1) nil per os (NPO) vs. 2) trophic (10 cc/kg/day) breast milk feeds. At three time points (pre-op, post-op day 7, and post-op day 14), subjects were administered an oral lactulose/mannitol solution and subsequent L/M ratios were measured using gas chromatography, with higher ratios indicative of increased intestinal permeability. Trends over time in the mean urine L/M ratios for each group were estimated using a general linear mixed model. Results There were no adverse events related to pre-operative trophic feeding. In the NPO group (n=13), the mean urine L/M ratios at pre-op, post-op day 7, and post-op day 14 were 0.06, 0.12, and 0.17, respectively. In the trophic breast milk feeds group (n=14), the mean urine L/M ratios at pre-op, post-op day 7, and post-op day 14 were 0.09, 0.19, and 0.15, respectively. Both groups had significantly higher L/M ratios at post-op day 7 and 14 compared with pre-op (p<0.05). Conclusions Neonates have increased intestinal permeability after cardiac surgery extending to at least post-op day 14. This pilot study was not powered to detect differences in benefit or adverse events comparing NPO with breast milk feeds. Further studies to identify mechanisms of intestinal injury and therapeutic interventions are warranted. Trial registration Registered with ClinicalTrials.gov: NCT01475357. PMID:25962930

  18. 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

  19. Organo-montmorillonite Barrier Layers Formed by Combustion: Nanostructure and Permeability

    SciTech Connect

    Fox, James B; Ambuken, Preejith V.; Stretz, Holly A; Meisner, Roberta Ann; Payzant, E Andrew

    2010-01-01

    Self-assembly of nanoparticles into barrier layers has been the most cited theoretical explanation for the significant reduction in flammability often noted for nanocomposites formed from polymers and montmorillonite organoclays. Both mass and heat transport reductions have been credited for such improvements, and in most cases a coupled mechanism is expected. To provide validation for early models, new model barrier layers were produced from organoclays, and these barrier layers subjected to novel permeability analysis to obtain a flux. The effects of surfactant, temperature and pressure on barrier layer structure were examined. XRD versus TGA results suggest that chemical degradation of four different organoclays and physical collapse on heating are not correlated. Addition of pressure as low as 7kPa also altered the structure produced. Permeability of Ar through the ash was found to be sensitive to structural change/self assembly of high aspect ratio MMT nanoparticles. Actual fluxes ranged from 0.139 to 0.151 mol(m2.sec)-1, values which will provide useful limits in verifying models for the coupled contribution of mass and heat transfer to flammability parameters such as peak heat release rate.

  20. Role of lipids in the formation and maintenance of the cutaneous permeability barrier.

    PubMed

    Feingold, Kenneth R; Elias, Peter M

    2014-03-01

    The major function of the skin is to form a barrier between the internal milieu and the hostile external environment. A permeability barrier that prevents the loss of water and electrolytes is essential for life on land. The permeability barrier is mediated primarily by lipid enriched lamellar membranes that are localized to the extracellular spaces of the stratum corneum. These lipid enriched membranes have a unique structure and contain approximately 50% ceramides, 25% cholesterol, and 15% free fatty acids with very little phospholipid. Lamellar bodies, which are formed during the differentiation of keratinocytes, play a key role in delivering the lipids from the stratum granulosum cells into the extracellular spaces of the stratum corneum. Lamellar bodies contain predominantly glucosylceramides, phospholipids, and cholesterol and following the exocytosis of lamellar lipids into the extracellular space of the stratum corneum these precursor lipids are converted by beta glucocerebrosidase and phospholipases into the ceramides and fatty acids, which comprise the lamellar membranes. The lipids required for lamellar body formation are derived from de novo synthesis by keratinocytes and from extra-cutaneous sources. The lipid synthetic pathways and the regulation of these pathways are described in this review. In addition, the pathways for the uptake of extra-cutaneous lipids into keratinocytes are discussed. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

  1. A calcite permeable reactive barrier for the remediation of Fluoride from spent potliner (SPL) contaminated groundwater.

    PubMed

    Turner, Brett D; Binning, Philip J; Sloan, Scott W

    2008-01-28

    The use of calcite (CaCO3) as a substrate for a permeable reactive barrier (PRB) for removing fluoride from contaminated groundwater is proposed and is illustrated by application to groundwater contaminated by spent potliner leachate (SPL), a waste derived from the aluminium smelting process. The paper focuses on two issues in the implementation of calcite permeable reactive barriers for remediating fluoride contaminated water: the impact of the groundwater chemical matrix and CO2 addition on fluoride removal. Column tests comparing pure NaF solutions, synthetic SPL solutions, and actual SPL leachate indicate that the complex chemical matrix of the SPL leachate can impact fluoride removal significantly. For SPL contaminant mixtures, fluoride removal is initially less than expected from idealized, pure, solutions. However, with time, the effect of other contaminants on fluoride removal diminishes. Column tests also show that pH control is important for optimizing fluoride removal with the mass removed increasing with decreasing pH. Barrier pH can be regulated by CO2 addition with the point of injection being critical for optimising the remediation performance. Experimental and model results show that approximately 99% of 2300 mg/L fluoride can be removed when CO2 is injected directly into the barrier. This can be compared to approximately 30-50% removal when the influent solution is equilibrated with atmospheric CO2 before contact with calcite.

  2. Saccharomyces cerevisiae strain UFMG 905 protects against bacterial translocation, preserves gut barrier integrity and stimulates the immune system in a murine intestinal obstruction model.

    PubMed

    Generoso, Simone V; Viana, Mirelle; Santos, Rosana; Martins, Flaviano S; Machado, José A N; Arantes, Rosa M E; Nicoli, Jacques R; Correia, Maria I T D; Cardoso, Valbert N

    2010-06-01

    Probiotic is a preparation containing microorganisms that confers beneficial effect to the host. This work assessed whether oral treatment with viable or heat-killed yeast Saccharomyces cerevisiae strain UFMG 905 prevents bacterial translocation (BT), intestinal barrier integrity, and stimulates the immunity, in a murine intestinal obstruction (IO) model. Four groups of mice were used: mice undergoing only laparotomy (CTL), undergoing intestinal obstruction (IO) and undergoing intestinal obstruction after previous treatment with viable or heat-killed yeast. BT, determined as uptake of (99m)Tc-E. coli in blood, mesenteric lymph nodes, liver, spleen and lungs, was significantly higher in IO group than in CTL group. Treatments with both yeasts reduced BT in blood and all organs investigated. The treatment with both yeasts also reduced intestinal permeability as determined by blood uptake of (99m)Tc-DTPA. Immunological data demonstrated that both treatments were able to significantly increase IL-10 levels, but only viable yeast had the same effect on sIgA levels. Intestinal lesions were more severe in IO group when compared to CTL and yeasts groups. Concluding, both viable and heat-killed cells of yeast prevent BT, probably by immunomodulation and by maintaining gut barrier integrity. Only the stimulation of IgA production seems to depend on the yeast viability.

  3. Intestinal permeability in subjects from two different race groups with diverse stone-risk profiles.

    PubMed

    Theka, Takalani; Rodgers, Allen; Ravenscroft, Neil; Lewandowski, Sonja

    2013-04-01

    It is well established that calcium oxalate stones may be caused by colonic or ileum oxalate (Ox) hyperabsorption (secondary to intestinal dysfunction). Studies have reported that increased intestinal permeability (IP) can cause hyperabsorption of nutrients culminating in passive diffusion of Ox. In South Africa, renal stones occur in the white population (W) but are extremely rare in the black population (B). Previous studies have shown that despite B having a hyperoxalurogenic diet relative to W, urinary Ox in the former is not higher. It has been suggested that different Ox handling mechanisms in the groups are the cause of this disparity. The present study was undertaken to examine whether the IP index, a reliable and accurate measure of intestinal integrity, plays a role in this anomaly. Ten healthy males from each group ingested a dual-sugar isotonic solution containing 5 g lactulose (LA) and 2 g mannitol (MA). IP was assessed by comparing the LA:MA ratio in 5 h urine samples using high performance anion exchange chromatography coupled with pulse amperometric detection to measure the concentration of each sugar. 24 h dietary intake and urine composition were also determined. LA excretion was identical in both groups (0.03 %) while MA excretion was 8.3 % in B and 11.3 % in W. IP index was 0.004 for B and 0.003 for W. It is concluded that IP is not a contributory factor in the apparent different handling of dietary Ox in B and W South Africans. It is speculated that differences in renal transporters may play a role. PMID:23503872

  4. The effect of concanavalin A and wheat germ agglutinin on the ultrastructure and permeability of rat intestine. A possible model for an intestinal allergic reaction.

    PubMed

    Sjölander, A; Magnusson, K E; Latkovic, S

    1984-01-01

    Sprague-Dawley rats were exposed to lectins, either concanavalin A (Con A) or wheat germ agglutinin (WGA). The lectins were instilled into a ligated segment of the distal small intestine together with permeability markers, fluoresceinated dextran (MW 3,000) or a mixture of differently sized polyethylene glycols (MW 400, 600 and 1,000). WGA-treated rats showed a decreased permeability to small molecules (MW less than 600) of polyethylene glycol but an increase for a larger dextran molecule (MW 3,000). These effects as well as the morphological findings might mimic the situation in patients with food allergy or celiac disease. Con A-treated rats had decreased intestinal permeability to the larger dextran molecules (MW 3,000), whereas the passage of small molecules was unaffected and the ultrastructural effects were minute. The Con A-induced changes could result from a mucotractive effect, associated with a low-grade gut allergy. These observations suggest that lectins can affect both the ultrastructure and the permeability of the intestine, in a way assumed to mimic allergic reactions to food constituents.

  5. Effect of some drugs on ethanol-induced changes in blood brain barrier permeability for /sup 14/C-tyrosine

    SciTech Connect

    Borisenko, S.A.; Burov, Yu.V.

    1987-06-01

    This investigation seeks to compare the effects of membrane stabilizers chlorpromazine and alpha-tocopherol, and also the dopaminergic antagonist haloperidol, in changes in permeability of the blood-brain barrier for carbon 14-labelled tyrosine.

  6. CARBON AND SULFUR ACCUMULATION AND IRON MINERAL TRANSFORMATION IN PERMEABLE REACTIVE BARRIERS CONTAINING ZERO-VALENT IRON

    EPA Science Inventory

    Permeable reactive barrier technology is an in-situ approach for remediating groundwater contamination that combines subsurface fluid flow management with passive chemical treatment. Factors such as the buildup of mineral precipitates, buildup of microbial biomass (bio-fouling...

  7. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: AN UPDATE ON A U.S. MULTI-AGENCY INITIATIVE

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating contaminated groundwater that combine subsurface fluid flow management with a passive chemical treatment zone. PRB's are a potentially more cost effective treatment option at seve...

  8. Application of the 51Cr-EDTA urinary recovery test for assessment of intestinal permeability in the horse.

    PubMed

    Escala, J; Gatherer, M E; Voûte, L; Love, S

    2006-04-01

    Altered intestinal permeability is implicated in the pathogenesis of diverse equine medical conditions including alimentary laminitis and protein-losing enteropathies associated with parasitic infection. The aims of this study were to assess the feasibility of applying the 51Cr-EDTA absorption test for the assessment of intestinal permeability in the horse, and to apply this test in horses with experimentally induced alterations in gastrointestinal function. Four healthy ponies were administered 36 MBq of 51Cr-EDTA via naso-gastric tube, and urine samples were collected into polythene bags strapped to the pony's abdomen. Total urine voided every 6 h was collected during each test, and 1 ml samples were taken for measurement of gamma-radiation. Urinary recovery of 51Cr-EDTA was measured following intravenous atropine sulphate or bethanecol, and following 22 and 46 days of administration of 250,000 third-stage cyathostome larvae. There was no significant difference in urinary 51Cr-EDTA recovery following the control treatment, and following atropine or bethanecol administration, but significant increases were detected in the animals with experimental cyathostome infection consistent with increased permeability of the intestinal membrane. Motility modifying agents (bethanecol and atropine) did not affect absorption of 51Cr-EDTA, suggesting that subtle changes in motility might not affect the ability of this test to detect altered intestinal permeability. The finding of increased urinary recovery of 51Cr-EDTA in ponies with cyathostome infection suggests that 51Cr-EDTA may be a useful marker for assessment of intestinal permeability in the horse.

  9. Frog intestinal perfusion to evaluate drug permeability: application to p-gp and cyp3a4 substrates

    PubMed Central

    Yerasi, Neelima; Vurimindi, Himabindu; Devarakonda, Krishna

    2015-01-01

    To evaluate the reliability of using in situ frog intestinal perfusion technique for permeability assessment of carrier transported drugs which are also substrates for CYP enzymes. Single Pass Intestinal Perfusion (SPIP) studies were performed in frogs of the species Rana tigrina using established method for rats with some modifications after inducing anesthesia. Effective permeability coefficient (Peff) of losartan and midazolam was calculated in the presence and absence of inhibitors using the parallel-tube model. Peff of losartan when perfused alone was found to be 0.427 ± 0.27 × 10-4cm/s and when it was co-perfused with inhibitors, significant change in Peff was observed. Peff of midazolam when perfused alone was found to be 2.03 ± 0.07 × 10-4cm/s and when it was co-perfused with inhibitors, no significant change in Peff was observed. Comparison of Peff calculated in frog with that of other available models and also humans suggested that the Peff-values are comparable and reflected well with human intestinal permeability. It is possible to determine the Peff-value for compounds which are dual substrates of P-glycoprotein and CYP3A4 using in situ frog intestinal perfusion technique. The calculated Peff-values correlated well with reported Peff-values of probe drugs. comparison of the Peff-value of losartan obtained with that of reported human’s Peff and Caco 2 cell data, and comparison of the Peff-value of midazolam with that of reported rat’s Peff, we could conclude that SPIP from model can be reliably used in preclinical studies for permeability estimation. This model may represent a valuable alternative to the low speed and high cost of conventional animal models (typically rodents) for the assessment of intestinal permeability. PMID:26236236

  10. The effect of a tin barrier layer on the permeability of hydrogen through mild steel and ferritic stainless steel

    SciTech Connect

    Bowker, J.; Piercy, G.R.

    1984-11-01

    Experiments were performed to measure the effectiveness of a commercially electroplated tin layer as a barrier to hydrogen, and to see how this altered when the tin layer was converted to FeSn. The authors measured the permeability of hydrogen through AISI 410 ferritic stainless steel and determined the effectiveness of tin as a surface barrier on it. The measured values for the permeability of hydrogen in iron and ferritic stainless steel are shown.

  11. Geochemistry of a permeable reactive barrier for metals and acid mine drainage

    SciTech Connect

    Benner, S.G.; Blowes, D.W.; Herbert, R.B. Jr.; Ptacek, C.J.; Gould, W.D.

    1999-08-15

    A permeable reactive barrier, designed to remove metals and generate alkalinity by promoting sulfate reduction and metal sulfide precipitation, was installed in August 1995 into an aquifer containing effluent from mine tailings. Passage of groundwater through the barrier results in striking improvement in water quality. Dramatic changes in concentrations of SO{sub 4}, Fe, trace metals, and alkalinity are observed. Populations of sulfate reducing bacteria are 10,000 times greater, and bacterial activity, as measured by dehydrogenase activity, is 10 times higher within the barrier compared to the up-gradient aquifer. Dissolved sulfide concentrations increase by 0.2--120 mg/L, and the isotope {sup 34}S is enriched relative to {sup 32}S in the dissolved phase SO{sub 4}{sup 2{minus}} within the barrier. Water chemistry, coupled with geochemical speciation modeling, indicates the pore water in the barrier becomes supersaturated with respect to amorphous Fe sulfide. Solid phase analysis of the reactive mixture indicates the accumulation of Fe monosulfide precipitates. Shifts in the saturated states of carbonate, sulfate, and sulfide minerals and most of the observed changes in water chemistry in the barrier and down-gradient aquifer can be attributed, either directly or indirectly, to bacterially mediated sulfate reduction.

  12. Separation methods that are capable of revealing blood-brain barrier permeability.

    PubMed

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  13. Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption.

    PubMed

    Olivares-Morales, Andrés; Lennernäs, Hans; Aarons, Leon; Rostami-Hodjegan, Amin

    2015-09-01

    Regional intestinal effective permeability (P(eff)) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P(eff) values. These new intestinal P(eff) values or "intrinsic" P(eff)(P(eff,int)) were subsequently employed for the prediction of the ileal absorption clearance (CL(abs,ileum)) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that P(eff,int) can successfully be employed for the prediction of the ileal CL(abs) and the f(abs). P(eff,int) also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P(eff) values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.

  14. TIMP-1 attenuates blood–brain barrier permeability in mice with acute liver failure

    PubMed Central

    Chen, Feng; Radisky, Evette S; Das, Pritam; Batra, Jyotica; Hata, Toshiyuki; Hori, Tomohide; Baine, Ann-Marie T; Gardner, Lindsay; Yue, Mei Y; Bu, Guojun; del Zoppo, Gregory; Patel, Tushar C; Nguyen, Justin H

    2013-01-01

    Blood–brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and 𝒟-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF. PMID:23532086

  15. Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis

    PubMed Central

    Noubade, Rajkumar; del Rio, Roxana; McElvany, Benjamin; Zachary, James F.; Millward, Jason M.; Wagner, Denisa D.; Offner, Halina; Blankenhorn, Elizabeth P.; Teuscher, Cory

    2008-01-01

    Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli. PMID:18688020

  16. Sizing nanomaterials in bio-fluids by cFRAP enables protein aggregation measurements and diagnosis of bio-barrier permeability

    PubMed Central

    Xiong, Ranhua; Vandenbroucke, Roosmarijn E.; Broos, Katleen; Brans, Toon; Van Wonterghem, Elien; Libert, Claude; Demeester, Jo; De Smedt, Stefaan C.; Braeckmans, Kevin

    2016-01-01

    Sizing nanomaterials in complex biological fluids, such as blood, remains a great challenge in spite of its importance for a wide range of biomedical applications. In drug delivery, for instance, it is essential that aggregation of protein-based drugs is avoided as it may alter their efficacy or elicit immune responses. Similarly it is of interest to determine which size of molecules can pass through biological barriers in vivo to diagnose pathologies, such as sepsis. Here, we report on continuous fluorescence recovery after photobleaching (cFRAP) as a analytical method enabling size distribution measurements of nanomaterials (1–100 nm) in undiluted biological fluids. We demonstrate that cFRAP allows to measure protein aggregation in human serum and to determine the permeability of intestinal and vascular barriers in vivo. cFRAP is a new analytical technique that paves the way towards exciting new applications that benefit from nanomaterial sizing in bio-fluids. PMID:27653841

  17. Sizing nanomaterials in bio-fluids by cFRAP enables protein aggregation measurements and diagnosis of bio-barrier permeability

    NASA Astrophysics Data System (ADS)

    Xiong, Ranhua; Vandenbroucke, Roosmarijn E.; Broos, Katleen; Brans, Toon; van Wonterghem, Elien; Libert, Claude; Demeester, Jo; de Smedt, Stefaan C.; Braeckmans, Kevin

    2016-09-01

    Sizing nanomaterials in complex biological fluids, such as blood, remains a great challenge in spite of its importance for a wide range of biomedical applications. In drug delivery, for instance, it is essential that aggregation of protein-based drugs is avoided as it may alter their efficacy or elicit immune responses. Similarly it is of interest to determine which size of molecules can pass through biological barriers in vivo to diagnose pathologies, such as sepsis. Here, we report on continuous fluorescence recovery after photobleaching (cFRAP) as a analytical method enabling size distribution measurements of nanomaterials (1-100 nm) in undiluted biological fluids. We demonstrate that cFRAP allows to measure protein aggregation in human serum and to determine the permeability of intestinal and vascular barriers in vivo. cFRAP is a new analytical technique that paves the way towards exciting new applications that benefit from nanomaterial sizing in bio-fluids.

  18. Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia.

    PubMed

    Chau, Jennifer Y; Tiffany, Caitlin M; Nimishakavi, Shilpa; Lawrence, Jessica A; Pakpour, Nazzy; Mooney, Jason P; Lokken, Kristen L; Caughey, George H; Tsolis, Renee M; Luckhart, Shirley

    2013-10-01

    Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing L-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans. PMID:23690397

  19. Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia.

    PubMed

    Chau, Jennifer Y; Tiffany, Caitlin M; Nimishakavi, Shilpa; Lawrence, Jessica A; Pakpour, Nazzy; Mooney, Jason P; Lokken, Kristen L; Caughey, George H; Tsolis, Renee M; Luckhart, Shirley

    2013-10-01

    Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing L-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans.

  20. Malaria-Associated l-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal Salmonella Bacteremia

    PubMed Central

    Chau, Jennifer Y.; Tiffany, Caitlin M.; Nimishakavi, Shilpa; Lawrence, Jessica A.; Pakpour, Nazzy; Mooney, Jason P.; Lokken, Kristen L.; Caughey, George H.; Tsolis, Renee M.

    2013-01-01

    Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop l-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of l-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with l-arginine or l-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with l-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing l-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans. PMID:23690397

  1. 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

  2. Quantification of pore clogging characteristics in potential permeable reactive barrier (PRB) substrates using image analysis.

    PubMed

    Wantanaphong, J; Mooney, S J; Bailey, E H

    2006-08-10

    Permeable reactive barriers (PRBs) are now an established approach for groundwater remediation. However, one concern is the deterioration of barrier material performance due to pore clogging. This study sought to quantify the effect of pore clogging on the alteration of the physical porous architecture of two novel potential PRB materials (clinoptilolite and calcified seaweed) using image analysis of SEM-derived images. Results after a water treatment contaminated with heavy metals over periods of up to 10 months identified a decrease in porosity from c. 22% to c. 15% for calcified seaweed and from c. 22% to c. 18% for clinoptilolite. Porosity was reduced by as much as 37% in a calcified seaweed column that clogged. The mean pore size (2D) of both materials slightly decreased after water treatment with c. 11% reduction in calcified seaweed and c. 7% reduction in clinoptilolite. An increase in the proportion of crack-shaped pores was observed in both materials after the contaminated water treatment, most noticeably in the bottom of columns where contaminated water first reacted with the material. The distribution of pores (within a given image) derived from the distance transform indicated the largest morphological differences in materials was recorded in calcified seaweed columns, which is likely to impact significantly on their performance as barrier materials. The magnitude of porosity reduction over a short time period in relation to predicted barrier longevity suggest these and similar materials may be unsuited for barrier installation in their present form.

  3. Model-based hypothesis of gut microbe populations and gut/brain barrier permeabilities in the development of regressive autism.

    PubMed

    Downs, Ryan; Perna, Jonathon; Vitelli, Andrew; Cook, Daniel; Dhurjati, Prasad

    2014-12-01

    Regressive autism is a devastating disorder affecting children between the ages of 15-30 months. The disorder is characterized by the loss of social interaction and communication ability following otherwise healthy development. In spite of rising autism prevalence, current detection methods and treatment options for this disease are lacking. Therefore, this study introduces a systems-level model, which suggests that gut microbes and intestinal inflammation influence the onset of regressive autism through increasing gut permeability. This computational model provides a framework for quantitative understanding of how imbalances in populations of gut microbes alters the whole-body and brain distributions of neurotoxins produced by GI tract bacteria. Our results indicate that increased levels of the bacteria Bacteroides vulgatus lead to increased brain levels of propionic acid, a neurotoxin which has been known to cause symptoms characteristic of autism when injected into the brain of rats. Our results further indicate that immune response to virulence factors produced by bacteria in the gut leads to increased systemic levels of inflammatory cytokines, such as IL-1β, which significantly alter the permeability of the gut epithelial layer and the blood-brain barrier. Due to the large size of cytokines, however, we predict the time required for concentrations in the brain to stabilize to be on the order of years. This suggests that treatments preventing autism development could be administered after identifying microbial biomarkers of disease but before debilitating brain inflammation leads to regressive autism progression. Future research extending this work could provide new treatment options and diagnostic techniques to help combat regressive autism.

  4. 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

  5. Protective effects of Lactobacillus plantarum on epithelial barrier disruption caused by enterotoxigenic Escherichia coli in intestinal porcine epithelial cells.

    PubMed

    Wu, Yunpeng; Zhu, Cui; Chen, Zhuang; Chen, Zhongjian; Zhang, Weina; Ma, Xianyong; Wang, Li; Yang, Xuefen; Jiang, Zongyong

    2016-04-01

    Tight junctions (TJs) play an important role in maintaining the mucosal barrier function and gastrointestinal health of animals. Lactobacillus plantarum (L. plantarum) was reported to protect the intestinal barrier function of early-weaned piglets against enterotoxigenic Escherichia coli (ETEC) K88 challenge; however, the underlying cellular mechanism of this protection was unclear. Here, an established intestinal porcine epithelia cell (IPEC-J2) model was used to investigate the protective effects and related mechanisms of L. plantarum on epithelial barrier damages induced by ETEC K88. Epithelial permeability, expression of inflammatory cytokines, and abundance of TJ proteins, were determined. Pre-treatment with L. plantarum for 6h prevented the reduction in transepithelial electrical resistance (TEER) (P<0.05), inhibited the increased transcript abundances of interleukin-8 (IL-8) and tumor necrosis factor (TNF-α) (P<0.05), decreased expression of claudin-1, occludin and zonula occludens (ZO-1) (P<0.05) and protein expression of occludin (P<0.05) of IPEC-J2 cells caused by ETEC K88. Moreover, the mRNA expression of negative regulators of toll-like receptors (TLRs) [single Ig Il-1-related receptor (SIGIRR), B-cell CLL/lymphoma 3 (Bcl3), and mitogen-activated protein kinase phosphatase-1 (MKP-1)] in IPEC-J2 cells pre-treated with L. plantarum were higher (P<0.05) compared with those in cells just exposed to K88. Furthermore, L. plantarum was shown to regulate proteins of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. These results indicated that L. plantarum may improve epithelial barrier function by maintenance of TEER, inhibiting the reduction of TJ proteins, and reducing the expression of proinflammatory cytokines induced by ETEC K88, possibly through modulation of TLRs, NF-κB and MAPK pathways.

  6. LONG-TERM GEOCHEMICAL BEHAVIOR OF A ZEROVALENT IRON PERMEABLE REACTIVE BARRIER FOR THE TREATMENT OF HEXAVALENT CHROMIUM IN GROUNDWATER

    EPA Science Inventory

    Passive, in-situ reactive barriers have proven to be viable, cost-effective systems for the remediation of Cr-contaminated groundwater at some sites. Permeable reactive barriers (PRBs) are installed in the flow-path of groundwater, most typically as vertical treatment walls. Re...

  7. Emerging roles for anionic non-bilayer phospholipids in fortifying the outer membrane permeability barrier.

    PubMed

    Bishop, Russell E

    2014-09-01

    Lately, researchers have been actively investigating Escherichia coli lptD mutants, which exhibit reduced transport of lipopolysaccharide to the cell surface. In this issue of the Journal of Bacteriology, Sutterlin et al. (H. A. Sutterlin, S. Zhang, and T. J. Silhavy, J. Bacteriol. 196:3214-3220, 2014) now reveal an important functional role for phosphatidic acid in fortifying the outer membrane permeability barrier in certain lptD mutant backgrounds. These findings come on the heels of the first reports of two LptD crystal structures, which now provide a structural framework for interpreting lptD genetics.

  8. Emerging Roles for Anionic Non-Bilayer Phospholipids in Fortifying the Outer Membrane Permeability Barrier

    PubMed Central

    2014-01-01

    Lately, researchers have been actively investigating Escherichia coli lptD mutants, which exhibit reduced transport of lipopolysaccharide to the cell surface. In this issue of the Journal of Bacteriology, Sutterlin et al. (H. A. Sutterlin, S. Zhang, and T. J. Silhavy, J. Bacteriol. 196:3214–3220, 2014) now reveal an important functional role for phosphatidic acid in fortifying the outer membrane permeability barrier in certain lptD mutant backgrounds. These findings come on the heels of the first reports of two LptD crystal structures, which now provide a structural framework for interpreting lptD genetics. PMID:25022852

  9. Long-Term Blood-Brain Barrier Permeability Changes in Binswanger’s Disease

    PubMed Central

    Huisa, Branko N; Caprihan, Arvind; Thompson, Jeffrey; Prestopnik, Jillian; Qualls, Clifford R; Rosenberg, Gary A

    2015-01-01

    Background and Purpose The blood brain-barrier (BBB) is disrupted in small vessel disease (SVD) patients with lacunes and white matter hyperintensities (WMHs). The relationship of WMHs and regional BBB permeability changes has not been studied. We hypothesized that BBB disruption occurs in normal appearing WM (NAWM) and regions near the WMHs. To test the hypothesis, we repeated BBB permeability measurements in patients with extensive WMHs related to Binswanger’s disease (BD). Methods We selected a subset of 22 BD subjects from a well-characterized larger prospective vascular cognitive impairment cohort. We used 16 age-matched controls for comparison. The abnormal WM permeability (WMP) was measured twice over several years using dynamic contrast-enhanced MRI (DCEMRI). WMP maps were constructed from voxels above a predetermined threshold. Scans from first and second visits were co-registered. WM was divided into 3 regions: NAWM, WMH ring and WMH core. The ring was defined as 2mm on each side of the WMH border. WMP was calculated in each of the three specific regions. We used paired t-test, ANOVA and Fisher’s exact test to compare individual changes. Results WMP was significantly higher in subjects than controls (p<0.001). There was no correlation between WMH load and WMP. High permeability regions had minimal overlap between first and second scans. Nine percent of WMP was within the WMHs, 49% within the NAWM, and 52% within the WMH ring (p<0.001; ANOVA). Conclusions Increased BBB permeability in NAWM and close to the WMH borders supports a relationship between BBB disruption and development of WMHs. PMID:26205374

  10. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    PubMed

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  11. Fish dispersal in fragmented landscapes: a modeling framework for quantifying the permeability of structural barriers.

    PubMed

    Pépino, Marc; Rodríguez, Marco A; Magnan, Pierre

    2012-07-01

    Dispersal is a key determinant of the spatial distribution and abundance of populations, but human-made fragmentation can create barriers that hinder dispersal and reduce population viability. This study presents a modeling framework based on dispersal kernels (modified Laplace distributions) that describe stream fish dispersal in the presence of obstacles to passage. We used mark-recapture trials to quantify summer dispersal of brook trout (Salvelinus fontinalis) in four streams crossed by a highway. The analysis identified population heterogeneity in dispersal behavior, as revealed by the presence of a dominant sedentary component (48-72% of all individuals) characterized by short mean dispersal distance (<10 m), and a secondary mobile component characterized by longer mean dispersal distance (56-1086 m). We did not detect evidence of barrier effects on dispersal through highway crossings. Simulation of various plausible scenarios indicated that detectability of barrier effects was strongly dependent on features of sampling design, such as spatial configuration of the sampling area, barrier extent, and sample size. The proposed modeling framework extends conventional dispersal kernels by incorporating structural barriers. A major strength of the approach is that ecological process (dispersal model) and sampling design (observation model) are incorporated simultaneously into the analysis. This feature can facilitate the use of prior knowledge to improve sampling efficiency of mark-recapture trials in movement studies. Model-based estimation of barrier permeability and its associated uncertainty provides a rigorous approach for quantifying the effect of barriers on stream fish dispersal and assessing population dynamics of stream fish in fragmented landscapes.

  12. Intestinal barrier function of Atlantic salmon (Salmo salar L.) post smolts is reduced by common sea cage environments and suggested as a possible physiological welfare indicator

    PubMed Central

    2010-01-01

    Background Fish farmed under high intensity aquaculture conditions are subjected to unnatural environments that may cause stress. Therefore awareness of how to maintain good health and welfare of farmed fish is important. For Atlantic salmon held in sea cages, water flow, dissolved oxygen (DO) levels and temperature will fluctuate over time and the fish can at times be exposed to detrimentally low DO levels and high temperatures. This experimental study investigates primary and secondary stress responses of Atlantic salmon post smolts to long-term exposure to reduced and fluctuating DO levels and high water temperatures, mimicking situations in the sea cages. Plasma cortisol levels and cortisol release to the water were assessed as indicators of the primary stress response and intestinal barrier integrity and physiological functions as indicators of secondary responses to changes in environmental conditions. Results Plasma cortisol levels were elevated in fish exposed to low (50% and 60% saturation) DO levels and low temperature (9°C), at days 9, 29 and 48. The intestinal barrier function, measured as electrical resistance (TER) and permeability of mannitol at the end of the experiment, were reduced at 50% DO, in both proximal and distal intestine. When low DO levels were combined with high temperature (16°C), plasma cortisol levels were elevated in the cyclic 1:5 h at 85%:50% DO group and fixed 50% DO group compared to the control (85% DO) group at day 10 but not at later time points. The intestinal barrier function was clearly disturbed in the 50% DO group; TER was reduced in both intestinal regions concomitant with increased paracellular permeability in the distal region. Conclusions This study reveals that adverse environmental conditions (low water flow, low DO levels at low and high temperature), that can occur in sea cages, elicits primary and secondary stress responses in Atlantic salmon post smolts. The intestinal barrier function was significantly

  13. Blood-brain barrier permeability of bioactive withanamides present in Withania somnifera fruit extract.

    PubMed

    Vareed, Shaiju K; Bauer, Alison K; Nair, Kavitha M; Liu, Yunbao; Jayaprakasam, Bolleddula; Nair, Muraleedharan G

    2014-08-01

    The neuroprotective effect of Withania somnifera L. Dunal fruit extract, in rodent models, is known. Withanamides, the primary active constituents in W.somnifera fruit extract exhibited neuroprotective effects against β-amyloid-induced cytotoxicity in neuronal cell culture studies. Therefore, we investigated the blood-brain barrier permeability of withanamides in W.somnifera fruit extract in mice using HPLC coupled with high resolution quadrupole time of flight mass spectrometer (Q-TOF/MS) detection. Mice were administered with 250 mg/kg of W.somnifera extract by intraperitoneal injection, and the blood and brain samples analyzed by Q-TOF/MS detection. Four major withanamides were detected in brain and blood of mice administered with W.somnifera extract. The results suggested that the withanamides crossed the blood-brain barrier. These results may help to develop W.somnifera fruit extract as a preventive or therapeutic botanical drug for stress-induced neurological disorders.

  14. Heavy metals removal and hydraulic performance in zero-valent iron/pumice permeable reactive barriers.

    PubMed

    Moraci, Nicola; Calabrò, Paolo S

    2010-11-01

    Long-term behaviour is a major issue related to the use of zero-valent iron (ZVI) in permeable reactive barriers for groundwater remediation; in fact, in several published cases the hydraulic conductivity and removal efficiency were progressively reduced during operation, potentially compromising the functionality of the barrier. To solve this problem, the use of granular mixtures of ZVI and natural pumice has recently been proposed. This paper reports the results of column tests using aqueous nickel and copper solutions of various concentrations. Three configurations of reactive material (ZVI only, granular mixture of ZVI and pumice, and pumice and ZVI in series) are discussed. The results clearly demonstrate that iron-pumice granular mixtures perform well both in terms of contaminant removal and in maintaining the long-term hydraulic conductivity. Comparison with previous reports concerning copper removal by ZVI/sand mixtures reveals higher performance in the case of ZVI/pumice.

  15. Chemistry and microbiology of permeable reactive barriers for in situ groundwater clean up.

    PubMed

    Scherer, M M; Richter, S; Valentine, R L; Alvarez, P J

    2000-01-01

    Permeable reactive barriers (PRBs) are receiving a great deal of attention as an innovative, cost-effective technology for in situ clean up of groundwater contamination. A wide variety of materials are being proposed for use in PRBs, including zero-valent metals (e.g., iron metal), humic materials, oxides, surfactant-modified zeolites (SMZs), and oxygen- and nitrate-releasing compounds. PRB materials remove dissolved groundwater contaminants by immobilization within the barrier or transformation to less harmful products. The primary removal processes include: (1) sorption and precipitation, (2) chemical reaction, and (3) biologically mediated reactions. This article presents an overview of the mechanisms and factors controlling these individual processes and discusses the implications for the feasibility and long-term effectiveness of PRB technologies.

  16. 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.

  17. Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction

    PubMed Central

    Katzenberger, Rebeccah J; Chtarbanova, Stanislava; Rimkus, Stacey A; Fischer, Julie A; Kaur, Gulpreet; Seppala, Jocelyn M; Swanson, Laura C; Zajac, Jocelyn E; Ganetzky, Barry; Wassarman, David A

    2015-01-01

    Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood–brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction. DOI: http://dx.doi.org/10.7554/eLife.04790.001 PMID:25742603

  18. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability

    PubMed Central

    Mooney, Skyler J.; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

    2016-01-01

    Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID:27459643

  19. A procedure to design a Permeable Adsorptive Barrier (PAB) for contaminated groundwater remediation.

    PubMed

    Erto, A; Lancia, A; Bortone, I; Di Nardo, A; Di Natale, M; Musmarra, D

    2011-01-01

    A procedure to optimize the design of a Permeable Adsorptive Barrier (PAB) for the remediation of a contaminated aquifer is presented in this paper. A computer code, including different routines that describe the groundwater contaminant transport and the pollutant capture by adsorption in unsteady conditions over the barrier solid surface, has been developed. The complete characterization of the chemical-physical interactions between adsorbing solids and the contaminated water, required by the computer code, has been obtained by experimental measurements. A case study in which the procedure developed has been applied to a tetrachloroethylene (PCE)-contaminated aquifer near a solid waste landfill, in the district of Napoli (Italy), is also presented and the main dimensions of the barrier (length and width) have been evaluated. Model results show that PAB is effective for the remediation of a PCE-contaminated aquifer, since the concentration of PCE flowing out of the barrier is everywhere always lower than the concentration limit provided for in the Italian regulations on groundwater quality.

  20. Effects of Ligusticum chuanxiong and Gastrodia elata on blood-brain barrier permeability in migraine rats.

    PubMed

    Wang, Qiang; Shen, Lan; Ma, Shiyu; Chen, Meiwan; Lin, Xiao; Hong, Yanlong; Liang, Shuang; Feng, Yi

    2015-06-01

    The two herbs Ligusticum chuanxiong (LC) Hort. (Umbelliferae) and Gastrodia elata (GE) Blume (Orchidaceae), are widely used in the clinic for the treatment of migraine. This article aims to understand the effects of LC and GE on blood-brain barrier (BBB) permeability in migraine rats. Serotonin, excitatory amino acids (EAAs) and matrix metalloproteinase-9 (MMP-9) were determined at different sampling times to assess BBB disruption during a migraine attack. BBB permeability was examined by fluorescence imaging and Evans blue dye (EBD) extravasation. The results showed that the expression of serotonin in migraine rat brain was enhanced from 30 min to 120 min and glutamate (Glu) was suppressed from 30 min to 60 min in LC-GE group compared with the model group (p < 0.05 or 0.01), while the MMP-9 levels in migraine rat blood was increased at 30 min as well as decreased at 120 min in LC-GE group compared with the model group (p < 0.05 or 0.01). EBD levels in rat brain were significantly lower at 30-60 min and 120-150 min in LC-GE group than that of the model group (p < 0.05 or 0.01). Our findings demonstrated that LC and GE might decrease BBB permeability and maintain its integrity through regulating serotonin, EAAs and MMP-9 in migraine rats. PMID:26189306

  1. Aging and sex influence the permeability of the blood-brain barrier in the rat

    SciTech Connect

    Saija, A.; Princi, P.; D'Amico, N.; De Pasquale, R.; Costa, G.

    1990-01-01

    The aim of the present study was to investigate the existence of aging- and sex-related alterations in the permeability of the blood-brain barrier (BBB) in the rat, by calculating a unidirectional blood-to-brain transfer constant (Ki) for the circulating tracer ({sup 14}C)-{alpha}-aminoisobutyric acid. The authors observed that: (a) the permeability of the BBB significantly increased within the frontal and temporo-parietal cortex, hypothalamus and cerebellum in 28-30 week old rats, in comparison with younger animals; (b) in several brain areas of female intact rats higher Ki values (even though not significantly different) were calculated at oestrus than at proestrus; (c) in 1-week ovariectomized rats there was a marked increase of Ki values at the level of the frontal, temporo-parietal and occipital cortex, cerebellum and brain-stem. One can speculate that aging and sex-related alterations in thee permeability of the BBB reflect respectively changes in brain neurochemical system activity and in plasma steroid hormone levels.

  2. Heavy metal uptake and leaching from polluted soil using permeable barrier in DTPA-assisted phytoextraction.

    PubMed

    Zhao, Shulan; Shen, Zhiping; Duo, Lian

    2015-04-01

    Application of sewage sludge (SS) in agriculture is an alternative technique of disposing this waste. But unreasonable application of SS leads to excessive accumulation of heavy metals in soils. A column experiment was conducted to test the availability of heavy metals to Lolium perenne grown in SS-treated soils following diethylene triamine penta acetic acid (DTPA) application at rates of 0, 10 and 20 mmol kg(-1) soil. In order to prevent metal leaching in DTPA-assisted phytoextraction process, a horizontal permeable barrier was placed below the treated soil, and its effectiveness was also assessed. Results showed that DTPA addition significantly increased metal uptake by L. perenne shoots and metal leaching. Permeable barriers increased metal concentrations in plant shoots and effectively decreased metal leaching from the treated soil. Heavy metals in SS-treated soils could be gradually removed by harvesting L. perenne many times in 1 year and adding low dosage of DTPA days before each harvest.

  3. A2A adenosine receptor regulates the human blood brain barrier permeability

    PubMed Central

    Kim, Do-Geun; Bynoe, Margaret S.

    2015-01-01

    The blood brain barrier (BBB) symbolically represents the gateway to the central nervous system. It is a single layer of specialized endothelial cells that coats the central nervous system (CNS) vasculature and physically separates the brain environment from the blood constituents, to maintain the homeostasis of the CNS. However, this protective measure is a hindrance to the delivery of therapeutics to treat neurological diseases. Here, we show that activation of A2A adenosine receptor (AR) with an FDA-approved agonist potently permeabilizes an in vitro primary human brain endothelial barrier (hBBB) to the passage of chemotherapeutic drugs and T cells. T cell migration under AR signaling occurs primarily by paracellular transendothelial route. Permeabilization of the hBBB is rapid, time-dependent and reversible and is mediated by morphological changes in actin-cytoskeletal reorganization induced by RhoA signaling and a potent down-regulation of Claudin-5 and VE-Cadherin. Moreover, the kinetics of BBB permeability in mice closely overlaps with the permeability kinetics of the hBBB. These data suggest that activation of A2A AR is an endogenous mechanism that may be used for CNS drug delivery in human. PMID:25262373

  4. An overview of permeable reactive barriers for in situ sustainable groundwater remediation.

    PubMed

    Obiri-Nyarko, Franklin; Grajales-Mesa, S Johana; Malina, Grzegorz

    2014-09-01

    Permeable reactive barriers (PRBs) are one of the innovative technologies widely accepted as an alternative to the 'pump and treat' (P&T) for sustainable in situ remediation of contaminated groundwater. The concept of the technology involves the emplacement of a permeable barrier containing reactive materials across the flow path of the contaminated groundwater to intercept and treat the contaminants as the plume flows through it under the influence of the natural hydraulic gradient. Since the invention of PRBs in the early 1990s, a variety of materials has been employed to remove contaminants including heavy metals, chlorinated solvents, aromatic hydrocarbons, and pesticides. Contaminant removal is usually accomplished via processes such as adsorption, precipitation, denitrification and biodegradation. Despite wide acknowledgment, there are still unresolved issues about long term-performance of PRBs, which have somewhat affected their acceptability and full-scale implementation. The current paper presents an overview of the PRB technology, which includes the state of art, the merits and limitations, the reactive media used so far, and the mechanisms employed to transform or immobilize contaminants. The paper also looks at the design, construction and the long-term performance of PRBs.

  5. Fungal permeable reactive barrier to remediate groundwater in an artificial aquifer.

    PubMed

    Folch, Albert; Vilaplana, Marcel; Amado, Leila; Vicent, Teresa; Caminal, Glòria

    2013-11-15

    Biobarriers, as permeable reactive barriers (PRBs), are a common technology that mainly uses bacteria to remediate groundwater in polluted aquifers. In this study, we propose to use Trametes versicolor, a white-rot fungus, as the reactive element because of its capacity to degrade a wide variety of highly recalcitrant and xenobiotic compounds. A laboratory-scale artificial aquifer was constructed to simulate groundwater flow under real conditions in shallow aquifers. Orange G dye was chosen as a contaminant to visually monitor the hydrodynamic behaviour of the system and any degradation of the dye by the fungus. Batch experiments at different pH values (6 and 7) and several temperatures (15 °C, 18 °C, 20 °C and 25 °C) were performed to select the appropriate residence time and glucose consumption rate required for continuous treatment. The maximum Orange G degradation was 97%. Continuous degradation over 85% was achieved for more than 8 days. Experimental results indicate for the first time that this fungus can potentially be used as a permeable reactive barrier in real aquifers.

  6. An overview of permeable reactive barriers for in situ sustainable groundwater remediation.

    PubMed

    Obiri-Nyarko, Franklin; Grajales-Mesa, S Johana; Malina, Grzegorz

    2014-09-01

    Permeable reactive barriers (PRBs) are one of the innovative technologies widely accepted as an alternative to the 'pump and treat' (P&T) for sustainable in situ remediation of contaminated groundwater. The concept of the technology involves the emplacement of a permeable barrier containing reactive materials across the flow path of the contaminated groundwater to intercept and treat the contaminants as the plume flows through it under the influence of the natural hydraulic gradient. Since the invention of PRBs in the early 1990s, a variety of materials has been employed to remove contaminants including heavy metals, chlorinated solvents, aromatic hydrocarbons, and pesticides. Contaminant removal is usually accomplished via processes such as adsorption, precipitation, denitrification and biodegradation. Despite wide acknowledgment, there are still unresolved issues about long term-performance of PRBs, which have somewhat affected their acceptability and full-scale implementation. The current paper presents an overview of the PRB technology, which includes the state of art, the merits and limitations, the reactive media used so far, and the mechanisms employed to transform or immobilize contaminants. The paper also looks at the design, construction and the long-term performance of PRBs. PMID:24997925

  7. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection.

    PubMed

    Tincati, Camilla; Douek, Daniel C; Marchetti, Giulia

    2016-01-01

    Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota. PMID:27073405

  8. Quantitative assessment of the permeability of the rat blood-retinal barrier to small water-soluble non-electrolytes.

    PubMed

    Lightman, S L; Palestine, A G; Rapoport, S I; Rechthand, E

    1987-08-01

    1. The passive permeability of the blood-retinal barrier (b.r.b.) to the water-soluble non-electrolytes, sucrose and mannitol, was determined using a multiple time point-graphical approach as has been used in the assessment of blood-brain barrier (b.b.b.) permeability. 2. The calculated permeability surface area product for the b.r.b. for sucrose was 0.44 (+/- 0.081 S.E. of mean) X 10(-5) ml g-1 s-1 (n = 20) and for mannitol was 1.25 (+/- 0.30) X 10(-5) ml g-1 s-1 (n = 18). These values are similar and comparable to those found for the capillaries in the brain (P greater than 0.05) and significantly different from zero (P less than 0.01). 3. Data on the concentrations of sucrose in different parts of the eye show that the permeability of the blood-retinal barrier, rather than the more permeable blood-aqueous barrier permeability, was being measured by our technique. PMID:3119820

  9. LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms

    PubMed Central

    Schwarz, Brad T.; Wang, Fengjun; Shen, Le; Clayburgh, Daniel R.; Su, Liping; Wang, Yingmin; Fu, Yang-Xin; Turner, Jerrold R.

    2009-01-01

    BACKGROUND & AIMS LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a TNF core family member that regulates T cell activation and causes experimental inflammatory bowel disease. Additional data suggest that LIGHT may be involved in the pathogenesis of human inflammatory bowel disease. The aim of this study was to determine if LIGHT was capable of signaling directly to intestinal epithelia and to define the mechanisms and consequences of such signaling. METHODS The effects of LIGHT and interferon-γ (IFN-γ) on barrier function, cytoskeletal regulation, and tight junction structure were assessed in mice and intestinal epithelial monolayers. RESULTS LIGHT induced barrier loss in cultured epithelia via myosin II regulatory light chain (MLC) phosphorylation; both barrier loss and MLC phosphorylation were reversed by MLC kinase (MLCK) inhibition. IFN-γ pretreatment, which induced lymphotoxin β receptor (LTβR) expression, was required for these effects and neither barrier dysfunction nor intestinal epithelial MLC phosphorylation occurred in LTβR-knockout mice. In cultured monolayers, endocytosis of the tight junction protein occludin correlated with barrier loss. Internalized occludin co-localized with caveolin-1. LIGHT-induced occludin endocytosis and barrier loss were both prevented by inhibition of caveolar endocytosis. CONCLUSIONS T cell-derived LIGHT activates intestinal epithelial LTβR to disrupt barrier function. This requires MLCK activation and caveolar endocytosis. These data suggest a novel role for LIGHT in disease pathogenesis and suggest that inhibition of MLCK-dependent caveolar endocytosis may represent an approach to restoring barrier function in inflammatory bowel disease. PMID:17570213

  10. Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain.

    PubMed

    Morita, Shoko; Furube, Eriko; Mannari, Tetsuya; Okuda, Hiroaki; Tatsumi, Kouko; Wanaka, Akio; Miyata, Seiji

    2016-02-01

    Fenestrated capillaries of the sensory circumventricular organs (CVOs), including the organum vasculosum of the lamina terminalis, the subfornical organ and the area postrema, lack completeness of the blood-brain barrier (BBB) to sense a variety of blood-derived molecules and to convey the information into other brain regions. We examine the vascular permeability of blood-derived molecules and the expression of tight-junction proteins in sensory CVOs. The present tracer assays revealed that blood-derived dextran 10 k (Dex10k) having a molecular weight (MW) of 10,000 remained in the perivascular space between the inner and outer basement membranes, but fluorescein isothiocyanate (FITC; MW: 389) and Dex3k (MW: 3000) diffused into the parenchyma. The vascular permeability of FITC was higher at central subdivisions than at distal subdivisions. Neither FITC nor Dex3k diffused beyond the dense network of glial fibrillar acidic protein (GFAP)-positive astrocytes/tanycytes. The expression of tight-junction proteins such as occludin, claudin-5 and zonula occludens-1 (ZO-1) was undetectable at the central subdivisions of the sensory CVOs but some was expressed at the distal subdivisions. Electron microscopic observation showed that capillaries were surrounded with numerous layers of astrocyte processes and dendrites. The expression of occludin and ZO-1 was also observed as puncta on GFAP-positive astrocytes/tanycytes of the sensory CVOs. Our study thus demonstrates the heterogeneity of vascular permeability and expression of tight-junction proteins and indicates that the outer basement membrane and dense astrocyte/tanycyte connection are possible alternative mechanisms for a diffusion barrier of blood-derived molecules, instead of the BBB. PMID:26048259

  11. Gold Nanoparticles Increase Endothelial Paracellular Permeability by Altering Components of Endothelial Tight Junctions, and Increase Blood-Brain Barrier Permeability in Mice.

    PubMed

    Li, Ching-Hao; Shyu, Ming-Kwang; Jhan, Cheng; Cheng, Yu-Wen; Tsai, Chi-Hao; Liu, Chen-Wei; Lee, Chen-Chen; Chen, Ruei-Ming; Kang, Jaw-Jou

    2015-11-01

    Gold nanoparticles (Au-NPs) are being increasingly used as constituents in cosmetics, biosensors, bioimaging, photothermal therapy, and targeted drug delivery. This elevated exposure to Au-NPs poses systemic risks in humans, particularly risks associated with the biodistribution of Au-NPs and their potent interaction with biological barriers. We treated human umbilical vein endothelial cells with Au-NPs and comprehensively examined the expression levels of tight junction (TJ) proteins such as occludin, claudin-5, junctional adhesion molecules, and zonula occludens-1 (ZO-1), as well as endothelial paracellular permeability and the intracellular signaling required for TJ organization. Moreover, we validated the effects of Au-NPs on the integrity of TJs in mouse brain microvascular endothelial cells in vitro and obtained direct evidence of their influence on blood-brain barrier (BBB) permeability in vivo. Treatment with Au-NPs caused a pronounced reduction of PKCζ-dependent threonine phosphorylation of occludin and ZO-1, which resulted in the instability of endothelial TJs and led to proteasome-mediated degradation of TJ components. This impairment in the assembly of TJs between endothelial cells increased the permeability of the transendothelial paracellular passage and the BBB. Au-NPs increased endothelial paracellular permeability in vitro and elevated BBB permeability in vivo. Future studies must investigate the direct and indirect toxicity caused by Au-NP-induced endothelial TJ opening and thereby address the double-edged-sword effect of Au-NPs.

  12. 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

  13. Evaluation of intestinal absorption of ginsenoside Rg1 incorporated in microemulison using parallel artificial membrane permeability assay.

    PubMed

    Han, Min; Fu, Shao; Gao, Jian-Qing; Fang, Xiao-Ling

    2009-06-01

    In the present study, ginsenoside Rg(1) (Rg(1)), a naturally occurring drug which is hardly absorbed in gastrointestinal (GI) tract due to its high hydrophilicity and low membrane permeability, was incorporated in different compositions of water-in-oil microemulsions (MEs). And parallel artificial membrane permeability assay (PAMPA) that have been mainly utilized for the evaluation of in vitro permeability of early drug candidates was introduced in present study, as well as rat in vivo pharmacokinetics and in vitro permeability measurements, to investigate the effect of w/o ME on Rg(1) absorption. Correlation between various models as mentioned above was further performed to estimate the feasibility of PAMPA in the application of pharmaceutical preparation studies. After being administrated intraduodenally to rats, most of MEs can enhance the intestinal absorption of Rg(1) to various extents with relative bioavailability (F(re)) ranging from 268 to 1270% using drug solution as control. This enhanced absorption of Rg(1) may be related to its increased membrane permeability induced by ME as exhibited in the PAMPA and rat in vitro permeability measurements. Meanwhile, rat in vivo pharmacokinetics-PAMPA correlation (r(2)=0.6082) is significant (p<0.05) for ME, representing a potential prospect for the application of PAMPA in the study of pharmaceutical preparation in some conditions. PMID:19483317

  14. Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.

    PubMed

    Booth, R; Kim, H

    2014-12-01

    This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.

  15. Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability.

    PubMed

    Heye, Anna K; Thrippleton, Michael J; Armitage, Paul A; Valdés Hernández, Maria del C; Makin, Stephen D; Glatz, Andreas; Sakka, Eleni; Wardlaw, Joanna M

    2016-01-15

    There is evidence that subtle breakdown of the blood-brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n=201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a "sham" DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and K(Trans) estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability

  16. Tracer kinetic modelling for DCE-MRI quantification of subtle blood–brain barrier permeability

    PubMed Central

    Heye, Anna K.; Thrippleton, Michael J.; Armitage, Paul A.; Valdés Hernández, Maria del C.; Makin, Stephen D.; Glatz, Andreas; Sakka, Eleni; Wardlaw, Joanna M.

    2016-01-01

    There is evidence that subtle breakdown of the blood–brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n = 201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a “sham” DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and KTrans estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model

  17. Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum.

    PubMed

    Hegan, Peter S; Chandhoke, Surjit K; Barone, Christina; Egan, Marie; Bähler, Martin; Mooseker, Mark S

    2016-04-01

    Genetic studies have implicated MYO9B, which encodes myosin IXb (Myo9b), a motor protein with a Rho GTPase activating domain (RhoGAP), as a susceptibility gene for inflammatory bowel disease (IBD). Moreover, we have recently shown that knockdown of Myo9b in an intestinal epithelial cell line impairs wound healing and barrier function. Here, we investigated whether mice lacking Myo9b have impaired intestinal barrier function and features of IBD. Myo9b knock out (KO) mice exhibit impaired weight gain and fecal occult blood (indicator of gastrointestinal bleeding), and increased intestinal epithelial cell apoptosis could be detected along the entire intestinal axis. Histologic analysis revealed intestinal mucosal damage, most consistently observed in the ileum, which included superficial ulceration and neutrophil infiltration. Focal lesions contained neutrophils and ultrastructural examination confirmed epithelial discontinuity and the deposition of extracellular matrix. We also observed impaired mucosal barrier function in KO mice. Transepithelial electrical resistance of KO ileum is >3 fold less than WT ileum. The intestinal mucosa is also permeable to high molecular weight dextran, presumably due to the presence of mucosal surface ulcerations. There is loss of tight junction-associated ZO-1, decreased lateral membrane associated E-cadherin, and loss of terminal web associated cytokeratin filaments. Consistent with increased Rho activity in the KO, there is increased subapical expression of activated myosin II (Myo2) based on localization of phosphorylated Myo2 regulatory light chain. Except for a delay in disease onset in the KO, no difference in dextran sulfate sodium-induced colitis and lethality was observed between wild-type and Myo9b KO mice.

  18. An Injectable Apatite Permeable Reactive Barrier for In Situ 90Sr Immobilization

    SciTech Connect

    Vermeul, Vincent R.; Szecsody, James E.; Fritz, Brad G.; Williams, Mark D.; Moore, Robert C.; Fruchter, Jonathan S.

    2014-04-16

    An injectable permeable reactive barrier (PRB) technology was developed to sequester 90Sr in groundwater through the in situ formation of calcium-phosphate mineral phases, specifically apatite that incorporates 90Sr into the chemical structure. An integrated, multi-scale development and testing approach was used that included laboratory bench-scale experiments, an initial pilot-scale field test, and the emplacement and evaluation of a 300-ft-long treatability-test-scale PRB. Standard groundwater wells were used for emplacement of the treatment zone, allowing treatment of contaminants too deep below ground surface for trench-and-fill type PRB technologies. The apatite amendment formulation uses two separate precursor solutions, one containing a Ca-citrate complex and the other a Na-phosphate solution, to form apatite precipitate in situ. Citrate is needed to keep calcium in solution long enough to achieve a more uniform and areally extensive distribution of precipitate formation. In the summer of 2008, the apatite PRB technology was applied as a 91-m (300-ft) -long permeable reactive barrier on the downgradient edge of a 90Sr plume beneath the Hanford Site in Washington State. The technology was deployed to reduce 90Sr flux discharging to the Columbia River. Performance assessment monitoring data collected to date indicate the barrier is meeting performance objectives. The average reduction in 90Sr concentrations at four downgradient compliance monitoring locations was 95% relative to the high end of the baseline range approximately 1 year after treatment, and continues to meet remedial objectives more than 4 years after treatment.

  19. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

    PubMed Central

    Bode, Lars; Salvestrini, Camilla; Park, Pyong Woo; Li, Jin-Ping; Esko, Jeffrey D.; Yamaguchi, Yu; Murch, Simon; Freeze, Hudson H.

    2007-01-01

    Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-γ, TNF-α, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate– or syndecan-1–deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-γ, TNF-α, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients. PMID:18064305

  20. FG/FxFG as well as GLFG repeats form a selective permeability barrier with self-healing properties

    PubMed Central

    Frey, Steffen; Görlich, Dirk

    2009-01-01

    The permeability barrier of nuclear pore complexes (NPCs) controls all nucleo-cytoplasmic exchange. It is freely permeable for small molecules. Objects larger than ≈30 kDa can efficiently cross this barrier only when bound to nuclear transport receptors (NTRs) that confer translocation-promoting properties. We had shown earlier that the permeability barrier can be reconstituted in the form of a saturated FG/FxFG repeat hydrogel. We now show that GLFG repeats, the other major FG repeat type, can also form highly selective hydrogels. While supporting massive, reversible importin-mediated cargo influx, FG/FxFG, GLFG or mixed hydrogels remained firm barriers towards inert objects that lacked nuclear transport signals. This indicates that FG hydrogels immediately reseal behind a translocating species and thus possess ‘self-healing' properties. NTRs not only left the barrier intact, they even tightened it against passive influx, pointing to a role for NTRs in establishing and maintaining the permeability barrier of NPCs. PMID:19680227

  1. Zinc’s impact on intestinal barrier function and zinc trafficking during coccidial caccine challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to evaluate the effects of Zn supplementation on intestinal barrier function and Zn trafficking, three dietary regimens were formulated: a basal corn/SBM diet formulated with a Zn-free vitamin/mineral premix (Basal), and two Zn regimens formulated to provide 90 mg/kg total dietary Zn from ...

  2. Enhancing Effect of Trachelogenin from Trachelospermi caulis Extract on Intestinal Barrier Function.

    PubMed

    Shin, Hee Soon; Bae, Min-Jung; Jung, Sun Young; See, Hye-Jeong; Kim, Yun Tai; Do, Jeong-Ryong; Back, Su Yeon; Choi, Sang-Won; Shon, Dong-Hwa

    2015-01-01

    Trachelospermi caulis is used widely as an herbal medicine in oriental countries to attenuate fever and pain. We wished to reveal the novel function of this herb and its active component on barrier function in intestinal epithelial cells. Monolayers of intestinal epithelial cells (Caco-2) were used to evaluate the transepithelial electrical resistance (TEER) and quantity of permeated ovalbumin (OVA) as indices of barrier function. T. caulis increased TEER values on cell monolayers and decreased OVA permeation across cell monolayers. To ascertain the active component of T. caulis, the extract was isolated to five fractions, and the effect of each of these fractions on intestinal barrier function examined. Chloroform and ethyl acetate fractions showed increased TEER values and decreased OVA flux. Chloroform and ethyl acetate fractions contained mainly trachelogenin and its glycoside, tracheloside. Trachelogenin increased TEER values and decreased OVA flux by enhancing the tight-junction protein occludin (but not tracheloside) in Caco-2 monolayers. These findings demonstrated that trachelogenin, an active component of T. caulis, might help to attenuate food allergy or inflammatory bowel disease through inhibition of allergen permeation or enhancement of the intestinal barrier. PMID:26268064

  3. Age-related differences in mucosal barrier function and morphology of the small intestine in low and normal birth weight piglets.

    PubMed

    Huygelen, V; De Vos, M; Willemen, S; Fransen, E; Casteleyn, C; Van Cruchten, S; Van Ginneken, C

    2014-08-01

    To test the hypothesis that the mucosal maturation of the small intestine is altered in low birth weight piglets, pairs of naturally suckled low birth weight (LBW, n = 20) and normal birth weight (NBW, n = 20) littermate piglets were selected and sampled after 0, 3, 10, and 28 d of suckling. In vivo intestinal permeability was evaluated via a lactulose-mannitol absorption test. Other indirect measurements for mucosal barrier functioning included sampling for histology and immunohistochemistry (intestinal trefoil factor [ITF]), measuring intestinal alkaline phosphatase (IAP) activity, and immunoblotting for occludin, caspase-3, and proliferating cell nuclear antigen (PCNA). The lactulose-mannitol ratio did not differ between NBW and LBW piglets, but a significant increase in this ratio was observed in 28-d-old piglets (P = 0.001). Small intestinal villus height did not differ with age (P = 0.02) or birth weight (P = 0.20). In contrast, villus width (P = 0.02) and crypt depth (P < 0.05) increased gradually with age, but no birth-weight-related differences were observed. LBW piglets had significantly (P = 0.03) more ITF immunoreactive positive cells per villus area compared to NBW piglets, whereas no age (P = 0.82) or region-related (P = 0.13) differences could be observed. The activity of IAP in the small intestine was higher in newborn piglets compared to the older piglets. No significant differences in cell proliferation in the small intestine was observed (P = 0.47) between NBW and LBW piglets; the highest proliferation was seen in piglets of 28 d of age (P = 0.01). Newborn piglets had significantly fewer apoptotic cells, whereas more apoptotic cells were seen in piglets of 10 d of age (P < 0.01). In conclusion, birth weight did not affect the parameters related to intestinal barrier function investigated in this study, suggesting that the mucosal barrier function is not altered in LBW piglets. Nevertheless, these results confirm that the mucosal barrier function

  4. Yersinia enterocolitica Affects Intestinal Barrier Function in the Colon.

    PubMed

    Hering, Nina A; Fromm, Anja; Kikhney, Judith; Lee, In-Fah M; Moter, Annette; Schulzke, Jörg D; Bücker, Roland

    2016-04-01

    Infection with Yersinia enterocolitica causes acute diarrhea in early childhood. A mouse infection model presents new findings on pathological mechanisms in the colon. Symptoms involve diarrhea with watery feces and weight loss that have their functional correlates in decreased transepithelial electrical resistance and increased fluorescein permeability. Y. enterocolitica was present within the murine mucosa of both ileum and colon. Here, the bacterial insult was of focal nature and led to changes in tight junction protein expression and architecture. These findings are in concordance with observations from former cell culture studies and suggest a leak flux mechanism of diarrhea.

  5. Remediation of TCE-contaminated groundwater by a permeable reactive barrier filled with plant mulch (Biowall).

    PubMed

    Lu, Xiaoxia; Wilson, John T; Shen, Hai; Henry, Bruce M; Kampbell, Donald H

    2008-01-01

    A pilot-scale permeable reactive barrier filled with plant mulch was installed at Altus Air Force Base in Oklahoma, USA to treat trichloroethylene (TCE) contamination in groundwater emanating from a landfill. The barrier was constructed in June 2002. It was 139 meters long, 7 meters deep, and 0.5 meters wide. The barrier is also called a Biowall because one of the mechanisms for removal of TCE is anaerobic biodegradation. This study aimed at evaluating the performance of the pilot-scale Biowall after its installation. Data from over four years' monitoring indicated that the Biowall greatly changed geochemistry in the study area and stimulated TCE removal. The concentration of TCE in the Biowall and downgradient of the Biowall was greatly reduced as compared to that in ground water upgradient of the Biowall, while the concentration of cis-DCE in the Biowall and downgradient of the Biowall was much higher than that observed upgradient of the Biowall. Over time, the concentration of vinyl chloride in the Biowall and downgradient of the Biowall increased. Dehalococcoides DNA was detected within and downgradient of the Biowall, corresponding to the observation that vinyl chloride was produced at these locations. Results from a tracer study indicated that the regional groundwater flow pattern ultimately determined the flow direction in the area around the Biowall. The natural groundwater velocity was estimated at an average of 0.060 +/- 0.015 m/d.

  6. Performance evaluation of a permeable reactive barrier for remediation of dissolved chlorinated solvents in groundwater.

    PubMed

    Vogan, J L; Focht, R M; Clark, D K; Graham, S L

    1999-08-12

    A pilot-scale permeable reactive barrier (PRB) consisting of granular iron was installed in May 1995 at an industrial facility in New York to evaluate the use of this technology for remediation of chlorinated volatile organic compounds (VOCs) in groundwater. The performance of the barrier was monitored over a 2-year period. Groundwater velocity through the barrier was determined using water level measurements, tracer tests, and in situ velocity measurements. While uncertainty in the measured groundwater velocity hampered interpretation of results, the VOC concentration data from wells in the PRB indicated that VOC degradation rates were similar to those anticipated from laboratory results. Groundwater and core analyses indicated that formation of carbonate precipitates occurred in the upgradient section of the iron zone, however, these precipitates did not appear to adversely affect system performance. There was no indication of microbial fouling of the system over the monitoring period. Based on the observed performance of the pilot, a full-scale iron PRB was installed at the site in December 1997.

  7. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease.

    PubMed

    Nalle, S C; Turner, J R

    2015-07-01

    Compromised intestinal barrier function is a prominent feature of inflammatory bowel disease (IBD). However, links between intestinal barrier loss and disease extend much further, including documented associations with celiac disease, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Intestinal barrier loss has also been proposed to have a critical role in the pathogenesis of graft-versus-host disease (GVHD), a serious, potentially fatal consequence of hematopoietic stem cell transplantation. Experimental evidence has begun to support this view, as barrier loss and its role in initiating and establishing a pathogenic inflammatory cycle in GVHD is emerging. Here we discuss similarities between IBD and GVHD, mechanisms of intestinal barrier loss in these diseases, and the crosstalk between barrier loss and the immune system, with a special focus on natural killer (NK) cells. Unanswered questions and future research directions on the topic are discussed along with implications for treatment.

  8. Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice

    PubMed Central

    Sun, Xiaofeng; Cárdenas, Andrés; Wu, Yan; Enjyoji, Keichi; Robson, Simon C.

    2009-01-01

    Vasoactive factors that regulate splanchnic hemodynamics include nitric oxide, catecholamines, and possibly extracellular nucleosides/nucleotides (adenosine, ATP). CD39/ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1) is the major vascular ectonucleotidase that hydrolyzes extracellular nucleotides. CD39 activity may be modulated by vascular injury, inflammation, and altered oxygen tension. Altered Cd39 expression by the murine hepatosplanchnic vasculature may impact hemodynamics and portal hypertension (PHT) in vivo. We noted that basal portal pressures (PPs) were comparable in wild-type and Cd39-null mice (n = 9). ATP infusions resulted in increments in PP in wild-type mice, but, in contrast, this significantly decreased in Cd39-null mice (n = 9) post-ATP in a nitric oxide-dependent manner. We then studied Cd39/NTPDase1 deletion in the regulation of portal hemodynamics, vascular integrity, and intestinal permeability in a murine model of PHT. Partial portal vein ligation (PPVL) was performed in Cd39-null (n = 44) and wild-type (n = 23) mice. Sequential measurements obtained after PPVL were indicative of comparable levels of PHT (ranges 14–29 mmHg) in both groups. There was one death in the wild-type group and eight in the Cd39-null group from intestinal bleeding (P = 0.024). Circulatory stasis in the absence of overt portal vein thrombosis, portal congestion, intestinal hemorrhage, and increased permeability were evident in all surviving Cd39-null mice. Deletion of Cd39 results in deleterious outcomes post-PPVL that are associated with significant microcirculatory derangements and major intestinal congestion with hemorrhage mimicking acute mesenteric occlusion. Absent Cd39/NTPDase1 and decreased generation of adenosine in the splanchnic circulation cause heightened vascular permeability and gastrointestinal hemorrhage in PPVL. PMID:19520738

  9. Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

    PubMed Central

    Braniste, Viorica; Jouault, Aurore; Gaultier, Eric; Polizzi, Arnaud; Buisson-Brenac, Claire; Leveque, Mathilde; Martin, Pascal G.; Theodorou, Vassilia; Fioramonti, Jean; Houdeau, Eric

    2009-01-01

    Bisphenol A (BPA), a chemical estrogen widely used in the food-packaging industry and baby bottles, is recovered in human fluids (0.1–10 nM). Recent studies have reported that BPA is hormonally active at low doses, emphasizing the debate of a risk for human health. Estrogen receptors are expressed in the colon, and although the major route of BPA exposure is food, the effects on gut have received no attention. We first examined the endocrine disrupting potency of BPA on colonic paracellular permeability (CPP), experimental colitis, and visceral sensitivity in ovariectomized rats orally exposed to 5 mg/kg/d BPA (i.e., the no observed adverse effect level), 50 μg/kg/d BPA (i.e., tolerable daily intake), or lower doses. BPA dose-dependently decreased basal CPP, with a half-maximal inhibitory dose of 5.2 μg/kg/d, 10-fold below the tolerable daily intake. This correlated with an increase in epithelial tight junction sealing, also observed in Caco-2 cells exposed to 10 nM BPA. When ovariectomized rats were fed with BPA at the no observed adverse effect level, the severity of colitis was reduced, whereas the same dose increased pain sensitivity to colorectal stimuli. We then examined the impact of perinatal exposure to BPA on intestinal permeability and inflammatory response in the offspring. In female rats, but not in male rats, perinatal BPA evoked a decrease of CPP in adulthood, whereas the proinflammatory response of colonic mucosa was strengthened. This study first demonstrates that the xenoestrogen BPA at reference doses influences intestinal barrier function and gut nociception. Moreover, perinatal exposure promotes the development of severe inflammation in adult female offspring only. PMID:20018722

  10. Organic/inorganic nanocomposites, methods of making, and uses as a permeable reactive barrier

    DOEpatents

    Harrup, Mason K.; Stewart, Frederick F.

    2007-05-15

    Nanocomposite materials having a composition including an inorganic constituent, a preformed organic polymer constituent, and a metal ion sequestration constituent are disclosed. The nanocomposites are characterized by being single phase, substantially homogeneous materials wherein the preformed polymer constituent and the inorganic constituent form an interpenetrating network with each other. The inorganic constituent may be an inorganic oxide, such as silicon dioxide, formed by the in situ catalyzed condensation of an inorganic precursor in the presence of the solvated polymer and metal ion sequestration constituent. The polymer constituent may be any hydrophilic polymer capable of forming a type I nanocomposite such as, polyacrylonitrile (PAN), polyethyleneoxide (PEO), polyethylene glycol (PEG), polyvinyl acetate (PVAc), polyvinyl alcohol (PVA), and combinations thereof. Nanocomposite materials of the present invention may be used as permeable reactive barriers (PRBs) to remediate contaminated groundwater. Methods for making nanocomposite materials, PRB systems, and methods of treating groundwater are also disclosed.

  11. Evaluation of a permeable reactive barrier to capture and degrade hydrocarbon contaminants.

    PubMed

    Mumford, K A; Powell, S M; Rayner, J L; Hince, G; Snape, I; Stevens, G W

    2015-08-01

    A permeable reactive barrier (PRB) was installed during 2005/2006 to intercept, capture and degrade a fuel spill at the Main Power House, Casey Station, Antarctica. Here, evaluation of the performance of the PRB is conducted via interpretation of total petroleum hydrocarbon (TPH) concentrations, degradation indices and most probable number (MPN) counts of total heterotroph and fuel degrading microbial populations. Results indicate that locations which contained the lowest TPH concentrations also exhibited the highest levels of degradation and numbers of fuel degrading microbes, based on the degradation indices and MPN methods selected. This provides insights to the most appropriate reactive materials for use in PRB's in cold and nutrient-limited environments. PMID:25899942

  12. AN IN-SITU PERMEABLE REACTIVE BARRIER FOR THE TREATMENT OF HEXAVALENT CHROMIUM AND TRICHLOROETHYLENE IN GROUNDWATER: VOLUME 3 MULTICOMPONENT REACTIVE TRANSPORT MODELING

    EPA Science Inventory

    Reactive transport modeling has been conducted to describe the performance of the permeable reactive barrier at the Coast Guard Support Center near Elizabeth City, NC. The reactive barrier was installed to treat groundwater contaminated by hexavalent chromium and chlorinated org...

  13. Effects of Probiotics on Intestinal Mucosa Barrier in Patients With Colorectal Cancer after Operation

    PubMed Central

    Liu, Dun; Jiang, Xiao-Ying; Zhou, Lan-Shu; Song, Ji-Hong; Zhang, Xuan

    2016-01-01

    Abstract Many studies have found that probiotics or synbiotics can be used in patients with diarrhea or inflammatory bowel disease for the prevention and treatment of some pathologies by improving gastrointestinal barrier function. However, there are few studies availing the use of probiotics in patients with colorectal cancer. To lay the foundation for the study of nutritional support in colorectal cancer patients, a meta-analysis has been carried out to assess the efficacy of probiotics on the intestinal mucosa barrier in patients with colorectal cancer after operation. To estimate the efficacy of probiotics on the intestinal mucosa barrier in patients with colorectal cancer after operation, a meta-analysis of randomized controlled trials has been conducted. Databases including PubMed, Ovid, Embase, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure have been searched to identify suitable studies. Stata 12.0 was used for statistical analysis, and sensitivity analysis was also conducted. Six indicators were chosen to evaluate probiotics in protecting the intestinal mucosa barrier in patients with colorectal cancer. Ratios of lactulose to mannitol (L/M) and Bifidobacterium to Escherichia (B/E), occludin, bacterial translocation, and levels of secretory immunoglobulin A (SIgA), interleukin-6 (IL-6), and C-reactive protein (CRP) were chosen to evaluate probiotics in protecting the intestinal mucosa barrier in patients with colorectal cancer. Seventeen studies including 1242 patients were selected for meta-analysis, including 5 English studies and 12 Chinese studies. Significant effects were found in ratios of L/M (standardized mean difference = 3.83, P = 0.001) and B/E (standardized mean difference = 3.91, P = 0.000), occludin (standardized mean difference = 4.74, P = 0.000), bacterial translocation (standardized mean difference = 3.12, P = 0.002), and levels of SIgA (standardized mean

  14. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    PubMed

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  15. High therapeutic efficacy of Cathelicidin-WA against postweaning diarrhea via inhibiting inflammation and enhancing epithelial barrier in the intestine

    PubMed Central

    Yi, Hongbo; Zhang, Lin; Gan, Zhenshun; Xiong, Haitao; Yu, Caihua; Du, Huahua; Wang, Yizhen

    2016-01-01

    Diarrhea is a leading cause of death among young mammals, especially during weaning. Here, we investigated the effects of Cathelicidin-WA (CWA) on diarrhea, intestinal morphology, inflammatory responses, epithelial barrier and microbiota in the intestine of young mammals during weaning. Piglets with clinical diarrhea were selected and treated with saline (control), CWA or enrofloxacin (Enro) for 4 days. Both CWA and Enro effectively attenuated diarrhea. Compared with the control, CWA decreased IL-6, IL-8 and IL-22 levels and reduced neutrophil infiltration into the jejunum. CWA inhibited inflammation by down-regulating the TLR4-, MyD88- and NF-κB-dependent pathways. Additionally, CWA improved intestinal morphology by increasing villus and microvillus heights and enhancing intestinal barrier function by increasing tight junction (TJ) protein expression and augmenting wound-healing ability in intestinal epithelial cells. CWA also improved microbiota composition and increased short-chain fatty acid (SCFA) levels in feces. By contrast, Enro not only disrupted the intestinal barrier but also negatively affected microbiota composition and SCFA levels in the intestine. In conclusion, CWA effectively attenuated inflammation, enhanced intestinal barrier function, and improved microbiota composition in the intestines of weaned piglets. These results suggest that CWA could be an effective and safe therapy for diarrhea or other intestinal diseases in young mammals. PMID:27181680

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

    PubMed

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

    2015-02-16

    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.

  17. 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

  18. Dimethyl sulfoxide inhibits zymosan-induced intestinal inflammation and barrier dysfunction

    PubMed Central

    Li, Yu-Meng; Wang, Hai-Bin; Zheng, Jin-Guang; Bai, Xiao-Dong; Zhao, Zeng-Kai; Li, Jing-Yuan; Hu, Sen

    2015-01-01

    AIM: To investigate whether dimethyl sulfoxide (DMSO) inhibits gut inflammation and barrier dysfunction following zymosan-induced systemic inflammatory response syndrome and multiple organ dysfunction syndrome. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham with administration of normal saline (SS group); sham with administration of DMSO (SD group); zymosan with administration of normal saline (ZS group); and zymosan with administration of DMSO (ZD group). Each group contained three subgroups according to 4 h, 8 h, and 24 h after surgery. At 4 h, 8 h, and 24 h after intraperitoneal injection of zymosan (750 mg/kg), the levels of intestinal inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-10] and oxides (myeloperoxidase, malonaldehyde, and superoxide dismutase) were examined. The levels of diamine oxidase (DAO) in plasma and intestinal mucosal blood flow (IMBF) were determined. Intestinal injury was also evaluated using an intestinal histological score and apoptosis of intestinal epithelial cells was determined by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The intestinal epithelial tight junction protein, ZO-1, was observed by immunofluorescence. RESULTS: DMSO decreased TNF-α and increased IL-10 levels in the intestine compared with the ZS group at the corresponding time points. The activity of intestinal myeloperoxidase in the ZS group was higher than that in the ZD group 24 h after zymosan administration (P < 0.05). DMSO decreased the content of malondialdehyde (MDA) and increased the activity of superoxide dehydrogenase (SOD) 24 h after zymosan administration. The IMBF was lowest at 24 h and was 49.34% and 58.26% in the ZS group and ZD group, respectively (P < 0.05). DMSO alleviated injury in intestinal villi, and the gut injury score was significantly lower than the ZS group (3.6 ± 0.2 vs 4.2 ± 0.3, P < 0.05). DMSO decreased the level of DAO in plasma compared with the ZS

  19. Partial Enteral Nutrition Mitigated Ischemia/Reperfusion-Induced Damage of Rat Small Intestinal Barrier

    PubMed Central

    Wu, Chao; Wang, Xinying; Jiang, Tingting; Li, Chaojun; Zhang, Li; Gao, Xuejin; Tian, Feng; Li, Ning; Li, Jieshou

    2016-01-01

    Background and Aims: This study was designed to investigate a relatively optimum dose of partial enteral nutrition (PEN) which effectively attenuates intestinal barrier dysfunction initiated by ischemia/reperfusion injury (IRI). Methods: In experiment 1, 60 male Sprague-Dawley (SD) rats were subjected to intestinal IRI and assigned to six groups according to the different proportion of EN administrations: namely total parenteral nutrition (TPN or 0%EN), 10%EN, 20%EN, 40%EN, 60%EN, and total enteral nutrition (TEN or 100%) groups, the deficits of intraluminal calorie were supplemented by PN. In experiment 2, 50 male SD rats were subjected to intestinal IRI and divided into five groups based on the results of experiment 1: TPN, TEN, 20%EN, TPN plus pretreatment with NF-κB antagonist 30 min before IRI (TPN+PDTC), and TPN plus pretreatment with HIF-1α antagonist 30 min before IRI (TPN+YC-1) groups. Results: In experiment 1, previous IRI combined with subsequent EN shortage disrupted the structure of intestinal epithelial cell and tight junctions (TJs). While 20% dose of EN had an obviously protective effect on these detrimental consequences. In experiment 2, compared with TPN only, 20%EN exerted a significant protection of barrier function of intestinal epithelium. Analogous results were observed when TPN combined with specific NF-κB/HIF-1α inhibitors (PDTC and YC-1). Meanwhile, the expression of NF-κB/HIF-1α had a similar trend among the groups. Conclusions: Our findings indicate that 20%EN is the minimally effective dosage of EN which promotes the recovery of intestinal barrier function after IRI in a rat model. Furthermore, we discreetly speculate that this benefit is, at least partly, related to NF-κB/HIF-1α pathway expression. PMID:27548209

  20. Extracellular fluid movement in the pulp; the pulp/dentin permeability barrier.

    PubMed

    Bishop, M A

    1992-01-01

    Fluid movement in the pulp depends largely upon the physiology of the blood vessels; normally there is a net efflux of fluid and proteins from the capillaries into the extracellular environment. Most pulp capillaries lie close to the odontoblast layer and in order to see whether fluid can pass between the odontoblasts into the predentin we have perfused the vessels of molar tooth germs in anesthetized piglets with the electron dense tracer lanthanum. The results show that the tracer permeates the capillaries but encounters a barrier to permeability at the apical (predentinal) ends of the odontoblasts. The completeness of the barrier to the tracer lanthanum is discussed together with structural evidence of tight junctions between odontoblasts in both pigs and humans and the presence of collagen fibers through the tight junctional zone. It is concluded that there is little or no evidence that pulp fluid is normally confluent with predentin. An advantage of this arrangement may be that by maintaining an enclosed microenvironment it permits regulation of the orderly process of matrix deposition and mineralization of predentin to dentin. In order to maintain constant vascular and extracellular fluid pressures the capillary efflux has to be balanced by fluid removal; recent work in cats has shown that lymphatic vessels are available to transport fluid out of the pulp. In this paper the differences in the intrapulpal distribution of these vessels have been extrapolated to human teeth in an attempt to explain certain variations in the symptoms and progress of pulpal inflammatory conditions. PMID:1508889

  1. Asef controls vascular endothelial permeability and barrier recovery in the lung

    PubMed Central

    Tian, Xinyong; Tian, Yufeng; Gawlak, Grzegorz; Meng, Fanyong; Kawasaki, Yoshihiro; Akiyama, Tetsu; Birukova, Anna A.

    2015-01-01

    Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac-GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef−/− mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury. PMID:25518936

  2. Asef controls vascular endothelial permeability and barrier recovery in the lung.

    PubMed

    Tian, Xinyong; Tian, Yufeng; Gawlak, Grzegorz; Meng, Fanyong; Kawasaki, Yoshihiro; Akiyama, Tetsu; Birukova, Anna A

    2015-02-15

    Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac-GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef(-/-) mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury. PMID:25518936

  3. Iron hydroxy carbonate formation in zerovalent iron permeable reactive barriers: characterization and evaluation of phase stability.

    PubMed

    Lee, Tony R; Wilkin, Richard T

    2010-07-30

    Predicting the long-term potential of permeable reactive barriers for treating contaminated groundwater relies on understanding the endpoints of biogeochemical reactions between influent groundwater and the reactive medium. Iron hydroxy carbonate (chukanovite) is frequently observed as a secondary mineral precipitate in granular iron PRBs. Mineralogical characterization was carried out using X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, and X-ray absorption spectroscopy on materials collected from three field-based PRBs in the US (East Helena, MT; Elizabeth City, NC; Denver Federal Center, CO). These PRBs were installed to treat a range of contaminants, including chlorinated organics, hexavalent chromium, and arsenic. Results obtained indicate that chukanovite is a prevalent secondary precipitate in the PRBs. Laboratory experiments on high-purity chukanovite separates were carried out to constrain the room-temperature solubility for this mineral. An estimated Gibbs energy of formation (Delta(f)G degrees) for chukanovite is -1174.4 +/- 6 kJ/mol. A mineral stability diagram is consistent with observations from the field. Water chemistry from the three reactive barriers falls inside the predicted stability field for chukanovite, at inorganic carbon concentrations intermediate to the stability fields of siderite and ferrous hydroxide. These new data will aid in developing better predictive models of mineral accumulation in zerovalent iron PRBs.

  4. Injection-extraction treatment well pairs: an alternative to permeable reactive barriers.

    PubMed

    Cunningham, Jeffrey A; Reinhard, Martin

    2002-01-01

    Two of the biggest drawbacks of using permeable reactive barriers (PRBs) to treat contaminated ground water are the high capital cost of installation, particularly when the contaminated ground water is deep below ground surface, and the uncertainty of whether or not PRBs remain effective for the long time scales (e.g., decades) needed for many contaminant plumes. The use of an injection-extraction treatment well pair (IETWP) for capture and treatment of contaminated ground water can circumvent these difficulties, while still providing many of the same advantages offered by PRBs. In this paper, the hydraulics of IETWPs and PRBs are compared, focusing primarily on the width of the captured plume. It is demonstrated that IETWPs act as hydraulic barriers in a manner similar to PRBs, and that IETWPs provide excellent plume capture. A mathematical expression is presented for the plume capture width of an IETWP oriented perpendicular to the ground water flow direction in a homogeneous aquifer. Also discussed are other practical considerations that might determine whether an IETWP is better suited than a PRB for a particular contaminated site; these considerations include operating and maintenance costs, and the conditions under which an IETWP system can be used for in situ remediation.

  5. Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test

    PubMed Central

    Gerova, Vanya A; Stoynov, Simeon G; Katsarov, Dimitar S; Svinarov, Dobrin A

    2011-01-01

    AIM: To study intestinal permeability (IP) and its relationship to the disease activity in patients with inflammatory bowel diseases (IBD) - Crohn’s disease (CD) and ulcerative colitis (UC). METHODS: Fifty-eight patients with active IBD (32 with CD and 26 with UC) and 25 healthy controls consented to participate in the study. The clinical activity of CD was estimated using the Crohn’s Disease Activity Index (CDAI), and the endoscopic activity of UC using the Mayo scoring system. IP was assessed by the rise in levels of iohexol, which was administered orally (25 mL, 350 mg/mL) 2 h after breakfast. Three and six hours later serum (SIC mg/L) and urine (UIC g/mol) iohexol concentrations were determined by a validated HPLC-UV technique. RESULTS: In the CD group, SIC values at 3 h (2.95 ± 2.11 mg/L) and at 6 h after ingestion (2.63 ± 2.18 mg/L) were significantly higher compared to those of healthy subjects (1.25 ± 1.40 mg/L and 1.11 ± 1.10 mg/L, respectively, P < 0.05). UIC (g/mol) values were also higher in patients, but the differences were significant only for UIC at 6 h. Significant positive correlation (P < 0.05) was found between the CDAI and IP, assessed by SIC at 3 h (r = 0.60) and 6 h (r = 0.74) after the ingestion. In comparison to controls, SIC and UIC of UC patients were higher in the two studied periods, but the differences were significant at 6 h only. Significantly higher values of SIC (P < 0.05) were found in patients with severe endoscopic activity of UC compared to those of patients with mild and moderate activity (3.68 ± 3.18 vs 0.92 ± 0.69 mg/L). CONCLUSION: Serum levels of iohexol at 3 h and 6 h after its ingestion reflect increased IP, which is related to the disease activity in patients with IBD. PMID:21633531

  6. PERMEABLE REACTIVE SUBSURFACE BARRIERS FOR THE INTERCEPTION AND REMEDIATION OF CHLORINATED HYDROCARBON AND CHROMIUM (VI) PLUMES IN GROUND WATER

    EPA Science Inventory

    This document concerns the use of permeable reactive subsurface barriers for the remediation of plumes of chlorinated hydrocarbons and Cr(VI) species in ground water, using zero-valent iron (Fe0) as the reactive substrate. Such systems have undergone thorough laboratory research,...

  7. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS USING ZERO-VALENT IRON: GEOCHEMICAL AND MICROBIOLOGICAL EFFECTS

    EPA Science Inventory

    Geochemical and microbiological factors that control long-term performance of subsurface permeable reactive barriers were evaluated at the Elizabeth City, NC and the Denver Federal Center, CO sites. These ground water treatment systems use zero-valent iron filings (Peerless Meta...

  8. SCANNING ELECTRON ANALYSIS OF IRON FILINGS FROM A ZERO-VALENT IRON PERMEABLE BARRIER USED FOR GROUND WATER RESTORATION

    EPA Science Inventory

    Permeable iron reactive barriers have become a popular way to remediate contaminated ground water. Although this technology has been in use for about a decade, there is still little knowledge about long-term performance issues (l). One of the biggest concerns is the corrosion of ...

  9. Fifteen-year Assessment of a Permeable Reactive Barrier for Treatment of Chromate and Trichloroethylene in Groundwater

    EPA Science Inventory

    The fifteen-year performance of a granular iron, permeable reactive barrier (PRB; Elizabeth City, North Carolina) is reviewed with respect to contaminant treatment (hexavalent chromium and trichloroethylene) and hydraulic performance. Due to in-situ treatment of the chromium sou...

  10. Transformation of Reactive Iron Minerals in a Permeable Reactive Barrier (Biowall) Used to Treat TCE in Groundwater

    EPA Science Inventory

    Abstract: Iron and sulfur reducing conditions are generally created in permeable reactive barrier (PRB) systems constructed for groundwater treatment, which usually leads to formation of iron sulfide phases. Iron sulfides have been shown to play an important role in degrading ch...

  11. TREATMENT OF METALS IN GROUND WATER USING AN ORGANIC-BASED SULFATE-REDUCING PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    A pilot permeable reactive barrier (PRB) consisting of a mixture of leaf compost, zero-valent iron (ZVI) filings, limestone and pea gravel was evaluated at a former phosphate fertilizer manufacturing facility in Charleston, S.C. The PRB is designed to treat arsenic and heavy met...

  12. Calcium carbonate-based permeable reactive barriers for iron and manganese groundwater remediation at landfills.

    PubMed

    Wang, Yu; Pleasant, Saraya; Jain, Pradeep; Powell, Jon; Townsend, Timothy

    2016-07-01

    High concentrations of iron (Fe(II)) and manganese (Mn(II)) reductively dissolved from soil minerals have been detected in groundwater monitoring wells near many municipal solid waste landfills. Two in situ permeable reactive barriers (PRBs), comprised of limestone and crushed concrete, were installed downgradient of a closed, unlined landfill in Florida, USA, to remediate groundwater containing high concentrations of these metals. Influent groundwater to the PRBs contained mean Fe and Mn concentrations of approximately 30mg/L and 1.62mg/L, respectively. PRBs were constructed in the shallow aquifer (maximum depth 4.6m below land surface) and groundwater was sampled from a network of nearby monitoring wells to evaluate barrier performance in removing these metals. PRBs significantly (p<0.05) removed dissolved Fe and Mn from influent groundwater; Fe was removed from influent water at average rates of 91% and 95% (by mass) for the limestone and crushed concrete PRBs, respectively, during the first year of the study. The performance of the PRBs declined after 3years of operation, with Fe removal efficiency decreasing to 64% and 61% for limestone and concrete PRBs, respectively. A comparison of water quality in shallow and deep monitoring wells showed a more dramatic performance reduction in the deeper section of the concrete PRB, which was attributed to an influx of sediment into the barrier and settling of particulates from the upper portions of the PRBs. Although removal of Fe and Mn from redox impacts was achieved with the PRBs, the short time frame of effectiveness relative to the duration of a full-scale remediation effort may limit the applicability of these systems at some landfills because of the construction costs required.

  13. 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.

  14. Effects of oral adenosine 5'-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study

    PubMed Central

    Bours, Martijn JL; Bos, Hilde J; Meddings, Jon B; Brummer, Robert-Jan M; van den Brandt, Piet A; Dagnelie, Pieter C

    2007-01-01

    Background It is well-known that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the small bowel associated with disruption of mucosal barrier function. In healthy human volunteers, we showed previously that topical administration of adenosine 5'-triphosphate (ATP) by naso-intestinal tube attenuated a rise in small intestinal permeability induced by short-term challenge with the NSAID indomethacin. This finding suggested that ATP may be involved in the preservation of intestinal barrier function. Our current objective was to corroborate the favourable effect of ATP on indomethacin-induced permeability changes in healthy human volunteers when ATP is administered via enteric-coated capsules, which is a more practically feasible mode of administration. Since ATP effects may have been partly mediated through its breakdown to adenosine, effects of encapsulated adenosine were tested also. Methods By ingesting a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by five-hour collection of total urine, small intestinal permeability was assessed in 33 healthy human volunteers by measuring the urinary lactulose/rhamnose excretion ratio. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal permeability of the small intestine was assessed as a control condition (no indomethacin, no ATP/adenosine). As a model of increased small intestinal permeability, two dosages of indomethacin were ingested at 10 h (75 mg) and 1 h (50 mg) before ingesting the lactulose/rhamnose test drink. At 1.5 h before indomethacin ingestion, two dosages of placebo, ATP (2 g per dosage) or adenosine (1 g per dosage) were administered via enteric-coated hydroxypropyl methylcellulose (HPMC) capsules with Eudragit© L30D-55. Results Median urinary lactulose/rhamnose excretion ratio (g/g) in the control condition was 0.032 (interquartile range: 0.022–0.044). Compared to the control condition

  15. Morphological evidence for a permeability barrier in the testis and spermatic duct of Gymnotus carapo (Teleostei: Gymnotidae).

    PubMed

    Meneguelli De Souza, Lara C; Retamal, Claudio A; Rocha, Gustavo M; Lopez, Maria Luisa

    2015-09-01

    Cell-cell interactions play essential roles in the regulation of gametogenesis. The involvement of junctional complexes in permeability barriers, for example, provides structural and physiological support for male germ-cell development. This study describes morphological characteristics of the reproductive system of Gymnotus carapo, a neo-tropical freshwater fish widely distributed in South and Central America, focusing on the detection of permeability barriers using morphological and biochemical approaches. Ultrastructural analysis of testes treated with the lanthanum nitrate exclusion technique showed that the tracer penetrated the interstitial compartment of the testis, surrounding and appearing within cysts containing spermatogonia and spermatocytes in early stages of meiosis, but was not detected in the spermatid cysts or inside the lumen of spermatogenic tubules. These results suggest the presence of a permeability barrier that is stabilized after meiosis is completed and serves to protect the haploid cells from the vascular system. In the spermatic-duct region, the tracer was obstructed near the lumen of the duct. Junctional complexes and focal tight junctions between adjacent cells were observed in the testis and spermatic duct. Freeze-fracture methods indeed confirmed the presence of tight junctions, which were visualized as parallel rows of individual particles between adjacent cells. More evidence supporting the existence of a permeability barrier was gathered from differences observed in the electrophoretic protein profiles of testis and spermatic-duct fluids compared to blood plasma. Together, these observations demonstrate the existence of a permeability barrier formed by tight junctions in the testis and spermatic duct of G. carapo. PMID:26073744

  16. Application Of Immobilized Sulfate Reducing Bacteria For Permeable Reactive Barriers In Abandoned Coal Mines

    NASA Astrophysics Data System (ADS)

    Kim, K.; Hur, W.; Choi, S.; Min, K.; Baek, H.

    2006-05-01

    The decline of the Korean coal industry has been drastic in production and consumption. This has been resulted mainly from the environmental concern and the collapse of commercial viability, which has eventually necessitated the government to implement the coal industry rationalization policies to reduce coal production and close down uneconomical mines. The overall drainage rates from abandoned coal mines reaches up to 80,000 ton/day. As a measure of controlling the acid mine drainage from abandoned coal mines, reactive materials in the pathways of drainage, designed to intercept and to transform the contaminants into environmentally acceptable forms can be applied at mines with small drainage rates. The main objective of this study is to design a permeable reactive barrier(PRB) to treat low flow and/or low contaminant loads of acid mine drainage. The PRB is comprised of immobilized sulfate reducing bacteria in hard beads and limestone to remove heavy metals and to raise the pH of AMD. A laboratory reactor was used to prepare a mixed culture of sulfate reducing bacteria. The microbes were separated and mixed with biodegradable matrix to form spherical beads. In order to maintain the viability of micro-organisms for a prolonged period, substrates such as saw dust, polysaccharide or glycerol was supplemented for the beads preparation. The strength of beads fortified by powered limestone to control the permeability of PRB. Different mixtures of limestone and the immobilized beads were tested to determine hydraulic conductivity and AMD treatment capacities. The characteristics of the spherical beads at various pH of AMD was investigated.

  17. Remediation of RDX- and HMX-contaminated groundwater using organic mulch permeable reactive barriers.

    PubMed

    Ahmad, Farrukh; Schnitker, Stephen P; Newell, Charles J

    2007-02-20

    Organic mulch is a complex organic material that is typically populated with its own consortium of microorganisms. The organisms in mulch breakdown complex organics to soluble carbon, which can then be used by these and other microorganisms as an electron donor for treating RDX and HMX via reductive pathways. A bench-scale treatability study with organic mulch was conducted for the treatment of RDX- and HMX-contaminated groundwater obtained from a plume at the Pueblo Chemical Depot (PCD) in Pueblo, Colorado. The site-specific cleanup criteria of 0.55 ppb RDX and 602 ppb HMX were used as the logical goals of the study. Column flow-through tests were run to steady-state at the average site seepage velocity, using a 70%:30% (vol.:vol.) mulch:pea gravel packing to approach the formation's permeability. Significant results included: (1) Complete removal of 90 ppb influent RDX and 8 ppb influent HMX in steady-state mulch column effluent; (2) pseudo-first-order steady-state kinetic rate constant, k, of 0.20 to 0.27 h(-1) based on RDX data, using triplicate parallel column runs; (3) accumulation of reduced RDX intermediates in the steady-state column effluent at less than 2% of the influent RDX mass; (4) no binding of RDX to the column fill material; and (5) no leaching of RDX, HMX or reduction intermediates from the column fill material. The results of the bench-scale study will be used to design and implement a pilot-scale organic mulch/pea gravel permeable reactive barrier (PRB) at the site.

  18. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    NASA Astrophysics Data System (ADS)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  19. Remediation of RDX- and HMX-contaminated groundwater using organic mulch permeable reactive barriers

    NASA Astrophysics Data System (ADS)

    Ahmad, Farrukh; Schnitker, Stephen P.; Newell, Charles J.

    2007-02-01

    Organic mulch is a complex organic material that is typically populated with its own consortium of microorganisms. The organisms in mulch breakdown complex organics to soluble carbon, which can then be used by these and other microorganisms as an electron donor for treating RDX and HMX via reductive pathways. A bench-scale treatability study with organic mulch was conducted for the treatment of RDX- and HMX-contaminated groundwater obtained from a plume at the Pueblo Chemical Depot (PCD) in Pueblo, Colorado. The site-specific cleanup criteria of 0.55 ppb RDX and 602 ppb HMX were used as the logical goals of the study. Column flow-through tests were run to steady-state at the average site seepage velocity, using a 70%:30% (vol.:vol.) mulch:pea gravel packing to approach the formation's permeability. Significant results included: (1) Complete removal of 90 ppb influent RDX and 8 ppb influent HMX in steady-state mulch column effluent; (2) pseudo-first-order steady-state kinetic rate constant, k, of 0.20 to 0.27 h - 1 based on RDX data, using triplicate parallel column runs; (3) accumulation of reduced RDX intermediates in the steady-state column effluent at less than 2% of the influent RDX mass; (4) no binding of RDX to the column fill material; and (5) no leaching of RDX, HMX or reduction intermediates from the column fill material. The results of the bench-scale study will be used to design and implement a pilot-scale organic mulch/pea gravel permeable reactive barrier (PRB) at the site.

  20. Polyphenol-Rich Propolis Extracts Strengthen Intestinal Barrier Function by Activating AMPK and ERK Signaling

    PubMed Central

    Wang, Kai; Jin, Xiaolu; Chen, Yifan; Song, Zehe; Jiang, Xiasen; Hu, Fuliang; Conlon, Michael A.; Topping, David L.

    2016-01-01

    Propolis has abundant polyphenolic constituents and is used widely as a health/functional food. Here, we investigated the effects of polyphenol-rich propolis extracts (PPE) on intestinal barrier function in human intestinal epithelial Caco-2 cells, as well as in rats. In Caco-2 cells, PPE increased transepithelial electrical resistance and decreased lucifer yellow flux. PPE-treated cells showed increased expression of the tight junction (TJ) loci occludin and zona occludens (ZO)-1. Confocal microscopy showed organized expressions in proteins related to TJ assembly, i.e., occludin and ZO-1, in response to PPE. Furthermore, PPE led to the activation of AMPK, ERK1/2, p38, and Akt. Using selective inhibitors, we found that the positive effects of PPE on barrier function were abolished in cells in which AMPK and ERK1/2 signaling were inhibited. Moreover, rats fed a diet supplemented with PPE (0.3% in the diet) exhibited increased colonic epithelium ZO-1 expression. Overall, these data suggest that PPE strengthens intestinal barrier function by activating AMPK and ERK signaling and provide novel insights into the potential application of propolis for human gut health. PMID:27164138

  1. Evaluation of a permeable reactive barrier technology for use at Rocky Flats Environmental Technology Site (RFETS)

    SciTech Connect

    DWYER,BRIAN P.

    2000-01-01

    Three reactive materials were evaluated at laboratory scale to identify the optimum treatment reagent for use in a Permeable Reactive Barrier Treatment System at Rocky Flats Environmental Technology Site (RFETS). The contaminants of concern (COCS) are uranium, TCE, PCE, carbon tetrachloride, americium, and vinyl chloride. The three reactive media evaluated included high carbon steel iron filings, an iron-silica alloy in the form of a foam aggregate, and a peculiar humic acid based sorbent (Humasorb from Arctech) mixed with sand. Each material was tested in the laboratory at column scale using simulated site water. All three materials showed promise for the 903 Mound Site however, the iron filings were determined to be the least expensive media. In order to validate the laboratory results, the iron filings were further tested at a pilot scale (field columns) using actual site water. Pilot test results were similar to laboratory results; consequently, the iron filings were chosen for the fill-scale demonstration of the reactive barrier technology. Additional design parameters including saturated hydraulic conductivity, treatment residence time, and head loss across the media were also determined and provided to the design team in support of the final design. The final design was completed by the Corps of Engineers in 1997 and the system was constructed in the summer of 1998. The treatment system began fill operation in December, 1998 and despite a few problems has been operational since. Results to date are consistent with the lab and pilot scale findings, i.e., complete removal of the contaminants of concern (COCs) prior to discharge to meet RFETS cleanup requirements. Furthermore, it is fair to say at this point in time that laboratory developed design parameters for the reactive barrier technology are sufficient for fuel scale design; however,the treatment system longevity and the long-term fate of the contaminants are questions that remain unanswered. This

  2. TNFα/IFNγ Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells

    PubMed Central

    Beard, Richard S.; Eitner, Rebecca A.; Chen, Liwei; Wu, Mack H.

    2016-01-01

    transepithelial electrical resistance (TER), as well as excluded FoxO1 from the nucleus. Our results indicate that PTK6 may act as a novel mediator of intestinal epithelial permeability during inflammatory injury, and miR-93 may protect intestinal epithelial barrier function, at least in part, by targeting PTK6. PMID:27119373

  3. Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA).

    PubMed

    Petit, Charlotte; Bujard, Alban; Skalicka-Woźniak, Krystyna; Cretton, Sylvian; Houriet, Joëlle; Christen, Philippe; Carrupt, Pierre-Alain; Wolfender, Jean-Luc

    2016-03-01

    At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay is one of the most frequently used in vitro models to predict transcellular passive absorption. While thousands of new chemical entities have been screened with the parallel artificial membrane permeability assay, in general, permeation properties of natural products have been scarcely evaluated. In this study, the parallel artificial membrane permeability assay through a hexadecane membrane was used to predict the passive intestinal absorption of a representative set of frequently occurring natural products. Since natural products are usually ingested for medicinal use as components of complex extracts in traditional herbal preparations or as phytopharmaceuticals, the applicability of such an assay to study the constituents directly in medicinal crude plant extracts was further investigated. Three representative crude plant extracts with different natural product compositions were chosen for this study. The first extract was composed of furanocoumarins (Angelica archangelica), the second extract included alkaloids (Waltheria indica), and the third extract contained flavonoid glycosides (Pueraria montana var. lobata). For each medicinal plant, the effective passive permeability values Pe (cm/s) of the main natural products of interest were rapidly calculated thanks to a generic ultrahigh-pressure liquid chromatography-UV detection method and because Pe calculations do not require knowing precisely the concentration of each natural product within the extracts. The original parallel artificial membrane permeability assay through a hexadecane membrane was found to keep its predictive power when applied to constituents directly in crude plant extracts provided that higher quantities of the extract were initially loaded in the assay in order to ensure suitable detection of the individual constituents of the extracts. Such an approach is thus valuable for the high

  4. Delivery of a mucin domain enriched in cysteine residues strengthens the intestinal mucous barrier

    PubMed Central

    Gouyer, Valérie; Dubuquoy, Laurent; Robbe-Masselot, Catherine; Neut, Christel; Singer, Elisabeth; Plet, Ségolène; Geboes, Karel; Desreumaux, Pierre; Gottrand, Frédéric; Desseyn, Jean-Luc

    2015-01-01

    A weakening of the gut mucous barrier permits an increase in the access of intestinal luminal contents to the epithelial cells, which will trigger the inflammatory response. In inflammatory bowel diseases, there is an inappropriate and ongoing activation of the immune system, possibly because the intestinal mucus is less protective against the endogenous microflora. General strategies aimed at improving the protection of the intestinal epithelium are still missing. We generated a transgenic mouse that secreted a molecule consisting of 12 consecutive copies of a mucin domain into its intestinal mucus, which is believed to modify the mucus layer by establishing reversible interactions. We showed that the mucus gel was more robust and that mucin O-glycosylation was altered. Notably, the gut epithelium of transgenic mice housed a greater abundance of beneficial Lactobacillus spp. These modifications were associated with a reduced susceptibility of transgenic mice to chemically induced colitis. Furthermore, transgenic mice cleared faster Citrobacter rodentium bacteria which were orally given and mice were more protected against bacterial translocation induced by gavage with adherent–invasive Escherichia coli. Our data show that delivering the mucin CYS domain into the gut lumen strengthens the intestinal mucus blanket which is impaired in inflammatory bowel diseases. PMID:25974250

  5. Mycotoxins Deoxynivalenol and Fumonisins Alter the Extrinsic Component of Intestinal Barrier in Broiler Chickens.

    PubMed

    Antonissen, Gunther; Van Immerseel, Filip; Pasmans, Frank; Ducatelle, Richard; Janssens, Geert P J; De Baere, Siegrid; Mountzouris, Konstantinos C; Su, Shengchen; Wong, Eric A; De Meulenaer, Bruno; Verlinden, Marc; Devreese, Mathias; Haesebrouck, Freddy; Novak, Barbara; Dohnal, Ilse; Martel, An; Croubels, Siska

    2015-12-23

    Deoxynivalenol (DON) and fumonisins (FBs) are secondary metabolites produced by Fusarium fungi that frequently contaminate broiler feed. The aim of this study was to investigate the impact of DON and/or FBs on the intestinal barrier in broiler chickens, more specifically on the mucus layer and antioxidative response to oxidative stress. One-day-old broiler chicks were divided into four groups, each consisting of eight pens of seven birds each, and were fed for 15 days either a control diet, a DON-contaminated diet (4.6 mg DON/kg feed), a FBs-contaminated diet (25.4 mg FB1 + FB2/kg feed), or a DON+FBs-contaminated diet (4.3 mg DON and 22.9 mg FB1 + FB2/kg feed). DON and FBs affected the duodenal mucus layer by suppressing intestinal mucin (MUC) 2 gene expression and altering the mucin monosaccharide composition. Both mycotoxins decreased gene expression of the intestinal zinc transporter (ZnT)-1 and regulated intracellular methionine homeostasis, which are both important for preserving the cell's critical antioxidant activity. Feeding a DON- and/or FBs-contaminated diet, at concentrations close to the European Union maximum guidance levels (5 mg DON and 20 mg FB1 + FB2/kg feed) changes the intestinal mucus layer and several intestinal epithelial antioxidative mechanisms.

  6. Permeable Reactive Barriers Designed To Mitigate Eutrophication Alter Bacterial Community Composition and Aquifer Redox Conditions

    PubMed Central

    Hiller, Kenly A.; Foreman, Kenneth H.; Weisman, David

    2015-01-01

    Permeable reactive barriers (PRBs) consist of a labile carbon source that is positioned to intercept nitrate-laden groundwater to prevent eutrophication. Decomposition of carbon in the PRB drives groundwater anoxic, fostering microbial denitrification. Such PRBs are an ideal habitat to examine microbial community structure under high-nitrate, carbon-replete conditions in coastal aquifers. We examined a PRB installed at the Waquoit Bay National Estuarine Research Reserve in Falmouth, MA. Groundwater within and below the PRB was depleted in oxygen compared to groundwater at sites upgradient and at adjacent reference sites. Nitrate concentrations declined from a high of 25 μM upgradient and adjacent to the barrier to <0.1 μM within the PRB. We analyzed the total and active bacterial communities filtered from groundwater flowing through the PRB using amplicons of 16S rRNA and of the 16S rRNA genes. Analysis of the 16S rRNA genes collected from the PRB showed that the total bacterial community had high relative abundances of bacteria thought to have alternative metabolisms, such as fermentation, including candidate phyla OD1, OP3, TM7, and GN02. In contrast, the active bacteria had lower abundances of many of these bacteria, suggesting that the bacterial taxa that differentiate the PRB groundwater community were not actively growing. Among the environmental variables analyzed, dissolved oxygen concentration explained the largest proportion of total community structure. There was, however, no significant correlation between measured environmental parameters and the active microbial community, suggesting that controls on the active portion may differ from the community as a whole. PMID:26231655

  7. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances

    SciTech Connect

    Trnovec, T.; Kallay, Z.; Bezek, S. )

    1990-12-01

    Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultrastructural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. 68 references.

  8. Permeable Reactive Barriers Designed To Mitigate Eutrophication Alter Bacterial Community Composition and Aquifer Redox Conditions.

    PubMed

    Hiller, Kenly A; Foreman, Kenneth H; Weisman, David; Bowen, Jennifer L

    2015-10-01

    Permeable reactive barriers (PRBs) consist of a labile carbon source that is positioned to intercept nitrate-laden groundwater to prevent eutrophication. Decomposition of carbon in the PRB drives groundwater anoxic, fostering microbial denitrification. Such PRBs are an ideal habitat to examine microbial community structure under high-nitrate, carbon-replete conditions in coastal aquifers. We examined a PRB installed at the Waquoit Bay National Estuarine Research Reserve in Falmouth, MA. Groundwater within and below the PRB was depleted in oxygen compared to groundwater at sites upgradient and at adjacent reference sites. Nitrate concentrations declined from a high of 25 μM upgradient and adjacent to the barrier to <0.1 μM within the PRB. We analyzed the total and active bacterial communities filtered from groundwater flowing through the PRB using amplicons of 16S rRNA and of the 16S rRNA genes. Analysis of the 16S rRNA genes collected from the PRB showed that the total bacterial community had high relative abundances of bacteria thought to have alternative metabolisms, such as fermentation, including candidate phyla OD1, OP3, TM7, and GN02. In contrast, the active bacteria had lower abundances of many of these bacteria, suggesting that the bacterial taxa that differentiate the PRB groundwater community were not actively growing. Among the environmental variables analyzed, dissolved oxygen concentration explained the largest proportion of total community structure. There was, however, no significant correlation between measured environmental parameters and the active microbial community, suggesting that controls on the active portion may differ from the community as a whole.

  9. A Claudin-9–Based Ion Permeability Barrier Is Essential for Hearing

    PubMed Central

    Nakano, Yoko; Kim, Sung H.; Kim, Hyoung-Mi; Sanneman, Joel D.; Zhang, Yuzhou; Smith, Richard J. H.; Marcus, Daniel C.; Wangemann, Philine; Nessler, Randy A.; Bánfi, Botond

    2009-01-01

    Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)–mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU–induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9–defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9–defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function. PMID:19696885

  10. Insulin increases glomerular filtration barrier permeability through PKGIα-dependent mobilization of BKCa channels in cultured rat podocytes.

    PubMed

    Piwkowska, Agnieszka; Rogacka, Dorota; Audzeyenka, Irena; Kasztan, Małgorzata; Angielski, Stefan; Jankowski, Maciej

    2015-08-01

    Podocytes are highly specialized cells that wrap around glomerular capillaries and comprise a key component of the glomerular filtration barrier. They are uniquely sensitive to insulin; like skeletal muscle and fat cells, they exhibit insulin-stimulated glucose uptake and express glucose transporters. Podocyte insulin signaling is mediated by protein kinase G type I (PKGI), and it leads to changes in glomerular permeability to albumin. Here, we investigated whether large-conductance Ca²⁺-activated K⁺ channels (BKCa) were involved in insulin-mediated, PKGIα-dependent filtration barrier permeability. Insulin-induced glomerular permeability was measured in glomeruli isolated from Wistar rats. Transepithelial albumin flux was measured in cultured rat podocyte monolayers. Expression of BKCa subunits was detected by RT-PCR. BKCa, PKGIα, and upstream protein expression were examined in podocytes with Western blotting and immunofluorescence. The BKCa-PKGIα interaction was assessed with co-immunoprecipitation. RT-PCR showed that primary cultured rat podocytes expressed mRNAs that encoded the pore-forming α subunit and four accessory β subunits of BKCa. The BKCa inhibitor, iberiotoxin (ibTX), abolished insulin-dependent glomerular albumin permeability and PKGI-dependent transepithelial albumin flux. Insulin-evoked albumin permeability across podocyte monolayers was also blocked with BKCa siRNA. Moreover, ibTX blocked insulin-induced disruption of the actin cytoskeleton and changes in the phosphorylation of PKG target proteins, MYPT1 and RhoA. These results indicated that insulin increased filtration barrier permeability through mobilization of BKCa channels via PKGI in cultured rat podocytes. This molecular mechanism may explain podocyte injury and proteinuria in diabetes. PMID:25952906

  11. Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent

    PubMed Central

    Boudry, Gaëlle; Lemay, Danielle G.

    2015-01-01

    A causal relationship between the pathophysiological changes in the gut epithelium and altered gut microbiota with the onset of obesity have been suggested but not defined. The aim of this study was to determine the temporal relationship between impaired intestinal barrier function and microbial dysbiosis in the small and large intestine in rodent high-fat (HF) diet-induced obesity. Rats were fed HF diet (45% fat) or normal chow (C, 10% fat) for 1, 3, or 6 wk; food intake, body weight, and adiposity were measured. Barrier function ex vivo using FITC-labeled dextran (4,000 Da, FD-4) and horseradish peroxidase (HRP) probes in Ussing chambers, gene expression, and gut microbial communities was assessed. After 1 wk, there was an immediate but reversible increase in paracellular permeability, decrease in IL-10 expression, and decrease in abundance of genera within the class Clostridia in the ileum. In the large intestine, HRP flux and abundance of genera within the order Bacteroidales increased with time on the HF diet and correlated with the onset of increased body weight and adiposity. The data show immediate insults in the ileum in response to ingestion of a HF diet, which were rapidly restored and preceded increased passage of large molecules across the large intestinal epithelium. This study provides an understanding of microbiota dysbiosis and gut pathophysiology in diet-induced obesity and has identified IL-10 and Oscillospira in the ileum and transcellular flux in the large intestine as potential early impairments in the gut that might lead to obesity and metabolic disorders. PMID:25747351

  12. 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.

  13. Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent.

    PubMed

    Hamilton, M Kristina; Boudry, Gaëlle; Lemay, Danielle G; Raybould, Helen E

    2015-05-15

    A causal relationship between the pathophysiological changes in the gut epithelium and altered gut microbiota with the onset of obesity have been suggested but not defined. The aim of this study was to determine the temporal relationship between impaired intestinal barrier function and microbial dysbiosis in the small and large intestine in rodent high-fat (HF) diet-induced obesity. Rats were fed HF diet (45% fat) or normal chow (C, 10% fat) for 1, 3, or 6 wk; food intake, body weight, and adiposity were measured. Barrier function ex vivo using FITC-labeled dextran (4,000 Da, FD-4) and horseradish peroxidase (HRP) probes in Ussing chambers, gene expression, and gut microbial communities was assessed. After 1 wk, there was an immediate but reversible increase in paracellular permeability, decrease in IL-10 expression, and decrease in abundance of genera within the class Clostridia in the ileum. In the large intestine, HRP flux and abundance of genera within the order Bacteroidales increased with time on the HF diet and correlated with the onset of increased body weight and adiposity. The data show immediate insults in the ileum in response to ingestion of a HF diet, which were rapidly restored and preceded increased passage of large molecules across the large intestinal epithelium. This study provides an understanding of microbiota dysbiosis and gut pathophysiology in diet-induced obesity and has identified IL-10 and Oscillospira in the ileum and transcellular flux in the large intestine as potential early impairments in the gut that might lead to obesity and metabolic disorders.

  14. Evaluation of the increase in permeability of the blood–brain barrier during tumor progression after pulsed focused ultrasound

    PubMed Central

    Yang, Feng-Yi; Wang, Hsin-Ell; Lin, Guan-Liang; Lin, Hui-Hsien; Wong, Tai-Tong

    2012-01-01

    Purpose The purpose of this study was to evaluate the permeability of the blood–brain barrier after sonication by pulsed high-intensity focused ultrasound and to determine if such an approach increases the tumor:ipsilateral brain permeability ratio. Materials and methods F98 glioma-bearing Fischer 344 rats were injected intravenously with Evans blue with or without blood–tumor barrier disruption induced by transcranial pulsed high-intensity focused ultrasound. Sonication was applied at a frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The permeability of the blood–brain barrier was assessed by the extravasation of Evans blue. Contrast-enhanced magnetic resonance images were used to monitor the gadolinium deposition path associated with transcranial pulsed high-intensity focused ultrasound, and the influencing size and location was also investigated. In addition, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t-test. Results The accumulation of Evans blue in brains and the tumor:ipsilateral brain permeability ratio of Evans blue were significantly increased after pulsed high-intensity focused ultrasound exposure. Evans blue injection followed by sonication showed an increase in the tumor:ipsilateral brain ratio of the target tumors (9.14:1) of about 2.23-fold compared with the control tumors (x4.09) on day 6 after tumor implantation. Magnetic resonance images showed that pulsed high-intensity focused ultrasound locally enhances the permeability of the blood–tumor barrier in the glioma-bearing rats. Conclusion This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens. PMID:22359451

  15. Activation of muscarinic cholinoceptor ameliorates tumor necrosis factor-α-induced barrier dysfunction in intestinal epithelial cells.

    PubMed

    Khan, Md Rafiqul Islam; Uwada, Junsuke; Yazawa, Takashi; Islam, Md Tariqul; Krug, Susanne M; Fromm, Michael; Karaki, Shin-ichiro; Suzuki, Yuichi; Kuwahara, Atsukazu; Yoshiki, Hatsumi; Sada, Kiyonao; Muramatsu, Ikunobu; Anisuzzaman, Abu Syed Md; Taniguchi, Takanobu

    2015-11-30

    Impaired intestinal barrier function is one of the critical issues in inflammatory bowel diseases. The aim of this study is to investigate muscarinic cholinoceptor (mAChR)-mediated signaling for the amelioration of cytokine-induced barrier dysfunction in intestinal epithelium. Rat colon challenged with TNF-α and interferon γ reduced transepithelial electrical resistance (TER). This barrier injury was attenuated by muscarinic stimulation. In HT-29/B6 intestinal epithelial cells, muscarinic stimulation suppressed TNF-α-induced activation of NF-κB signaling and barrier disruption. Finally, muscarinic stimulation promoted the shedding of TNFR1, which would be a mechanism for the attenuation of TNF-α/NF-κB signaling and barrier disruption via mAChR.

  16. Use of ground tire rubber in reactive permeable barriers to mitigate BTEX compounds

    SciTech Connect

    Kershaw, D.S.; Pamukcu, S.

    1997-12-31

    The ability of ground tire rubber to sorb BTEX compounds from groundwater was examined. The current study consisted of running both batch and packed bed column tests to determine the sorption capacity, the flow through utilization efficiency and the reversibility of BTEX sorption to ground tire rubber. Sorption tests for an equilibrium concentration of the contaminant in solution of 10 mg/L showed that the adsorption capacity of ground tire rubber based on a percentage of the adsorption capacity of activated carbon is: 5% for benzene, 4% for toluene, 4% for ethylbenzene, and 8% for p-xylene. Column tests produced utilization efficiencies for ground tire rubber of 32% to 61% when in contact with the contaminant for 36 minutes. Sorption tests indicate no measurable reduction in sorption capacity after 8 consecutive sorption/desorption tests. Possible future uses of ground rubber as a sorption media could include the use of ground rubber as an aggregate in slurry cut-off walls, or as a sorption media in in-situ reactive permeable barriers.

  17. Early breakthrough of molybdenum and uranium in a permeable reactive barrier.

    PubMed

    Morrison, Stan J; Mushovic, Paul S; Niesen, Preston L

    2006-03-15

    A permeable reactive barrier (PRB) using zerovalent iron (ZVI) was installed at a site near Cañon City, CO, to treat molybdenum (Mo) and uranium (U) in groundwater. The PRB initially decreased Mo concentrations from about 4.8 to less than 0.1 mg/L; however, Mo concentrations in the ZVI increased to 2.0 mg/L after about 250 days and continued to increase until concentrations in the ZVI were about 4 times higherthan in the influent groundwater. Concentrations of U were reduced from 1.0 to less than 0.02 mg/L during the same period. Investigations of solid-phase samples indicate that (1) calcium carbonate, iron oxide, and sulfide minerals had precipitated in pores of the ZVI; (2) U and Mo were concentrated in the upgradient 5.1 cm of the ZVI; and (3) calcium was present throughout the ZVI accounting for up to 20.5% of the initial porosity. Results of a column test indicated that the ZVI from the PRB was still reactive for removing Mo and that removal rates were dependenton residence time and pH. The chemical evolution of the PRB is explained in four stages that present a progression from porous media flow through preferential flow and, finally, complete bypass of the ZVI. PMID:16570630

  18. Investigating dominant processes in ZVI permeable reactive barriers using reactive transport modeling.

    PubMed

    Weber, Anne; Ruhl, Aki S; Amos, Richard T

    2013-08-01

    The reactive and hydraulic efficacy of zero valent iron permeable reactive barriers (ZVI PRBs) is strongly affected by geochemical composition of the groundwater treated. An enhanced version of the geochemical simulation code MIN3P was applied to simulate dominating processes in chlorinated hydrocarbons (CHCs) treating ZVI PRBs including geochemical dependency of ZVI reactivity, gas phase formation and a basic formulation of degassing. Results of target oriented column experiments with distinct chemical conditions (carbonate, calcium, sulfate, CHCs) were simulated to parameterize the model. The simulations demonstrate the initial enhancement of anaerobic iron corrosion due to carbonate and long term inhibition by precipitates (chukanovite, siderite, iron sulfide). Calcium was shown to enhance long term corrosion due to competition for carbonate between siderite, chukanovite, and aragonite, with less inhibition of iron corrosion by the needle like aragonite crystals. Application of the parameterized model to a field site (Bernau, Germany) demonstrated that temporarily enhanced groundwater carbonate concentrations caused an increase in gas phase formation due to the acceleration of anaerobic iron corrosion. PMID:23743511

  19. Solid phase studies and geochemical modelling of low-cost permeable reactive barriers.

    PubMed

    Bartzas, Georgios; Komnitsas, Kostas

    2010-11-15

    A continuous column experiment was carried out under dynamic flow conditions in order to study the efficiency of low-cost permeable reactive barriers (PRBs) to remove several inorganic contaminants from acidic solutions. A 50:50 w/w waste iron/sand mixture was used as candidate reactive media in order to activate precipitation and promote sorption and reduction-oxidation mechanisms. Solid phase studies of the exhausted reactive products after column shutdown, using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD), confirmed that the principal Fe corrosion products identified in the reactive zone are amorphous iron (hydr)oxides (maghemite/magnetite and goethite), intermediate products (sulfate green rust), and amorphous metal sulfides such as amFeS and/or mackinawite. Geochemical modelling of the metal removal processes, including interactions between reactive media, heavy metal ions and sulfates, and interpretation of the ionic profiles was also carried out by using the speciation/mass transfer computer code PHREEQC-2 and the WATEQ4F database. Mineralogical characterization studies as well as geochemical modelling calculations also indicate that the effect of sulfate and silica sand on the efficiency of the reactive zone should be considered carefully during design and operation of low-cost field PRBs. PMID:20678863

  20. Assessment of solid reactive mixtures for the development of biological permeable reactive barriers.

    PubMed

    Pagnanelli, Francesca; Viggi, Carolina Cruz; Mainelli, Sara; Toro, Luigi

    2009-10-30

    Solid reactive mixtures were tested as filling material for the development of biological permeable reactive barriers for the treatment of heavy metals contaminated waters. Mixture selection was performed by taking into account the different mechanisms operating in sulphate and cadmium removal with particular attention to bioprecipitation and sorption onto the organic matrices in the mixtures. Suspensions of eight reactive mixtures were tested for sulphate removal (initial concentration 3 g L(-1)). Each mixture was made up of four main functional components: a mix of organic sources for bacterial growth, a neutralizing agent, a porous medium and zero-valent iron. The best mixture among the tested ones (M8: 6% leaves, 9% compost, 3% zero-valent iron, 30% silica sand, 30% perlite, 22% limestone) presented optimal conditions for SRB growth (pH 7.8 +/- 0.1; E(h)= -410 +/- 5 mV) and 83% sulphate removal in 22 days (25% due to bioreduction, 32% due to sorption onto compost and 20% onto leaves). M8 mixture allowed the complete abatement of cadmium with a significant contribution of sorption over bioprecipitation (6% Cd removal due to SRB activity). Sorption properties, characterised by potentiometric titrations and related modelling, were mainly due to carboxylic sites of organic components used in reactive mixtures.

  1. Solid phase studies and geochemical modelling of low-cost permeable reactive barriers.

    PubMed

    Bartzas, Georgios; Komnitsas, Kostas

    2010-11-15

    A continuous column experiment was carried out under dynamic flow conditions in order to study the efficiency of low-cost permeable reactive barriers (PRBs) to remove several inorganic contaminants from acidic solutions. A 50:50 w/w waste iron/sand mixture was used as candidate reactive media in order to activate precipitation and promote sorption and reduction-oxidation mechanisms. Solid phase studies of the exhausted reactive products after column shutdown, using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD), confirmed that the principal Fe corrosion products identified in the reactive zone are amorphous iron (hydr)oxides (maghemite/magnetite and goethite), intermediate products (sulfate green rust), and amorphous metal sulfides such as amFeS and/or mackinawite. Geochemical modelling of the metal removal processes, including interactions between reactive media, heavy metal ions and sulfates, and interpretation of the ionic profiles was also carried out by using the speciation/mass transfer computer code PHREEQC-2 and the WATEQ4F database. Mineralogical characterization studies as well as geochemical modelling calculations also indicate that the effect of sulfate and silica sand on the efficiency of the reactive zone should be considered carefully during design and operation of low-cost field PRBs.

  2. Microbial Sulfate Reduction Enhances Arsenic Mobility Downstream of Zerovalent-Iron-Based Permeable Reactive Barrier.

    PubMed

    Kumar, Naresh; Couture, Raoul-Marie; Millot, Romain; Battaglia-Brunet, Fabienne; Rose, Jérôme

    2016-07-19

    We assessed the potential of zerovalent-iron- (Fe(0)) based permeable reactive barrier (PRB) systems for arsenic (As) remediation in the presence or absence of microbial sulfate reduction. We conducted long-term (200 day) flow-through column experiments to investigate the mechanisms of As transformation and mobility in aquifer sediment (in particular, the PRB downstream linkage). Changes in As speciation in the aqueous phase were monitored continuously. Speciation in the solid phase was determined at the end of the experiment using X-ray absorption near-edge structure (XANES) spectroscopy analysis. We identified thio-As species in solution and AsS in solid phase, which suggests that the As(V) was reduced to As(III) and precipitated as AsS under sulfate-reducing conditions and remained as As(V) under abiotic conditions, even with low redox potential and high Fe(II) content (4.5 mM). Our results suggest that the microbial sulfate reduction plays a key role in the mobilization of As from Fe-rich aquifer sediment under anoxic conditions. Furthermore, they illustrate that the upstream-downstream linkage of PRB affects the speciation and mobility of As in downstream aquifer sediment, where up to 47% of total As initially present in the sediment was leached out in the form of mobile thio-As species. PMID:27309856

  3. Mechanisms involved in the blood-testis barrier increased permeability induced by EMP.

    PubMed

    Wang, Xiao-Wu; Ding, Gui-Rong; Shi, Chang-Hong; Zeng, Li-Hua; Liu, Jun-Ye; Li, Jing; Zhao, Tao; Chen, Yong-Bin; Guo, Guo-Zhen

    2010-09-30

    The blood-testis barrier (BTB) plays an important role in male reproductive system. Lots of environmental stimulations can increase the permeability of BTB and then result in antisperm antibody (AsAb) generation, which is a key step in male immune infertility. Here we reported the results of male mice exposed to electromagnetic pulse (EMP) by measuring the expression of tight-junction-associated proteins (ZO-1 and Occludin), vimentin microfilaments, and transforming growth factor-beta (TGF-beta3) as well as AsAb level in serum. Male BALB/c mice were sham exposed or exposed to EMP at two different intensities (200kV/m and 400kV/m) for 200 pulses. The testes were collected at different time points after EMP exposure. Immunofluorescence histocytochemistry, western blotting, laser confocal microscopy and RT-PCR were used in this study. Compared with sham group, the expression of ZO-1 and TGF-beta3 significantly decreased accompanied with unevenly stained vimentin microfilaments and increased serum AsAb levels in EMP-exposed mice. These results suggest a potential BTB injury and immune infertility in male mice exposed to a certain intensity of EMP.

  4. Bioaugmented remediation of high concentration BTEX-contaminated groundwater by permeable reactive barrier with immobilized bead.

    PubMed

    Xin, Bao-Ping; Wu, Chih-Hung; Wu, Cheng-Han; Lin, Chi-Wen

    2013-01-15

    Ineffective biostimulation requires immediate development of new technologies for remediation of high concentration BTEX-contaminated (benzene, toluene, ethylbenzene and xylene) groundwater. In this study, bioaugmentation with Mycobacterium sp. CHXY119 and Pseudomonas sp. YATO411 immobilized bead was used to remediate BTEX-contaminated groundwater with about 100 mg l(-1) in total concentration. The batch test results showed that the CHXY119 and YATO411 immobilized bead completely biodegraded each BTEX compound, and the maximum biodegradation rates were 0.790 mg l(-1) h(-1) for benzene, 1.113 mg l(-1) h(-1) for toluene, 0.992 mg l(-1) h(-1) for ethylbenzene and 0.231 mg l(-1) h(-1) for p-xylene. The actual mineralization rates were 10.8% for benzene, 10.5% for toluene, 5.8% for ethylbenzene and 11.4% for p-xylene, which indicated that the bioremediation of BTEX by the immobilized bead requires a rather small oxygen supply. Degradation rates achieved by the bioaugmented permeable reactive barrier (Bio-PRB) system of the immobilized bead were 97.8% for benzene, 94.2% for toluene, 84.7% for ethylbenzene and 87.4% for p-xylene; and the toxicity of the groundwater fell by 91.2% after bioremediation by the bioaugmented PRB, which confirmed its great potential for remediating groundwater with high concentrations of contaminants.

  5. Mineral Precipitation Upgradient from a Zero-Valent Iron Permeable Reactive Barrier

    SciTech Connect

    Johnson, R. L.; Thoms, R. B.; Johnson, R. O.; Nurmi, J. T.; Tratnyek, Paul G.

    2008-07-01

    Core samples taken from a zero-valent iron permeable reactive barrier (ZVI PRB) at Cornhusker Army Ammunition Plant, Nebraska, were analyzed for physical and chemical characteristics. Precipitates containing iron and sulfide were present at much higher concentrations in native aquifer materials just upgradient of the PRB than in the PRB itself. Sulfur mass balance on core solids coupled with trends in ground water sulfate concentrations indicates that the average ground water flow after 20 months of PRB operation was approximately twenty fold less than the regional ground water velocity. Transport and reaction modeling of the aquifer PRB interface suggests that, at the calculated velocity, both iron and hydrogen could diffuse upgradient against ground water flow and thereby contribute to precipitation in the native aquifer materials. The initial hydraulic conductivity (K) of the native materials is less than that of the PRB and, given the observed precipitation in the upgradient native materials, it is likely that K reduction occurred upgradient to rather than within the PRB. Although not directly implicated, guar gum used during installation of the PRB is believed to have played a role in the precipitation and flow reduction processes by enhancing microbial activity.

  6. Laboratory study on sequenced permeable reactive barrier remediation for landfill leachate-contaminated groundwater.

    PubMed

    Jun, Dong; Yongsheng, Zhao; Weihong, Zhang; Mei, Hong

    2009-01-15

    Permeable reactive barrier (PRB) was a promising technology for groundwater remediation. Landfill leachate-polluted groundwater riches in various hazardous contaminants. Two lab-scale reactors (reactors A and B) were designed for studying the feasibility of PRB to remedy the landfill leachate-polluted groundwater. Zero valent iron (ZVI) and the mixture of ZVI and zeolites constitute the first section of the reactors A and B, respectively; the second section of two reactors consists of oxygen releasing compounds (ORCs). Experimental results indicated that BOD5/COD increased from initial 0.32 up to average 0.61 and 0.6 through reactors A and B, respectively. Removal efficiency of mixed media for pollutants was higher than that of single media (ZVI only). Zeolites exhibited selective removal of Zn, Mn, Mg, Cd, Sr, and NH4+, and removal efficiency was 97.2%, 99.6%, 95.9%, 90.5% and 97.4%, respectively. The maximum DO concentration of reactors A and B were 7.64 and 6.78mg/L, respectively, while the water flowed through the ORC. Therefore, sequenced PRB system was effective and was proposed as an alternative method to remedy polluted groundwater by landfill leachate.

  7. Ammonium removal from groundwater using a zeolite permeable reactive barrier: a pilot-scale demonstration.

    PubMed

    Li, Shengpin; Huang, Guoxin; Kong, Xiangke; Yang, Yingzhao; Liu, Fei; Hou, Guohua; Chen, Honghan

    2014-01-01

    In situ remediation of ammonium-contaminated groundwater is possible through a zeolite permeable reactive barrier (PRB); however, zeolite's finite sorption capacity limits the long-term field application of PRBs. In this paper, a pilot-scale PRB was designed to achieve sustainable use of zeolite in removing ammonium (NH(4)(+)-N) through sequential nitrification, adsorption, and denitrification. An oxygen-releasing compound was added to ensure aerobic conditions in the upper layers of the PRB where NH(4)(+)-N was microbially oxidized to nitrate. Any remaining NH(4)(+)-N was removed abiotically in the zeolite layer. Under lower redox conditions, nitrate formed during nitrification was removed by denitrifying bacteria colonizing the zeolite. During the long-term operation (328 days), more than 90% of NH(4)(+)-N was consistently removed, and approximately 40% of the influent NH(4)(+)-N was oxidized to nitrate. As much as 60% of the nitrate formed in the PRB was reduced in the zeolite layer after 300 days of operation. Removal of NH(4)(+)-N from groundwater using a zeolite PRB through bacterial nitrification and abiotic adsorption is a promising approach. The zeolite PRB has the advantage of achieving sustainable use of zeolite and immediate NH(4)(+)-N removal.

  8. Microbial Sulfate Reduction Enhances Arsenic Mobility Downstream of Zerovalent-Iron-Based Permeable Reactive Barrier.

    PubMed

    Kumar, Naresh; Couture, Raoul-Marie; Millot, Romain; Battaglia-Brunet, Fabienne; Rose, Jérôme

    2016-07-19

    We assessed the potential of zerovalent-iron- (Fe(0)) based permeable reactive barrier (PRB) systems for arsenic (As) remediation in the presence or absence of microbial sulfate reduction. We conducted long-term (200 day) flow-through column experiments to investigate the mechanisms of As transformation and mobility in aquifer sediment (in particular, the PRB downstream linkage). Changes in As speciation in the aqueous phase were monitored continuously. Speciation in the solid phase was determined at the end of the experiment using X-ray absorption near-edge structure (XANES) spectroscopy analysis. We identified thio-As species in solution and AsS in solid phase, which suggests that the As(V) was reduced to As(III) and precipitated as AsS under sulfate-reducing conditions and remained as As(V) under abiotic conditions, even with low redox potential and high Fe(II) content (4.5 mM). Our results suggest that the microbial sulfate reduction plays a key role in the mobilization of As from Fe-rich aquifer sediment under anoxic conditions. Furthermore, they illustrate that the upstream-downstream linkage of PRB affects the speciation and mobility of As in downstream aquifer sediment, where up to 47% of total As initially present in the sediment was leached out in the form of mobile thio-As species.

  9. Chromium-removal processes during groundwater remediation by a zerovalent iron permeable reactive barrier.

    PubMed

    Wilkin, Richard T; Su, Chunming; Ford, Robert G; Paul, Cynthia J

    2005-06-15

    Solid-phase associations of chromium were examined in core materials collected from a full-scale, zerovalent iron permeable reactive barrier (PRB) at the U.S. Coast Guard Support Center located near Elizabeth City, NC. The PRB was installed in 1996 to treat groundwater contaminated with hexavalent chromium. After eight years of operation, the PRB remains effective at reducing concentrations of Cr from average values >1500 microg L(-1) in groundwater hydraulically upgradient of the PRB to values <1 microg L(-1) in groundwater within and hydraulically downgradient of the PRB. Chromium removal from groundwater occurs at the leading edge of the PRB and also within the aquifer immediately upgradient of the PRB. These regions also witness the greatest amount of secondary mineral formation due to steep geochemical gradients that result from the corrosion of zerovalent iron. X-ray absorption near-edge structure (XANES) spectroscopy indicated that chromium is predominantly in the trivalent oxidation state, confirming that reductive processes are responsible for Cr sequestration. XANES spectra and microscopy results suggest that Cr is, in part, associated with iron sulfide grains formed as a consequence of microbially mediated sulfate reduction in and around the PRB. Results of this study provide evidence that secondary iron-bearing mineral products may enhance the capacity of zerovalent iron systems to remediate Cr in groundwater, either through redox reactions at the mineral-water interface or by the release of Fe(II) to solution via mineral dissolution and/or metal corrosion.

  10. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

    PubMed

    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (p<0.01). 1800MHz pulse modulated radio-frequency radiation exposure was found more effective on the male animals (p<0.01). For female groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed

  11. Dietary management of acute diarrhoea in children: effect of fermented and amylase-digested weaning foods on intestinal permeability.

    PubMed

    Willumsen, J F; Darling, J C; Kitundu, J A; Kingamkono, R R; Msengi, A E; Mduma, B; Sullivan, K R; Tomkins, A M

    1997-03-01

    The effect of three dietary treatments on intestinal permeability during acute diarrhea was compared in 86 Tanzanian children 6-25 months of age admitted to Muhimbili Medical Center's Pediatric Diarrhea Treatment Unit in Dar es Salaam in 1992. 55 children (64%) had received foods other than breast milk during the first week of life. After rehydration, children were randomly assigned to receive a conventional low-energy density porridge (n = 33), a high-energy density amylase digested (AMD) porridge (n = 28), or AMD porridge followed by fermented amylase digested (FAD) porridge (n = 25). Lactulose/mannitol (L/M) permeability tests were performed at admission, after 3 days, and at 2 and 4 weeks after hospital discharge. Children with diarrhea had higher L/M ratios (geometric mean, 0.85; 95% confidence interval (CI), 0.68-1.05) at admission than the 30 age-matched healthy controls (mean, 0.14; 95% CI, 0.12-0.17). The L/M ratio of study children fell over time and approached values recorded among healthy controls by the first follow-up visit. The change in L/M ratio between admission and day 3 of hospitalization was significantly greater in the FAD group (89%) than the conventional or AMD groups (44% and 75%, respectively). Dietary treatment and intestinal damage at admission explained 13.5% of the variation in this L/M ratio, while age at admission and age at weaning explained an additional 8.4%. These findings suggest that a porridge that has been both amylase digested and fermented effectively repairs mucosal damage through trophic effects on intestinal epithelium and should be administered to children with acute diarrhea to prevent malnutrition.

  12. Intestinal Cell Barrier Function In Vitro Is Severely Compromised by Keratin 8 and 18 Mutations Identified in Patients with Inflammatory Bowel Disease

    PubMed Central

    Zupancic, Tina; Stojan, Jure; Lane, Ellen Birgitte; Komel, Radovan; Bedina-Zavec, Apolonija; Liovic, Mirjana

    2014-01-01

    Keratin 8 and 18 (K8/K18) mutations have been implicated in the aetiology of certain pathogenic processes of the liver and pancreas. While some K8 mutations (K8 G62C, K8 K464N) are also presumed susceptibility factors for inflammatory bowel disease (IBD), the only K18 mutation (K18 S230T) discovered so far in an IBD patient is thought to be a polymorphism. The aim of our study was to demonstrate that these mutations might also directly affect intestinal cell barrier function. Cell monolayers of genetically engineered human colonocytes expressing these mutations were tested for permeability, growth rate and resistance to heat-stress. We also calculated the change in dissociation constant (Kd, measure of affinity) each of these mutations introduces into the keratin protein, and present the first model of a keratin dimer L12 region with in silico clues to how the K18 S230T mutation may affect keratin function. Physiologically, these mutations cause up to 30% increase in paracellular permeability in vitro. Heat-stress induces little keratin clumping but instead cell monolayers peel off the surface suggesting a problem with cell junctions. K18 S230T has pronounced pathological effects in vitro marked by high Kd, low growth rate and increased permeability. The latter may be due to the altered distribution of tight junction components claudin-4 and ZO-1. This is the first time intestinal cells have been suggested also functionally impaired by K8/K18 mutations. Although an in vitro colonocyte model system does not completely mimic the epithelial lining of the intestine, nevertheless the data suggest that K8/K18 mutations may be also able to produce a phenotype in vivo. PMID:24915158

  13. Design, installation, and performance of a multi-layered permeable reactive barrier, Los Alamos National Laboratory

    SciTech Connect

    Kaszuba, J. P.; Longmire, P. A.; Strietelmeier, E. A.; Taylor, T. P.; Den-Baars, P. S.

    2004-01-01

    A multi-layered permeable reactive barrier (PRB) has been installed in Mortandad Canyon, on the Pajarito Plateau in the north-central part of LANL, to demonstrate in-situ treatment of a suite of contaminants with dissimilar geochemical properties. The PRB will also mitigate possible vulnerabilities from downgradient contaminant movement within alluvial and deeper perched groundwater. Mortandad Canyon was selected as the location for this demonstration project because the flow of alluvial groundwater is constrained by the geology of the canyon, a large network of monitoring wells already were installed along the canyon reach, and the hydrochemistry and contaminant history of the canyon is well-documented. The PRB uses a funnel-and-gate system with a series of four reactive media cells to immobilize or destroy contaminants present in alluvial groundwater, including strontium-90, plutonium-238,239,240, americium-241, perchlorate, and nitrate. The four cells, ordered by sequence of contact with the groundwater, consist of gravel-sized scoria (for colloid removal); phosphate rock containing apatite (for metals and radionuclides); pecan shells and cotton seed admixed with gravel (bio-barrier, to deplete dissolved oxygen and destroy potential RCRA organic compounds, nitrate and perchlorate); and limestone (pH buffering and anion adsorption). Design elements of the PRB are based on laboratory-scale treatability studies and on a field investigation of hydrologic, geochemical, and geotechnical parameters. The PRB was designed with the following criteria: 1-day residence time within the biobarrier, 10-year lifetime, minimization of surface water infiltration and erosion, optimization of hydraulic capture, and minimization of excavated material requiring disposal. Each layer has been equipped with monitoring wells or ports to allow sampling of groundwater and reactive media, and monitor wells are located immediately adjacent to the up- and down-gradient perimeter of the

  14. Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology

    PubMed Central

    Yu, Linda Chia-Hui; Wang, Jin-Town; Wei, Shu-Chen; Ni, Yen-Hsuan

    2012-01-01

    The gastrointestinal tract is the largest reservoir of commensal bacteria in the human body, providing nutrients and space for the survival of microbes while concurrently operating mucosal barriers to confine the microbial population. The epithelial cells linked by tight junctions not only physically separate the microbiota from the lamina propria, but also secrete proinflammatory cytokines and reactive oxygen species in response to pathogen invasion and metabolic stress and serve as a sentinel to the underlying immune cells. Accumulating evidence indicates that commensal bacteria are involved in various physiological functions in the gut and microbial imbalances (dysbiosis) may cause pathology. Commensal bacteria are involved in the regulation of intestinal epithelial cell turnover, promotion of epithelial restitution and reorganization of tight junctions, all of which are pivotal for fortifying barrier function. Recent studies indicate that aberrant bacterial lipopolysaccharide-mediated signaling in gut mucosa may be involved in the pathogenesis of chronic inflammation and carcinogenesis. Our perception of enteric commensals has now changed from one of opportunistic pathogens to active participants in maintaining intestinal homeostasis. This review attempts to explain the dynamic interaction between the intestinal epithelium and commensal bacteria in disease and health status. PMID:22368784

  15. Type I Interferon Response Limits Astrovirus Replication and Protects against Increased Barrier Permeability In Vitro and In Vivo

    PubMed Central

    Marvin, Shauna A.; Huerta, C. Theodore; Sharp, Bridgett; Freiden, Pamela

    2015-01-01

    ABSTRACT Little is known about intrinsic epithelial cell responses against astrovirus infection. Here we show that human astrovirus type 1 (HAstV-1) infection induces type I interferon (beta interferon [IFN-β]) production in differentiated Caco2 cells, which not only inhibits viral replication by blocking positive-strand viral RNA and capsid protein synthesis but also protects against HAstV-1-increased barrier permeability. Excitingly, we found similar results in vivo using a murine astrovirus (MuAstV) model, providing new evidence that virus-induced type I IFNs may protect against astrovirus replication and pathogenesis in vivo. IMPORTANCE Human astroviruses are a major cause of pediatric diarrhea, yet little is known about the immune response. Here we show that type I interferon limits astrovirus infection and preserves barrier permeability both in vitro and in vivo. Importantly, we characterized a new mouse model for studying astrovirus replication and pathogenesis. PMID:26656701

  16. Cerebrospinal Fluid Secretory Ca2+-Dependent Phospholipase A2 Activity: A Biomarker of Blood-Cerebrospinal Fluid Barrier Permeability

    PubMed Central

    Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj; Fladby, Tormod; Grundke-Iqbal, Inge; Iqbal, Khalid

    2010-01-01

    The blood-brain barrier, the blood-cerebrospinal fluid barrier (BCB) and other specialized brain barriers are increasingly recognized as a major obstacle to the treatment of most brain disorders. The impairment of these barriers has been implicated in neuropathology of several diseases, such as autism, ischemia, multiple sclerosis and Alzheimer disease. This dual function of the blood-neural barriers points out the importance and need for the development of techniques that can evaluate the nature and level of their integrity. Here we report the discovery of CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity as a measure of BCB permeability. Lumbar CSF from BCB-impaired (n=26), multiple sclerosis (n=18) and healthy control (n=32) cases was analyzed using both a newly developed continuous fluorescence assay for CSF sPLA2 activity and CSF/Serum albumin ratio (QAlb), the most common and established method to evaluate BCB permeability. While both measurements showed no significant differences between multiple sclerosis and age-matched normal healthy cases, they were highly correlated. Though the CSF sPLA2 activity and QAlb had over 95 % agreement, the former was found to be more sensitive than the latter in measuring low levels of BCB impairment. PMID:20470866

  17. High paracellular nutrient absorption in intact bats is associated with high paracellular permeability in perfused intestinal segments.

    PubMed

    Brun, Antonio; Price, Edwin R; Gontero-Fourcade, Manuel N; Fernandez-Marinone, Guido; Cruz-Neto, Ariovaldo P; Karasov, William H; Caviedes-Vidal, Enrique

    2014-09-15

    Water-soluble nutrients are absorbed by the small intestine via transcellular and paracellular mechanisms. Based on a few previous studies, the capacity for paracellular nutrient absorption seems greater in flying mammals than in nonflying mammals, but there has been little investigation of the mechanisms driving this difference. Therefore, we studied three species each of bats (Artibeus lituratus, Sturnira lilium and Carollia perspicillata) and nonflying mammals (Akodon montensis, Mus musculus and Rattus norvegicus). Using standard pharmacokinetic techniques in intact animals, we confirmed the greater paracellular nutrient absorption in the fliers, comparing one species in each group. Then we conducted in situ intestinal perfusions on individuals of all species. In both approaches, we measured the absorption of 3OMD-glucose, a nonmetabolizable glucose analog absorbed both paracellularly and transcellularly, as well as L-arabinose, which has no mediated transport. Fractional absorption of L-arabinose was three times higher in the bat (S. lilium: 1.2±0.24) than in the rodent (A. montensis: 0.35±0.04), whereas fractional absorption of 3OMD-glucose was complete in both species (1.46±0.4 and 0.97±0.12, respectively). In agreement, bats exhibited two to 12 times higher l-arabinose clearance per square centimeter nominal surface area than rodents in intestinal perfusions. Using L-arabinose, we estimated that the contribution of the paracellular pathway to total glucose absorption was higher in all three bats (109-137%) than in the rodents (13-39%). These findings contribute to an emerging picture that reliance on the paracellular pathway for nutrient absorption is much greater in bats relative to nonflying mammals and that this difference is driven by differences in intestinal permeability to nutrient-sized molecules.

  18. Lactobacillus protects the integrity of intestinal epithelial barrier damaged by pathogenic bacteria

    PubMed Central

    Yu, Qinghua; Yuan, Lixia; Deng, Jun; Yang, Qian

    2015-01-01

    Pathogens invade intestinal mucosal barrier through phagocytosis of antigen presenting cells (dendritic cell, microfold cells), or through the invasion into the intestinal epithelial directly. Some pathogens could damage the cell junction between epithelial cells and use the paracellular pathway as an entrance to invade. Moreover, some Lactobacillus could inhibit the adhesion of the pathogens and protect the integrity of the cell junction and mucosal barrier. This research focused on the potential therapeutic effect of Lactobacillus fructosus (L. fructosus) C2 to attenuate ETEC K88 or S. typhimurium SL1344 induced changes to mucosal barrier. The results demonstrated that treatment of polarized Caco-2 cells with L. fructosus C2 reduced the permeation of dextran, and expression of IL-8, p-ERK, and p-JNK when cells were infected with pathogenic bacteria. The findings indicated that L. fructosus C2 exerted a protective effect against the damage to the integrity of Caco-2 cells by ETEC or S. typhimurium infection. PMID:25859435

  19. Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression

    PubMed Central

    Watari, Akihiro; Hasegawa, Maki; Yagi, Kiyohito; Kondoh, Masuo

    2016-01-01

    Several stressors are known to influence epithelial tight junction (TJ) integrity, but the association between DNA damage and TJ integrity remains unclear. Here we examined the effects of daunorubicin and rebeccamycin, two anti-tumor chemicals that induce DNA damage, on TJ integrity in human intestinal epithelial cells. Daunorubicin and rebeccamycin dose-dependently enhanced transepithelial electrical resistance (TER) and decreased flux of the 4 kDa FITC-dextran in Caco-2 cell monolayer. Daunorubicin- or rebeccamycin-induced enhancement of the TJ barrier function partly rescued attenuation of the barrier function by the inflammatory cytokines TNF-α and IFN-γ. Daunorubicin and rebeccamycin increased claudin-5 expression and the product was distributed in the actin cytoskeleton fraction, which was enriched with TJ proteins. Caffeine, which is an inhibitor of ataxia telangiectasia mutated protein (ATM) and ataxia telangiectasia mutated and Rad3-related protein (ATR), and the Chk1 inhibitor inhibited the TER increases induced by daunorubicin and rebeccamycin, whereas a Chk2 inhibitor did not. Treatment with Chk1 siRNA also significantly inhibited the TER increases. Induction of claudin-5 expression was inhibited by Chk1 inhibitor and by siRNA treatment. Our results suggest that Chk1 activation by daunorubicin and rebeccamycin induced claudin-5 expression and enhanced TJ barrier function in Caco-2 cell monolayer, which suggests a link between DNA damage and TJ integrity in the human intestine. PMID:26727128

  20. Chromium-Removal Processes during Groundwater Remediation by a Zerovalent Iron Permeable Reactive Barrier

    SciTech Connect

    Wilkin, Richard T.; Su, Chunming; Ford, Robert G.; Paul, Cynthia J.

    2008-06-09

    Solid-phase associations of chromium were examined in core materials collected from a full-scale, zerovalent iron permeable reactive barrier (PRB) at the U.S. Coast Guard Support Center located near Elizabeth City, NC. The PRB was installed in 1996 to treat groundwater contaminated with hexavalent chromium. After eight years of operation, the PRB remains effective at reducing concentrations of Cr from average values >1500 {micro}g L{sup -1} in groundwater hydraulically upgradient of the PRB to values <1 {micro}g L{sup -1} in groundwater within and hydraulically downgradient of the PRB. Chromium removal from groundwater occurs at the leading edge of the PRB and also within the aquifer immediately upgradient of the PRB. These regions also witness the greatest amount of secondary mineral formation due to steep geochemical gradients that result from the corrosion of zerovalent iron. X-ray absorption near-edge structure (XANES) spectroscopy indicated that chromium is predominantly in the trivalent oxidation state, confirming that reductive processes are responsible for Cr sequestration. XANES spectra and microscopy results suggest that Cr is, in part, associated with iron sulfide grains formed as a consequence of microbially mediated sulfate reduction in and around the PRB. Results of this study provide evidence that secondary iron-bearing mineral products may enhance the capacity of zerovalent iron systems to remediate Cr in groundwater, either through redox reactions at the mineral-water interface or by the release of Fe(II) to solution via mineral dissolution and/or metal corrosion.

  1. Remediation of MSW landfill leachate by permeable reactive barrier with vegetation.

    PubMed

    Chiemchaisri, Chart; Chiemchaisri, Wilai; Witthayapirom, Chayanid

    2015-01-01

    This research was conducted to investigate in situ treatment of leachate by pilot-scale permeable reactive barrier (PRB) with vegetation. Two different types of PRB media, with and without the presence of ferric chloride sludge, for the removal of pollutants were examined. The composite media of PRB comprised a clay and sand mixture of 40:60%w/w (system