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https://www.readbyqxmd.com/read/28214380/application-of-the-mechpeff-model-to-predict-passive-effective-intestinal-permeability-in-the-different-regions-of-the-rodent-small-intestine-and-colon
#1
D Pade, M Jamei, A Rostami-Hodjegan, D B Turner
A major component of Physiologically-Based Pharmacokinetic (PBPK) models is prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff ) is essential. Single pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters...
February 18, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28214100/nlrp6-a-multifaceted-innate-immune-sensor
#2
REVIEW
Maayan Levy, Hagit Shapiro, Christoph A Thaiss, Eran Elinav
NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, regulates inflammation and host defense against microorganisms. Similar to other NLRs, NLRP6 not only participates in inflammasome formation, but is also involved in nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling regulation and facilitation of gastrointestinal antiviral effector functions. Additionally, NLRP6 contributes to the regulation of mucus secretion and antimicrobial peptide production, thereby impacting intestinal microbial colonization and associated microbiome-related infectious, autoinflammatory, metabolic, and neoplastic diseases...
February 14, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28212861/accumulation-of-phosphatidylcholine-on-gut-mucosal-surface-is-not-dominated-by-electrostatic-interactions
#3
Agatha Korytowski, Wasim Abuillan, Federico Amadei, Ali Makky, Andrea Gumiero, Irmgard Sinning, Annika Gauss, Wolfgang Stremmel, Motomu Tanaka
The accumulation of phosphatidylcholine (PC) in the intestinal mucus layer is crucial for the protection of colon epithelia from the bacterial attack. It has been reported that the depletion of PC is a distinct feature of ulcerative colitis. Here we addressed the question how PC interacts with its binding proteins, the mucins, which may establish the hydrophobic barrier against colonic microbiota. In the first step, the interactions of dioleoylphosphatidylcholine (DOPC) with two mucin preparations from porcine stomach, have been studied using dynamic light scattering, zeta potential measurement, and Langmuir isotherms, suggesting that mucin binds to the surface of DOPC vesicles...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28206729/gut-microbiota-and-gastric-disease
#4
Dolores Sgambato, Agnese Miranda, Lorenzo Romano, Marco Romano
The gut microbiota may be considered a crucial "organ" of human body because of its role in the maintenance of the balance between health as well as disease. It is mainly located in the small bowel and colon, while, the stomach was long thought to be sterile in particular for its high acid production. In particular, stomach was considered "an hostile place" for bacterial growth until the identification of Helicobacter pylori (HP). Now, the stomach and its microbiota can be considered as two different "organs" that share the same place and they have an impact on each other...
15, 2017: Minerva Gastroenterologica e Dietologica
https://www.readbyqxmd.com/read/28195642/functional-mucous-layer-and-healing-of-proximal-colonic-anastomoses-in-an-experimental-model
#5
J W A M Bosmans, A C H M Jongen, G M H Birchenough, E E L Nyström, M J J Gijbels, J P M Derikx, N D Bouvy, G C Hansson
BACKGROUND: Anastomotic leakage (AL) is the most dreaded complication after colorectal surgery, causing high morbidity and mortality. Mucus is a first line of defence against external factors in the gastrointestinal tract. In this study, the structural mucus protein Muc2 was depleted in genetically engineered mice and the effect on healing of colonic anastomoses studied in an experimental model. METHODS: Mice of different Muc2 genotypes were used in a proximal colonic AL model...
February 13, 2017: British Journal of Surgery
https://www.readbyqxmd.com/read/28167669/mucosal-antibodies-to-the-c-terminus-of-toxin-a-prevent-colonization-of-clostridium-difficile
#6
Huynh A Hong, Krisztina Hitri, Siamand Hosseini, Natalia Kotowicz, Donna Bryan, Fatme Mawas, Anthony J Wilkinson, Annie van Broekhoven, Jonathan Kearsey, Simon M Cutting
Mucosal immunity is considered important for protection to Clostridium difficile infection (CDI). We show that in hamsters immunized with Bacillus subtilis spores expressing a carboxy-terminal segment (TcdA26-39) of C. difficile toxin A no colonization occurs in protected animals when challenged with C. difficile strain 630. By contrast, animals immunized with toxoids showed no protection and remained fully colonized. As well as neutralizing toxins, antibodies to TcdA26-39 (but not to toxoids), whether raised to the recombinant protein, or to TcdA26-39 expressed on the B...
February 6, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28147355/improvement-of-a-leaky-intestinal-barrier
#7
REVIEW
Eduard F Stange
In Crohn's disease, the mucus layer appears to be defective in terms of low defensin levels and lack of antibacterial activity. These deficiencies actually explain the Montreal phenotypes and the stable localization of disease in the terminal ileum with low α-defensins from Paneth cells and/or low β-defensins in colonic disease, respectively. Conversely, in ulcerative colitis (UC) the defensin production is normal or even induced, but the mucus layer is thinner and patchy, more in the liquid form and also chemically altered so that antibacterial peptides are not retained and lost into the luminal bacterial bulk...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28133201/-long-term-survival-in-response-to-multimodality-therapy-in-a-patient-with-invasive-pancreatic-cancer-with-cyst-formation
#8
Hironobu Makino, Hisashi Kametaka, Tadaomi Fukada, Kazuhiro Seike, Akio Hasegawa, Masaru Isozaki
The patient was a 61-year-old man. Computed tomography(CT)in April 2007 revealed a pancreatic cyst in the tail of the pancreas. Rapid enlargement was noted in November 2007, and the patient was referred to the surgery department. CT showed a cystic lesion containing a nodular shadow in the pancreatic tail. Tumor marker measurements yielded normal carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9)levels, but the duke pancreatic monoclonal antigen type 2(DUPAN-2)level was elevated. A diagnosis of mucinous cystic neoplasm(MCN)of the pancreas was made in December 2007, and distal pancreatectomy and partial colectomy were performed...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28122822/intestinal-muc2-mucin-o-glycosylation-is-affected-by-microbiota-and-regulated-by-differential-expression-of-glycosyltranferases
#9
Liisa Arike, Jessica Holmén-Larsson, Gunnar C Hansson
Intestinal cells are covered by mucus. In the small intestine, a single unattached mucus is present whereas the colon has both an inner attached mucus layer and an outer loose mucus. The attached mucus of the colon is impenetrable to bacteria while the loose mucus acts as a habitat for commensal bacteria. In germ-free (GF) mice, small intestinal mucus is attached to the epithelium and the inner colon mucus is penetrable. O-glycosylation plays an important role in the host-microbiota interactions as the commensal bacteria use glycans as nutrient sources and attachment sites...
January 24, 2017: Glycobiology
https://www.readbyqxmd.com/read/28120846/cortactin-deficiency-causes-increased-rhoa-rock1-dependent-actomyosin-contractility-intestinal-epithelial-barrier-dysfunction-and-disproportionately-severe-dss-induced-colitis
#10
A F Citalán-Madrid, H Vargas-Robles, A García-Ponce, M Shibayama, A Betanzos, P Nava, C Salinas-Lara, K Rottner, R Mennigen, M Schnoor
The intestinal epithelium constitutes a first line of defense of the innate immune system. Epithelial dysfunction is a hallmark of intestinal disorders such as inflammatory bowel diseases (IBDs). The actin cytoskeleton controls epithelial barrier integrity but the function of actin regulators such as cortactin is poorly understood. Given that cortactin controls endothelial permeability, we hypothesized that cortactin is also important for epithelial barrier regulation. We found increased permeability in the colon of cortactin-KO mice that was accompanied by reduced levels of ZO-1, claudin-1, and E-cadherin...
January 25, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28093882/the-gastrointestinal-tract-of-farmed-mink-neovison-vison-maintains-a-diverse-mucosa-associated-microbiota-following-a-3-day-fasting-period
#11
Martin I Bahl, Anne S Hammer, Tove Clausen, Anabelle Jakobsen, Søren Skov, Lars Andresen
Although it is well documented that the gut microbiota plays an important role in health and disease in mammalian species, this area has been poorly studied among carnivorous animals, especially within the mustelidae family. The gastrointestinal tract of carnivores is characterized by its short length and fast transit time, as compared to omnivores and herbivores, which is due to the low level of inherent fermentation. Mink represents an example of this, which have a GI tract only four times the length of the body and a transit time of approximately 4-5 hr...
January 16, 2017: MicrobiologyOpen
https://www.readbyqxmd.com/read/28069817/quorum-sensing-regulators-are-required-for-metabolic-fitness-in-vibrio-parahaemolyticus
#12
Sai Siddarth Kalburge, Megan R Carpenter, Sharon Rozovsky, E Fidelma Boyd
Quorum sensing (QS) is a process by which bacteria alter gene expression in response to cell density changes. In Vibrio species, at low cell density, the sigma 54-dependent response regulator LuxO, is active, and regulates the two QS master regulators AphA, which is induced and OpaR, which is repressed. At high cell density the opposite occurs, LuxO is inactive, therefore OpaR is induced and AphA is repressed. In V. parahaemolyticus, a significant enteric pathogen of humans, the role of these regulators in pathogenesis is less known...
January 9, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28069814/muc2-mucin-and-butyrate-contribute-to-the-synthesis-of-the-antimicrobial-peptide-cathelicidin-in-response-to-e-histolytica-and-dss-induced-colitis
#13
Eduardo R Cobo, Vanessa Kissoon-Singh, France Moreau, Ravi Holani, Kris Chadee
Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP), LL-37/hCAP-18 and Cramp respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica (Eh) are not well characterized...
January 9, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28062699/cathelicidin-wa-improves-intestinal-epithelial-barrier-function-and-enhances-host-defense-against-enterohemorrhagic-escherichia-coli-o157-h7-infection
#14
Hongbo Yi, Wangyang Hu, Shan Chen, Zeqing Lu, Yizhen Wang
Impaired epithelial barrier function disrupts immune homeostasis and increases inflammation in intestines, leading to many intestinal diseases. Cathelicidin peptides suppress intestinal inflammation and improve intestinal epithelial barrier function independently of their antimicrobial activity. In this study, we investigated the effects of Cathelicidin-WA (CWA) on intestinal epithelial barrier function, as well as the underlying mechanism, by using enterohemorrhagic Escherichia coli (EHEC)-infected mice and intestinal epithelial cells...
January 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28054754/the-stce-metalloprotease-of-enterohaemorrhagic-escherichia-coli-reduces-the-inner-mucus-layer-and-promotes-adherence-to-human-colonic-epithelium-ex-vivo
#15
Claire L Hews, Seav-Ly Tran, Udo Wegmann, Bernard Brett, Alistair D S Walsham, Devon Kavanaugh, Nicole J Ward, Nathalie Juge, Stephanie Schüller
Enterohaemorrhagic E. coli (EHEC) is a major foodborne pathogen and tightly adheres to human colonic epithelium by forming attaching/effacing lesions. To reach the epithelial surface, EHEC must penetrate the thick mucus layer protecting the colonic epithelium. In this study, we investigated how EHEC interacts with the intestinal mucus layer using mucin-producing LS174T colon carcinoma cells and human colonic mucosal biopsies. The level of EHEC binding and A/E lesion formation in LS174T cells was higher compared to mucin-deficient colon carcinoma cell lines, and initial adherence was independent of the presence of flagellin, E...
January 5, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28053172/protein-synthesis-in-mucin-producing-tissues-is-conserved-when-dietary-threonine-is-limiting-in-piglets
#16
Lalani L Munasinghe, Jason L Robinson, Scott V Harding, Janet A Brunton, Robert F Bertolo
BACKGROUND: The neonatal gastrointestinal tract extracts the majority of dietary threonine on the first pass to maintain synthesis of threonine-rich mucins in mucus. As dietary threonine becomes limiting, this extraction must limit protein synthesis in extraintestinal tissues at the expense of maintaining protein synthesis in mucin-producing tissues. OBJECTIVE: The objective was to determine the dietary threonine concentration at which protein synthesis is reduced in various tissues...
January 4, 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28006108/digitoxin-for-airway-inflammation-in-cystic-fibrosis-preliminary-assessment-of-safety-pharmacokinetics-and-dose-finding
#17
Pamela L Zeitlin, Marie Diener-West, Karen A Callahan, Seakwoo Lee, C Conover Talbot, Bette Pollard, Michael P Boyle, Noah Lechtzin
RATIONALE: Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly neutrophilic and complicates airway clearance therapies through cellular debris; excessive DNA; excessive and viscous mucus; and high concentrations of neutrophils, IL-8, and related cytokines liberated along the nuclear factor-κB signaling pathway. OBJECTIVES: We conducted a preliminary, single-site, randomized, double-blind, placebo-controlled study to evaluate the effects over 28 days of two dose levels (0...
February 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27983971/immune-protective-effect-of-echinococcosis-on-colitis-experimental-model-is-dependent-of-down-regulation-of-tnf-%C3%AE-and-no-production
#18
Lila Khelifi, Imene Soufli, Moussa Labsi, Chafia Touil-Boukoffa
Hydatid disease (echinococcosis) is a chronic, endemic helminthic disease caused by the larval stage of the tapeworm, Echinococcus granulosus. This disease is endemic in many parts of the world, such as the Mediterranean area, and in particular in Algeria. Helminth parasites have developed complex strategies to modulate the immune responses of their hosts through versatile immune-regulatory mechanisms. These mechanisms may regulate immune responses associated with inflammatory diseases such as inflammatory bowel diseases (IBD)...
February 2017: Acta Tropica
https://www.readbyqxmd.com/read/27938674/mannheimia-haemolytica-biofilm-formation-on-bovine-respiratory-epithelial-cells
#19
Ismail Boukahil, Charles J Czuprynski
Mannheimia haemolytica is the most important bacterial agent associated with the bovine respiratory disease complex (BRDC), which causes worldwide economic losses to the cattle industry. M. haemolytica cells initially colonize the tonsillar crypts in the upper respiratory tract of cattle, from where they can subsequently descend into the lungs to cause disease. Many bacteria exist as biofilms inside their hosts. We hypothesize that M. haemolytica colonization of cattle during its commensal state may include biofilm formation...
December 25, 2016: Veterinary Microbiology
https://www.readbyqxmd.com/read/27927890/massively-increased-caries-susceptibility-in-an-irf6-cleft-lip-palate-model
#20
B Tamasas, T C Cox
Patients with cleft lip/palate (CLP) have been reported, in some studies, to exhibit an increased prevalence of caries, although the underlying cause for this increase is unknown. In genetically defined mouse models, studies of postnatal sequelae associated with CLP have been hampered by neonatal lethality. Using a conditional targeting approach, we ablated the major CLP gene Irf6 only in the late embryonic oral epithelium (Irf6 cKO), bypassing the role of the gene in lip and palate morphogenesis and thus ensuring survival to adulthood...
December 7, 2016: Journal of Dental Research
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