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Oriented continua play an important role in micropolar elasticity modelling. All realizations of micropolar theories are conceptually possible only within the framework of the pseudotensor formalism and the orientable manifold notion. This particularly concerns the theory of micropolar hemitropic elastic media. In this paper, a pseudotensor description is used in contrast to Kartan's formalism. The pseudotensor formulation of Stokes' integral theorem is almost unknown in the current scientific literature. Here we consider various formulations of Stokes' integral theorem for an arbitrary asymmetric covariant pseudotensor field of a given weight and valency. This extends the theorem to the case of pseudotensors. This fact makes it possible to use the mentioned generalization for micropolar continua. The study mostly relies on the class of special coordinate systems often employed in classical physical field theories. A procedure for orientations consistency inside and on the boundary of a manifold is discussed for various formulations of Stokes' integral theorem.

Several disease-modulatory FDA-approved drugs are being used in patients with neurodegenerative diseases. However, information on their toxicity-related profiles is very limited. Therefore, measurement of drug toxicity is essential to increase the knowledge of their side effects. This study aimed to identify compounds that can modulate M-cell regeneration by causing neuro-protection and -toxicity. Here, we developed a simple and efficient in vivo assay using Tg (hsp: Gal4FF62A; UAS: nfsB-mCherry) transgenic zebrafish larvae. Interestingly, via the phenotype-based drug screening approach, we rapidly investigated 1,260 compounds from the United States drug collection and validated these in large numbers, including 14 compounds, that were obstructing this regeneration process. Next, 4 FDA-approved drugs out of 14 compounds were selected as the lead hits for in silico analysis to clarify their binding patterns with PTEN and SOCS3 signaling due to their significant potential in the inhibition of axon regeneration. Molecular docking studies indicated good binding affinity of all 4 drugs with the respective signaling molecules. This may point to PTEN and SOCS3 as the signaling molecules responsible for reducing axon regeneration. Moreover, the acute effect of compounds in reducing M-cell regeneration delineated their toxic effect. In conclusion, our in vivo along with in silico screening strategy will promote the rapid translation of new therapeutics to improve knowledge of the toxicity profile of approved/non-approved drugs efficiently.

The paper deals with the problems of the tensor element of volume (area) of an M-cell for a manifold immersed in a "plane" multidimensional space. The corresponding considerations imply the choice of the reper orientation, which determines the volume (area) element. The latter circumstance is of exceptional importance in micropolar theories of elasticity. The indicated theories can be correctly developed only within the framework of the pseudotensor formalism. This is especially true for the theory of hemitropic elastic continua. The governing information from the algebra of pseudotensors is presented. Manifolds given by Gaussian parametrization are considered. The concept of an M-cell on a manifold and its orientation is introduced. An algorithm for comparing the orientations of M-dimensional cells is described. The concept of the tensor element of volume (area) for the M- cell is determined. The formula for transformation a natural volume element to an invariant volume element is shown. Important applications for the mechanics of the micropolar continuum are noted and discussed. [ABSTRACT FROM AUTHOR]

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To improve current mucosal allergen immunotherapy Vibrio cholerae neuraminidase (NA) was evaluated as a novel epithelial targeting molecule for functionalization of allergen-loaded, poly(D,L-lactide- co -glycolide) (PLGA) microparticles (MPs) and compared to the previously described epithelial targeting lectins wheat germ agglutinin (WGA) and Aleuria aurantia lectin (AAL). All targeters revealed binding to Caco-2 cells, but only NA had high binding specificity to α-L fucose and monosialoganglioside-1. An increased transepithelial uptake was found for NA-MPs in a M-cell co-culture model. NA and NA-MPs induced high levels of IFN-γ and IL10 in naive mouse splenocytes and CCL20 expression in Caco-2. Repeated oral gavage of NA-MPs resulted in a modulated, allergen-specific immune response. In conclusion, NA has enhanced M-cell specificity compared to the other targeters. NA functionalized MPs induce a Th1 and T-regulatory driven immune response and avoid allergy effector cell activation. Therefore, it is a promising novel, orally applied formula for allergy therapy. [ABSTRACT FROM AUTHOR]

The oral uptake of intact nanocarriers through Peyer’s patches is an important uptake pathway. We report Rifampicin Lipid-Polymer hybrid nanoparticles (RIF-LIPOMER) using glyceryl monostearate as lipid and the mucoadhesive polymer, Gantrez, with the objective of balancing hydrophobicity and mucoadhesion for enhanced Peyer’s patch uptake. RIF-LIPOMER was optimized for size, hydrophobicity, and mucoadhesion using Box-Behnken. Designed RIF-LIPOMER (RIF-LIPO-120) exhibited average particle size in the range 300–400 nm with drug loading >12%. DSC and XRD confirmed complete amorphization. Contact angle and mucoadhesion force revealed that RIF-LIPO-120 exhibited greater hydrophobicity and lower mucoadhesion compared to Gantrez nanoparticles (RIF-GzNP). Comparative uptake of fluorescent labelled RIF-LIPO-120 and RIF-GzNP, through Peyer’s patch following intraduodenal administration in rats, revealed the high accumulation of RIF-GzNP at the villi border, and high Peyer’s patch uptake of RIF-LIPO-120. Furthermore, lower accumulation of RIF-LIPO-120 in the liver, compared to RIF-GzNP, suggested bypass of the portal circulation and lymphatic uptake through Peyer’s patches. Significantly higher lung: plasma concentration ratio exhibited by RIF-LIPO-120 compared to RIF-GzNP confirmed the same (p < 0.05). Our study demonstrated that optimization of hydrophobicity and mucoadhesion of nanoparticles could favor Peyer’s patch uptake, which in turn could enable enhanced drug accumulation in the lungs with advantage in the therapy of pulmonary afflictions. [ABSTRACT FROM AUTHOR]

This article reviews the field of oral uptake of nanoparticles across the gastrointestinal epithelium for the period 2006–2016. Analysis is conducted from the viewpoint of i) M-cell genetics and model development, ii) drug targeting to Peyer's patches and M-cells, and iii) physicochemical interactions of nanoparticles in the intestinal milieu. In light of these recent developments, regulatory considerations in the development of orally-absorbable nanoparticle drug products are discussed and focused on Module 3.2.P sub-sections of the Common Technical Document. Particular attention is paid to novel excipients, ligands and the non-standard method of manufacture. The novelty of this drug delivery system demands not only a multi-disciplinary scientific and regulatory approach but also a risk-adjusted consideration for a system defined by both processes and specifications. Given the current state of scientific development in the field it is suggested (in the author's personal opinion) that the design of nanoparticulate drug delivery systems should be kept as simple as possible (from a regulatory and manufacturing perspective) and to target the entire gastrointestinal epithelium. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (Vmax) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of Vmax with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10μM, although a tendency toward prolongation was observed at 20μM. A moderate lengthening of APD90 by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of Vmax was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak INa with class I/B antiarrhythmic characteristics. Although peak INa inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD90 values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug. [Copyright &y& Elsevier]

galactose- and N-acetyl-D-galactosamine-specific lectin ( Viscum album L. var. coloratum agglutinin, VCA), which is known for its anti-tumor activity, was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously because of the unstability and poor absorption in the GI tract. In this study, we investigated the effect of incubation time and glucose on the VCA transport across the in vitro model of human FAE (follicle-associated epithelium) by two different cell models: Caco-2 cell monolayers mimicking human enterocytes and a model of the human FAE which is mainly composed of M-cells and enterocytes. As a result, the VCA transport across the FAE monolayer cells was higher and faster than the transport across the Caco-2 monolayer cells, and glucose increased VCA transport across both monolayer cells. In addition, IL-12 was secreted from myeloid DC1 and lymphoid DC2.4 cells which were co-treated simultaneously with LPS and VCA. Furthermore, the FAE model associated with underlying immune cells was established and VCA was added to the inserts apically. There was a greater IL-12 secretion in dendritic cells situated below FAE monolayer than Caco-2 monolayer. The results from this study provide important insight into the possible oral application of mistletoe on anti-tumor therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Antigen uptake has been shown to occur in the teleost intestine, but so far, limited information is available on the distribution and nature of cells involved in the process, and M cells, known for their antigen-sampling abilities in mammals, have not been identified. Here, different intestinal segments from salmonid fish were exposed to gold-BSA to identify antigen-sampling cells. Sections from exposed intestine were examined by light and electron microscopy. Uptake of gold-BSA was restricted to very few dendritic-like cells and to a limited number of epithelial cells located in the mucosal folds in the second segment of the mid-intestine. Gold-positive epithelial cells displayed diverging and electron-dense microvilli with channels intruding into the cytoplasm. A lectin binding experiment demonstrated the presence of cells with mammalian M-cell characteristics in the identical regions. As the identified epithelial cells shared some morphological similarities with immature mammalian M cells, this phenotype may represent evolutionary early antigen-sampling enterocytes. [Copyright &y& Elsevier]

Bovine serum albumin (BSA) microspheres of ferric pyrophosphate (FPP) intended for passive targeting to the Peyer’s patches has been proposed for oral iron supplementation. Microspheres prepared by emulsification chemical cross linking method were characterized for surface topography, entrapment efficiency, particle size, particle charge and in vitro drug release. Microspheres of batch C with FPP to BSA ratio of 1:5 were found to be most suitable for targeting as they exhibited high entrapment (83.88 ± 4.31), high monodispersity (span = 1.24 ± 0.01), and least particle size ( dvm = 4.40 ± 0.01). In addition the amount of iron retained in these microspheres despite exposure to simulated gastrointestinal conditions for 5 h was found to be 83.72 ± 4.22%, the highest in the three batches. The in vivo serum iron profiles in normal rats following oral administration displayed a reduced Tmax (2 h), elevated Cmax (106.06 ± 12.18 μg/dL) and increased AUC 0–16 h (647.44 ± 52.33 μg.h/dL) for these microspheres which significantly differed ( P <0.05) from FPP solution indicating a higher iron repletion potential of the BSA microspheres. [ABSTRACT FROM AUTHOR]

Rifampicin-encapsulated liposome suspensions were prepared by a chloroform-film method and converted to dry powders by freeze-drying with mannitol as a cryoprotectant. The liposome suspension had multilamellar nanovesicles with 50% rifampicin encapsulation. The liposome dry powder comprised particles with a mass median aerodynamic diameter of 3.4 μm, with 60% present as a fine particle fraction. Rifampicin-encapsulated liposomes were evidently nontoxic to respiratory associated cells, including bronchial epithelial cells, small airway epithelial and alveolar macrophages (AMs). Furthermore, the liposomes did not activate AMs to produce interleukin-1β, tumor necrosis factor-α, and nitric oxide at a level that would cascade to other inflammatory effects. The minimum inhibitory concentrations against Mycobacterium bovis was 0.2 and 0.8 μM for liposomes containing rifampicin and free rifampicin, respectively. The less negatively charged reconstituted liposome displayed the greatest activity against intracellular growth of M. bovis. [ABSTRACT FROM AUTHOR]

Abstract: The paired palatine tonsils, located at the junction of the nasopharynx and oropharynx, are ideally positioned to sample antigens entering through the nasal cavity or oral cavity. Entering antigens will first contact tonsilar epithelium. To better understand the cellular composition of this important epithelial layer, palatine tonsils were collected from six, 7-month-old calves and examined by light microscopy, immunohistochemistry and electron microscopy. Morphometric analysis showed that epithelium overlying lymphoid follicles (reticular epithelium) contained more B-cells, CD4+, CD8+, CD11c+, CD172a+ and γ/δ TCR+ cells than non-reticular epithelium, with B-cells, CD4+ cells and CD11c+ cells being most numerous. Scanning and transmission electron microscopy of reticular epithelium identified an interrupted basement membrane and vascular elements within the epithelium, as well as cells with characteristics morphologically consistent with cells identified as M-cells in other species. Bovine palatine tonsilar reticular epithelium contains key immune cells, as well as potential M-cell-like cells; elements essential for antigen uptake, antigen processing and initiation of immune responses. [Copyright &y& Elsevier]

Nasal vaccination is a promising alternative to classical parental vaccination, as it is non-invasive and, in principle, capable of eliciting strong systemic and local immune responses. However, the protective efficacy of nasally administered antigens is often impaired because of delivery problems: free antigens are readily cleared from the nasal cavity, poorly absorbed by nasal epithelial cells and generally have low intrinsic immunogenicity. In this review paper, we describe the main physiological hurdles to nasal vaccine delivery, survey the progress made in technological approaches to overcome these hurdles and discuss emerging opportunities for improving nasal vaccines. According to current insights, encapsulation of the antigen into bioadhesive (nano)particles is a promising approach towards successful nasal vaccine delivery. These antigen-loaded particles can be tailor made by supplying them with targeting ligands, adjuvants or endosomal escape mediators to form the desired vaccine that provides long-lasting protective immunity. [ABSTRACT FROM AUTHOR]

Although polymeric nanoparticles/microparticles are well established for the mucosal administration of conventional drugs, they have not yet been developed commercially for vaccine delivery. The limitation of the mucosal (particularly oral) route of delivery, including low pH, gastric enzymes, rapid transit and poor absorption of large molecules, has made mucosal vaccine delivery challenging. Nevertheless, several polymeric delivery systems for mucosal vaccine delivery are currently being evaluated. The polymer-based approaches are designed to protect the antigen in the gut, to target the antigen to the gut-associated lymphoid tissue or to increase the residence time of the antigen in the gut through bioadhesion. M-cell targeting is a potential approach for mucosal vaccine delivery, which can be achieved using M-cell-specific lectins, microbial adhesins or immunoglobulins. While many hurdles must be overcome before targeted mucosal vaccine delivery becomes a practical reality, this is a potential area of research that has important implications for future vaccine development. This review comprises various aspects that could be decisive in the development of polymer based mucosal vaccine delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: Neuraminidases act as a virulence factors for several pathogens that invade the human body through Peyer''s patch M-cells. Because of the structural similarity of Aleuria aurantia lectin (AAL) to neuraminidases, we hypothesized that AAL might also target human M-cells. In an in vitro human M-cell co-culture model significantly more particles were transported across the epithelium when microparticles were functionalized with AAL versus those that were not. Moreover, high concentrations of AAL induced no detectable cytotoxic effects on the related intestinal epithelial cell cultures, epithelial Caco2- and HT29-MTX-E12-cells. Upon incubation with AAL, PBMCs of allergic volunteers proliferated in response to AAL and secreted the cytokines, IL-2, IFN-γ, IL-10 and IL-5 in a concentration-dependent manner, indicating immune-stimulatory properties of the lectin. We conclude that AAL-coated microparticles may have the potential to target entrapped antigens to human M-cells for oral vaccination. [Copyright &y& Elsevier]

Lymphoid follicles cluster in the terminal rectum of various animal species and of man and hence this site may be important in the development of immune responses to pathogens. For the induction of immune responses at mucosal sites, interplay is required between various cell types performing functions ranging from antigen-sampling cells via antigen-presenting cells to antigen-specific lymphocytes. Therefore, we have characterised the cell populations and relevant functioning of follicle-associated epithelium (FAE) and associated follicles in the terminal portion of rectum in cattle as a representative mammal. Immunohistochemical studies of this region identified immune cell subsets (CD4+, CD8+, WC1+γδ, CD2+, CD21+ and CD40+ cells) characteristic of an immune-inductive site. Examination of FAE identified a subset of cells with structural and functional features of antigen-sampling M-cells. Cells of the FAE and adjacent follicle-associated crypts expressed vimentin and a subset of these cells internalised microparticles, a further attribute of M-cells. The FAE cells were phenotypically heterogeneous and therefore the function and phenotype of these cell subsets requires further characterisation, particularly with respect to their potentially important role in the interaction of hosts with pathogens and the development of immune responses. [ABSTRACT FROM AUTHOR]

This study has evaluated an in vitro model of the follicle-associated epithelia that overlie Peyer’s patches of the small intestine. The model shares many phenotypic characteristics of M cells in vivo. Co-cultures of the human adenocarcinoma cell line Caco-2 and freshly isolated Peyer’s patch cells were established. Fluorescence microscopy and quantitative image analysis were used to validate the model against known markers of M-cell phenotype. Apical expression of alkaline phosphatase was down-regulated in co-cultures and villin was re-distributed from the apical membrane to the cytoplasm. α5β1 integrin was found on the apical surfaces of the monolayers and B and T lymphocytes integrated into the monolayers. Particle transport was temperature-dependent in co-cultures, indicating that a transcytotic route was responsible. This model provides opportunities to study factors that influence M-cell development, assess putative Peyer’s patch targeting in oral vaccine technologies, and study intestinal uptake in vitro. [Copyright &y& Elsevier]

The adenoid and tonsils are lymphoid tissues located in the pharynx that play an important role in host defense against invading antigens of the upper respiratory tract. Histologically, these structures consist of four well-defined microcompartments which all participate in the immune response: the cryptepithelium, the follicular germinal center with the mantle zone and interfollicular area. With the uptake of antigen by M-cells present in the cryptepithelium a process is initiated which ultimately results in the generation and dissemination of antigen-specific memory and mainly dimeric IgA-producing effector B-lymphocytes. This process requires successful cognate interactions between antigen-presenting cells and lymphocytes and mutually between lymphocytes, which depend not only on antigen-specific signals but also on the expression of various complementary adhesion and costimulatory molecules.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The distribution of intestinal membranous (M) cells has been studied within the follicle-associated epithelium of rabbit Peyer's patches and appendix. Vimentin expression has been assessed as a primary criterion to identify rabbit M cells in tissue sections and in whole tissue preparations. This criterion has been compared to the use of the absence of alkaline phosphatase which, due to its heterogeneous distribution within the enterocyte population, is less reliable than vimentin expression as a marker for rabbit M cells. The pattern of vimentin immunostaining revealed that the majority of M cells are located in the periphery of the follicle-associated epithelium, the dome apex being largely free of M cells. This distribution was confirmed by scanning electron microscopy. Vimentin is also expressed by follicle-associated epithelial cells in the vicinity of crypts which lack the typical lymphocyte-containing pocket of M cells. Cytoplasmic peanut agglutinin binding coincides with vimentin-expression throughout the follicle-associated epithelium but is absent from vimentin-negative enterocytes. The co-localisation of these two phenotypic markers in both M cells and epithelial cells adjacent to crypts, which lack the typical morphology of fully developed rabbit M cells, suggests that they correspond to immature M cells which by their location appear to derive directly from undifferentiated crypt stem cells and not from mature columnar enterocytes. [ABSTRACT FROM AUTHOR]

Yersinia enterocolitica is an invasive pathogen capable of causing a wide spectrum of gastrointestinal diseases in man. While there is a considerable body of data on the invasiveness of Y. enterocolitica in vitro, little is known about the events in vivo leading to the translocation of the bacteria from the intestinal lumen into the ileal tissue. There is no detailed ultrastructural information describing the course of infection of pathogenic Y. enterocolitica in comparison with an avirulent strain. We compared a virulent plasmid-bearing strain and an isogenic avirulent plasmid-free derivative strain of Y. enterocolitica serotype O∶8 at the ultrastructural level, in the established model of murine yersiniosis. At 12 h postinoculation we found no indications of an active invasion of the intestinal epithelium, although microcolonies of the pathogenic strain were detectable closely under the follicle-associated epithelium of the Peyer's patches. The plasmid-bearing strain of Y. enterocolitica affected the gut-associated lymphoid tissue which was destroyed 36 h post-infection. Unlike the pathogenic strain of Y. enterocolitica, the nonpathogenic plasmid-free strain caused no detectable morphological alterations in the ileal tissue by this time. Morphological evidence is provided that Yersinia does not invade the ileal epithelium in an active manner, as has been observed in vitro, but appears to be transported across the epithelial barrier by M-cells. [ABSTRACT FROM AUTHOR]

The zonulae occludentes of the dome epithelia and adjacent non-dome epithelia in four locations of the gut-associated lymphoid tissue (GALT) in the rabbit ileum and caecum (Peyer's patches, sacculus rotundus, caecal lymphoid patches, appendix) were studied in freeze-fracture replicas. In all locations the zonulae occludentes of the dome epithelium are composed of more junctional strands than in the corresponding non-dome epithelium. In the dome epithelia of Peyer's and caecal lymphoid patches the zonulae occludentes show considerable structural variation; the number of superimposed strands is ∼10 (range 5-18). In the dome epithelia of sacculus rotundus and appendix, in addition to zonulae occludentes, extended networks of junctional strands (fasciae occludentes) are present particularly between M-cells and enterocytes. The zonulae occludentes consist of ∼8 to 9 (range 5-15) superimposed strands; the fasciae occludentes extend up to a depth of 20μm on the lateral membranes. The presence of the fasciae occludentes correlates with the appearance of regularly shaped clusters of lymphocytes, which are most developed in the dome epithelia of sacculus rotundus and appendix. These results suggest (1) that in contrast to the dome epithelia of Peyer's and caecal lymphoid patches those of sacculus rotundus and appendix are compartmentalized, and (2) that the mobility of lymphocytes and diffusion of antigens in the dome epithelia of sacculus rotundus and appendix is restricted. [ABSTRACT FROM AUTHOR]