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tight junction [keywords]
- Morphology of the ampullae of Lorenzini in juvenile freshwater Carcharhinus leucas. [JOURNAL ARTICLE]
- J Morphol 2014 Dec 17.
Ampullae of Lorenzini were examined from juvenile Carcharhinus leucas (831-1,045 mm total length) captured from freshwater regions of the Brisbane River. The ampullary organ structure differs from all other previously described ampullae in the canal wall structure, the general shape of the ampullary canal, and the apically nucleated supportive cells. Ampullary pores of 140-205 µm in diameter are distributed over the surface of the head region with 2,681 and 2,913 pores present in two sharks that were studied in detail. The primary variation of the ampullary organs appears in the canal epithelial cells which occur as either flattened squamous epithelial cells or a second form of pseudostratified contour-ridged epithelial cells; both cell types appear to release material into the ampullary lumen. Secondarily, this ampullary canal varies due to involuted walls that form a clover-like canal wall structure. At the proximal end of the canal, contour-ridged cells abut a narrow region of cuboidal epithelial cells that verge on the constant, six alveolar sacs of the ampulla. The alveolar sacs contain numerous receptor and supportive cells bound by tight junctions and desmosomes. Pear-shaped receptor cells that possess a single apical kinocilium are connected basally by unmyelinated neural boutons. Opposed to previously described ampullae of Lorenzini, the supportive cells have an apical nucleus, possess a low number of microvilli, and form a unique, jagged alveolar wall. A centrally positioned centrum cap of cuboidal epithelial cells overlies a primary afferent lateral line nerve. J. Morphol., 2014. © 2014 Wiley Periodicals, Inc.
- [Importance of cellular tight junction complexes in the development of periprosthetic leakage after prosthetic voice rehabilitation.] [JOURNAL ARTICLE]
- HNO 2014 Dec 18.
The use of voice prostheses is currently the gold standard in voice rehabilitation after total laryngectomy. This method combines low complication rates and excellent rehabilitation results; however, approximately 30 % of patients show periprosthetic leakage or severe fistula enlargement after laryngectomy and prosthetic voice restoration within the first 4 years. The development of this enlargement is controversially discussed in the literature but recently published studies have shown that high esophageal reflux plays a key role in this process, which leads to an inflammatory reaction and disturbs the intercellular tight junctions in the sense of an epithelial mesenchymal transition (EMT).A total of 44 patients underwent 24 h pH monitoring, a sample biopsy from the region of the fistula and a subsequent biomolecular examination for intracellular junction proteins as well as a correlation between the severity of reflux and tracheoesophageal fistula problems before and after antireflux therapy with proton pump inhibitors (PPI).Immunohistochemical staining revealed decreases in membrane E-cadherin and β-catenin and a significant increase in the cytoplasmic fraction, depending on the severity of inflammation in the fistula tissue. In patients with an improvement of clinical fistula problems under oral PPI treatment an increase of membrane E-cadherin could be shown, whereas patients with persisting fistula enlargement demonstrated a further decrease of E-cadherin.The data indicate a central role of EMT in the development of fistula enlargement after total laryngectomy. Patients with periprosthetic leakage showed a loss of membrane bound E-cadherin and β-catenin with an up-regulation of vimentin expression. In patients with mild or no leakage problems EMT could be resolved by aggressive antireflux treatment, whereas patients without any effect of PPI treatment on the fistula showed no reversal of EMT. These data contribute to the understanding of treatment resistant fistula enlargement after total laryngectomy.
- Modeling bioavailability to organs protected by biological barriers. [Journal Article, Review]
- In Silico Pharmacol 2013.:8.
Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.
- Cilostazol prevents retinal ischemic damage partly via inhibition of tumor necrosis factor-α-induced nuclear factor-kappa B/activator protein-1 signaling pathway. [Journal Article]
- Pharmacol Res Perspect 2013 Oct; 1(1):e00006.
Cilostazol is a specific inhibitor of phosphodiesterase III and is widely used to treat ischemic symptoms of peripheral vascular disease. We evaluated the protective effects of cilostazol in a murine model of ocular ischemic syndrome in which retinal ischemia was induced by 5-h unilateral ligation of both the pterygopalatine artery (PPA) and the external carotid artery (ECA) in anesthetized mice. The effects of cilostazol (30 mg/kg, p.o.) on ischemia/reperfusion (I/R)-induced retinal damage were examined by histological, retinal vascular permeability, and electrophysiological analyses. Using immunoblotting, the protective mechanism for cilostazol was evaluated by examining antiinflammatory effects of cilostazol on the expression of tumor necrosis factors-α (TNF-α) and tight junction proteins (ZO-1 and claudin-5), and the phosphorylations of nuclear factor-kappa B (NF-κB) and c-Jun. The histological analysis revealed that I/R decreased the cell number in the ganglion cell layer (GCL) and the thicknesses of the inner plexiform layer (IPL) and inner nuclear layer (INL), and that cilostazol attenuated these decreases. Additionally, cilostazol prevented the hyperpermeability of blood vessels. Electroretinogram (ERG) measurements revealed that cilostazol prevented the I/R-induced reductions in a-, b-, and oscillatory potential (OP) wave amplitudes seen at 5 days after I/R. Cilostazol inhibited the increased expression of TNF-α and the phosphorylation levels of NF-κB and c-Jun in the retina after I/R. In addition, cilostazol prevented TNF-α-induced reduction of ZO-1 and claudin-5 expression in human retinal microvascular endothelial cells (HRMECs). These findings indicate that cilostazol may prevent I/R-induced retinal damage partly through inhibition of TNF-α-induced NF-κB/AP-1 signaling pathway.
- Homoharringtonine increases intestinal epithelial permeability by modulating specific claudin isoforms in Caco-2 cell monolayers. [JOURNAL ARTICLE]
- Eur J Pharm Biopharm 2014 Dec 13.
Homoharringtonine (HHT), a natural alkaloid produced by various Cephalotaxus species, has antileukemic activity in acute and chronic myelogenous leukemia. However, HHT can also induce unanticipated effects in the gastrointestinal tract, such as diarrhea and nausea/vomiting, but the mechanism behind these adverse effects has not been clarified. In the present study, we show that HHT affects the epithelial permeability of intestinal Caco-2 cell monolayers. HHT reduced the transepithelial electrical resistance (TER) of Caco-2 cells in a dose- and time-dependent manner. The HHT effect was reversible and no cytotoxicity was observed at the concentrations used. HHT simultaneously increased the paracellular flux of the 4 kDa and 40 kDa FITC-dextrans associated with the TER reduction. Immunoblotting analysis revealed that HHT decreased the protein expression of TJ components such as claudin-3, -5, and -7. However, the transcription levels of these claudins were not repressed by HHT treatment. HHT also disturbed the cellular localization of claudin-1 and -4. These changes coincided with the reduced barrier function. Our findings suggest that HHT enhances the paracellular permeability of Caco-2 cell monolayers by modulating the protein expression and localization of claudin isoforms; these actions might be responsible for the gastrointestinal effects of HHT.
- c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elongation of human pancreatic cancer cell line HPAC in a Ca-switch model. [JOURNAL ARTICLE]
- Histochem Cell Biol 2014 Dec 16.
c-Jun N-terminal kinase (JNK), known as a stress-activated protein kinase, regulates normal epithelial biological processes, including assembly of adherens and tight junctions, and it is involved in the development of several cancers. The JNK inhibitor SP600125 enhances epithelial barrier function through modulation of tight junction molecules in normal human pancreatic epithelial cells. Furthermore, this JNK inhibitor suppresses the growth of human pancreatic cancer cells. However, the effects of SP600125 on the epithelial barrier in human pancreatic cancer cells remain unknown. In the present study, the JNK inhibitor SP600125 markedly enhanced the barrier function and cell elongation of well-differentiated human pancreatic cancer cell line HPAC in a Ca-switch model. The epithelial barrier function induced by SP600125 was regulated by phosphorylated β-catenin without changes in the tight junction molecules. The cell elongation induced by SP600125 was closely related to the expression of the F-actin-binding protein DrebrinE. These findings suggest that JNK is involved in the regulation of the epithelial barrier function and cell shape during remodeling of pancreatic cancer cells. The JNK inhibitor SP600125 may have potential as a therapeutic drug for pancreatic cancer via induction of differentiation.
- Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum. [JOURNAL ARTICLE]
- J Dermatol Sci 2014 Nov 22.
The tight junction (TJ) barrier is located in the granular layer of the epidermis. Filaggrin deficiency predisposes patients to atopic dermatitis (AD) by impairing stratum corneum (SC) barrier function. Altered TJ barrier function has been observed in the skin of patients with AD; however, it remains unclear whether TJ function is influenced by filaggrin deficiency directly or secondarily via skin inflammation.To investigate the in vivo effects of filaggrin deficiency and skin inflammation on epidermal TJ function.Morphological changes in the TJ were investigated in filaggrin knockout mice and mice with hapten-induced dermatitis using en face visualization of epidermal sheets, and functional changes in the TJ were assessed with an in vivo permeation assay using tracers of various sizes.In filaggrin knockout mice, there was no apparent change in the honeycomb morphology of the TJ, TJ component mRNA expression, or TJ barrier function in neonates and adults, indicating that filaggrin-deficiency had no direct effects on the TJ. By contrast, in mice with hapten-induced dermatitis, the mRNA expression of TJ components was decreased markedly and the TJ barrier function was size-dependently impaired: the TJ leaked small tracers (<5kDa), but not large tracers (>30kDa).Filaggrin deficiency did not affect the epidermal TJ barrier directly, but once dermatitis occurred, the skin inflammation induced TJ dysfunction. Since TJ dysfunction induces the SC barrier impairment, skin inflammation will enhance skin permeability to external antigens and result in a vicious cycle of barrier dysfunction and skin inflammation.
- Estrogen receptor alpha deficiency protects against development of cognitive impairment in murine lupus. [JOURNAL ARTICLE]
- J Neuroinflammation 2014 Dec 16; 11(1):171.
BackgroundOne of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ER¿ deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ER¿ deficiency would be similarly protective in the brain, and that ER¿ may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.MethodsMRL/lpr ER¿+/+ and ER¿KO mice (n¿=¿46) were ovariectomized, received 17β-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.ResultsMRL/lpr ER¿KO mice (n¿=¿21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n¿=¿25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ER¿KO mice. There were significant differences in NOR testing, particularly total exploration time, with ER¿ deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ER¿KO mice, as evidenced by immunohistochemietry (IHC).ConclusionER¿ deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ER¿KO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.
- Protection of epithelial tight junction: a new therapeutic approach in the treatment of infectious diarrhea. [Letter]
- Acta Gastroenterol Belg 2014 Sep; 77(3):366-7.
- Neuroinvasion of the Highly Pathogenic Influenza Virus H7N1 Is Caused by Disruption of the Blood Brain Barrier in an Avian Model. [Journal Article]
- PLoS One 2014; 9(12):e115138.
Influenza A virus (IAV) causes central nervous system (CNS) lesions in avian and mammalian species, including humans. However, the mechanism used by IAV to invade the brain has not been determined. In the current work, we used chickens infected with a highly pathogenic avian influenza (HPAI) virus as a model to elucidate the mechanism of entry of IAV into the brain. The permeability of the BBB was evaluated in fifteen-day-old H7N1-infected and non-infected chickens using three different methods: (i) detecting Evans blue (EB) extravasation into the brain, (ii) determining the leakage of the serum protein immunoglobulin Y (IgY) into the brain and (iii) assessing the stability of the tight-junction (TJ) proteins zonula occludens-1 and claudin-1 in the chicken brain at 6, 12, 18, 24, 36 and 48 hours post-inoculation (hpi). The onset of the induced viremia was evaluated by quantitative real time RT-PCR (RT-qPCR) at the same time points. Viral RNA was detected from 18 hpi onward in blood samples, whereas IAV antigen was detected at 24 hpi in brain tissue samples. EB and IgY extravasation and loss of integrity of the TJs associated with the presence of viral antigen was first observed at 36 and 48 hpi in the telencephalic pallium and cerebellum. Our data suggest that the mechanism of entry of the H7N1 HPAI into the brain includes infection of the endothelial cells at early stages (24 hpi) with subsequent disruption of the TJs of the BBB and leakage of virus and serum proteins into the adjacent neuroparenchyma.