Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients
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To evaluate the significance of circulating tight-junction (TJ) proteins as predictors of hemorrhagic transformation (HT) in ischemic stroke patients.We examined 458 consecutive ischemic stroke patients, 7.2% of whom had clinically evident HT. None of the patients was treated with thrombolytic drugs. Serum levels of standard markers of blood-brain barrier (BBB) breakdown (S100B, neuron-specific enolase), TJ proteins (occludin [OCLN], claudin 5 [CLDN5], zonula occludens 1 [ZO1]), and molecules involved in BBB disintegration (matrix metalloproteinase 9 and vascular endothelial growth factor [VEGF]) were assessed upon admission to the emergency department. A clinical deterioration caused by HT (cdHT) was defined as an increase of ≥4 points in the NIH Stroke Scale score in combination with a visible HT on a CT scan performed immediately after the onset of new neurologic symptoms.Patients with cdHT had higher concentrations of OCLN, S100B, and the CLDN5/ZO1 ratio, and a lower level of VEGF than those without cdHT. CLDN5 levels also correlated with cdHT occurrence when estimated within 3 hours of stroke onset. We also demonstrated correlations between the levels of circulating TJ molecules and the level of S100B, which is a previously established marker of BBB disruption.Analyzing serum levels of TJ proteins, like CLDN5, OCLN, and CLDN5/ZO1 ratio, as well as S100B and VEGF, is an effective way to screen for clinical deterioration caused by HT in ischemic stroke patients, both within and after the IV thrombolysis time window.Keywords:
Occludin
Enolase
Stroke
Brain ischemia
Objective To investigate the changes of intestinal epithelial tight junction and the expression and distribution of occludin in non-alcoholic fatty liver disease(NAFLD) rats.Methods Thirty male SD rats were divided into two groups.The rats in control group were fed with normal diets while the rats in model group were fed with high fat diets.All the rats were sacrificed after 12 weeks.HE staining of hepatic tissue in model group showed that the NAFLD was established.Small intestinal epithelial tight junctions were observed by electron microscope in all groups,and the distribution and expression of tight junction protein occludin were detected by immunohistochemistry.Results Electron microscope demonstrated tight junction in model group(0.50±0.21)μm was significantly shorter than that in control group(0.78±0.19)μm(P0.05).The immunohistochemistry revealed the occludin in control group was localized in the apical region of the lateral plasma membrane and linear distributed representing the region of tight junctions in surface and crypt epithelial cells,while the occludin distributed non-continuous in model group and expressing obviously attenuated.Conclusion The expression of occludin decreased in NAFLD rats and the intestinal epithelial tight junction was shortened.It suggests that intestinal barrier may play an important role in the pathophysiologic mechanism of NAFLD.
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Barrier function
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Occludin is one of the best characterized protein in tight junction associated proteins,it seals paracellular way to form the basic structure of tight junction.It performs major functions including fence function and paracellular barrier function.Downregulation of occludin protein might induce the disruption of pulmonary epithelial barrier,blood-brain barrier,intestinal epithelium barrier,blood-testis barrier,which has been proved to be associated with the cause and progress of many diseases.Therefore,the regulation mechanism and clinical significance of occludin protein have been the focus at home and abroad.
Key words:
Occludin protein; Tight junction; Barrier function; Regulation mechanism
Occludin
Paracellular transport
Claudin
Barrier function
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Occludin
Claudin
Blood–retinal barrier
Immunoelectron microscopy
Septate junctions
Adherens junction
Outer plexiform layer
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Occludin
Barrier function
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Epithelial cells are the first line of mucosal defense. In the intestine, a single layer of epithelial cells must establish a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing the leakage of potentially harmful luminal materials. Key to this is the tight junction, which seals the paracellular space and prevents unrestricted leakage. The tight junction is a protein complex established by interactions between members of the claudin, zonula occludens, and tight junction-associated MARVEL protein (TAMP) families. Claudins form the characteristic tight junction strands seen by freeze-fracture microscopy and create paracellular channels, but the functions of ZO-1 and occludin, founding members of the zonula occludens and TAMP families, respectively, are less well defined. Recent studies have revealed that these proteins have essential noncanonical (nonbarrier) functions that allow them to regulate epithelial apoptosis and proliferation, facilitate viral entry, and organize specialized epithelial structures. Surprisingly, neither is required for intestinal barrier function or overall health in the absence of exogenous stressors. Here, we provide a brief overview of ZO-1 and occludin canonical (barrier-related) functions, and a more detailed examination of their noncanonical functions.
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Background Specific‐sized species of the carbohydrate hyaluronan elicit a variety of cellular responses mediating tissue integrity and repair, as well as regulating inflammatory responses. Orally provided hyaluronan with an average molecular weight of 35 kDa (HA35) protects mice from short‐term ethanol (EtOH)‐induced liver injury. This protection was associated with maintenance of the colocalization of zonula occludens‐1 (ZO‐1) and occludin at tight junctions in the proximal colon. However, it is not known whether HA35 also protects other regions of the intestine or whether protection is due to a direct and/or indirect interaction of HA35 with the intestinal epithelium. Methods Female C57BL/6J mice were fed an EtOH containing diet or pair‐fed control diet (4 days) and treated with or without HA35 via daily gavage during the last 3 days of EtOH feeding. Intestinal morphology and tight junction integrity were assessed. Differentiated Caco‐2 cells were transfected or not with scrambled siRNA or siRNA targeting layilin, a hyaluronan receptor. Caco‐2 cells were treated with or without HA35 prior to challenge with EtOH. Localization of tight junction proteins, fluorescein isothiocyanate (FITC)‐dextran permeability, and transepithelial electrical resistance (TEER) were evaluated. Results While short‐term EtOH did not result in any apparent changes in the gross morphology of the intestine, colocalization of ZO‐1 and occludin at tight junctions was decreased in the proximal and distal colon. HA35 prevented these effects of EtOH. In differentiated Caco‐2 cells, EtOH decreased the localization of ZO‐1 and occludin at tight junctions and increased permeability of FITC‐dextran. At higher concentrations, EtOH also decreased TEER. Pretreatment with HA35 prevented these changes. When the hyaluronan receptor layilin was knocked down in Caco‐2 cells, HA35 no longer protected cells from EtOH‐induced loss of tight junctions. Conclusions Taken together, these data indicate that HA35 interacts with layilin on intestinal epithelial cells and maintains intestinal tight junction integrity during short‐term EtOH exposure.
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Claudin
Colocalization
Caco-2
Intestinal epithelium
Fluorescein isothiocyanate
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ABSTRACT The tight junction is the most apical intercellular junction of epithelial cells and forms a diffusion barrier between individual cells. Occludin is an integral membrane protein specifically associated with the tight junction which may contribute to the function or regulation of this intercellular seal. In order to elucidate the role of occludin at the tight junction, a full length and an N-terminally truncated murine occludin construct, both FLAG-tagged at the N terminus, were stably introduced into the murine epithelial cell line CSG 120/7. Both constructs were correctly targeted to the tight junction, as defined by colocalization with another tight junction protein, ZO-1. The construct lacking the N terminus and extracellular domains of occludin was found to exert a dramatic effect on tight junction integrity. Cell monolayers failed to develop an efficient permeability barrier, as demonstrated by low transcellular electrical resistance values and an increased paracellular flux to small molecular mass tracers. Furthermore, gaps were found to have been induced in the P-face associated tight junction strands, as visualized by freeze-fracture electron microscopy. These findings demonstrate an important role for the N-terminal half of occludin in tight junction assembly and maintaining the barrier function of the tight junction.
Occludin
Paracellular transport
Claudin
Septate junctions
Barrier function
Adherens junction
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Objective To discuss the effect of hyperthermia on tight junctions of the endothelial cells in the blood-brain barrier and explore the molecular mechanism. Methods An in vitro blood-brain barrier model was established by coculture of ECV304 and astrocytes. Transendothelial resistance (TER) of in vitro blood-brain barrier was determined by Millicell-ERS system. The morphological change of tight junctions of the endothelial cells in the in vitro blood-brain barrier was determined by the method of silver staining. The expression levels of zonula occluden 1 (ZO-1) and occludin were analyzed by means of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western bloting. Results After two hours at 43℃, the mean value of TER was decreased from (321.30± 58.59) Ω·cm2 to (65.67±6.02) Ω·cm2. The integrity of tight junctions was destroyed and the expressions of ZO-1 and occludin decreased significantly. Conclusions Hyperthermia can destroy the tight junctions of the endothelial cells in the in vitro blood-brain barrier. The expression decrease of ZO-1 and occludin induced by hyperthermia is one of the most important molecular mechanisms.
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Homeostasis of the central nervous system (CNS) microenvironment is maintained by the blood-brain barrier (BBB) which regulates the transport of molecules from blood into brain and back. Many disorders change the functionality and integrity of the BBB. Glucocorticoids are being used sucessfully in the treatment of some disorders while their effects on others are questionable. In addition, conflicting results between clinical and experimental experience using animal models has arisen, so that the results of molecular studies in animal models need to be revisited in an appropriate in vitro model of the human BBB for more effective treatment strategies. Using the human brain microvascular endothelial cell line hCMEC/D3, the influence of glucocorticoids on the expression of barrier constituting adherens junction and tight junction transmembrane proteins (VE-cadherin, occludin, claudins) was investigated and compared to other established BBB models. In hCMEC/D3 cells the administration of glucocorticoids induced expression of the targets occludin 2.75 +/- 0.04-fold and claudin-5 up to 2.32 +/- 0.11-fold, which is likely to contribute to the more than threefold enhancement of transendothelial electrical resistance reflecting barrier tightness. Our analyses further provide direct evidence that the GC hydrocortisone prevents endothelial barrier breakdown in response to pro-inflammatory stimuli (TNFalpha administration), which could be demonstrated to be partly based on maintenance of occludin levels. Our studies strongly suggest stabilization of BBB function as a mode of GC action on a molecular level in the human brain vasculature.
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Adherens junction
Claudin
Barrier function
Human brain
Paracellular transport
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