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tight junction [keywords]
- Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing nrf2 expression. [Journal Article]
- Exp Neurobiol 2014 Mar; 23(1):93-103.
Glutathione (GSH) protects cells against oxidative stress by playing an antioxidant role. Protecting brain endothelial cells under oxidative stress is key to treating cerebrovascular diseases and neurodegenerative diseases including Alzheimer's disease and Huntington's disease. In present study, we investigated the protective effect of GSH on brain endothelial cells against hydrogen peroxide (H2O2). We showed that GSH attenuates H2O2-induced production of nitric oxide (NO), reactive oxygen species (ROS), and 8-Oxo-2'-deoxyguanosine (8-OHdG), an oxidized form of deoxiguanosine. GSH also prevents H2O2-induced reduction of tight junction proteins. Finally, GSH increases the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and activates Nrf2-mediated signaling pathways. Thus, GSH is a promising target to protect brain endothelial cells in conditions of brain injury and disease.
- Low expression of claudin-4: an indicator of recurrence in esophageal squamous cell carcinoma after Ivor Lewis esophagectomy? [Journal Article]
- Med Oncol 2014 May; 31(5):951.
The high recurrence rate after surgery is the main reason for the poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. Finding indicators of recurrence and taking adjuvant therapy may be useful for patients in high risk of recurrence. claudin-4 (CLDN4) is the core protein to form the tight junction, which plays an important role in cell adhesion, and its aberrant expression were detected in various cancers while its expression and functions in ESCC still remained unclear. Here, we detected the expression of CLDN4 in 114 ESCC tissue samples by real-time RT-PCR and immunohistochemistry, and the result showed that the low expression of CLDN4 correlated with a higher T staging (P = 0.010), lymphatic metastasis (P < 0.001) and recurrence status (P = 0.002). And the Cox regression analysis showed that the T classification (P = 0.005), lymph node metastasis (P = 0.003) and low CLDN4 expression (P = 0.029) were independent risk factors of recurrence. Further, we proved the CLDN4 in inhibiting growth, colony formation and invasion in vitro by establishing two stable CLDN4-silencing ESCC cell lines. In conclusion, CLDN4 played an important role in preventing metastasis and could be an effective biomarker to predict the recurrence of ESCC.
- Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis. [Journal Article]
- Cancer Cell 2014 Apr 14; 25(4):501-15.
Cancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer.
- High Tricellulin Expression Is Associated With Better Survival In Human Hepatoblastoma. [JOURNAL ARTICLE]
- Histopathology 2014 Apr 16.
The more differentiated fetal component of hepatoblastoma (HB) is characterized by increased expression of tight junction (TJ) proteins claudin-1 and -2 when compared with embryonal component. Expression patterns of recently identified TJ protein, tricellulin and epigenetic regulator enzyme EZH2 were investigated in epithelial subtypes of HB and related to survival.21 cases of epithelial HBs subtyped as pure fetal (n=12) and embryonal/fetal (n=9), along with 16 non-tumorous surrounding liver samples were analysed. by immunohistochemistry for tricellulin, β-catenin and EZH2 expression.No significant differences were revealed in overall survival between fetal and embryonal/fetal types of HBs. Fetal component, however, showed considerably increased tricellulin expression while embryonal component displayed significantly increased nuclear EZH2 positivity in comparison to other epithelial subtype and non-tumorous surrounding hepatocytes. Strong nuclear β-catenin staining was notably more frequent in embryonal than in fetal type. High tricellulin expression was associated with significantly increased overall survival (p=0.03), while elevated EZH2 expression was linked to presence of distant metastases (p=0.013).Our data indicate that treated HBs showing high expression of tricellulin reveal significantly better overall survival independent of histological subtype. Increased nuclear expression ofEZH2 was associated with the presence of distant metastases. This article is protected by copyright. All rights reserved.
- Enteropathogenic Escherichia coli inhibits type I interferon- and RNase-L-mediated host defense to disrupt intestinal epithelial cell barrier function. [JOURNAL ARTICLE]
- Infect Immun 2014 Apr 14.
Enteropathogenic Escherichia coli (EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through Type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis, however its role in the immune response to enteric pathogens such as EPEC, and its impact on IEC barrier function, have not been examined. Here we report that IFNβ is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFNβ induction and enhancing tumor necrosis factor-α to promote barrier disruption. The endoribonuclease RNase-L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase-L in a T3SS-dependent manner providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFNβ and RNase-L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN/RNase-L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.
- Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation. [JOURNAL ARTICLE]
- Hum Vaccin Immunother 2014 Apr 14; 10(6)
Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain, discomfort, and bloating. Interestingly, there is now evidence of the presence of a low grade inflammation status in many IBS patients, including histopathological and mucosal cytokine levels in the colon, as well as the presence of IBS-like symptoms in quiescent inflammatory bowel disease (IBD). The use of a genetically engineered food-grade bacterium, such as Lactococcus lactis, secreting the anti-inflammatory cytokine IL-10 has been proven by many pre-clinical studies to be a successful therapy to treat colon inflammation. In this study, we first reproduced the recovery-recurrence periods observed in IBS-patients in a new chronic model characterized by two episodes of DiNitro-BenzeneSulfonic-acid (DNBS)-challenge and we tested the effects of a recombinant strain of L. lactis secreting IL-10 under a Stress-Inducible Controlled Expression (SICE) system. In vivo gut permeability, colonic serotonin levels, cytokine profiles and spleen cell populations were then measured as readouts of a low-grade inflammation. In addition, since there is increasing evidence that gut microbiota tightly regulates gut barrier function, tight junction proteins were also measured by qRT-PCR after administration of recombinant L. lactis in DNBS-treated mice. Strikingly, oral administration of L. lactis secreting active IL-10 in mice resulted in significant protective effects in terms of permeability, immune activation and gut-function parameters. Although genetically engineered bacteria are, for now, used only as a "proof of concept," our study validates the interest in the use of the novel SICE system in L. lactis to express therapeutic molecule, such as IL-10, locally at mucosal surfaces.
- Brain microvascular endothelial cells resist elongation due to curvature and shear stress. [Journal Article]
- Sci Rep 2014.:4681.
The highly specialized endothelial cells in brain capillaries are a key component of the blood-brain barrier, forming a network of tight junctions that almost completely block paracellular transport. In contrast to vascular endothelial cells in other organs, we show that brain microvascular endothelial cells resist elongation in response to curvature and shear stress. Since the tight junction network is defined by endothelial cell morphology, these results suggest that there may be an evolutionary advantage to resisting elongation by minimizing the total length of cell-cell junctions per unit length of vessel.
- Barrier properties of cultured retinal pigment epithelium. [REVIEW]
- Exp Eye Res 2014 Apr 14.
The principal function of an epithelium is to form a dynamic barrier that regulates movement between body compartments. Each epithelium is specialized with barrier functions that are specific for the tissues it serves. The apical surface commonly faces a lumen, but the retinal pigment epithelium (RPE) appears to be unique by a facing solid tissue, the sensory retina. Nonetheless, there exists a thin (subretinal) space that can become fluid filled during pathology. RPE separates the subretinal space from the blood supply of the outer retina, thereby forming the outer blood-retinal barrier. The intricate interaction between the RPE and sensory retina presents challenges for learning how accurately culture models reflect native behavior. The challenge is heightened by findings that detail the variation of RPE barrier proteins both among species and at different stages of the life cycle. Among the striking differences is the expression of claudin family members. Claudins are the tight junction proteins that regulate ion diffusion across the spaces that lie between the cells of a monolayer. Claudin expression by RPE varies with species and life-stage, which implies functional differences among commonly used animal models. Investigators have turned to transcriptomics to supplement functional studies when comparing native and cultured tissue. The most detailed studies of the outer blood-retinal barrier have focused on human RPE with transcriptome and functional studies reported for human fetal, adult, and stem-cell derived RPE.
- The effect of oxidized cholesterol on barrier functions and IL-10 mRNA expression in human intestinal epithelium co-cultured with dendritic cells in the transwell system. [JOURNAL ARTICLE]
- Food Chem Toxicol 2014 Apr 10.
The intestinal epithelium is exposed to oxygenated cholesterol products present in foodstuffs. In vitro studies demonstrate the effect of oxysterols on cytokine release by intestinal cells cultured alone. However, physiologically, the response of the intestinal epithelium to external agents occurs in the presence of dendritic cells (DCs). The aim of the study was to analyze the effect of 7-ketocholesterol on the barrier functions and IL-10 mRNA expression of Caco-2 cells in the presence of DCs, and secondly, on IL-10 mRNA expression in DCs. Caco-2 cells were co-cultured with monocyte-derived dendritic cells and induced with 7-ketocholesterol in a transwell system. DCs did not affect the transepithelial electrical resistance (TER) of the Caco-2 cell monolayer, but increased IL-10 mRNA expression in Caco-2 cells. 7-ketocholesterol decreased the TER of Caco-2 cells co-cultured with DCs and diminished IL-10 mRNA expression in Caco-2 cells induced by the presence of DCs. IL-10 mRNA expression fell in DCs co-cultured with Caco-2 cells after treatment with 7-ketocholesterol. Oxidized cholesterols present in gut mucosa may contribute to the decrease of epithelial barrier functions and the inappropriate development of an inflammatory response to food compounds.
- Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy. [JOURNAL ARTICLE]
- Free Radic Biol Med 2014 Apr 12.
Renal complications in diabetes are severe and may lead to renal insufficiency. Early alterations in tight junction (TJ) proteins in diabetic nephropathy (DN) have not been explored and the role of oxidative stress in their disassembly has been poorly characterized. We investigated the expression and distribution of TJ proteins: claudin-5 in glomeruli (GL), occludin and claudin-2 in proximal tubules (PTs), and ZO-1 and claudin-1, -4, and -8 in distal tubules (DTs) of rats 21 days after streptozotocin injection. Redox status along the nephron segments was evaluated. Diabetes increased kidney injury molecule-1 expression. Expression of sodium glucose cotransporters (SGLT1 and SGLT2) and facilitative glucose transporter (GLUT2) was induced. Increased oxidative stress was present in GL and PTs and to a lesser extent in DTs (measured by superoxide production and PKCβ2 expression), owing to NADPH oxidase activation and uncoupling of the endothelial nitric oxide synthase-dependent pathway. Claudin-5, occludin, and claudin-2 expression was decreased, whereas claudin-4 and -8 expression increased. ZO-1 was redistributed from membrane to cytosol. Increased nitration of tyrosine residues in claudin-2 was found, which might contribute to decrement of this protein in proximal tubule. In contrast, occludin was not nitrated. We suggest that loss of claudin-2 is associated with increased natriuresis and that loss of glomerular claudin-5 might explain early presence of proteinuria. These findings suggest that oxidative stress is related to alterations in TJ proteins in the kidney that are relevant to the pathogenesis and progression of DN and for altered sodium regulation in diabetes.