Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A common property of brain tumours is their ability to cause oedema in the surrounding brain. Oedema forms as a result of a leaky blood-tumour barrier and persists when the brain fails to clear the excess fluid. It is a significant source of morbidity and mortality. The principal anatomical component of the blood-brain barrier is the endothelial tight junction which opens in glioma microvessels. Multiple tight junction proteins have recently been identified, such as occludin, claudin, ZO-1, ZO-2 and ZO-3. We propose a model to explain tight junction opening in gliomas based on vascular endothelial growth factor secretion and loss of tight junction inducing factor production by tumour cells. The level of expression of the water channel aquaporin-4 in peritumoural astrocytes may determine the rate of oedema fluid clearance. The identification of the molecular mechanisms of brain tumour oedema may allow the design of novel anti-oedema medications.
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PMID:Emerging molecular mechanisms of brain tumour oedema. 1136 Mar 71

Caldesmon is a cytoskeleton-associated protein which has not yet been related to neoplastic angiogenesis. In this study we investigated the expression of the caldesmon gene (CALD1) splicing variants and the protein expression level in glioma microvessels versus normal brain microvasculature. To exclude sources of splice variant expression from non-vascular components all possible cellular components present in control and glioma samples were pre-screened by laser-capture microdissection followed by RT-PCR before the cohort study. We discovered differential expression of the splicing variants of CALD1 in the tumor microvessels in contrast to normal brain microvasculature. Missplicing of exons 1, 1 + 4, and 1' + 4 of the gene is exclusively found in glioma microvessels. To exclude the possibility that this missplicing results from splice-site mutations, mutation scanning was performed by a coupled in vitro transcription/translation assay (IVTT). No premature stop mutations were traced by the IVTT. The transcriptional changes consequently resulted in up-regulation at the protein expression level. The up-regulated expression of caldesmon was coincident with the down-regulated expression of tight junction proteins (occludin and ZO-1). The results support the notion that missplicing of the CALD1 gene in glioma microvasculature is an independent epigenetic event regulated at the transcriptional level. The event coexists with tight junction (TJ) breakdown of the endothelial cells in glioma microvasculature. The data reveal a novel mechanism contributing to dysfunctionality of glioma neovascularization.
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PMID:Differential expression of splicing variants of the human caldesmon gene (CALD1) in glioma neovascularization versus normal brain microvasculature. 1516 54

Phoneutria nigriventer spider venom (PNV) induces, in rats, local edema as result of an increased vascular permeability, as well as causes blood-brain barrier (BBB) breakdown by altering transendothelial transport routes in hippocampal microvessels. In this work we investigated the in vitro effects of PNV on cell viability and cellular transport routes using three cell lines, the ECV304 endothelial-, the C6 glioma- and the MDCK epithelial cells. We showed that PNV (14.6 and 292 microg crude venom/ml culture medium) had no direct cytotoxic effect on both the ECV304 and the MDCK cell lines but slightly reduced the viability of C6 glioma cells (P<0.05) at the highest concentration, as revealed by the cellular neutral red uptake assay. The PNV effects on cell transport were evaluated in MDCK cell line. PNV seems do not cause any disturbance in the paracellular barrier function of the cultured MDCK cells, as shown by the lack of a significant change in the distribution and expression of the junctional proteins, ZO-1, occludin, E-cadherin and the cytoskeletal F-actin. In contrast, PNV-treated MDCK monolayers showed an enhancement in the transepithelial electrical resistance and a tendency towards an increased occludin expression. In addition, the PNV significantly increased the apical endocytosis of HRP, which was not followed by an equivalent exocytosis at the basal side, as revealed by biochemical and ultrastructural methods. We conclude that the venom of P. nigriventer displays a relatively low cytotoxicity in vitro as well as activates directly the endocytic transport pathway in MDCK cells without disrupting the paracellular route.
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PMID:In vitro effect of the Phoneutria nigriventer spider venom on cell viability, paracellular barrier function and transcellular transport in cultured cell lines. 1594 33

Basolateral condition of the brain microvascular endothelium is believed to influence blood-brain barrier (BBB) phenotype, although the precise transcriptional and post-translational mechanisms involved are poorly defined. In vivo, the basolateral surface of the blood-brain endothelium is bathed in serum-free interstitial fluid and encompassed by astrocytic end-feet. We hypothesized that these conditions impact on BBB function by directly modulating expression and biochemical properties of tight junctions. To investigate this, an in vitro transwell culture model was employed to selectively modify the basolateral environment of bovine brain microvascular endothelial cells (BBMvECs). In the absence of basolateral (but not apical) serum, we observed higher levels of expression, association and plasma membrane localization for the tight junction proteins, occludin and zonula occludens-1 (ZO-1), in parallel with elevated transendothelial electrical resistance (TEER) and reduced (14)[C]-sucrose permeability of BBMvEC monolayers. We further examined the effects of non-contact co-culture with basolateral astrocytes (C6 glioma) on indices of BBMvEC barrier function in both the presence and absence of serum. Astrocyte co-culture with serum led to enhanced occludin protein expression, occludin/ZO-1 association, and ZO-1 membrane localization, in parallel with increased TEER of BBMvEC monolayers. Astrocyte co-culture in the absence of serum (i.e. basolateral conditions most consistent with in vivo BBB physiology) however, gave the highest increases in BBMvEC barrier indices. Thus, we can conclude that factors influencing condition of the basolateral environment of the brain microvasculature can directly, and independently, modify BBB properties by regulating the expression and biochemical properties of the tight junction proteins, occludin and ZO-1.
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PMID:Influence of basolateral condition on the regulation of brain microvascular endothelial tight junction properties and barrier function. 1817 46

Bradykinin (BK) has been shown to open blood-tumor barrier (BTB) selectively and to increase permeability of the BTB transiently, but the mechanism is unclear. This study was performed to determine whether BK opens the BTB by affecting the tight junction (TJ)-associated proteins zonula occluden-1 (ZO-1), occludin, and caludin-5 and cytoskeleton protein filamentous actin (F-actin). In rat brain glioma model and BTB model in vitro, we find that the protein expression levels of ZO-1, occludin, and claudin-5 are attenuated by BK induction. Immunohistochemistry and immunofluorescence assays show that the attenuated expression of ZO-1, occludin, and claudin-5 and F-actin is most obvious in the smaller tumor capillaries (<20 microm) after BK infusion, and there is no change in the larger tumor capillaries (>20 microm). The redistribution of ZO-1, occludin, and claudin-5 and rearrangement of F-actin in brain microvascular endothelial cells are observed at the same time. Meanwhile, Evans blue assay shows that the permeability of BTB increases after BK infusion. Transmission electron microscopy indicates that TJ is opened and that pinocytotic vesicular density is increased. Transendothelial electrical resistance (TEER) and horseradish peroxidase flux assays also reveal that TJ is opened by BK induction. In addition, radioimmunity and Western blot assay reveal a significant decrease in expression levels of cAMP and catalytic subunit of protien kinase A (PKAcs) of tumor tissue. This study demonstrates that the increase of BK-mediated BTB permeability is associated with the down-regulation of ZO-1, occludin, and claudin-5 and the rearrangement of F-actin and that cAMP/PKA signal transduction system might be involved in the modulating process.
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PMID:Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. 1818 15

Gliomas, particularly glioblastoma multiforme, perturb the blood-brain barrier and cause brain edema that contributes to morbidity and mortality. The mechanisms underlying this vasogenic edema are poorly understood. We examined the effects of cocultured primary cultured human glioblastoma cells and glioma-derived growth factors on the endothelial cell tight junction proteins claudin 1, claudin 5, occludin, and zonula occludens 1 of brain-derived microvascular endothelial cells and a human umbilical vein endothelial cell line. Cocultured glioblastoma cells and glioma-derived factors (e.g. transforming growth factor beta2) enhanced the paracellular flux of endothelial cell monolayers in conjunction with downregulation of the tight junction proteins. Neutralizing anti-transforming growth factor beta2 antibodies partially restored the barrier properties in this in vitro blood-brain barrier model. The involvement of endothelial cell-derived matrix metalloproteinases (MMPs) was demonstrated by quantitative reverse-transcriptase-polymerase chain reaction analysis and by the determination of MMP activities via zymography and fluorometry in the presence or absence of the MMP inhibitor GM6001. Occludin, claudin 1, and claudin 5 were expressed in microvascular endothelial cells in nonneoplastic brain samples but were significantly reduced in anaplastic astrocytoma and glioblastoma samples. Taken together, these in vitro and in vivo results indicate that glioma-derived factors may induce MMPs and downregulate endothelial tight junction protein and, thus, play a key role in glioma-induced impairment of the blood-brain barrier.
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PMID:Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins. 1843 Dec 53

Low-frequency ultrasound (LFU) and bradykinin (BK) have been shown separately to increase the permeability of the blood-tumor barrier (BTB) in the rat model of C6 glioma. This study examined the hypothesis that the combination of LFU and low-dose BK has a synergistic effect on increasing the permeability of BTB and explored the possible underlying mechanism including the involvement of tight junction (TJ). The rats were divided into six groups: control group, LFU group, BK group, 2/3LFU + 1/2BK group, 5/6LFU + 2/3BK group, and LFU + BK group. The BTB permeability was assessed by Evans blue extravasation. The mRNA and protein expressions of TJ-related proteins ZO-1, occludin, and claudin-5 were determined by reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunolocalization, and Western blot test. BTB permeability increased in all the experimental groups, accompanied by opening of local TJ of the BTB, observed by transmission electron microscopy, and decreased mRNA and protein expressions of ZO-1, occludin, and claudin-5. In addition, there was a further increase in BTB permeability and a further reduction in the expressions of TJ-related proteins in 5/6LFU + 2/3BK and LFU + BK groups, compared with LFU or BK group. These results indicate that LFU and low-dose BK applied in combination act in a synergistic manner to increase BTB permeability. The down-regulation of TJ-related proteins ZO-1, occludin, and claudin-5 may be one of the underlying mechanisms of the increase in BTB permeability induced by LFU and BK.
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PMID:Synergistic effect of low-frequency ultrasound and low-dose bradykinin on increasing permeability of the blood-tumor barrier by opening tight junction. 1932 37

This study was performed to determine whether endothelial-monocyte-activating polypeptide (EMAP) II increases the permeability of the blood-tumor barrier (BTB) in the rat model of C6 glioma, and whether EMAP II opens the BTB by affecting tight junction (TJ) associated proteins zonula occluden-1 (ZO-1), occludin and claudin-5. The rats were divided into eight groups randomly: control group, EMAPII 0h group, EMAPII 0.5h group, EMAPII 1h group, EMAPII 2h group, EMAPII 3h group, EMAPII 6h group and EMAPII 12h group. The BTB permeability was assessed by Evans blue extravasation. The mRNA and protein expressions of ZO-1, occludin, and claudin-5 were determined by reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemistry assays. The BTB permeability significantly increased after EMAP II injection in different doses (40ng/kg, 80ng/kg and 160ng/kg). The BTB permeability started to increase from 0.5h, reached a peak at 1h, and finally returned to the level of EMAP II 0h group after EMAP II injection at dose of 80ng/kg. The mRNA and protein expression levels of ZO-1, occludin and claudin-5 were significantly decreased after EMAP II injection. This study demonstrates for the first time that EMAP II increases the permeability of BTB selectively, and the possible mechanism is associated with the down-regulation of ZO-1, occludin and claudin-5.
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PMID:Endothelial-monocyte-activating polypeptide II increases blood-tumor barrier permeability by down-regulating the expression levels of tight junction associated proteins. 2008 91

Brain glioma is a malignant tumor which needs surgery followed by chemotherapy. Low-frequency ultrasound (LFU) and Optison could open blood-tumor barrier (BTB) selectively and noninvasively and thus increase the permeability of BTB. Endothelial monocyte-activating polypeptide II (EMAP-II) induces cytoskeletal remodeling in endothelial cells. In this study, we asked whether LFU, Optison, and/or EMAP-II used in combination have additive effects on increasing the permeability of BTB by tight junction (TJ)-associated protein-dependent manner and thus help understand the possible mechanisms for TJ-based drug delivery to the central nervous system through BTB. Evans Blue assay was used to measure the permeability of BTB in rat model of C6 glioma. The mRNA and protein levels of TJ-associated proteins, claudin-5, occludin, and ZO-1, were determined. Results showed that Evans blue content significantly increased and the mRNA and protein levels of claudin-5, occludin, and ZO-1 significantly reduced after the treatment in groups treated with EMAP-II and LFU combined with or without Optison (LFU+EMAP-II and LFU+Optison+EMAP-II groups) and in the group treated with LFU and Optison (LFU+Optison group). In conclusion, LFU and EMAP-II used in combination have additive effects on increasing the permeability of BTB and remodeling of TJ-associated proteins.
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PMID:Additive effect of low-frequency ultrasound and endothelial monocyte-activating polypeptide II on blood-tumor barrier in rats with brain glioma. 2060 Jun 13

This study was performed to determine whether low frequency ultrasound (LFU) irradiation, Papaverine (PA) infusion and combination LFU irradiation with PA infusion opened the blood-tumor barrier (BTB) by affecting tight junctions (TJ)-associated proteins zonula occluden-1 (ZO-1), occludin and caludin-5. In a rat brain glioma model, we found that the mRNA and protein expression levels of ZO-1, occludin and claudin-5 were decreased by LFU irradiation and PA infusion. LFU-induced and PA-induced decrease of ZO-1, occludin and claudin-5 was further decreased after combining LFU irradiation with PA infusion. Immunohistochemistry assay showed that the decreased expression of ZO-1, occludin and claudin-5 was the most obvious in the tumor capillaries. Meanwhile, Evans blue assay showed that the permeability of BTB was increased, and transmission electron microscopy (TEM) indicated that TJ was opened. This led to the conclusion that LFU irradiation and PA infusion together can open the BTB by paracellular pathway. Significantly down-regulated expression levels of ZO-1, occludin and claudin-5 might be one of the molecular mechanisms of combining LFU and PA enhancing the permeability of BTB.
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PMID:Effects of combining low frequency ultrasound irradiation with papaverine on the permeability of the blood-tumor barrier. 2068 58


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