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      Aquaporins and Brain Tumors

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          Abstract

          Brain primary tumors are among the most diverse and complex human cancers, and they are normally classified on the basis of the cell-type and/or the grade of malignancy (the most malignant being glioblastoma multiforme (GBM), grade IV). Glioma cells are able to migrate throughout the brain and to stimulate angiogenesis, by inducing brain capillary endothelial cell proliferation. This in turn causes loss of tight junctions and fragility of the blood–brain barrier, which becomes leaky. As a consequence, the most serious clinical complication of glioblastoma is the vasogenic brain edema. Both glioma cell migration and edema have been correlated with modification of the expression/localization of different isoforms of aquaporins (AQPs), a family of water channels, some of which are also involved in the transport of other small molecules, such as glycerol and urea. In this review, we discuss relationships among expression/localization of AQPs and brain tumors/edema, also focusing on the possible role of these molecules as both diagnostic biomarkers of cancer progression, and therapeutic targets. Finally, we will discuss the possibility that AQPs, together with other cancer promoting factors, can be exchanged among brain cells via extracellular vesicles (EVs).

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          Most cited references126

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          Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin

          Occludin is the only known integral membrane protein localizing at tight junctions (TJ), but recent targeted disruption analysis of the occludin gene indicated the existence of as yet unidentified integral membrane proteins in TJ. We therefore re-examined the isolated junction fraction from chicken liver, from which occludin was first identified. Among numerous components of this fraction, only a broad silver-stained band ∼22 kD was detected with the occludin band through 4 M guanidine-HCl extraction as well as sonication followed by stepwise sucrose density gradient centrifugation. Two distinct peptide sequences were obtained from the lower and upper halves of the broad band, and similarity searches of databases allowed us to isolate two full-length cDNAs encoding related mouse 22-kD proteins consisting of 211 and 230 amino acids, respectively. Hydrophilicity analysis suggested that both bore four transmembrane domains, although they did not show any sequence similarity to occludin. Immunofluorescence and immunoelectron microscopy revealed that both proteins tagged with FLAG or GFP were targeted to and incorporated into the TJ strand itself. We designated them as “claudin-1” and “claudin-2”, respectively. Although the precise structure/function relationship of the claudins to TJ still remains elusive, these findings indicated that multiple integral membrane proteins with four putative transmembrane domains, occludin and claudins, constitute TJ strands.
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            Physiology of cell volume regulation in vertebrates.

            The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most cases, activation of volume regulatory osmolyte transport. After acute swelling, cell volume is regulated by the process of regulatory volume decrease (RVD), which involves the activation of KCl cotransport and of channels mediating K(+), Cl(-), and taurine efflux. Conversely, after acute shrinkage, cell volume is regulated by the process of regulatory volume increase (RVI), which is mediated primarily by Na(+)/H(+) exchange, Na(+)-K(+)-2Cl(-) cotransport, and Na(+) channels. Here, we review in detail the current knowledge regarding the molecular identity of these transport pathways and their regulation by, e.g., membrane deformation, ionic strength, Ca(2+), protein kinases and phosphatases, cytoskeletal elements, GTP binding proteins, lipid mediators, and reactive oxygen species, upon changes in cell volume. We also discuss the nature of the upstream elements in volume sensing in vertebrate organisms. Importantly, cell volume impacts on a wide array of physiological processes, including transepithelial transport; cell migration, proliferation, and death; and changes in cell volume function as specific signals regulating these processes. A discussion of this issue concludes the review.
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              Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier.

              Disruption of the tight junctions (TJs) of the blood-brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial meningitis. Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment. By allowing the "loosening" of TJs and an increase in paracellular permeability, the BBB is able to "bend without breaking"; thereby, maintaining structural integrity.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 June 2016
                July 2016
                : 17
                : 7
                : 1029
                Affiliations
                [1 ]Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo I-90127, Italy; rosario.maugeri1977@ 123456gmail.com (R.M.); anna.fricano@ 123456unipa.it (A.F.); gerardo.iacopino@ 123456unipa.it (D.G.I.)
                [2 ]Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo (UNIPA), Palermo I-90128, Italy; gabriella.schiera@ 123456unipa.it (G.S.); carlomaria.diliegro@ 123456unipa.it (C.M.D.L.)
                Author notes
                [* ]Correspondence: italia.diliegro@ 123456unipa.it ; Tel.: +39-091-2389-7415 or +39-091-2389-7446
                Article
                ijms-17-01029
                10.3390/ijms17071029
                4964405
                27367682
                f6eb1a9d-21b7-4889-b5a0-bf23ae6e994a
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 May 2016
                : 22 June 2016
                Categories
                Review

                Molecular biology
                aquaporins (aqps),brain tumors,glioblastoma multiforme,blood–brain barrier (bbb),extracellular vesicles (evs)

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