Modulation of Amyloid-beta and Tau in Alzheimer's Disease Plasma Neuronal-Derived Extracellular Vesicles by Cerebrolysin (R) and Donepezil

Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. Objective: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin (R), donepezil, and a combination therapy in AD. Methods: Plasma NDEV levels of A beta(42), total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin (R), donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. Results: NDEV levels of A beta(42), total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV A beta 42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-alpha (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV A beta(42) with respect to monotherapies ( p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). Conclusion: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) AG058252 AG073979 AG051848 AG057437 AG010483 AG062429Ever Neuro Pharma GmbH (Unterach, Austria) research gran

Borax induces osteogenesis by stimulating NaBC1 transporter via activation of BMP pathway

[EN] The intrinsic properties of mesenchymal stem cells (MSCs) make them ideal candidates for tissue engineering applications. Efforts have been made to control MSC behavior by using material systems to engineer synthetic extracellular matrices and/or include soluble factors in the media. This work proposes a simple approach based on ion transporter stimulation to determine stem cell fate that avoids the use of growth factors. Addition of borax alone, transported by the NaBC1-transporter, enhanced MSC adhesion and contractility, promoted osteogenesis and inhibited adipogenesis. Stimulated-NaBC1 promoted osteogenesis via the BMP canonical pathway (comprising Smad1/YAP nucleus translocation and osteopontin expression) through a mechanism that involves simultaneous NaBC1/BMPR1A and NaBC1/alpha (5)beta (1)/alpha (v)beta (3) co-localization. We describe an original function for NaBC1 transporter, besides controlling borate homeostasis, capable of stimulating growth factor receptors and fibronectin-binding integrins. Our results open up new biomaterial engineering approaches for biomedical applications by a cost-effective strategy that avoids the use of soluble growth factors. Rico et al. propose a simple approach based on borax stimulation of NaBC1 transporter, which enhances FN-binding integrin-dependent mesenchymal stem cell adhesion and contractility, promotes osteogenesis and inhibits adipogenesis. Osteogenic differentiation depends on activation of the BMP pathway through a mechanism that involves simultaneous co-localization of NaBC1 with FN-binding integrins and BMPR1A.P.R. acknowledges support from the Spanish Ministry of Science, Innovation and Universities (RTI2018-096794), and Fondo Europeo de Desarrollo Regional (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. M.S.S. acknowledges support from the UK Engineering and Physical Sciences Research Council (EPSRC-EP/P001114/1).Rico Tortosa, PM.; Rodrigo Navarro, A.; Sánchez-Pérez, L.; Salmerón Sánchez, M. (2020). Borax induces osteogenesis by stimulating NaBC1 transporter via activation of BMP pathway. Communications Biology. 3(1):1-15. https://doi.org/10.1038/s42003-020-01449-4S11531Akhurst, R. J. & Hata, A. Targeting the TGFbeta signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).Brizzi, M. F., Tarone, G. & Defilippi, P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 24, 645–651 (2012).Watt, F. M. & Huck, W. T. S. Role of extracellular matrix regulating stem cell fate. Nat. Rev. Mol. Cell Biol. 14, 467–473 (2013).Benoit, D. S. W., Schwartz, M. P., Durney, A. R. & Anseth, K. S. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat. Mater. 7, 816–823 (2008).Baker, B. M., Trappmann, B., Wang, W. Y., Sakar, M. S., Kim, I. L., Shenoy, V. B., Burdick, J. A. & Chen, C. S. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillary microenvironments. Nat. Mater. 14, 1262–1268 (2015).Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F. & Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325 (2015).Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).Yang, J., McNamara, L. E., Gadegaard, N., Alakpa, E. V., Burgess, K. V., Dominic Meek, R. M. & Dalby, M. J. Nanotopographical induction of osteogenesis through adhesion, bone morphogenetic protein cosignaling, and regulation of microRNAs. ACS Nano. 8, 9941–9953 (2014).Dalby, M. J., García, A. J. & Salmeron-Sanchez, M. Receptor control in mesenchymal stem cell engineering. Nat. Rev. 3, 17091 (2018).Carragee, E. J., Hurwitz, E. L. & Weiner, B. K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 11, 471–491 (2011).Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behavior in development and regeneration. Nat. Rev. 18, 728–742 (2017).Biggs, M. J., Richards, R. G., Gadegaard, N., Wilkinson, C. D., Oreffo, R. O. & Dalby, M. J. The use of nanoscale topography to modulate the dynamics of adhesion formation in primary osteoblasts and ERK/MAPK signaling in STRO-1+ enriched skeletal stem cells. Biomaterials 30, 5094–5103 (2009).McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell. 6, 483–495 (2004).Hille, B. Ion Channels of Excitable Membranes. (Sinauer Associates Inc, Sunderland, MA, 2001).Lauritzen, I., Chemin, J., Honoré, E., Martine, J., Guy, N., Lazdunski, M. & Patel, A. J. Cross-talk between the mechano-gated K2p channel TREK-1 and the actin cytoskeleton. EMBO Rep. 6, 642–648 (2005).Gasparski, A. N. & Beningo, K. A. Mechanoreception at the cell membrane: more than the integrins. Arch. Biochem. Biophys. 586, 20–26 (2015).Pillozzi, S. & Becchetti, A. Ion channels in hematopoietic and mesenchymal stem cells. Stem Cells Int. 2012, 217910 (2012).Park, M., Li, Q., Shcheynikov, N., Zeng, W. & Muallem, S. NaBC1 is a ubiquitous electrogenic Na+-coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation. Mol. Cell. 16, 331–341 (2004).Vithana, E. N., Morgan, P., Sundaresan, P., Ebenezer, N. D., Tan, D. T., Mohamed, M. D., Anand, S., Khine, K. O., Venkataraman, D., Yong, V. H., Salto-Tellez, M., Venkatraman, A., Guo, K., Hemadevi, B., Srinivasan, M., Prajna, V., Khine, M., Casey, J. R., Inglehearn, C. F. & Aung, T. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endotelial dystrophy (CHED2). Nat. Genet. 38, 755–757 (2006).Lopez, I. A., Rosenblatt, M. I., Kim, C., Galbraith, G. C., Jones, S. M., Kao, L., Newman, D., Liu, W., Yeh, S., Pushkin, A., Abuladze, N. & Kurtz, I. Slc4a11 gene disruption in mice: cellular targets of sensorineural abnormalities. J. Biol. Chem. 284, 26882–26896 (2009).Rico, P., Rodrigo-Navarro, A. & Salmeron-Sanchez, M. Borax-loaded PLLA for promotion of myogenic differentiation. Tissue Eng. Part A. 21, 2662–2672 (2015).Rico, P., Rodrigo-Navarro, A., de la Peña, M., Moulisová, V., Costell, M. & Salmeron-Sanchez, M. Simultaneous boron ion-channel activation for enhanced vascularization. Adv. Biosyst. 3, 1800220 (2019).Cifti, E., Köse, S., Korkusuz, P., Timuçin, M. & Korkusuz, F. Boron containing nano hydroxyapatites (Bn-HAp) stimulate mesenchymal stem cell adhesion, proliferation and differentiation. Key Eng. Mater. 631, 373–378 (2015).Li, X., Wang, X., Jiang, X., Yamaguchi, M., Ito, A., Bando, Y. & Golberg, D. Boron nitride nanotube-enhanced osteogenic differentiation of mesenchymal stem cells. J. Biomed. Res. 104, 323–329 (2015).Liu, Y. J., Su, W. T. & Chen, P. H. Magnesium and zinc borate enhance osteoblastic differentiation of stem cells from human exfoliated deciduous teeth in vitro. J. Biomater. Appl. 32, 765–774 (2018).Dogan, A., Demirci, S., Apdik, H., Bayrak, O. F., Gulluoglu, S., Tuysuz, E. C., Gusev, O., Rizanov, A. A., Nikerel, E. & Sahin, F. A new hope for obesity management: boron inhibits adipogenesis in progenitor cells through the Wnt/β-catenin pathway. Metabolism 69, 130–142 (2017).Abdik, E. A., Abdik, H., Tasli, P. N., Asli, A., Deniz, H. & Sahin, F. Suppressive role of boron on adipogenic differentiation and fat deposition in human mesenchymal stem cells. Biol. Trace Elem. Res. 188, 384–392 (2018).Humphries, M. J., Travis, M. A., Clark, K. & Mould, A. P. Mechanisms of integration of cells and extracellular matrices by integrins. Biochem. Soc. Trans. 32, 822–825 (2004).Burns, A. E. & Varin, J. Poly-L-lactic acid rod fixation results in foot surgery. J. Foot Ankle Surg. 37, 37–41 (1998).Harada, S. & Rodan, G. A. Control of osteoblast function and regulation of bone mass. Nature 423, 349–355 (2003).Gregory, C. A., Ylostalo, J. & Prockop, D. J. Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental niches in culture: a two-stage hypothesis for regulation of MSC fate. Sci. Stke. 294, pe37 (2005).Jones, D. R. H. & Ashby, M. F. Engineering Materials 1. (Butterworth-Heinemann, 2019).Farah, S., Anderson, D. G. & Langer, R. Physical and mechanical properties of PLA, and their functions in widespread applications-A comprehensive review. Adv. Drug Deliv. Rev. 107, 367–392 (2016).González-García, C., Moratal, D., Oreffo, R. O. C., Dalby, M. J. & Salmeron-Sanchez, M. Surface mobility regulates skeletal stem cell differentiation. Integr. Biol. 4, 531–539 (2012).Liddington, R. C. & Ginsberg, M. H. Integrin activation takes shape. J. Cell Biol. 158, 833–839 (2002).Ganor, Y., Besser, M. & Ben-Zakay, N. et al. Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. J. Immunol. 170, 4362–4372 (2003).Puklin-Faucher, E. & Sheetz, M. P. The mechanical integrin cycle. J. Cell Sci. 122, 179–186 (2009).Liao, S. F., Monegue, J. S., Lindemann, M. D., Cromwell, G. L. & Matthews, J. C. Dietary supplementation of boron differentially alters expression of borate transporter (NaBC1) mRNA by jejunum and kidney of growing pigs. Biol. Trace Elem. Res. 143, 901–912 (2011).Saidak, Z., Le Henaff, C., Azzi, S., Marty, C., Da Nascimento, S., Sonnet, P. & Marie, P. J. Wnt/β-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5β1 integrin priming in Mesenchymal Skeletal Cells. J. Biol. Chem. 290, 6903–6912 (2015).Chen, Q., Shou, P., Zhang, L., Xu, C., Zheng, C., Han, Y., Li, W., Huang, Y., Zhang, X., Shao, C., Roberts, A. I., Rabson, A. B., Ren, G., Zhang, Y., Wang, Y., Denhardt, D. T. & Shi, Y. An osteopontine-integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells. Stem Cells 32, 327–337 (2014).Hofmann, G., Bernabei, P. A. & Crociani, O. et al. HERG K+ channels activation during β1 integrin-mediated adhesion to fibronectin induces an up-regulation of αvβ3 integrin in the preosteoclastic leukemia cell line FLG 29.1. J. Biol. Chem. 276, 4923–4931 (2001).Becchetti, A. et al. Response to fibronectin-integrin interaction in leukaemia cells: delayed enhancing of a K + current. Proc. R. Soc. Lond. 248, 235–240 (1992).Arcangeli, A. & Becchetti, A. Complex functional interaction between integrin receptors and ion channels. TRENDS Cell Biol. 16, 631–639 (2006).Jing, J., Hinton, R. J. & Feng, J. Q. BMR1A signaling in cartilage development and endochondral bone formation. Vitam. Hormones. 99, 273–291 (2015).Kimura, M., Ito, M., Amano, K., Chihara, Y., Fukata, M., Nakafuku, B., Yamamori, J., Feng, J., Nakano, T. & Okawa, K. et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245–248 (1996).Pelham, R. J. & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).Kovacs, M., Tóth, J., Hetényi, C., Málnási-Csizmadia, A. & Sellers, J. Mechanism of blebbistatin inhibition of myosin II. J. Biol. Chem. 279, 35557–35563 (2004).Narumiya, S., Ishizaki, T. & Ufhata, M. Use and properties of ROCK-specific inhibitor Y-27632. Methods Enzymol. 325, 273–284 (2000).Schmierer, B. & Hill, C. S. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. 8, 970–982 (2007).Zhao, B., Li, L. & Guan, K. L. Hippo signaling at a glance. J. Cell Sci. 123, 4001–4006 (2010).Varelas, X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141, 1614–1626 (2014).Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S. & Marshak, D. R. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).Kirkham, G. R. & Cartmell, S. H. Genes and proteins involved in the regulation of osteogenesis. Top. Tissue Eng. 3, 1–22 (2007).Chamberlain, G., Fox, J., Ashton, B. & Middleton, J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25, 2739–2749 (2007).Lowe, C. E., O´Rahilly, S. & Rochford, J. J. Adipogenesis at a glance. J. Cell Sci. 124, 2681–2686 (2011).MacQueen, L., Sun, Y. & Simmons, C. A. Mesenchymal stem cell mechanobiology and emerging experimental platforms. J. R. Soc. Interface 10, 20130179 (2013).Ivanovska, I. L., Shin, J. W., Swift, J. & Discher, D. E. Stem cell mechanobiology: diverse lessons from bone marrow. Trends Cell Biol. 25, 523–532 (2015).Phimphilai, M., Zhao, Z., Boules, H., Roca, H. & Franceschi, R. T. BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J. Bone Miner. Res. 21, 637–646 (2006).Comoglio, P. M., Boccaccio, C. & Trusolino, L. Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr. Opin. Cell Biol. 15, 565–571 (2003).Fourel, L., Valat, A., Faurobert, E., Guillot, R., Bourrin-Reynard, I., Ren, K., Lafanechère, L., Planus, E., Picart, C. & Albiges-Rizo, C. β3 integrin-mediated spreading induced by matrix-bound BMP-2 controls Smad signaling in a stiffness-independent manner. J. Cell Biol. 212, 693–706 (2016).Morandi, E. M., Verstappen, R., Zwierzina, M. E., Geley, S., Pierer, G. & Ploner, C. ITGAV and ITGA5 diversely regulate proliferation and adipogenic differentiation of human adipose derived stem cells. Sci. Rep. 6, 28889 (2016).Brazil, D. P., Church, R. H., Surae, S., Godson, C. & Martin, F. BMP signalling: agony and antagony in the family. Trends Cell Biol. 25, 249–264 (2015).Nardone, G., Oliver-De La Cruz, J., Vrbsky, J., Martini, C., Pribyl, J., Skla´dal, P., Pesl, M., Caluori, G., Pagliari, S., martino, F., Maceckova, Z., Hajduch, M., Sanz-Garcia, A., Pugno, N. M., Stokin, G. B. & Forte, G. YAP regulates cell mechanics by controlling focal adhesion assembly. Nat. Commun. 8, 15321 (2017).Miyazono, K., Maeda, S. & Imamura, T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev. 16, 251–263 (2005).Rico, P., Rodrigo-Navarro, A., Sánchez Pérez, L. & Salmeron-Sanchez, M. Borax induces osteogenesis by stimulating NaBC1 transporter via activation of BMP pathway. Commun. Biol. https://doi.org/10.5525/gla.researchdata.1076 (2020)

Simultaneous boron ion-channel/growth factor receptor activation for enhanced vascularization

[EN] Boron ion is essential in metabolism and its concentration is regulated by ion-channel NaBC1. NaBC1 mutations cause corneal dystrophies such as Harboyan syndrome. Here we propose a 3D molecular model for NaBC1 and show that simultaneous stimulation of NaBC1 and vascular growth factor receptors (VEGFR) promote angiogenesis in vitro and in vivo with ultra-low concentrations of VEGF. We show Human Umbilical Vein Endothelial Cells (HUVEC) organization into tubular structures indicative of vascularization potential. Enhanced cell sprouting was found only in the presence of VEGF and boron, effect abrogated after blocking NaBC1. We demonstrate that stimulated NaBC1 promotes angiogenesis via PI3k-independent pathways and that ¿5ß1/¿vß3-integrin binding is not essential to enhanced HUVEC organization. We describe a novel vascularization mechanism that involves the crosstalk and colocalization between NaBC1/VEGFR receptors. This has important translational consequences: just by administering boron, taking advantage of endogenous VEGF, in vivo vascularization is shown in a chorioallantoic membrane assay.P.R. acknowledges support from the Ministerio de Economia, Industria y Competitividad, Gobierno de Espana (MINECO) (MAT2015-69315-C3-1-R), and European Regional Development Fund (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. M. S. S. acknowledges support from the European Research Council (ERC-HealInSynergy 306990) and the UK Engineering and Physical Sciences Research Council (EPSRC-EP/P001114/1). The authors are very grateful to Productos Florida farm for kindly providing chick embryos for CAM assay.Rico Tortosa, PM.; Rodrigo Navarro, A.; La Peña Del Rivero, MD.; Moulisova, V.; Costell, M.; Salmerón Sánchez, M. (2018). Simultaneous boron ion-channel/growth factor receptor activation for enhanced vascularization. Advanced Biosystems. 3(1):1-12. https://doi.org/10.1002/adbi.201800220S11231Yancopoulos, G. D., Davis, S., Gale, N. W., Rudge, J. S., Wiegand, S. J., & Holash, J. (2000). Vascular-specific growth factors and blood vessel formation. Nature, 407(6801), 242-248. doi:10.1038/35025215Carmeliet, P. (2005). Angiogenesis in life, disease and medicine. Nature, 438(7070), 932-936. doi:10.1038/nature04478Moulisová, V., Gonzalez-García, C., Cantini, M., Rodrigo-Navarro, A., Weaver, J., Costell, M., … Salmerón-Sánchez, M. (2017). Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization. Biomaterials, 126, 61-74. doi:10.1016/j.biomaterials.2017.02.024Briquez, P. S., Clegg, L. E., Martino, M. M., Gabhann, F. M., & Hubbell, J. A. (2016). Design principles for therapeutic angiogenic materials. Nature Reviews Materials, 1(1). doi:10.1038/natrevmats.2015.6Hanft, J. R., Pollak, R. A., Barbul, A., Gils, C. va., Kwon, P. S., Gray, S. M., … Breen, T. J. (2008). Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. Journal of Wound Care, 17(1), 30-37. doi:10.12968/jowc.2008.17.1.27917Woo, E. J. (2012). Recombinant human bone morphogenetic protein-2: adverse events reported to the Manufacturer and User Facility Device Experience database. The Spine Journal, 12(10), 894-899. doi:10.1016/j.spinee.2012.09.052United States Food and Drug Administration Product Description Regranex https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM142821.avi (accessed: May2008).Carmeliet, P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature, 473(7347), 298-307. doi:10.1038/nature10144Hynes, R. O. (2002). Integrins. Cell, 110(6), 673-687. doi:10.1016/s0092-8674(02)00971-6Mahabeleshwar, G. H., Feng, W., Reddy, K., Plow, E. F., & Byzova, T. V. (2007). Mechanisms of Integrin–Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis. Circulation Research, 101(6), 570-580. doi:10.1161/circresaha.107.155655Olsson, A.-K., Dimberg, A., Kreuger, J., & Claesson-Welsh, L. (2006). VEGF receptor signalling ? in control of vascular function. Nature Reviews Molecular Cell Biology, 7(5), 359-371. doi:10.1038/nrm1911Alexander, R. A., Prager, G. W., Mihaly-Bison, J., Uhrin, P., Sunzenauer, S., Binder, B. R., … Breuss, J. M. (2012). VEGF-induced endothelial cell migration requires urokinase receptor (uPAR)-dependent integrin redistribution. Cardiovascular Research, 94(1), 125-135. doi:10.1093/cvr/cvs017Herkenne, S., Paques, C., Nivelles, O., Lion, M., Bajou, K., Pollenus, T., … Struman, I. (2015). The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. Science Signaling, 8(403), ra117-ra117. doi:10.1126/scisignal.aaa2403Lauritzen, I., Chemin, J., Honoré, E., Jodar, M., Guy, N., Lazdunski, M., & Jane Patel, A. (2005). Cross‐talk between the mechano‐gated K 2P channel TREK‐1 and the actin cytoskeleton. EMBO reports, 6(7), 642-648. doi:10.1038/sj.embor.7400449Gasparski, A. N., & Beningo, K. A. (2015). Mechanoreception at the cell membrane: More than the integrins. Archives of Biochemistry and Biophysics, 586, 20-26. doi:10.1016/j.abb.2015.07.017Munaron, L., Genova, T., Avanzato, D., Antoniotti, S., & Fiorio Pla, A. (2012). Targeting Calcium Channels to Block Tumor Vascularization. Recent Patents on Anti-Cancer Drug Discovery, 8(1), 27-37. doi:10.2174/1574892811308010027Yao, X., & Garland, C. J. (2005). Recent Developments in Vascular Endothelial Cell Transient Receptor Potential Channels. Circulation Research, 97(9), 853-863. doi:10.1161/01.res.0000187473.85419.3eRico, P., Rodrigo-Navarro, A., & Salmerón-Sánchez, M. (2015). Borax-Loaded PLLA for Promotion of Myogenic Differentiation. Tissue Engineering Part A, 21(21-22), 2662-2672. doi:10.1089/ten.tea.2015.0044Park, M., Li, Q., Shcheynikov, N., Zeng, W., & Muallem, S. (2004). NaBC1 Is a Ubiquitous Electrogenic Na+-Coupled Borate Transporter Essential for Cellular Boron Homeostasis and Cell Growth and Proliferation. Molecular Cell, 16(3), 331-341. doi:10.1016/j.molcel.2004.09.030Vithana, E. N., Morgan, P., Sundaresan, P., Ebenezer, N. D., Tan, D. T. H., Mohamed, M. D., … Aung, T. (2006). Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nature Genetics, 38(7), 755-757. doi:10.1038/ng1824Lopez, I. A., Rosenblatt, M. I., Kim, C., Galbraith, G. C., Jones, S. M., Kao, L., … Kurtz, I. (2009). Slc4a11Gene Disruption in Mice. Journal of Biological Chemistry, 284(39), 26882-26896. doi:10.1074/jbc.m109.008102Parker, M. D., Ourmozdi, E. P., & Tanner, M. J. A. (2001). Human BTR1, a New Bicarbonate Transporter Superfamily Member and Human AE4 from Kidney. Biochemical and Biophysical Research Communications, 282(5), 1103-1109. doi:10.1006/bbrc.2001.4692Zangi, R., & Filella, M. (2012). Transport routes of metalloids into and out of the cell: A review of the current knowledge. Chemico-Biological Interactions, 197(1), 47-57. doi:10.1016/j.cbi.2012.02.001Tanjore, H., Zeisberg, E. M., Gerami-Naini, B., & Kalluri, R. (2007). β1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis. Developmental Dynamics, 237(1), 75-82. doi:10.1002/dvdy.21385Gerber, H.-P., Dixit, V., & Ferrara, N. (1998). Vascular Endothelial Growth Factor Induces Expression of the Antiapoptotic Proteins Bcl-2 and A1 in Vascular Endothelial Cells. Journal of Biological Chemistry, 273(21), 13313-13316. doi:10.1074/jbc.273.21.13313Tan, C., Cruet-Hennequart, S., Troussard, A., Fazli, L., Costello, P., Sutton, K., … Dedhar, S. (2004). Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell, 5(1), 79-90. doi:10.1016/s1535-6108(03)00281-2George, E. L., Baldwin, H. S., & Hynes, R. O. (1997). Fibronectins Are Essential for Heart and Blood Vessel Morphogenesis But Are Dispensable for Initial Specification of Precursor Cells. Blood, 90(8), 3073-3081. doi:10.1182/blood.v90.8.3073Fassler, R., & Meyer, M. (1995). Consequences of lack of beta 1 integrin gene expression in mice. Genes & Development, 9(15), 1896-1908. doi:10.1101/gad.9.15.1896Soldi, R., Mitola, S., Strasly, M., Defilippi, P., Tarone, G., & Bussolino, F. (1999). Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2. The EMBO Journal, 18(4), 882-892. doi:10.1093/emboj/18.4.882Takahashi, S., Leiss, M., Moser, M., Ohashi, T., Kitao, T., Heckmann, D., … Fässler, R. (2007). The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. Journal of Cell Biology, 178(1), 167-178. doi:10.1083/jcb.200703021Ribatti, D. (2008). Chapter 5 Chick Embryo Chorioallantoic Membrane as a Useful Tool to Study Angiogenesis. International Review of Cell and Molecular Biology, 181-224. doi:10.1016/s1937-6448(08)01405-6Novosel, E. C., Kleinhans, C., & Kluger, P. J. (2011). Vascularization is the key challenge in tissue engineering. Advanced Drug Delivery Reviews, 63(4-5), 300-311. doi:10.1016/j.addr.2011.03.004García, J. R., & García, A. J. (2015). Biomaterial-mediated strategies targeting vascularization for bone repair. Drug Delivery and Translational Research, 6(2), 77-95. doi:10.1007/s13346-015-0236-0Briquez, P. S., Hubbell, J. A., & Martino, M. M. (2015). Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing. Advances in Wound Care, 4(8), 479-489. doi:10.1089/wound.2014.0603Simón-Yarza, T., Formiga, F. R., Tamayo, E., Pelacho, B., Prosper, F., & Blanco-Prieto, M. J. (2012). Vascular Endothelial Growth Factor-Delivery Systems for Cardiac Repair: An Overview. Theranostics, 2(6), 541-552. doi:10.7150/thno.3682Kargozar, S., Baino, F., Hamzehlou, S., Hill, R. G., & Mozafari, M. (2018). Bioactive Glasses: Sprouting Angiogenesis in Tissue Engineering. Trends in Biotechnology, 36(4), 430-444. doi:10.1016/j.tibtech.2017.12.003Laplante, M., & Sabatini, D. M. (2009). mTOR signaling at a glance. Journal of Cell Science, 122(20), 3589-3594. doi:10.1242/jcs.051011Byzova, T. V., Goldman, C. K., Pampori, N., Thomas, K. A., Bett, A., Shattil, S. J., & Plow, E. F. (2000). A Mechanism for Modulation of Cellular Responses to VEGF. Molecular Cell, 6(4), 851-860. doi:10.1016/s1097-2765(05)00076-

Simultaneous boron ion-channel/growth factor receptor activation for enhanced vascularization

Boron ion is essential in metabolism and its concentration is regulated by ion-channel NaBC1. NaBC1 mutations cause corneal dystrophies such as Harboyan syndrome. Here we propose a 3D molecular model for NaBC1 and show that simultaneous stimulation of NaBC1 and vascular growth factor receptors (VEGFR) promote angiogenesis in vitro and in vivo with ultra-low concentrations of VEGF. We show Human Umbilical Vein Endothelial Cells (HUVEC) organization into tubular structures indicative of vascularization potential. Enhanced cell sprouting was found only in the presence of VEGF and boron, effect abrogated after blocking NaBC1. We demonstrate that stimulated NaBC1 promotes angiogenesis via Akt-independent pathways and that α5β1/αvβ3-integrin binding is not essential to enhanced HUVEC organization. We describe a novel vascularization mechanism that involves the crosstalk and colocalization between NaBC1/VEGFR receptors. This has important translational consequences: just by administering boron, taking advantage of endogenous VEGF, in vivo vascularization is shown in a chorioallantoic membrane assay

The dependence in Spain. A cuantitative analysis

El presente trabajo estudia el nivel de competencia funcional de los mayores españoles, en función de las necesidades de ayuda para realizar las actividades de la vida diaria. Se analiza además el tipo de personas que prestan dicha ayuda según la tarea realizada. Los resultados revelan que se requiere distinto grado de ayuda en función de las tareas, no existiendo un criterio común, de forma que las actividades instrumentales demandan mayor nivel de apoyo que las actividades básicas. Respecto a la persona que aporta la ayuda, la figura de la hija y el cónyuge resultan los apoyos más significativos en todos los tipos de actividades analizadas.The present article studies the functional competence of spanish elders, in relation to the need of help for carrying out everyday activities it also analyses the type of person that otters help and in wich activities. The results reveal that different grades of help are needed depending on the type of activity, instrumental activities need a higher grade of support than basic activities. As to the person that otters help it is daughters and partners that appear as the most important support giners, independently the activity

On the uniqueness of the Horrocks-Mumford-bundle

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman