Zinc and Traumatic Brain Injury: From Chelation to Supplementation

With a worldwide incidence rate of almost 70 million annually, traumatic brain injury (TBI) is a frequent cause of both disability and death. Our modern understanding of the zinc-regulated neurochemical, cellular, and molecular mechanisms associated with TBI is the result of a continuum of research spanning more than three decades. This review describes the evolution of the field beginning with the initial landmark work on the toxicity of excess neuronal zinc accumulation after injury. It further shows how the field has expanded and shifted to include examination of the cellular pools of zinc after TBI, identification of the role of zinc in TBI-regulated gene expression and neurogenesis, and the use of zinc to prevent cognitive and behavioral deficits associated with brain injury

Tracking stem cell migration and survival in brain injury: Current approaches and future prospects

In recent years, stem cell-mediated therapies have gained considerable ground as potential treatments for a wide variety of brain pathologies including traumatic brain injury, stroke and neurodegenerative diseases. Despite extensive preclinical studies, many of these therapies have not been fully translated into viable clinical approaches. This is partly due to our inability to reliably track and monitor transplanted stem cells longitudinally over long periods of time in vivo. In this review, we discuss the predominant histological cell tracing methodologies, such as immunohistochemistry, and fluorescent cellular dyes and proteins, and compare them to emerging cellular imaging technologies. We show that advances in magnetic resonance imaging (MRI) have resulted in opportunities to use this technology to further our understanding of stem cell characteristics and behaviors in vivo. While MRI may not completely replace conventional cell tracking methods in pre-clinical, mechanistic work, it is clear that it has the potential to function as a powerful diagnostic tool for tracking stem cell migration and survival as well as for evaluating the efficacy of stem cell-mediated therapies

Use of MRI, metabolomic, and genomic biomarkers to identify mechanisms of chemoresistance in glioma

Gliomas are the most common form of central nervous system tumor. The most prevalent form, glioblastoma multiforme, is also the most deadly with mean survival times that are less than 15 months. Therapies are severely limited by the ability of these tumors to develop resistance to both radiation and chemotherapy. Thus, new tools are needed to identify and monitor chemoresistance before and after the initiation of therapy and to maximize the initial treatment plan by identifying patterns of chemoresistance prior to the start of therapy. Here we show how magnetic resonance imaging, particularly sodium imaging, metabolomics, and genomics have all emerged as potential approaches toward the identification of biomarkers of chemoresistance. This work also illustrates how use of these tools together represents a particularly promising approach to understanding mechanisms of chemoresistance and the development individualized treatment strategies for patients

A Gold Nanoparticle Pentapeptide: Gene Fusion To Induce Therapeutic Gene Expression in Mesenchymal Stem Cells

Mesenchymal stem cells (MSC) have been identified as having great potential as autologous cell therapeutics to treat traumatic brain injury and spinal injury as well as neuronal and cardiac ischemic events. All future clinical applications of MSC cell therapies must allow the MSC to be harvested, transfected, and induced to express a desired protein or selection of proteins to have medical benefit. For the full potential of MSC cell therapy to be realized, it is desirable to systematically alter the protein expression of therapeutically beneficial biomolecules in harvested MSC cells with high fidelity in a single transfection event. We have developed a delivery platform on the basis of the use of a solid gold nanoparticle that has been surface modified to produce a fusion containing a zwitterionic, pentapeptide designed from Bax inhibiting peptide (Ku70) to enhance cellular uptake and a linearized expression vector to induce enhanced expression of brain-derived neurotrophic factor (BDNF) in rat-derived MSCs. Ku70 is observed to effect >80% transfection following a single treatment of femur bone marrow isolated rat MSCs with efficiencies for the delivery of a 6.6 kbp gene on either a Au nanoparticle (NP) or CdSe/ZnS quantum dot (QD). Gene expression is observed within 4 d by optical measurements, and secretion is observed within 10 d by Western Blot analysis. The combination of being able to selectively engineer the NP, to colocalize biological agents, and to enhance the stability of those agents has provided the strong impetus to utilize this novel class of materials to engineer primary MSCs

Integrated and Passive 1,2,3-Triazolyl Groups in Fluorescent Indicators for Zinc(II) Ions: Thermodynamic and Kinetic Evaluations

In addition to being a covalent linker in molecular conjugation chemistry, the function of a 1,2,3-triazolyl moiety resulting from the copper­(I)-catalyzed azide–alkyne cycloaddition reaction as a ligand for metal ions is receiving considerable attention. In this work, we characterize the thermodynamic and kinetic effects of incorporating a 1,2,3-triazolyl group in a multidentate ligand scaffold on metal coordination in the context of fluorescent zinc­(II) indicator development. Ligands <b>L14</b>, <b>BrL14</b>, and <b>FL14</b> (1,4-isomers) contain the 1,4-disubstituted-1,2,3-triazolyl group that is capable of binding with zinc­(II) in conjunction with a di­(2-picolylamino) (DPA) moiety within a multidentate ligand scaffold. Therefore, the 1,2,3-triazolyl in the 1,4-isomers is “integrated” in chelation. The 1,5-isomers <b>L15</b>, <b>BrL15</b>, and <b>FL15</b> contain 1,2,3-triazolyls that are excluded from participating in zinc­(II) coordination. These 1,2,3-triazolyls are “passive linkers”. Zinc­(II) complexes of 2:1 (ligand/metal) stoichiometry are identified in solution using ¹H NMR spectroscopy and isothermal titration calorimetry (ITC) and, in one case, characterized in the solid state. The 1:1 ligand/zinc­(II) affinity ratio of <b>L14</b> over <b>L15</b>, which is attributed to the affinity enhancement of a 1,2,3-triazolyl group to zinc­(II) over that of the solvent acetonitrile, is quantified at 18 (−1.7 kcal/mol at 298 K) using an ITC experiment. Fluorescent ligands <b>FL14</b> and <b>FL15</b> are evaluated for their potential in zinc­(II) sensing applications under pH neutral aqueous conditions. The 1,4-isomer <b>FL14</b> binds zinc­(II) both stronger and faster than the 1,5-isomer <b>FL15</b>. Visualization of free zinc­(II) ion distribution in live HeLa cells is achieved using both <b>FL14</b> and <b>FL15</b>. The superiority of <b>FL14</b> in staining endogenous zinc­(II) ions in live rat hippocampal slices is evident. In summation, this work is a fundamental study of 1,2,3-triazole coordination chemistry, with a demonstration of its utility in developing fluorescent indicators