18 research outputs found
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Efficient, nonātoxic anion transport by synthetic carriers in cells and epithelia
Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.info:eu-repo/semantics/publishe
Venture capital-backed firms, unavoidable value-destroying trade sales, and fair value protections
This paper investigates the implications of the fair value protections contemplated by the standard corporate contract (i.e., the standard contract form for which corporate law provides) for the entrepreneurāventure capitalist relationship, focusing, in particular, on unavoidable value-destroying trade sales. First, it demonstrates that the typical entrepreneurāventure capitalist contract does institutionalize the venture capitalistās liquidity needs, allowing, under some circumstances, for counterintuitive instances of contractually-compliant value destruction. Unavoidable value-destroying trade sales are the most tangible example. Next, it argues that fair value protections can prevent the entrepreneur and venture capitalist from allocating the value that these transactions generate as they would want. Then, it shows that the reality of venture capital-backed firms calls for a process of adaptation of the standard corporate contract that has one major step in the deactivation or re-shaping of fair value protections. Finally, it argues that a standard corporate contract aiming to promote social welfare through venture capital should feature flexible fair value protections.info:eu-repo/semantics/publishedVersio
A Synthetic Chloride Channel Restores Chloride Conductance in Human Cystic Fibrosis Epithelial Cells
Mutations in the gene-encoding cystic fibrosis transmembrane conductance regulator (CFTR) cause defective transepithelial transport of chloride (Clā) ions and fluid, thereby becoming responsible for the onset of cystic fibrosis (CF). One strategy to reduce the pathophysiology associated with CF is to increase Clā transport through alternative pathways. In this paper, we demonstrate that a small synthetic molecule which forms Clā channels to mediate Clā transport across lipid bilayer membranes is capable of restoring Clā permeability in human CF epithelial cells; as a result, it has the potential to become a lead compound for the treatment of human diseases associated with Clā channel dysfunction
Activation of PKC isoform Ī²I at the bloodābrain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain
P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the bloodābrain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-Ī± (TNF-Ī±) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-Ī±-induced reduction of P-glycoprotein activity was prevented by a PKCĪ²I/II inhibitor, LY333531, and mimicked by a PKCĪ²I/II activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCĪ²I, but not PKCĪ²II. Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [3H]-verapamil without compromising tight junction integrity. Thus, PKCĪ²I activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCĪ²I at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain