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      GPCR signalling from within the cell : Intracellular GPCR Signaling

      1 , 1 , 1

      British Journal of Pharmacology

      Wiley

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          Most cited references 78

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          Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors.

          The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein-coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the "efficacy" of receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural "unbiased" ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction.
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            NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells.

            The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca(2+) oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH(2)-terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.
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              Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery.

              The plasma membrane as a selectively permeable barrier of living cells is essential to cell survival and function. In many cases, however, the efficient passage of exogenous bioactive molecules through the plasma membrane remains a major hurdle for intracellular delivery of cargoes. During the last two decades, the potential of peptides for drug delivery into cells has been highlighted by the discovery of numerous cell-penetrating peptides (CPPs). CPPs serving as carriers can successfully intracellular transport cargoes such as siRNA, nucleic acids, proteins, small molecule therapeutic agents, quantum dots and MRI contrast agents. This review mainly introduces recent advances of CPPs as new carriers for the development of cellular imaging, nuclear localization, pH-sensitive and thermally targeted delivery systems. In particular, we highlight the exploiting of the synergistic effects of targeting ligands and CPPs. What's more, the classification and cellular uptake mechanisms of CPPs are briefly discussed as well. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                British Journal of Pharmacology
                British Journal of Pharmacology
                Wiley
                00071188
                November 2018
                November 2018
                October 03 2017
                : 175
                : 21
                : 4026-4035
                Affiliations
                [1 ]Department of Neuroscience; Washington University School of Medicine; St. Louis MO USA
                Article
                10.1111/bph.14023
                © 2017

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