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The Role of Aquaporins in Ocular Lens Homeostasis.
Schey KL, Petrova RS, Gletten RB, Donaldson PJ
(2017) Int J Mol Sci 18:
MeSH Terms: Animals, Aquaporins, Biological Transport, Active, Eye Proteins, Homeostasis, Humans, Lens, Crystalline, Permeability, Protein Isoforms, Water
Show Abstract · Added April 3, 2018
Aquaporins (AQPs), by playing essential roles in the maintenance of ocular lens homeostasis, contribute to the establishment and maintenance of the overall optical properties of the lens over many decades of life. Three aquaporins, AQP0, AQP1 and AQP5, each with distinctly different functional properties, are abundantly and differentially expressed in the different regions of the ocular lens. Furthermore, the diversity of AQP functionality is increased in the absence of protein turnover by age-related modifications to lens AQPs that are proposed to alter AQP function in the different regions of the lens. These regional differences in AQP functionality are proposed to contribute to the generation and directionality of the lens internal microcirculation; a system of circulating ionic and fluid fluxes that delivers nutrients to and removes wastes from the lens faster than could be achieved by passive diffusion alone. In this review, we present how regional differences in lens AQP isoforms potentially contribute to this microcirculation system by highlighting current areas of investigation and emphasizing areas where future work is required.
0 Communities
1 Members
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10 MeSH Terms
R1 correction in amide proton transfer imaging: indication of the influence of transcytolemmal water exchange on CEST measurements.
Li H, Li K, Zhang XY, Jiang X, Zu Z, Zaiss M, Gochberg DF, Gore JC, Xu J
(2015) NMR Biomed 28: 1655-62
MeSH Terms: Amides, Animals, Artifacts, Biological Transport, Active, Body Water, Brain Neoplasms, Cell Line, Tumor, Extracellular Fluid, Humans, Intracellular Fluid, Magnetic Resonance Spectroscopy, Molecular Imaging, Protons, Rats, Rats, Inbred F344, Reproducibility of Results, Sensitivity and Specificity, Transcytosis
Show Abstract · Added October 28, 2015
Amide proton transfer (APT) imaging may potentially detect mobile proteins/peptides non-invasively in vivo, but its specificity may be reduced by contamination from other confounding effects such as asymmetry of non-specific magnetization transfer (MT) effects and spin-lattice relaxation with rate R1 (=1/T1). Previously reported spillover, MT and R1 correction methods were based on a two-pool model, in which the existence of multiple water compartments with heterogeneous relaxation properties in real tissues was ignored. Such simple models may not adequately represent real tissues, and thus such corrections may be unreliable. The current study investigated the effectiveness and accuracy of correcting for R1 in APT imaging via simulations and in vivo experiments using tumor-bearing rats subjected to serial injections of Gd-DTPA that produced different tissue R1 values in regions of blood-brain-barrier breakdown. The results suggest that conventional measurements of APT contrast (such as APT* and MTRasym ) may be significantly contaminated by R1 variations, while the R1 -corrected metric AREX* was found to be relatively unaffected by R1 changes over a broad range (0.4-1 Hz). Our results confirm the importance of correcting for spin-lattice relaxation effects in quantitative APT imaging, and demonstrate the reliability of using the observed tissue R1 for corrections to obtain more specific and accurate measurements of APT contrast in vivo. The results also indicate that, due to relatively fast transcytolemmal water exchange, the influence of intra- and extracellular water compartments on CEST measurements with seconds long saturation time may be ignored in tumors.
Copyright © 2015 John Wiley & Sons, Ltd.
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2 Members
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18 MeSH Terms
Conjugation of palmitic acid improves potency and longevity of siRNA delivered via endosomolytic polymer nanoparticles.
Sarett SM, Kilchrist KV, Miteva M, Duvall CL
(2015) J Biomed Mater Res A 103: 3107-16
MeSH Terms: Animals, Biocompatible Materials, Biological Transport, Active, Drug Delivery Systems, Endosomes, Gene Silencing, HEK293 Cells, Humans, Materials Testing, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Nanoparticles, Palmitic Acid, Polymers, RNA, Small Interfering
Show Abstract · Added March 14, 2018
Clinical translation of siRNA therapeutics has been limited by the inability to effectively overcome the rigorous delivery barriers associated with intracellular-acting biologics. Here, to address both potency and longevity of siRNA gene silencing, pH-responsive micellar nanoparticle (NP) carriers loaded with siRNA conjugated to palmitic acid (siRNA-PA) were investigated as a combined approach to improve siRNA endosomal escape and stability. Conjugation to hydrophobic PA improved NP loading efficiency relative to unmodified siRNA, enabling complete packaging of siRNA-PA at a lower polymer:siRNA ratio. PA conjugation also increased intracellular uptake of the nucleic acid cargo by 35-fold and produced a 3.1-fold increase in intracellular half-life. The higher uptake and improved retention of siRNA-PA NPs correlated to a 2- and 11-fold decrease in gene silencing IC50 in comparison to siRNA NPs in fibroblasts and mesenchymal stem cells, respectively, for both the model gene luciferase and the therapeutically relevant gene prolyl hydroxylase domain protein 2 (PHD2) . PA conjugation also significantly increased longevity of silencing activity following a single treatment in fibroblasts. Thus, conjugation of PA to siRNA paired with endosomolytic NPs is a promising approach to enhance the functional efficacy of siRNA in tissue regenerative and other applications.
Copyright © 2015 Wiley Periodicals, Inc.
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1 Members
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17 MeSH Terms
Auto-inhibition of Drs2p, a yeast phospholipid flippase, by its carboxyl-terminal tail.
Zhou X, Sebastian TT, Graham TR
(2013) J Biol Chem 288: 31807-15
MeSH Terms: Biological Transport, Active, Calcium-Transporting ATPases, Golgi Apparatus, Phosphatidylinositol Phosphates, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added January 20, 2015
Drs2p, a yeast type IV P-type ATPase (P4-ATPase), or flippase, couples ATP hydrolysis to phosphatidylserine translocation and the establishment of membrane asymmetry. A previous study has shown that affinity-purified Drs2p, possessing an N-terminal tandem affinity purification tag (TAPN-Drs2), retains ATPase and translocase activity, but Drs2p purified using a C-terminal tag (Drs2-TAPC) was inactive. In this study, we show that the ATPase activity of N-terminally purified Drs2p associates primarily with a proteolyzed form of Drs2p lacking the C-terminal cytosolic tail. Truncation of most of the Drs2p C-terminal tail sequence activates its ATPase activity by ∼4-fold. These observations are consistent with the hypothesis that the C-terminal tail of Drs2p is auto-inhibitory to Drs2p activity. Phosphatidylinositol 4-phosphate (PI(4)P) has been shown to positively regulate Drs2p activity in isolated Golgi membranes through interaction with the C-terminal tail. In proteoliposomes reconstituted with purified, N-terminally TAP-tagged Drs2p, both ATPase and flippase activity were significantly higher in the presence of PI(4)P. In contrast, PI(4)P had no significant effect on the activity of a truncated form of Drs2p, which lacked the C-terminal tail. This work provides the first direct evidence, in a purified system, that a phospholipid flippase is subject to auto-inhibition by its C-terminal tail, which can be relieved by a phosphoinositide to stimulate flippase activity.
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7 MeSH Terms
Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis.
Ma Y, Krueger JJ, Redmon SN, Uppuganti S, Nyman JS, Hahn MK, Elefteriou F
(2013) J Biol Chem 288: 30105-13
MeSH Terms: Animals, Antidepressive Agents, Biological Transport, Active, Bone Remodeling, Bone Resorption, Humans, Mice, Mice, Mutant Strains, Morpholines, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Osteoclasts, Psychomotor Disorders, Reboxetine, Sympathetic Nervous System
Show Abstract · Added November 14, 2013
Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual.
1 Communities
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16 MeSH Terms
Identification of an Acinetobacter baumannii zinc acquisition system that facilitates resistance to calprotectin-mediated zinc sequestration.
Hood MI, Mortensen BL, Moore JL, Zhang Y, Kehl-Fie TE, Sugitani N, Chazin WJ, Caprioli RM, Skaar EP
(2012) PLoS Pathog 8: e1003068
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Biological Transport, Active, Carbapenems, Disease Models, Animal, Drug Resistance, Multiple, Bacterial, Humans, Leukocyte L1 Antigen Complex, Lung, Manganese, Mice, Mice, Knockout, Neutrophil Infiltration, Neutrophils, Pneumonia, Bacterial, Zinc
Show Abstract · Added March 7, 2014
Acinetobacter baumannii is an important nosocomial pathogen that accounts for up to 20 percent of infections in intensive care units worldwide. Furthermore, A. baumannii strains have emerged that are resistant to all available antimicrobials. These facts highlight the dire need for new therapeutic strategies to combat this growing public health threat. Given the critical role for transition metals at the pathogen-host interface, interrogating the role for these metals in A. baumannii physiology and pathogenesis could elucidate novel therapeutic strategies. Toward this end, the role for calprotectin- (CP)-mediated chelation of manganese (Mn) and zinc (Zn) in defense against A. baumannii was investigated. These experiments revealed that CP inhibits A. baumannii growth in vitro through chelation of Mn and Zn. Consistent with these in vitro data, Imaging Mass Spectrometry revealed that CP accompanies neutrophil recruitment to the lung and accumulates at foci of infection in a murine model of A. baumannii pneumonia. CP contributes to host survival and control of bacterial replication in the lung and limits dissemination to secondary sites. Using CP as a probe identified an A. baumannii Zn acquisition system that contributes to Zn uptake, enabling this organism to resist CP-mediated metal chelation, which enhances pathogenesis. Moreover, evidence is provided that Zn uptake across the outer membrane is an energy-dependent process in A. baumannii. Finally, it is shown that Zn limitation reverses carbapenem resistance in multidrug resistant A. baumannii underscoring the clinical relevance of these findings. Taken together, these data establish Zn acquisition systems as viable therapeutic targets to combat multidrug resistant A. baumannii infections.
1 Communities
3 Members
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17 MeSH Terms
Gle1 is a multifunctional DEAD-box protein regulator that modulates Ded1 in translation initiation.
Bolger TA, Wente SR
(2011) J Biol Chem 286: 39750-9
MeSH Terms: Biological Transport, Active, DEAD-box RNA Helicases, Gene Expression Regulation, Fungal, Mutation, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Peptide Chain Initiation, Translational, RNA, Fungal, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added March 7, 2014
DEAD-box protein (Dbp) family members are essential for gene expression; however, their precise roles and regulation are not fully defined. During messenger (m)RNA export, Gle1 bound to inositol hexakisphosphate (IP(6)) acts via Dbp5 to facilitate remodeling of mRNA-protein complexes. In contrast, here we define a novel Gle1 role in translation initiation through regulation of a different DEAD-box protein, the initiation factor Ded1. We find that Gle1 physically and genetically interacts with Ded1. Surprisingly, whereas Gle1 stimulates Dbp5, it inhibits Ded1 ATPase activity in vitro, and IP(6) does not affect this inhibition. Functionally, a gle1-4 mutant specifically suppresses initiation defects in a ded1-120 mutant, and ded1 and gle1 mutants have complementary perturbations in AUG start site recognition. Consistent with this role in initiation, Gle1 inhibits translation in vitro in competent extracts. These results indicate that Gle1 has a direct role in initiation and negatively regulates Ded1. Together, the differential regulation of two distinct DEAD-box proteins by a common factor (Gle1) establishes a new paradigm for controlling gene expression and coupling translation with mRNA export.
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11 MeSH Terms
Facilitated transport and diffusion take distinct spatial routes through the nuclear pore complex.
Fiserova J, Richards SA, Wente SR, Goldberg MW
(2010) J Cell Sci 123: 2773-80
MeSH Terms: Active Transport, Cell Nucleus, Biological Transport, Active, Diffusion, Microscopy, Electron, Transmission, Nuclear Envelope, Nuclear Pore, RNA Transport, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added March 21, 2014
Transport across the nuclear envelope is regulated by nuclear pore complexes (NPCs). Much is understood about the factors that shuttle and control the movement of cargos through the NPC, but less has been resolved about the translocation process itself. Various models predict how cargos move through the channel; however, direct observation of the process is missing. Therefore, we have developed methods to accurately determine cargo positions within the NPC. Cargos were instantly trapped in transit by high-pressure freezing, optimally preserved by low-temperature fixation and then localized by immunoelectron microscopy. A statistical modelling approach was used to identify cargo distribution. We found import cargos localized surprisingly close to the edge of the channel, whereas mRNA export factors were at the very centre of the NPC. On the other hand, diffusion of GFP was randomly distributed. Thus, we suggest that spatially distinguished pathways exist within the NPC. Deletion of specific FG domains of particular NPC proteins resulted in collapse of the peripheral localization and transport defects specific to a certain karyopherin pathway. This further confirms that constraints on the route of travel are biochemical rather than structural and that the peripheral route of travel is essential for facilitated import.
0 Communities
1 Members
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10 MeSH Terms
The nuclear pore complex and nuclear transport.
Wente SR, Rout MP
(2010) Cold Spring Harb Perspect Biol 2: a000562
MeSH Terms: Biological Transport, Active, Cell Nucleus, Eukaryotic Cells, Nuclear Pore Complex Proteins, Saccharomyces cerevisiae
Show Abstract · Added March 21, 2014
Internal membrane bound structures sequester all genetic material in eukaryotic cells. The most prominent of these structures is the nucleus, which is bounded by a double membrane termed the nuclear envelope (NE). Though this NE separates the nucleoplasm and genetic material within the nucleus from the surrounding cytoplasm, it is studded throughout with portals called nuclear pore complexes (NPCs). The NPC is a highly selective, bidirectional transporter for a tremendous range of protein and ribonucleoprotein cargoes. All the while the NPC must prevent the passage of nonspecific macromolecules, yet allow the free diffusion of water, sugars, and ions. These many types of nuclear transport are regulated at multiple stages, and the NPC carries binding sites for many of the proteins that modulate and modify the cargoes as they pass across the NE. Assembly, maintenance, and repair of the NPC must somehow occur while maintaining the integrity of the NE. Finally, the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation. All these requirements demonstrate the complex design of the NPC and the integral role it plays in key cellular processes.
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1 Members
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5 MeSH Terms
A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin.
Winnick JJ, An Z, Moore MC, Ramnanan CJ, Farmer B, Shiota M, Cherrington AD
(2009) Am J Physiol Endocrinol Metab 297: E358-66
MeSH Terms: Adipose Tissue, Animals, Biological Transport, Active, Blood Glucose, Dogs, Fructose, Glucagon, Glucose, Insulin, Lactic Acid, Lipid Metabolism, Liver, Liver Glycogen, Somatostatin, Up-Regulation
Show Abstract · Added June 2, 2014
To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline (n = 7) or fructose (n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 +/- 0.27 and 5.55 +/- 0.53 mg x kg(-1) x min(-1) and glycogen synthesis averaged 0.72 +/- 0.24 and 3.98 +/- 0.57 mg x kg(-1) x min(-1) in the saline and fructose groups, respectively (P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 +/- 0.4 and 0.9 +/- 0.2 to 3.1 +/- 0.6 and 2.5 +/- 0.5 mg x kg(-1) x min(-1) in the saline and fructose groups, respectively, a change of 1.6 mg x kg(-1) x min(-1) in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/hyperinsulinemic conditions in the dog.
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4 Members
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15 MeSH Terms