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Gold nanoparticles that target degraded elastin improve imaging and rupture prediction in an AngII mediated mouse model of abdominal aortic aneurysm.

Theranostics 2019 31;9(14):4156-4167. Epub 2019 May 31.

Department of Bioengineering, Clemson University.

: Abdominal aortic aneurysms (AAA) are characterized by a progressive disruption and weakening of the extracellular matrix (ECM) leading to dilation of the aorta which can be fatal if not treated. Current diagnostic imaging modalities provides little insight on the varying degree of ECM degeneration that precedes rupture in AAAs. Targeted delivery of contrast agents such as gold nanoparticles (GNPs) that bind to degraded matrix could prove useful when combined with computed tomography (CT) to provide a non-invasive surrogate marker of AAA rupture potential. Read More

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Characterization of Mitochondrial YME1L Protease Oxidative Stress-Induced Conformational State.

J Mol Biol 2019 03 5;431(6):1250-1266. Epub 2019 Feb 5.

Department of Chemistry, Middle Tennessee State University, 1301 East Main Street, Murfreesboro, TN 37132, USA. Electronic address:

Oxidative stress is a common challenge to mitochondrial function where reactive oxygen species are capable of significant organelle damage. The generation of mitochondrial reactive oxygen species occurs in the inner membrane and matrix compartments as a consequence of subunit function in the electron transport chain and citric acid cycle, respectively. Maintenance of mitochondrial proteostasis and stress response is facilitated by compartmentalized proteases that couple the energy of ATP hydrolysis to unfolding and the regulated removal of damaged, misfolded, or aggregated proteins. Read More

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VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle.

Autophagy 2019 06 29;15(6):1082-1099. Epub 2019 Jan 29.

a Department of Neurology, Hope Center for Neurological Diseases , Washington University School of Medicine , St Louis , MO , USA.

Differentiated tissue is particularly vulnerable to alterations in protein and organelle homeostasis. The essential protein VCP, mutated in hereditary inclusion body myopathy, amyotrophic lateral sclerosis and frontotemporal dementia, is critical for efficient clearance of misfolded proteins and damaged organelles in dividing cells, but its role in terminally differentiated tissue affected by disease mutations is less clear. To understand the relevance of VCP in differentiated tissue, we inactivated it in skeletal muscle of adult mice. Read More

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Two Cdc48 cofactors Ubp3 and Ubx2 regulate mitochondrial morphology and protein turnover.

J Biochem 2018 Nov;164(5):349-358

Department of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto, Japan.

Mitochondria continuously undergo coordinated fusion and fission during vegetative growth to keep their homogeneity and to remove damaged components. A cytosolic AAA ATPase, Cdc48, is implicated in the mitochondrial fusion event and turnover of a fusion-responsible GTPase in the mitochondrial outer membrane, Fzo1, suggesting a possible linkage of mitochondrial fusion and Fzo1 turnover. Here, we identified two Cdc48 cofactor proteins, Ubp3 and Ubx2, involving mitochondria regulation. Read More

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November 2018

AP-SWATH Reveals Direct Involvement of VCP/p97 in Integrated Stress Response Signaling Through Facilitating CReP/PPP1R15B Degradation.

Mol Cell Proteomics 2018 07 29;17(7):1295-1307. Epub 2018 Mar 29.

From the ‡Molecular Biology I, Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany;

The ubiquitin-directed AAA-ATPase VCP/p97 facilitates degradation of damaged or misfolded proteins in diverse cellular stress response pathways. Resolving the complexity of its interactions with partner and substrate proteins and understanding its links to stress signaling is therefore a major challenge. Here, we used affinity-purification SWATH mass spectrometry (AP-SWATH) to identify proteins that specifically interact with the substrate-trapping mutant, p97-E578Q. Read More

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Aflibercept Action in a Rabbit Model of Chronic Retinal Neovascularization: Reversible Inhibition of Pathologic Leakage With Dose-Dependent Duration.

Invest Ophthalmol Vis Sci 2018 02;59(2):1033-1044

Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States.

Purpose: We establish and characterize the chronic retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-α-aminoadipic acid (AAA) in a rabbit model and investigate the extent and duration of inhibitory actions induced by IVT aflibercept on the RNV.

Methods: Rabbits received a single IVT injection of AAA, with weekly follow-up fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT). After 10 weeks, they received a single IVT aflibercept or control injection. Read More

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February 2018

Structural determinants for protein unfolding and translocation by the Hsp104 protein disaggregase.

Biosci Rep 2017 12 22;37(6). Epub 2017 Dec 22.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, U.S.A.

The ring-forming Hsp104 ATPase cooperates with Hsp70 and Hsp40 molecular chaperones to rescue stress-damaged proteins from both amorphous and amyloid-forming aggregates. The ability to do so relies upon pore loops present in the first ATP-binding domain (AAA-1; loop-1 and loop-2 ) and in the second ATP-binding domain (AAA-2; loop-3) of Hsp104, which face the protein translocating channel and couple ATP-driven changes in pore loop conformation to substrate translocation. A hallmark of loop-1 and loop-3 is an invariable and mutational sensitive aromatic amino acid (Tyr and Tyr) involved in substrate binding. Read More

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December 2017

Identification of Physiological Substrates and Binding Partners of the Plant Mitochondrial Protease FTSH4 by the Trapping Approach.

Int J Mol Sci 2017 Nov 18;18(11). Epub 2017 Nov 18.

Faculty of Biotechnology, University of Wroclaw, Fryderyka Joliot-Curie 14A, 50-383 Wroclaw, Poland.

Maintenance of functional mitochondria is vital for optimal cell performance and survival. This is accomplished by distinct mechanisms, of which preservation of mitochondrial protein homeostasis fulfills a pivotal role. In plants, inner membrane-embedded -AAA protease, FTSH4, contributes to the mitochondrial proteome surveillance. Read More

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November 2017

VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling.

Mol Cell 2018 01 16;69(2):182-194. Epub 2017 Nov 16.

Molecular Biology I, Faculty of Biology, University of Duisburg-Essen, 45117 Essen, Germany. Electronic address:

The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins. Read More

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January 2018

[ATP-dependent proteases in the quality control of mitochondrial proteome].

Postepy Biochem 2016;62(2):206-215

University of Wroclaw, Faculty of Biotechnology, 14A F. Joliot-Curie St., 50-383 Wroclaw, Poland.

Mitochondria play the fundamental role in energy production and integration of many important metabolic and signalling pathways, which makes them essential for the function of a cell. The optimal operation of mitochondria depends on the qualitative and quantitative composition of the organellar proteins - the proteome. To maintain the homeostasis of the mitochondrial proteome, mitochondria developed a protein quality control system, which acts on the molecular, cellular and organellar levels. Read More

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December 2017

VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy.

EMBO J 2017 01 17;36(2):135-150. Epub 2016 Oct 17.

Molecular Biology I, Faculty of Biology, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany

Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Read More

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January 2017

Protein quality control at the mitochondrion.

Essays Biochem 2016 10;60(2):213-225

Institut für Biochemie und Molekularbiologie (IBMB), Universität Bonn, Nussallee 11, D-53115 Bonn, Germany.

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. Read More

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October 2016

A redox switch shapes the Lon protease exit pore to facultatively regulate proteolysis.

Nat Chem Biol 2015 Jan 10;11(1):46-51. Epub 2014 Nov 10.

1] RIKEN Systems and Structural Biology Center, Yokohama, Japan. [2] RIKEN Structural Biology Laboratory, Yokohama, Japan.

The Lon AAA+ protease degrades damaged or misfolded proteins in its intramolecular chamber. Its activity must be precisely controlled, but the mechanism by which Lon is regulated in response to different environments is not known. Facultative anaerobes in the Enterobacteriaceae family, mostly symbionts and pathogens, encounter both anaerobic and aerobic environments inside and outside the host's body, respectively. Read More

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January 2015

[Suppression of abdominal aortic aneurysm by hydrogen through chemokine-like factor1].

Zhonghua Yi Xue Za Zhi 2014 Jan;94(1):59-61


Objective: To explore the mechanism of hydrogen on the intervention of abdominal aortic aneurysm (AAA).

Methods: Healthy male Sprague-Dawley rats were divided into AAA group and AAA intervention group (saturated hydrogen saline administered intraperitoneally once daily). AAA was induced by infiltration of abdominal aorta with 0. Read More

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January 2014

Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue.

Atherosclerosis 2011 Jun 24;216(2):307-12. Epub 2011 Feb 24.

Department of Surgery, Kurume University School of Medicine, Japan.

Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. Read More

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Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1.

J Cell Biol 2009 Dec;187(7):1023-36

Institute for Genetics, University of Cologne, Germany.

Mitochondrial fusion depends on the dynamin-like guanosine triphosphatase OPA1, whose activity is controlled by proteolytic cleavage. Dysfunction of mitochondria induces OPA1 processing and results in mitochondrial fragmentation, allowing the selective removal of damaged mitochondria. In this study, we demonstrate that two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the adenosine triphosphate (ATP)-dependent matrix AAA (ATPase associated with diverse cellular activities [m-AAA]) protease, variable assemblies of the conserved subunits paraplegin, AFG3L1 and -2, and the ATP-independent peptidase OMA1. Read More

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December 2009

Visualizing the ATPase cycle in a protein disaggregating machine: structural basis for substrate binding by ClpB.

Mol Cell 2007 Jan;25(2):261-71

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

ClpB is a ring-shaped molecular chaperone that has the remarkable ability to disaggregate stress-damaged proteins. Here we present the electron cryomicroscopy reconstruction of an ATP-activated ClpB trap mutant, along with reconstructions of ClpB in the AMPPNP, ADP, and in the nucleotide-free state. We show that motif 2 of the ClpB M domain is positioned between the D1-large domains of neighboring subunits and could facilitate a concerted, ATP-driven conformational change in the AAA-1 ring. Read More

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January 2007

Endothelial progenitor cells and abdominal aortic aneurysms.

Ann N Y Acad Sci 2006 Nov;1085:327-30

Department of Vascular Surgery, St. George's Hospital and St. George's, University of London, London, UK.

Endothelial progenitor cells (EPCs) are a population of circulating stem cells that hone in to sites of vascular injury where they undergo differentiation to become incorporated into damaged tissue. The aim of this study was to enumerate EPCs in patients with abdominal aortic aneurysms (AAA). CD133(+) peripheral blood mononuclear cells were immunomagnetically selected and CD34/CD133 was used as a marker of EPCs. Read More

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November 2006

The aging myocardium: roles of mitochondrial damage and lysosomal degradation.

Heart Lung Circ 2005 Jun;14(2):107-14

Division of Pathology II, Faculty of Health Sciences, Linköping University, University Hospital, SE-58185 Linköping, Sweden.

Myocardial aging, leading to circulatory dysfunction, complicates numerous pathologies and is an important contributor to overall mortality at old age. In cardiac myocytes, mitochondria and lysosomes suffer remarkable age-related alterations. Mitochondrial changes include structural disorganization and enlargement, while lysosomes, which are responsible for autophagic turnover of mitochondria, accumulate lipofuscin (age pigment), a polymeric, autofluorescent, undegradable material. Read More

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[Role of Escherichia coli molecular chaperones in the protection of bacterial cells against irreversible aggregation induced by heat shock].

Postepy Biochem 2005 ;51(2):146-53

Department of Biochemistry, University of Gdańsk, 24 Kladki st., 80-822 Gdansk, Poland.

All living organisms respond to environmental stresses, such as heat or ethanol by increasing the synthesis of a specific group of proteins termed heat shock proteins (Hsps) or stress proteins. Major Hsps are molecular chaperones and proteases. Molecular chaperones facilitate the proper folding of polypeptides, protect other proteins from inactivation, and reactivate aggregated proteins. Read More

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December 2005

Unique base-step recognition by a platinum-acridinylthiourea conjugate leads to a DNA damage profile complementary to that of the anticancer drug cisplatin.

Biochemistry 2004 Jul;43(26):8560-7

Department of Chemistry, Wake Forest University, P.O. Box 7486 Reynolda Station, Winston-Salem, North Carolina 27109, USA.

The sequence specificity and time course of covalent DNA adduct formation of the novel platinum-acridine conjugate [PtCl(en)(ACRAMTU)](NO(3))(2) [PT-ACRAMTU, 2; en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea] have been investigated using restriction enzyme cleavage and transcription footprinting assays and compared to the damage produced by the clinical agent cis-diamminedichloroplatinum(II) (cisplatin, 1). The rate of DNA binding of 1 and 2 was also monitored by atomic emission spectrometry. Restriction enzymes were chosen that cleave the phosphodiester linkage at, or adjacent to, the predicted damage sites. Read More

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The Utrecht endovascular technologies (EVT) experience.

J Mal Vasc 1998 Dec;23(5):381-4

Department of Surgery, University Hospital Utrecht, The Netherlands.

The aim of this report is to review the single center, clinical experience with the Endovascular Grafting System (EGS/Ancure Endovascular Technologies, Menlo Park, Calif, USA) in the Netherlands. The program was started in January 1994 and at the moment of writing consists of 35 patients on an intention-to-treat basis. From January 1994 through January 1995, 11 patients (Group I) were treated. Read More

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December 1998

Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages.

J Clin Invest 1995 Jul;96(1):318-26

Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. Read More

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Stereospecific effects of the alpha-aminoadipic acid on the retina: a morphological and electrophysiological study.

Doc Ophthalmol 1985 Oct;61(1):71-7

In both frog and chicken an intravitreal injection of the dextrorotatory (D)-isomer of alpha-aminoadipic acid (alpha-aaa) leads to a progressive disappearance of the ERG b-wave without affecting a and c components. Tectal evoked potentials (TEP) are no longer recorded. These physiological effects are concomitant with a specific glial cell damage, without any apparent damage to neurons. Read More

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October 1985

Effects of DL-alpha-amino adipic acid on Müller cells in frog and chicken retinae in vivo: relation to ERG b wave, ganglion cell discharge and tectal evoked potentials.

Neurosci Lett 1981 Nov;27(1):81-7

In both frog and chicken, an intravitreal injection of DL-alpha-amino-adipic acid, (DL-alpha aaa) provoked a progressive depression and eventually the disappearance of the ERG b wave that was concomitant with severe damage to the Müller cells without any apparent damage to retinal neurons. Ganglion cell discharges as well as tectal evoked potentials were still recorded, i.e. Read More

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November 1981
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