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Tristan Rawling, Hassan Choucair, Nooshin Koolaji, Kirsi Bourget, Sarah E Allison, Yong-Juan Chen, Colin R Dunstan, Michael Murray
Cancer cell mitochondria are promising anticancer drug targets because they control cell death and are structurally and functionally different from normal cell mitochondria. We synthesized aryl-urea fatty acids and found that the analogue 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (13b) decreased proliferation and activated apoptosis in MDA-MB-231 breast cancer cells in vitro and in vivo. In mechanistic studies 13b emerged as the prototype of a novel class of mitochondrion-targeted agents that deplete cardiolipin and promote cancer cell death...
September 18, 2017: Journal of Medicinal Chemistry
Caroline Grönwall, Uta Hardt, Johanna T Gustafsson, Kerstin Elvin, Kerstin Jensen-Urstad, Marika Kvarnström, Giorgia Grosso, Johan Rönnelid, Leonid Padykov, Iva Gunnarsson, Gregg J Silverman, Elisabet Svenungsson
Natural IgM autoantibodies have been proposed to convey protection from autoimmune pathogenesis. Herein, we investigated the IgM responses in 396 systemic lupus erythematosus (SLE) patients, divided into subgroups based on distinct autoantibody profiles. Depressed IgM levels were more common in SLE than in matched population controls. Strikingly, an autoreactivity profile defined by IgG anti-Ro/La was associated with reduced levels of specific natural IgM anti-phosphorylcholine (PC) antigens and anti-malondialdehyde (MDA) modified-protein, as well total IgM, while no differences were detected in SLE patients with an autoreactivity profile defined by anti-cardiolipin/β2glycoprotein-I...
September 14, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Ahmed Saad, Sandra M S Herrmann, Alfonso Eirin, Christopher M Ferguson, James F Glockner, Haraldur Bjarnason, Michael A McKusick, Sanjay Misra, Lilach O Lerman, Stephen C Textor
BACKGROUND: Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function. We tested the hypothesis that elamipretide plus PTRA would improve renal function, oxygenation, and RBF in patients with atherosclerotic renal artery stenosis undergoing PTRA...
September 2017: Circulation. Cardiovascular Interventions
Rajagopalan Geetha, Chandrasekaran Sathiya Priya, Carani Venkatraman Anuradha
Mitochondrial oxidative stress plays a major role in the pathogenesis of myocardial apoptosis in metabolic syndrome (MS) patients. In this study, we investigated the effect of troxerutin (TX), an antioxidant on mitochondrial oxidative stress and apoptotic markers in heart of mice fed fat and fructose-rich diet. Adult male Mus musculus mice were fed either control diet or high fat, high fructose diet (HFFD) for 60 days to induce MS. Mice from each dietary group were divided into two on the 16th day and were either treated or untreated with TX (150 mg/kg bw, p...
September 12, 2017: Chemico-biological Interactions
Nicholas Cox, Stacy A Johnson, Sara Vazquez, Ryan P Fleming, Matthew T Rondina, David Kaplan, Stephanie Chauv, Gabriel V Fontaine, Scott M Stevens, Scott Woller, Daniel M Witt
BACKGROUND: Clinical guidelines recommend against routine use of thrombophilia testing in patients with acute thromboembolism. Thrombophilia testing rarely changes acute management of a thrombotic event. OBJECTIVE: To determine appropriateness of thrombophilia testing in a teaching hospital. DESIGN: Retrospective cohort study. SETTING: One academic medical center in Utah. PARTICIPANTS: All patients who received thrombophilia testing between July 1, 2014, and December 31, 2014...
September 2017: Journal of Hospital Medicine: An Official Publication of the Society of Hospital Medicine
Shoichiro Kameoka, Yoshihiro Adachi, Koji Okamoto, Miho Iijima, Hiromi Sesaki
Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases...
September 11, 2017: Trends in Cell Biology
Kerry A Morrone, Lydia H Pecker, Jacob Rand, Jennifer Davila, Suzette Oyeku, Jane A Little, Xue Xiaonan, Deepa Manwani
BACKGROUND: Sickle cell anemia (SCA) is characterized by abnormally shaped, adhesive RBCs that interact with white blood cells and the endothelium, leading to chronic hemolysis, vasculopathy and a prothrombotic state. About 10% of subjects with a thrombotic event in the general population will have an associated antiphospholipid (aPL) antibody. One proposed mechanism for the thrombophilic nature of aPL antibodies is the disruption of the potent anticoagulant annexin A5 or Annexin A5 resistance (A5R)...
September 4, 2017: Blood Cells, Molecules & Diseases
Rosebella A Iseme, Mark McEvoy, Brian Kelly, Linda Agnew, Frederick R Walker, Tonelle Handley, Christopher Oldmeadow, John Attia, Michael Boyle
An increased risk of cardiovascular disease (CVD) has long been recognized amongst people with autoimmune disease. It has been unclear whether this is due mainly to the ensuing treatment, particularly steroids, or whether some of this risk is due to the autoimmune process itself with subsequent inflammation. Indeed, a large body of evidence supports a role for chronic inflammation in atherogenesis, and autoantibodies have been identified as mediators in this complex inflammatory environment. Our aim is to carry out a systematic review of existing literature in order to formally establish the strength of the association between autoantibodies and atherosclerosis, amongst individuals without clinical autoimmune disease...
August 1, 2017: Cardiovascular Research
Reuben M Moncada, Katherine J Blackshear, Teresa A Garrett
The Arabidopsis thaliana lysophospholipid acyltransferase At1g78690 acylates a variety of lysophospholipids such as lyso phosphatidylglycerol, lyso phosphatidylethanolamine and lyso phosphatidylserine. Despite di-acylate phosphatidylglycerol being a substrate, overexpression of At1g78690 in Escherichia coli leads to the accumulation of acyl-PG. Here we show that cardiolipin also accumulates in cells overexpressing At1g78690. To help try and explain this observation, we show, using a liquid chromatography mass spectrometry (LC-MS) based assay, that At1g78690 utilizes both mono- and di-lyso cardiolipin as an acyl acceptor...
September 6, 2017: Biochemical and Biophysical Research Communications
Galyna P Gorbenko, Valeriya Trusova, Julian G Molotkovsky
Specific interactions between a mitochondrial hemoprotein cytochrome c (cyt c) and cardiolipin, a lipid component of mitochondrial membrane, are crucial to electron shuttling and apoptotic activities of this protein. In the present study the Förster resonance energy transfer (FRET) between anthrylvinyl-labeled phosphatidylcholine as a donor and heme moiety of cyt c as an acceptor was employed to give a quantitative characterization of the protein binding to the model membranes from the mixtures of phosphatidylcholine (PC) with phosphatidylglycerol (PG), phosphatidylserine (PS) or cardiolipin (CL) in different molar ratios...
September 6, 2017: Journal of Fluorescence
Ketan Malhotra, Arnab Modak, Shivangi Nangia, Tyler H Daman, Umut Gunsel, Victoria L Robinson, Dejana Mokranjac, Eric R May, Nathan N Alder
The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multisubunit mitochondrial TIM23 protein transport complex as a model system. The early stages of protein import by this complex require specific interactions between the polypeptide substrate receptor, Tim50, and the membrane-bound channel-forming subunit, Tim23...
September 2017: Science Advances
Christopher A Francy, Ryan W Clinton, Chris Fröhlich, Colleen Murphy, Jason A Mears
Dynamins are mechano-chemical GTPases involved in the remodeling of cellular membranes. In this study, we have investigated the mechanism of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission. To date, it is unclear how Drp1 assembles on the mitochondrial outer membrane in response to different lipid signals to induce membrane fission. Here, we present cryo-EM structures of Drp1 helices on nanotubes with distinct lipid compositions to mimic membrane interactions with the fission machinery...
September 6, 2017: Scientific Reports
Micheline El Khoury, Jitendriya Swain, Guillaume Sautrey, Louis Zimmermann, Patrick Van Der Smissen, Jean-Luc Décout, Marie-Paule Mingeot-Leclercq
Some bacterial proteins involved in cell division and oxidative phosphorylation are tightly bound to cardiolipin. Cardiolipin is a non-bilayer anionic phospholipid found in bacterial inner membrane. It forms lipid microdomains located at the cell poles and division plane. Mechanisms by which microdomains are affected by membrane-acting antibiotics and the impact of these alterations on membrane properties and protein functions remain unclear. In this study, we demonstrated cardiolipin relocation and clustering as a result of exposure to a cardiolipin-acting amphiphilic aminoglycoside antibiotic, the 3',6-dinonyl neamine...
September 6, 2017: Scientific Reports
Ewa Wielosz, Maria Majdan, Arkadiusz Koszarny, Magdalena Dryglewska, Jacek Tabarkiewicz
AIM OF THE STUDY: The aim of the study was the assessment of changes in the glomerular filtration rate (GFR) during long-term observation in a group of systemic sclerosis (SSc) patients with and without chronic antiphospholipid (aPL) antibody positivity. MATERIAL AND METHODS: The observation comprised 50 patients - 23 with diffuse cutaneous SSc - dcSSc and 27 limited cutaneous SSc - lcSSc. After 24 months we assessed 27 patients (9 died, 14 lost follow up); 24 patients (88%) were treated chronically with angiotensin-converting-enzyme inhibitors (ACEIs)...
2017: Central-European Journal of Immunology
Rachael M Rossi, Lauren Yum, Hervé Agaisse, Shelley M Payne
Cardiolipin, an anionic phospholipid that resides at the poles of the inner and outer membranes, is synthesized primarily by the putative cardiolipin synthase ClsA in Shigella flexneri An S. flexneri clsA mutant had no cardiolipin detected within its membrane, grew normally in vitro, and invaded cultured epithelial cells, but it failed to form plaques in epithelial cell monolayers, indicating that cardiolipin is required for virulence. The clsA mutant was initially motile within the host cell cytoplasm but formed filaments and lost motility during replication and failed to spread efficiently to neighboring cells...
August 29, 2017: MBio
Li Zeng, Xiue Jiang, Lie Wu, Li Liu
Interaction of cytochrome c (cyt c) with cardiolipin (CL) plays a crucial role in apoptotic functions, however, the changes of transmembrane potential in governing the protein behavior at membrane/water interface have not been studied due to the difficulties in simultaneously monitoring the interaction and regulating the electric field. Herein surface-enhanced infrared absorption (SEIRA) spectroelectrochemistry is employed to study the mechanism of how transmembrane potentials control the interaction of cyt c with CL membranes by regulating the electrode potentials of the Au film...
August 28, 2017: Chemistry: a European Journal
Ulaganathan Sivagnanam, Santosh Kumar Palanirajan, Sathyanarayana N Gummadi
Human phospholipid scramblases (hPLSCRs) are a family of four homologous single pass transmembrane proteins (hPLSCR1-4) initially identified as the proteins responsible for Ca(2+) mediated bidirectional phospholipid translocation in plasma membrane. Though in-vitro assays had provided evidence, the role of hPLSCRs in phospholipid translocation is still debated. Recent reports revealed a new class of proteins, TMEM16 and Xkr8 to exhibit scramblase activity challenging the function of hPLSCRs. Apart from phospholipid scrambling, numerous reports have emphasized the multifunctional roles of hPLSCRs in key cellular processes including tumorigenesis, antiviral defense, protein and DNA interactions, transcriptional regulation and apoptosis...
August 24, 2017: Biochimica et Biophysica Acta
Andrej Musatov, Erik Sedlák
Cardiolipin (CL) is a unique phospholipid with a dimeric structure having four acyl chains and two phosphate groups found almost exclusively in certain membranes of bacteria and of mitochondria of eukaryotes. CL interacts with numerous proteins and has been implicated in function and stabilization of several integral membrane proteins (IMPs). While both functional and stabilization roles of CL in IMPs has been generally acknowledged, there are, in fact, only limited number of quantitative analysis that support this function of CL...
August 23, 2017: Biochimie
Eun Mi Choi, Kwang Sik Suh, Woon-Won Jung, So Young Park, Sang Ouk Chin, Sang Youl Rhee, Youngmi Kim Pak, Suk Chon
The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to affect bone metabolism. We evaluated the protective effects of the triterpene glycoside actein from the herb black cohosh against TCDD-induced toxicity in MC3T3-E1 osteoblastic cells. We found that TCDD significantly reduced cell viability and increased apoptosis and autophagy in MC3T3-E1 osteoblastic cells (P < .05). In addition, TCDD treatment resulted in a significant increase in intracellular calcium concentration, mitochondrial membrane potential collapse, reactive oxygen species (ROS) production, and cardiolipin peroxidation, whereas pretreatment with actein significantly mitigated these effects (P < ...
August 24, 2017: Environmental Toxicology
Yoshihiro Adachi, Kie Itoh, Miho Iijima, Hiromi Sesaki
A mitochondrion is a dynamic intracellular organelle that actively divides and fuses to control its size, number and shape in cells. A regulated balance between mitochondrial division and fusion is fundamental to the function, distribution and turnover of mitochondria (Roy et al., 2015). Mitochondrial division is mediated by dynamin-related protein 1 (Drp1), a mechano-chemical GTPase that constricts mitochondrial membranes (Tamura et al., 2011). Mitochondrial membrane lipids such as phosphatidic acid and cardiolipin bind Drp1, and Drp1-phospholipid interactions provide key regulatory mechanisms for mitochondrial division (Montessuit et al...
May 5, 2017: Bio-protocol
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