VDAC1 Is Essential for Neurite Maintenance and the Inhibition Of
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Issn: 2455-7080
ISSN: 2455-7080 Contents lists available at http://www.albertscience.com ASIO Journal of Experimental Pharmacology & Clinical Research (ASIO-JEPCR) Volume 1, Issue 1, 2016, 01-07 AN OVERVIEW OF TUBERCULOSIS MANAGEMENT: MECHANISM AND THERAPEUTIC APPLICATIONS Nidhi Singh Joint Replacement Surgery Research Unit, Fortis Escort Hospital, Jaipur, Rajasthan, India ARTICLE INFO ABSTRACT Tuberculosis infections have exceptional virulence factors compared to other Review Article History pathogens and they infect host cell and persist inside phagosomes. First Received: 29 October, 2015 symptoms of active pulmonary TB can include weight loss, night sweats, fever, Accepted: 05 January, 2016 and loss of appetite etc. The infection can either go into remission or become more serious with onset of chest pain and coughing up bloody sputum. The exact Corresponding Author: symptoms of extra-pulmonary TB vary according to the site of infection in the body. The Mantoux tuberculin skin test, also called as the PPD (purified protein Nidhi Singh derivative) test, is primarily used to identify TB infection. According to their clinical utility the anti-TB drugs can be divided into, two categories; one is first Joint Replacement Surgery line, these drugs have high anti-tubercular efficiency as well as low toxicity; are Research Unit, Fortis Escort used routinely, as for examples- Rifampin (R), Isoniazid (H), Streptomycin (S), Hospital, Jaipur, Rajasthan, India Pyrazinamide (Z), Ethambutol (E) and another is second line, these drugs have either low anti-tubercular efficacy or high toxicity or both; are used in special circumstances only. There are six classes of second-line drugs likes amino Email: [email protected] glycosides, fluoro quinolones, polypeptides, thioamides, cycloserine, p-amino salicylic acid. -
Chloroquine Stimulates Cl Secretion by Ca Activated Cl Channels in Rat
Chloroquine Stimulates Cl2 Secretion by Ca2+ Activated Cl2 Channels in Rat Ileum Ning Yang1., Zhen Lei2., Xiaoyu Li1, Junhan Zhao1, Tianjian Liu1, Nannan Ning1, Ailin Xiao1, Linlin Xu1, Jingxin Li1* 1 Department of Physiology, Shandong University School of Medicine, Jinan, China, 2 Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, China Abstract Chloroquine (CQ), a bitter tasting drug widely used in treatment of malaria, is associated gastrointestinal side effects including nausea or diarrhea. In the present study, we investigated the effect of CQ on electrolyte transport in rat ileum using the Ussing chamber technique. The results showed that CQ evoked an increase in short circuit current (ISC) in rat ileum at lower concentration (#561024 M ) but induced a decrease at higher concentrations ($1023 M). These responses were not affected by tetrodotoxin (TTX). Other bitter compounds, such as denatoniumbenzoate and quinine, exhibited similar 24 + effects. CQ-evoked increase in ISC was partly reduced by amiloride(10 M), a blocker of epithelial Na channels. Furosemide 24 + + 2 2 (10 M), an inhibitor of Na -K -2Cl co-transporter, also inhibited the increased ISC response to CQ, whereas another Cl channel inhibitor, CFTR(inh)-172(1025M), had no effect. Intriguingly, CQ-evoked increases were almost completely abolished by niflumic acid (1024M), a relatively specific Ca2+-activated Cl2 channel (CaCC) inhibitor. Furthermore, other CaCC inhibitors, such as DIDS and NPPB, also exhibited similar effects. CQ-induced increases in ISC were also abolished by thapsigargin(1026M), a Ca2+ pump inhibitor and in the absence of either Cl2 or Ca2+ from bathing solutions. Further studies demonstrated that T2R and CaCC-TMEM16A were colocalized in small intestinal epithelial cells and the T2R agonist CQ evoked an increase of intracelluar Ca2+ in small intestinal epithelial cells. -
The Role of Caspase-2 in Regulating Cell Fate
cells Review The Role of Caspase-2 in Regulating Cell Fate Vasanthy Vigneswara and Zubair Ahmed * Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK; [email protected] * Correspondence: [email protected] Received: 15 April 2020; Accepted: 12 May 2020; Published: 19 May 2020 Abstract: Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. Keywords: caspase-2; procaspase; apoptosis; splice variants; activation; intrinsic; extrinsic; neurons 1. Introduction Apoptosis, or programmed cell death (PCD), plays a pivotal role during embryonic development through to adulthood in multi-cellular organisms to eliminate excessive and potentially compromised cells under physiological conditions to maintain cellular homeostasis [1]. However, dysregulation of the apoptotic signaling pathway is implicated in a variety of pathological conditions. For example, excessive apoptosis can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, whilst insufficient apoptosis results in cancer and autoimmune disorders [2,3]. Apoptosis is mediated by two well-known classical signaling pathways, namely the extrinsic or death receptor-dependent pathway and the intrinsic or mitochondria-dependent pathway. -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
DNA Damage Response Pathways in the Nematode C. Elegans
Cell Death and Differentiation (2004) 11, 21–28 & 2004 Nature Publishing Group All rights reserved 1350-9047/04 $25.00 www.nature.com/cdd Review Death and more: DNA damage response pathways in the nematode C. elegans L Stergiou1 and MO Hengartner*,1 telangiectasia mutated kinase; ATR, ataxia telangiectasia-related kinase; Tel1, telomere length regulation 1; Chk1, checkpoint 1 Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, kinase 1; Cdk, cyclin-dependent kinase; Cdc, cell division control; CH-8057 Zurich, Switzerland Apaf-1, apoptotic protease-activating factor-1; Bcl-2, B-cell * Corresponding author: MO Hengartner, Tel: þ 41 1 635 3140; Fax: þ 41 1 lymphoma 2; BH3, BCL-2 homology domain 3; PUMA, p53 635 6861; E-mail: [email protected] upregulated modulator of apoptosis; ced, cell death abnormal; Received 30.6.03; accepted 05.8.03 egl-1, egg-laying abnormal-1; mrt-2, mortal germ line-2; clk-2, Edited by G Melino clock gene; Spo 11, sporulation, meiosis-specific protein; msh, mismatch repair gene; cep-1, C. elegans p53 Abstract Genotoxic stress is a threat to our cells’ genome integrity. Introduction Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale Living organisms expend considerable energy to preserve integrity of their genomes. Multiple mechanisms have evolved genomic instability. Because such changes may have to ensure the fidelity of genome duplication and to guarantee tumorigenic potential, damaged cells are often eliminated faithful partitioning of chromosomes at each cell division. via apoptosis. Loss of this apoptotic response is actually one Furthermore, cells are under the constant threat of DNA of the hallmarks of cancer. -
Discovery, Characterization, and Development of Small
DISCOVERY, CHARACTERIZATION, AND DEVELOPMENT OF SMALL MOLECULE INHIBITORS OF GLYCOGEN SYNTHASE Buyun Tang Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology, Indiana University June 2020 Accepted by the Graduate Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee ______________________________________ Thomas D. Hurley, Ph.D., Chair ______________________________________ Peter J. Roach, Ph.D. April 30, 2020 ______________________________________ Millie M. Georgiadis, Ph.D. ______________________________________ Steven M. Johnson, Ph.D. ______________________________________ Jeffrey S. Elmendorf, Ph.D. ii © 2020 Buyun Tang iii Dedication I dedicate this work to my beloved family, my grandparents, my parents, and my brother. iv Acknowledgement First and foremost, I would like to express my deepest gratitude to my thesis advisor, Dr. Thomas D. Hurley. I am grateful to have him as my research mentor over the past four years. He has continuously guided, supported, and inspired me during my study at IUSM. His passion for science and devotion of mentorship offered me the best training experience I could ever receive in graduate school. His easygoing personality reminded me of all the wonderful times inside and outside of the lab. I remember him instructing me handling crystal instrument hand by hand, flying with me to San Diego for a conference, and driving me to a farm restaurant at Illinois. Dr. Hurley is not only an outstanding research mentor, but also a trustful friend. I deeply thank him for all his time, patience, and encouragement along my graduate training. -
Caspase Activation & Apoptosis
RnDSy-lu-2945 Caspase Activation & Apoptosis Extrinsic & Intrinsic Pathways of Caspase Activation CASPASE CLEAVAGE & ACTIVATION Caspases are a family of aspartate-specific, cysteine proteases that serve as the primary mediators of Pro-Domain Large Subunit (p20) Small Subunit (p10) apoptosis. Mammalian caspases can be subdivided into three functional groups, apoptotic initiator TRAIL Pro-Domain α chain β chain caspases (Caspase-2, -8, -9, -10), apoptotic effector caspases (Caspase-3, -6, -7), and caspases involved Asp-x Asp-x Proteolytic cleavage in inflammatory cytokine processing (Caspase-1, -4, -5, 11, and -12L/12S). All caspases are synthesized α chain as inactive zymogens containing a variable length pro-domain, followed by a large (20 kDa) and a small Fas Ligand TRAIL R1 Pro-Domain β chain TRAIL R2 Heterotetramer Formation (10 kDa) subunit. FADD FADD α chain α chain Pro-caspase-8, -10 Active caspase Pro-caspase-8, -10 TWEAK β chain Apoptotic caspases are activated upon the receipt of either an extrinsic or an intrinsic death signal. The Fas/CD95 extrinsic pathway (green arrows) is initiated by ligand binding to cell surface death receptors (TNF RI, Fas/ MAMMALIAN CASPASE DOMAINS & CLEAVAGE SITES FADD FADD TNF-α APOPTOTIC CASPASES CD95, DR3, TRAIL R1/DR4, TRAIL R2/DR5) followed by receptor oligomerization and cleavage of Pro- Extrinsic Pathway DR3 (or another TWEAK R) INITIATOR CASPASES 152 316 331 Pro-caspase-8, -10 Pro-caspase-8, -10 1 435 caspase-8 and -10. Activation of Caspase-8 and Caspase-10 results in the cleavage of BID and Caspase-2 CARD TRADD FLIP TRADD downstream effector caspases. -
Thirty Years of BCL-2: Translating Cell Death Discoveries Into Novel Cancer
PERSPECTIVES normal physiology and cancer remains TIMELINE unclear, and is beyond the scope of this article (for a review on these topics, see Thirty years of BCL-2: translating REF. 10). This Timeline article focuses on key advances in our understanding of the function of the BCL-2 protein family in cell death discoveries into novel cell death, in the development of cancer, cancer therapies and as targets in cancer therapy. Early studies on apoptosis Alex R. D. Delbridge, Stephanie Grabow, Andreas Strasser and David L. Vaux In their 1972 paper that adopted the word ‘apoptosis’ to describe a physiological Abstract | The ‘hallmarks of cancer’ are generally accepted as a set of genetic and process of cellular suicide, Kerr and epigenetic alterations that a normal cell must accrue to transform into a fully colleagues11 recognized the presence malignant cancer. It follows that therapies designed to counter these alterations of apoptotic cells in tissue sections of miht e effective as anti-cancer strateies ver the past 3 years, research on certain human cancers. Accordingly, the BCL-2-regulated apoptotic pathway has led to the development of they proposed that increasing the rate of apoptosis of neoplastic cells relative to their small-molecule compounds, nown as BH3-mimetics, that ind to pro-survival rate of production could potentially be BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline therapeutic. However, interest in cell death article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and its role in cancer languished until the and, specifically, its roles in cancer development and therapy late 1980s, when genetic abnormalities that prevented cell death were directly linked to malignancy in humans. -
Apoptosome Dependent Caspase-3 Activation Pathway Is Non-Redundant and Necessary for Apoptosis in Sympathetic Neurons
Cell Death and Differentiation (2007) 14, 625–633 & 2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons KM Wright1,3, AE Vaughn2,3 and M Deshmukh*,1,2,3 Although sympathetic neurons are a well-studied model for neuronal apoptosis, the role of the apoptosome in activating caspases in these neurons remains debated. We find that the ability of sympathetic neurons to undergo apoptosis in response to nerve growth factor (NGF) deprivation is completely dependent on having an intact apoptosome pathway. Genetic deletion of Apaf-1, caspase-9, or caspase-3 prevents apoptosis after NGF deprivation, and importantly, allows these neurons to recover and survive long-term following readdition of NGF. The inability of caspase-3 deficient sympathetic neurons to undergo apoptosis is particularly striking, as apoptosis in dermal fibroblasts and cortical neurons proceeds even in the absence of caspase-3. Our results show that in contrast to dermal fibroblasts and cortical neurons, sympathetic neurons express no detectable levels of caspase-7. The strict requirement for an intact apoptosome, coupled with a lack of effector caspase redundancy, provides sympathetic neurons with a markedly increased control over their apoptotic pathway. Cell Death and Differentiation (2007) 14, 625–633. doi:10.1038/sj.cdd.4402024; published online 25 August 2006 Apoptosis, a form of programmed cell death, is a critical multimeric complex termed the apoptosome.6 The apopto- component of normal organism development. The major some-mediated activation of caspases is initiated by the molecular events that occur during apoptosis have been release of cytochrome c from the mitochondria, a process that identified by many elegant biochemical studies, using both cell is regulated by interactions between the antiapoptotic and free systems and cell lines.1 However, differences in the proapoptotic members of the Bcl-2 family of proteins. -
Apaf-1/Cytochrome C Apoptosome: an Essential Initiator of Caspase Activation Or Just a Sideshow?
Cell Death and Differentiation (2003) 10, 16–18 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd News and Commentary Apaf-1/cytochrome c apoptosome: an essential initiator of caspase activation or just a sideshow? B Baliga1 and S Kumar*,1 1 or caspase-9-deficient cells than in their wild-type counter- parts, the cells show little defect in their ability to undergo 1 Hanson Institute, Frome Road, Adelaide, SA 5000, Australia apoptosis in response to physiological and pathological * Corresponding author: E-mail: [email protected] stimuli.7 Importantly, while Apaf-1 and caspase-9 are dis- pensable for cell death, BCL-2 does confer a survival Cell Death and Differentiation (2003) 10, 16–18. doi:10.1038/ advantage to these deficient cells. Thus, in an experimental sj.cdd.4401166 system where cytochrome c has no involvement, BCL-2 can still protect against cell death, arguing against the widely held view that BCL-2 solely protects cell death by preventing the Caspase activation in mammalian cells is mediated via two release of apoptogenic factors from mitochondria and main- main routes, often referred to as ‘the intrinsic pathway’ and taining mitochondrial membrane integrity.4 In addition, the ‘the extrinsic pathway’.1 The extrinsic pathway of apoptosis is authors show that treating cells with several highly specific induced by ligand-mediated activation of the tumour necrosis broad-spectrum caspase inhibitors produced a similar pheno- factor (TNF) family of cell surface receptors. A large protein -
A Voltage-Dependent Chloride Channel Fine-Tunes Photosynthesis in Plants
ARTICLE Received 19 Nov 2015 | Accepted 16 Apr 2016 | Published 24 May 2016 DOI: 10.1038/ncomms11654 OPEN A voltage-dependent chloride channel fine-tunes photosynthesis in plants Andrei Herdean1, Enrico Teardo2, Anders K. Nilsson1, Bernard E. Pfeil1, Oskar N. Johansson1, Rena´ta U¨nnep3,4, Gergely Nagy3,4, Otto´ Zsiros5, Somnath Dana1, Katalin Solymosi6,Gyoz+ o+ Garab5, Ildiko´ Szabo´2,7, Cornelia Spetea1 & Bjo¨rn Lundin1 In natural habitats, plants frequently experience rapid changes in the intensity of sunlight. To cope with these changes and maximize growth, plants adjust photosynthetic light utilization in electron transport and photoprotective mechanisms. This involves a proton motive force (PMF) across the thylakoid membrane, postulated to be affected by unknown anion (Cl À ) channels. Here we report that a bestrophin-like protein from Arabidopsis thaliana functions as a voltage-dependent Cl À channel in electrophysiological experiments. AtVCCN1 localizes to the thylakoid membrane, and fine-tunes PMF by anion influx into the lumen during illumination, adjusting electron transport and the photoprotective mechanisms. The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Our results reveal that AtVCCN1, a member of a conserved anion channel family, acts as an early component in the rapid adjustment of photosynthesis in variable light environments. 1 Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg 40530, Sweden. 2 Department of Biology, University of Padova, Padova 35121, Italy. 3 Laboratory for Neutron Scattering and Imaging, Paul Scherrer Institute, Villigen 5232, Switzerland. 4 Institute for Solid State Physics and Optics, Wigner Research Centre for Physics, Hungarian Academy of Sciences, Budapest 1121, Hungary. -
Visualizing Apoptosis As It Happens
Custom Publishing From: Sponsored By: VISUALIZING APOPTOSIS AS IT HAPPENS Page 3 Page 4 Page 5 Page 6 Apoptosis: Two Roads to It’s Just a Phase Please Eat Me: Apoptosis The Nucleus: At the a Single Destination Signs and Signals Center of it All NucView® Caspase-3 Substrates NucView® 530 Features NucView® 405 Real-time monitoring of caspase-3/7 activity in live cells Rapid, non-toxic, no-wash assay Available in 3 colors NucView® 488 For flow cytometry, microscopy or live cell imaging Formaldehyde fixable Validated in more than 100 cell types and 200 publications The only caspase substrates for real-time apoptosis detection NucView® technology: NucView® substrates consist of a fluorogenic DNA dye coupled to the caspase-3/7 DEVD recognition sequence. After enzyme cleavage in an apoptotic cell, the substrate releases the high-affinity DNA dye which binds DNA and fluoresces. NucView® caspase-3 substrates do not interfere with caspase activity, allowing monitoring of caspase activity in real time. Visit our website to find out more: biotium.com/technology/nucview-caspase-3-substrates/ Glowing products for science VISUALIZING APOPTOSIS AS IT HAPPENS Apoptosis: Two Roads to a Single Destination “[caspases] play a central role in apoptosis and ultimately ensure that programmed cell death occurs in a controlled manner with minimal impact to surrounding cells” etecting apoptosis is important for many areas of into caspase 8, which initiates the process of cell death. biological research, as well as for the development of Dnew drugs; the ability to monitor apoptosis is key in The Common Link: Caspases the assessment of anticancer drugs for example.