The AR/NADPH/DEG Ternary Complex Structure of Aldose Reductase

The AR/NADPH/DEG ternary complex structure was refined to 1.94 Å resolution with a final R of 21.6%. This structure showed well-defined electron density for the DEG substrate at the “top” of AR active site pocket A top view of the AR molecular surface (purple) with the active site occupied by DEG (yellow).

Affinity of GS-aldehydes Towards AR Active Site

Glutathione conjugates were synthesized by reacting unsaturated aldehydes with reduced glutathione and purified by HPLC. Since conjugation removes unsaturation, the kinetic constants obtained with the conjugates are compared with the corresponding free saturated aldehyde. Kinetic parameters were determined in 0.1 M potassium phosphate containing 1 mM EDTA, 150  M NADPH, and varied concentrations of the aldehyde.

Oxidative Stress & Signaling Core

The members of the Oxidative Stress and Signaling Core are interested in understanding various aspects of signaling, including ligand binding, activation, inactivation, formation of cAMP, G-protein coupling, various phosphorylation-dephosphorylation reactions, translocation of activated proteins to the membrane and nucleus, and gene transcription. These investigators are also involved in understanding the normal maintenance of cellular structure, cell survival, cell differentiation, and cell division, as well as cell death, and various pathologies. Understanding these relevant signaling mechanisms can provide opportunities to prevent and/or treat the pathological changes that cause human suffering.

Core Director and Members

Satish K. Srivastava, Ph.D., Director, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Biochemistry and Molecular Biology

Naseem Ansari, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Associate Professor, Department of Biochemistry and Molecular Biology

Paul J. Boor, M.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Pathology

Xiaodong Cheng, Ph.D., Co-Director, Oxidative Stress and Signaling Research Core, NIEHS Center, Assistant Professor, Department of Pharmacology and Toxicology

Ella Englander, Ph.D., Co-Director, Oxidative Stress and Signaling Research Core, NIEHS Center, Associate Professor, Department of Surgery

Robert O. Fox, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Biochemistry and Molecular Biology

M. Firoze Khan, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Associate Professor, Department of Pathology

Rolf König, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Associate Professor, Department of Microbiology and Immunology

James C. Lee, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Biochemistry and Molecular Biology

John Papaconstantinou, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Biochemistry and Molecular Biology

J. Regino Perez-Polo, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor and Chairman ad-iterim, Department of Biochemistry and Molecular Biology

Mary Treinen-Moslen, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Professor, Department of Pathology

Jingwu Xie, Ph.D., Member, Oxidative Stress and Signaling Research Core, NIEHS Center, Assistant Professor, Department of Pharmacology and Toxicology

Key Words

4-Hydroxynonenal, Atherogenesis, Cell Differentiation, Cytokines, Cytotoxicity, Inflammation, Ischemia/Reperfusion, NFkB, Oxidative Stress, Signal Transduction

2005 Publications

Ahmed AE, Jacob S, Campbell GA, Harirah HM, Perez-Polo JR, Johnson KM. 2005 Sep. Fetal origin of adverse pregnancy outcome: The Water disinfectant byproduct choloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain. Brain Res Dev Brain Res., 159(1):1-11.

Awasthi S, Singhal SS, Yadav S, Singhal J, Drake K, Nadkar A, Zajac E, Wickramarachchi D, Rowe N, Yacoub A, Boor P, Dwivedi S, Dent P, Jarman WE, John, B, Awasthi YC.  2005. RLIP76 is a major determinant of radiation sensitivity.  Cancer Resarch 65(14):1-7.

Awasthi S, Singhal SS, Yadav S, Singhal J, Drake K, Nadkar A, Zajac E, Wickramarachchi D, Rowe N, Yacoub A, Boor PJ, Dwivedi S, Dent P, Jarman WE, Berchmans J, Awasthi YC. 2005. RLIP76 is a major determinant of radiation sensitivity. Cancer Res 65:6022-28.

Cai P, Khan F, Kaphalia BS, Ansari GAS. 2005. Immunotoxic response of oleic acid anilide and its hydrolysis products in female MRL+/+ mice. J Immunotoxicol. 2. 231-236.

Chen Q, Long Y, Yuan X, Zou L, Sun J, Perez-Polo JR, Yang K. 2005 Jun. Protective effects of bone marrow stromal cell transplantation in injured rodent brain: synthesis of neurotrophic factors. J. Neurosci. Res., 80(5):611-9.

Cheng X. 2005. Understand signal transduction through functional proteomics. Expert Review in Proteomics, 2:103-116.

Choudhary S, Xiao T, Srivastava S, Nees D, Piatigorsky J, Ansari NH, 2005. Role of aldehydes dehydrogenase isozymes in the defense of rat lens and human lens epithelial cells against oxidative stress. Invest. Ophthalmol. & Vis. Sci. 46: 259-267, 2005.

Choudhary S, Xiao T, Srivastava S, Zhang W, Chan LL, Vergara MD, Van Kuijk FJGM, Ansari NH, 2005. Toxicity and detoxification of lipid-derived aldehydes in cultured retinal pigmented epithelial cells. Toxicol. Appl. Pharmacol. 204: 122-134, 2005.

Comer JE, Chopra AK, Peterson JW, König R. 2005. Direct inhibition of T lymphocyte activation by anthrax toxins in vivo. Infect. Immun. 73: 8275-8281.

Dao DD, Sierra-Torres CH, Robazetti SC, Naranjo de Gomez M, König R, Lema C, Lester LJ, Au WW, Tyring SK. 2005. HLA-DQB1 and cervical cancer in Venezuelan women. Gynecol. Oncol. 96: 349-354.

El-Zein RA, Hastings-Smith DA, Ammenheuser MM,Treinen-Moslen M,Gulland FM and Ward Jr, JB. 2005. Evaluation of two different biomarkersfor use in the assessment of toxic chemical exposure in California Sea Lions(Zalophus Californianus). Marine Pollution Bulletin PMID: 16298399.

Englander EW. 2005 Nov. Gene expression changes reveal patterns of aging in the rat digestive tract. Ageing Res Rev. 4 (4):564-78.

Gong B, Trent MB, Srivastava D, Boor PJ. 2005. Chemical-induced, nonlethal, developmental model of dissecting aortic aneurysm. Birth Defects Res. 73.

He N, Li C, Zhang X, Sheng T, Chi S, Chen K, Wang Q, Vertrees R, Logrono R, Xie J. 2005 Jan.  Regulation of lung cancer cell growth and invasiveness by beta-TRCP. Mol Carcinog. 42(1):18-28.

Hu X, Nesic-Taylor O, Qui J, Rea HC, Fabian R, Rassin DK, Perez-Polo JR. 2005 Apr. Activation of nuclear factor-k B signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. J. Neurochem. (93): 26-37.

Jeschke M, Schubert T, Krickhahn M, Polykandriotis E, Klein D, Perez-Polo JR, Przkora R, Herndon DN. 2005 May-Jun. Interaction of exogenous liposomal insulin-like growth factor-I cDNA gene transfer with growth factors on collagen expression in acute wounds. Wound Repair & Regeneration 13(3):269-77.

Lee HM, Greeley GH, Herndon DN, Sinha M, Luxon BA, Englander EW. 2005 Nov 1. A rat model of smoke inhalation injury: influence of combustion smoke on gene expression in the brain. Toxicol Appl Pharmacol. 208 (3):255-65.

Martin SS, Perez-Polo JR, Noppens KM, Grafe M. 2005 Dec. Biphasic changes in the levels of poly(ADP-ribose) polymerase-1 and caspase 3 in the immature brain following hypoxia-ischemia. Int J Dev Neurosci. 23(8):673-86.

Mei F, Cheng X. 2005. Interplay between Exchange Protein directly Activated by cAMP (Epac) and Microtubule Cytoskeleton.  Molecular Biosystems, 1: 325-331.

Mei FC, Young TW, Cheng X. Published online 2005 Dec 29. RAS-mediated epigenetic inactivation of OPCML in oncogenic transformation of human ovarian surface epithelial cells. FASEB Journal, 10.1096/fj.05-4586fje.

Nesic O, Lee J, Johnson KM, Ye Z, Xu GY, Unabia GC, Wood TG, McAdoo DJ, Westlund KN, Hulsebosch CE, Perez-Polo JR. 2005. Transcriptional profiling of spinal cord injury-induced control neuropathic pain. J Neurochem. 95:998-1014.

Nesic-Taylor O, Cittelly D, Ye Z, Xu GY, Unabia G, Lee JC, Svrakic NM, Lui XH, Youle RJ, Wood TG, McAdoo D, Westlund KN, Hulsebosch CE, Perez-Polo JR. 2005 Mar. Exogenous Bcl-xL fusion protein spares neurons after spinal cord injury. J. Neurosci. Res. 79 (5):628-37.

Papaconstantinou J, DeFord JH, Gerstner A, Hsieh CC, Boylston WH, Guigneaux MM, Flurkey K, Harrison DE. 2005 Jun-Jul. Hepatic Gene and Protein Expression of Primary Components of the IGF-1 Axis in Long Lived Snell Dwarf Mice. Mech. Ageing Dev. 126 (6-7):692-704.

Ramírez-Alcántara V, Castañeda-Hernández G, Rampy BA, Aronson JF,Treinen-Moslen M. 2005. Attenuated gastropathy but not enteropathy of diclofenac-cholestyraminecomplex in rats. Drug Development Research 64:19-27.

Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. 2005 Jan. The Alzheimer’s disease b-secretase BACE1 is not a neuron-specific enzyme. J. Neurochem., (92):226-34.

Srivastava SK, Ramana KV, Bhatnagar A. 2005 May 26. Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev. (3):380-92.

Susaki E, Wang G, Cao G, Wang HQ, Englander EW, Greeley GH, Jr. 2005 Jul 15. Apelin cells in the rat stomach. Regul Pept. 129 (1-3):37-41.

Vertrees RA, Das GC, Coscio AM, Xie J, Zwischenberger JB, Boor PJ. 2005 Oct. A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells.  Mol Carcinog. 44(2):111-21.

Vertrees RA, Gokul CD, Popov VL, Coscio AM, Goodwin TJ, Zwischenberger JB, Boor PJ. 2005. Synergistic interaction of hyperthermia and gemcitabine in lung cancer. Cancer Biol & Therapy 4:1144-53.

Wang J, Kannan S, Li H, Khan MF. 2005. Cytokine gene expression and activation of NF-қB in aniline-induced splenic toxicity.  Toxicol Appl Pharmacol 203:36-44.

Wei W, Wang G, Qi X, Englander EW, Greeley GH Jr. 2005 Mar. Characterization and regulation of the rat and human ghrelin promoters. Endocrinology 146 (3):1611-25.

Wickliffe JK, Galbert LA, Ammenheuser MM, Herring SM, Xie J, Masters OE 3rd, Friedberg EC, Lloyd RS, Ward JB Jr.  2005 Aug 10.  3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.  Environ Mol Mutagen. 47(1):67-70.

Wu X, Kannan S, Khan MF. 2005. Iron release and oxidative DNA damage in spleen following aniline intoxication. J Toxicol Environ Health, Part A 68:657-666.

Xiao T, Choudhary S, Vergara LA, Ansari NH, 2005. Modification of cytoskeletal proteins by lipid-derived aldehydes in the lens epithelial cells. J. Cell Tissue Res. 5(2): 403-408.

Young TW, Mei F, Liu J, Bast RC Jr., Kurosky A, Cheng X. 2005. Proteomic Analysis of H-Ras-mediated oncogenic transformation in a genetically defined human ovarian cancer model. Oncogene, 24:6174-6184.

Zhang L, Cui R, Cheng X, Du J. 2005. Anti-apoptotic effect of serum and glucocorticoid-induced protein kinase is mediated by a novel mechanism activating IkB Kinase. Cancer Research, 65:457-464.

Publications Archive

Important Links

NIEHS Annual Report http://www-apps.niehs.nih.gov/centers/Public/res-core/ctr1062-4499.htm