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Biotech / Medical : Guilford (GLFD) - Steadily Rising -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (444)	9/11/2003 9:02:22 PM
From: tuck	Read Replies (1) \| Respond to of 496

Well, here is something with more direct relevance: >>Bioorg Med Chem. 2003 Aug 15;11(17):3695-707. Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Ferraris D, Ficco RP, Dain D, Ginski M, Lautar S, Lee-Wisdom K, Liang S, Lin Q, Lu MX, Morgan L, Thomas B, Williams LR, Zhang J, Zhou Y, Kalish VJ. Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. ferrarisd@guilfordpharm.com A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.<< Cheers, Tuck

To: scaram(o)uche who wrote (444)	10/7/2003 12:59:59 AM
From: scaram(o)uche	Read Replies (1) \| Respond to of 496

J Clin Invest. 2003 Oct;112(7):1049-57. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M. Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461, USA. In this report, we show that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron transport chain activates the three major pathways of hyperglycemic damage found in aortic endothelial cells by inhibiting GAPDH activity. In bovine aortic endothelial cells, GAPDH antisense oligonucleotides activated each of the pathways of hyperglycemic vascular damage in cells cultured in 5 mM glucose to the same extent as that induced by culturing cells in 30 mM glucose. Hyperglycemia-induced GAPDH inhibition was found to be a consequence of poly(ADP-ribosyl)ation of GAPDH by poly(ADP-ribose) polymerase (PARP), which was activated by DNA strand breaks produced by mitochondrial superoxide overproduction. Both the hyperglycemia-induced decrease in activity of GAPDH and its poly(ADP-ribosyl)ation were prevented by overexpression of either uncoupling protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD), which decrease hyperglycemia-induced superoxide. Overexpression of UCP-1 or MnSOD also prevented hyperglycemia-induced DNA strand breaks and activation of PARP. Hyperglycemia-induced activation of each of the pathways of vascular damage was abolished by blocking PARP activity with the competitive PARP inhibitors PJ34 or INO-1001. Elevated glucose increased poly(ADP-ribosyl)ation of GAPDH in WT aortae, but not in the aortae from PARP-1-deficient mice. Thus, inhibition of PARP blocks hyperglycemia-induced activation of multiple pathways of vascular damage. (no direct relevance, that I know of, to anything ongoing at GLFD. Just parking.)

To: scaram(o)uche who wrote (444)	10/22/2003 11:55:03 PM
From: scaram(o)uche	Respond to of 496

no direct relevance, that I know of, to anything ongoing at GLFD. Just parking (AASLD abstract)....... Presentation Title: INHIBITION OF POLY(ADP-RIBOSE) POLYMERASE (PARP) PROTECTS MICE FROM CHOLESTATIC LIVER INJURY. Reviewing Code: DO1 Cell Death (Necrosis and Apoptosis) Author Block: Peter Fickert, Michael Trauner, Andrea Fuchsbichler, Gernot Zollner, Martin Wagner, Karl-Franzens University, Graz, Austria; Rainer Zenz, Research Insitute of Molecular Pathology, Vienna, Austria; Zsuzsanna Zsengeller, Csaba Szabo, Inotek Pharmaceuticals Corporation, Beverly, MA; Helmut Denk, Karl-Franzens University, Graz, Austria. Background & Aims: Cholestatic liver injury results from intrahepatic accumulation of toxic bile acids. The mechanisms leading to hepatocyte cell death in cholestasis are poorly defined. This study was designed to elucidate these mechanisms. Methods: Studies were performed in common-bile-duct-ligated (CBDL) and cholic-acid-fed (CA) mice as well as mice injected with the Fas agonist Jo2. In addition, PARP-/- mice and mice treated with the PARP inhibitor PJ34 (20 mg/kg i.p. 2/d) were fed CA. Cell death was determined using H & E staining, double immunofluorescence microscopy for terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assay, activated caspase-3 and cytokeratin (CK) 18, and electron microscopy (ELMI). Serum alanine aminotransferase (ALT), bilirubin and bile acid and hepatic ATP levels were investigated. Results: Jo2-challenged mice showed activation of caspase-3, breakdown of the CK intermediate filament network (characteristic of hepatocyte apoptosis), and classical morphologic features of apoptotic cell death in H & E stained sections and ELMI. In contrast, cholestatic mice lacked significant activation of caspase-3 and typical CK alterations were rarely seen despite a frequently positive TUNEL assay. Thus, oncosis was the primary type of cell death in cholestatic mouse models as determined by H & E staining and ELMI. Liver injury was significantly reduced in PARP-/- and PJ34-treated mice. Summary & Conclusions: Oncosis represents the main type of hepatocyte death in cholestatic mice. The relative contribution of apoptosis to cholestatic liver injury may be overestimated by the use of non-specific detection systems. Inhibition of PARP may represent a therapeutic target in cholestatic liver diseases.