Poly (Adp-Ribose) Synthetase Mediates Intestinal Mucosal Barrier Dysfunction After Mesenteric Ischemia

Liaudet, Lucas; Szabó, Andrea; Soriano, Francisco; Zingarelli, Basilia; Szabó, Csaba; Salzman, Andrew L.

doi:10.1097/00024382-200014020-00010

Cited by 80 publications

(52 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…34 The same effects including reduction of iNOS activity were obtained with pharmacologic PARP inhibition, but the oligonucleotide approach is far more specific. As Adprt knockout mice are protected against ischaemia-reperfusion damage induced by occlusion of the superior mesenteric artery, which in turn leads to the release of the same mediators as in Crohn's disease, 35 it is tempting to speculate about a pathophysiologic interaction between PARP-1 and PARP-2 in the context of inflammatory bowel disease.…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

“…Adprt (Ϫ/Ϫ) mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time as well as reduced lung neutrophil sequestration. 35 UV-induced acute photodamage in mouse skin could be reduced by topical application of a novel PARP inhibitor (BGP-15M) that was shown to decrease the number of single-strand DNA breaks and to downregulate IL-10 and TNF␣-levels in epidermal cells. 48 Finally, in a murine model of allergen-induced asthma, 3-AB prevented airway inflammation elicited by ovalbumin.…”

Section: Ischaemia-reperfusion Damage In Brain Heart Liver Kidneymentioning

confidence: 99%

See 1 more Smart Citation

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Beneke

Diefenbach

Bürkle

2004

Intl Journal of Cancer

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD ؉ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors. © 2004 Wiley-Liss, Inc. Key words: DNA damage; PARP; cancer chemotherapy; radiotherapy; ischaemia-reperfusion damage; diabetes; shock; Parkinson syndromePoly(ADP-ribosyl)ation is a posttranslational modification of proteins in eukaryotic cells performed by a family of NAD ϩ ADP-ribosyl transferases, the poly(ADP-ribose) polymerases (PARPs). NAD ϩ molecules as precursor are cleaved into nicotinamide and ADP-ribose moieties, and the latter are covalently attached to glutamic or aspartic acid residues of proteins, with PARP itself being the major acceptor. Poly(ADP-ribosyl)ation may alter the activity of acceptor protein, leading to inactivation due to the attachment of a highly complex, branched polymer carrying large numbers of negative charges (Fig. 1). The polymer is rapidly degraded by the enzyme poly(ADP-ribose) glycohydrolase (PARG), limiting the half-life of the polymer to approximately 1 min under conditions of DNA breakage. Poly(ADPribosyl)ation was originally discovered as an immediate response of cells to DNA strand-break-inducing agents, i.e., ionising radiation, alkylating agents and oxidants. Polymer formation in living cells after genotoxic stresses is mainly dependent on PARP-1 (encoded by the ADPRT gene), the first-discovered and best-investigated member of the PARP family. After binding of PARP-1 with its 2 zinc-fingers within the N-terminal DNA-binding domain to double...

show abstract

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

Section: Ischaemia-reperfusion Damage In Brain Heart Liver Kidneymentioning

confidence: 99%

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Beneke

Diefenbach

Bürkle

2004

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…It exerts an inhibitory effect on the poly (adenosine diphosphate (ADP)-ribose) synthase or polymerase (PARS and PARP, respectively). The nuclear enzyme can be activated by strand breaks in DNA caused by reactive oxygen and nitrogen species, and peroxynitrite [5,6]. PARP is cytotoxic due to massive depletion of intracellular nicotinamide adenine dinucleotide (NAD + ) and adenosine triphosphate (ATP).…”

mentioning

confidence: 99%

Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion

Su¹,

Liu²,

Kao³

et al. 2007

European Respiratory Journal

View full text Add to dashboard Cite

Poly (ADP-ribose) synthase or polymerase (PARS and PARP, respectively) is a cytotoxic enzyme which causes cellular damage. Nicotinamide, a compound of vitamin B complex, has been reported to exert an inhibitory effect on PARS or PARP. The present study tests the effects of nicotinamide on acute lung injury and associated alterations following ischaemia/reperfusion (I/R) of the isolated perfused rat's lung.I/R increased the lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, pulmonary arterial pressure and capillary permeability. The insult also increased nitrate/ nitrite, methyl guanidine, tumour necrosis factor-a and interleukin-1b in lung perfusate, while it decreased adenosine triphosphate content with an increase in PARP activity in lung tissue.Most of the I/R-induced changes were abrogated by post-treatment (30 min after I/R) with nicotinamide (100 mg?kg -1 body weight). However, the increase in pulmonary arterial pressure was enhanced by nicotinamide post-treatment. Following I/R, the inducible nitric oxide synthase (iNOS) mRNA expression was enhanced. Nicotinamide reduced the iNOS expression. The results suggest that nicotinamide exerted a protective effect on the acute lung injury caused by ischaemia/reperfusion. The mechanisms may be mediated through the inhibition on the poly (adenosine diphosphate-ribose) polymerase activity, inducible nitric oxide synthase expression and the subsequent suppression of nitric oxide, free radicals and pro-inflammatory cytokines with restoration of adenosine triphosphate.

show abstract

“…Although both isoforms exhibit exo-and endoglycosidase activity, PARG 110 is the major form of PARG in the nucleus (6,7) Inhibitors of PARP activity reduce the tissue injury caused by I/R of the heart (8,9), brain (10), gut (11), liver (12), and kidney (13). Most notable, the degree of tissue injury caused by I/R in the heart (14), brain (15), gut (16), and most recently kidney (17) is reduced in mice in which the gene encoding for PARP-1 has been disrupted (PARP-1 Ϫ/Ϫ mice). These studies support the view that the excessive activation of PARP-1 plays a key role in the pathophysiology of I/R injury.…”

mentioning

confidence: 99%

Mice Lacking the 110-kD Isoform of Poly(ADP-Ribose) Glycohydrolase Are Protected against Renal Ischemia/Reperfusion Injury

Patel

Cortes

Poala

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

Poly (Adp-Ribose) Synthetase Mediates Intestinal Mucosal Barrier Dysfunction After Mesenteric Ischemia

Cited by 80 publications

References 0 publications

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion

Mice Lacking the 110-kD Isoform of Poly(ADP-Ribose) Glycohydrolase Are Protected against Renal Ischemia/Reperfusion Injury

Contact Info

Product

Resources

About