Inhibition of poly(ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury

Mota, Rubén; Sánchez‐Bueno, Francisco; Sáenz, Luis; Hernández-Espinosa, David; Jimeno, Jaime; Tornel, Pedro L.; Martínez-Torrano, Alejandro; Ramı́rez, Pablo; Parrilla, Pascual; Yélamos, José

doi:10.1038/labinvest.3700326

Cited by 62 publications

(57 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The defect of PARP-2 seems to be associated with a narrower spectrum of diseases in murine models. The lack of PARP-2 impairs astrocyte activation [58] and provides protection against colitis [59], while it has no effect in models of contact hypersensitivity [60], irritative dermatitis [60] or pancreatitis [61]. Interestingly, a common set of genes (iNOS, Il-1, TNF) has been shown to be regulated by both PARP-1 and PARP-2 suggesting similar or overlapping mechanisms in inflammatory regulation by the two PARP isoforms.…”

Section: The Role Of Parp-2 In Thymopoesis and Inflammatory Regulationmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

show abstract

Section: The Role Of Parp-2 In Thymopoesis and Inflammatory Regulationmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Indeed, PARP-1 and other PARP family members have proven to be effectively inhibited by a broad array of small molecules (Rouleau et al 2010). The therapeutic application of PARP inhibitors has received a considerable amount of attention recently because of their potential utility in the treatment of cancers, but the possible therapeutic applications of PARP inhibitors extend far beyond cancer therapy to other types of stress-related diseases, such as cardiovascular diseases, stroke, metabolic disorders, diabetes, and autoimmunity, and virtually any disease or condition with acute or chronic inflammation as a root cause (Masutani et al 2005;Mota et al 2005;Pacher and Szabo 2007;Shevalye et al 2010;Ford and Lee 2011;Underhill et al 2011).…”

Section: Therapeutic Applications Of Parp Inhibitorsmentioning

confidence: 99%

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

Luo¹,

Kraus²

2012

Genes Dev.

635

607

View full text Add to dashboard Cite

Cellular stress responses are mediated through a series of regulatory processes that occur at the genomic, transcriptional, post-transcriptional, translational, and posttranslational levels. These responses require a complex network of sensors and effectors from multiple signaling pathways, including the abundant and ubiquitous nuclear enzyme poly(ADP-ribose) (PAR) polymerase-1 (PARP-1). PARP-1 functions at the center of cellular stress responses, where it processes diverse signals and, in response, directs cells to specific fates (e.g., DNA repair vs. cell death) based on the type and strength of the stress stimulus. Many of PARP-1's functions in stress response pathways are mediated by its regulated synthesis of PAR, a negatively charged polymer, using NAD + as a donor of ADP-ribose units. Thus, PARP-1's functions are intimately tied to nuclear NAD + metabolism and the broader metabolic profile of the cell. Recent studies in cell and animal models have highlighted the roles of PARP-1 and PAR in the response to a wide variety of extrinsic and intrinsic stress signals, including those initiated by oxidative, nitrosative, genotoxic, oncogenic, thermal, inflammatory, and metabolic stresses. These responses underlie pathological conditions, including cancer, inflammation-related diseases, and metabolic dysregulation. The development of PARP inhibitors is being pursued as a therapeutic approach to these conditions. In this review, we highlight the newest findings about PARP-1's role in stress responses in the context of the historical data.Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) is the most abundant and ubiquitous member of a family of 17 related mammalian proteins. Studies over the past two decades, complemented by some exciting recent reports, have begun to crystallize a clearer view of one of the most robust and consistent functions of PARP-1 across biological systems: as a stress sensor and a stress response mediator. In this review, we highlight the newest findings in this area in the context of the historical data. We did not attempt to provide a comprehensive review, but rather opted to focus on key findings that have clarified the role of PARP-1 (and related PARPs) in stress responses. The reader is directed to a variety of other excellent reviews that cover other aspects of PARP-1 biology (D

show abstract

“…PARP-1 activation during DNA damage induces energy failure by depleting NAD + ; the cell consumes ATP to replete the NAD + level, ultimately resulting in energy failure and DAMP release in necrosis (42). Genetic or pharmacologic blockade of PARP inhibits necrosis and demonstrates a reduced pancreatitis response (43). In addition to the passive ATP depletion-mediated mechanisms, several active mechanisms (for example, oxidative stress, calcium overload, mitochondrial permeability transition pore opening and cathepsin release) also participate in the regulation of the necrotic process in AP (34,44,45).…”

Section: Necrosismentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

129

View full text Add to dashboard Cite

The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

show abstract

Inhibition of poly(ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury

Cited by 62 publications

References 49 publications

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

Cell Death and DAMPs in Acute Pancreatitis

Contact Info

Product

Resources

About