INT99348

Context Info Confidence 0.58 First Reported 2001 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 38 Total Number 38 Disease Relevance 30.96 Pain Relevance 3.36

nucleoplasm (PARP1) nuclear envelope (PARP1) transferase activity, transferring glycosyl groups (PARP1) intracellular (PARP1) DNA binding (PARP1) nucleolus (PARP1)

Anatomy Link Frequency poly 5 lung 3 mononuclear cells 3 apoptotic cell 2 cleavage 1 PARP1 (Homo sapiens)

Pain Link Frequency Relevance Heat diabetic neuropathy 22 99.12 Inflammatory response 70 98.78 Inflammation 198 98.04 depression 5 98.00 agonist 13 88.60 nMDA receptor 18 88.28 cINOD 18 87.44 COX-2 inhibitor 1 81.92 Nicotine 4 79.56 anesthesia 10 79.00

Disease Link Frequency Relevance Heat Death 201 99.88 Toxicity 49 99.74 Lung Injury 327 99.56 Pressure And Volume Under Development 32 99.52 Apoptosis 348 99.44 Diabetic Neuropathy 14 99.12 Acute Renal Failure 108 98.82 Increased Venous Pressure Under Development 229 98.72 Adult Respiratory Distress Syndrome 69 98.66 INFLAMMATION 279 98.60

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However, the potential toxicity of complete PARP inhibition necessitates the utilization of weaker PARP inhibitors with additional therapeutic properties.

Negative_regulation (inhibition) of PARP associated with toxicity

1) Confidence 0.58 Published 2007 Journal J. Pharmacol. Exp. Ther. Section Abstract Doc Link 17021258 Disease Relevance 0.94 Pain Relevance 0.13

In cultured MNCs from healthy subjects, inhibition of PARP-1 prevented lipopolysaccharide-induced increase in DNA binding activity of NF-kappaB and the expression of TNF-alpha and IL-6.

Negative_regulation (inhibition) of PARP in MNCs

2) Confidence 0.58 Published 2008 Journal Arch. Med. Res. Section Body Doc Link 18996291 Disease Relevance 0.07 Pain Relevance 0

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN).

Negative_regulation (inhibition) of PARP in Poly associated with diabetic neuropathy

3) Confidence 0.52 Published 2005 Journal Diabetes Section Abstract Doc Link 15855340 Disease Relevance 0.54 Pain Relevance 0.19

However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects.

Negative_regulation (inhibition) of PARP associated with premature aging and genomic instability

4) Confidence 0.52 Published 2005 Journal Diabetes Section Abstract Doc Link 15855340 Disease Relevance 0.60 Pain Relevance 0.21

The cytoprotective effect of dipyrone is associated with a decrease in DNA fragmentation, as assessed by electrophoresis of genomic DNA and by flow cytometry; a reduction in the percentage of condensed nuclei, as evaluated by DNA staining with Hoescht 33342 and a decrease in poly(ADP)-ribose polymerase (PARP) cleavage, as assessed by Western blotting.

Negative_regulation (decrease) of PARP in poly

5) Confidence 0.52 Published 2001 Journal Int. Immunopharmacol. Section Abstract Doc Link 11710546 Disease Relevance 0.38 Pain Relevance 0

Although PJ-34 is a pharmacological inhibitor of PARP independent on the activating stimuli [5,16], WW85 is a novel metalloporphyrinic peroxynitrite decomposition catalyst, releasing of NO3.

Negative_regulation (inhibitor) of PARP

6) Confidence 0.46 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.95 Pain Relevance 0.03

Nicotinamide (vitamin B3) is a weak PARP inhibitor, antioxidant, and calcium modulator and can improve energy status and inhibit cell death in ischemic tissues.

Negative_regulation (inhibitor) of PARP associated with death

7) Confidence 0.43 Published 2007 Journal J. Pharmacol. Exp. Ther. Section Abstract Doc Link 17021258 Disease Relevance 0.95 Pain Relevance 0.13

PARP-1 is inhibited by nicotinamide and its analogues such as 3-aminobenzamide and metoclopramide [112, 113].

Negative_regulation (inhibited) of PARP-1

8) Confidence 0.42 Published 2010 Journal Journal of Nucleic Acids Section Body Doc Link PMC2915624 Disease Relevance 0.60 Pain Relevance 0

Nicotinamide as a precursor of NAD+, ATP, and as an endogenous inhibitor of PARP-1 therefore plays significant roles in cellular protection and in determining cellular fate in response to genotoxic DNA damage. 8.

Negative_regulation (inhibitor) of PARP-1

9) Confidence 0.42 Published 2010 Journal Journal of Nucleic Acids Section Body Doc Link PMC2915624 Disease Relevance 0.83 Pain Relevance 0.03

In various murine models, PARP-1 inhibition was shown to favor apoptotic cell death, reduce inflammatory response, and reduce genomic sensitivity to various carcinogens.

Negative_regulation (inhibition) of PARP-1 in apoptotic cell associated with inflammatory response, apoptosis and death

10) Confidence 0.42 Published 2010 Journal Journal of Nucleic Acids Section Body Doc Link PMC2915624 Disease Relevance 1.22 Pain Relevance 0.09

While PARP-1 inhibition could impair its role in DNA repair, PARP-1 overactivation is detrimental to the cells by depleting its substrate NAD+, which leads to cellular energy crisis and necrotic cell death.

Negative_regulation (inhibition) of PARP-1 associated with death

11) Confidence 0.42 Published 2010 Journal Journal of Nucleic Acids Section Body Doc Link PMC2915624 Disease Relevance 1.32 Pain Relevance 0.09

The expression levels of heat shock protein 70 (HSP70), c-jun and c-fos genes were remarkably up-regulated and those of c-myc and poly (ADP ribose) polymerase (PARP) were down-regulated in bupivacaine-treated cells.

Negative_regulation (down-regulated) of poly in poly associated with shock

12) Confidence 0.41 Published 2003 Journal J Toxicol Sci Section Abstract Doc Link 12820540 Disease Relevance 0.66 Pain Relevance 0

The inhibitor of caspase-3 blocked PARP-1 cleavage activity and protected against MEF-induced apoptotic cell death.

Negative_regulation (blocked) of PARP-1 in apoptotic cell associated with apoptosis and death

13) Confidence 0.39 Published 2004 Journal Life Sci. Section Abstract Doc Link 15350819 Disease Relevance 0.83 Pain Relevance 0.23

Finally, although unlikely according to the literature, we can not exclude that WW85 or PJ-34 affect microcirculatory hemodynamics with other mechanisms other than through catalysation of peroxynitrite decomposition and PARP inhibition, respectively.

Negative_regulation (inhibition) of PARP

14) Confidence 0.34 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 1.10 Pain Relevance 0.11

Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34.

Negative_regulation (inhibitor) of PARP

15) Confidence 0.34 Published 2010 Journal Crit Care Section Abstract Doc Link PMC2887157 Disease Relevance 0.90 Pain Relevance 0.06

Our current study extends previous observations [5] by further exploring the route of PARP inhibition involved in renal hemodynamic during LPS-induced lung injury aggravated by MV.

Negative_regulation (inhibition) of PARP in lung associated with lung injury

16) Confidence 0.34 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.94 Pain Relevance 0.03

The lung wet/dry ratio was higher in the high Vt+Vehicle than in the low Vt+Vehicle group, and the treatment with the peroxynitrite decomposition catalyst or PARP inhibitor attenuated lung edema (Figure 2b).

Negative_regulation (inhibitor) of PARP in lung associated with pressure and volume under development and pulmonary edema

17) Confidence 0.34 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.28 Pain Relevance 0

Peroxynitrite formation and PARP activation in lungs of animals with VILI have been demonstrated before [5,16,27] and our current study extends previous observations [5] by further exploring the route of PARP inhibition involved in renal hemodynamics during LPS-induced lung injury aggravated by MV.

Negative_regulation (inhibition) of PARP in lung associated with lung injury

18) Confidence 0.34 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.82 Pain Relevance 0.03

We demonstrated that inhibition of PARP activation by peroxynitrite attenuates VILI and renal hypoperfusion and dysfunction, by maintaining endothelium-dependent vasodilation and decreasing inflammation and tissue injury.

Negative_regulation (inhibition) of PARP in endothelium associated with lung injury, inflammation, injury and increased venous pressure under development

19) Confidence 0.33 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.85 Pain Relevance 0.05

The compound thus blocks peroxynitrite and thereby reduces PARP activation [24-26].

Negative_regulation (reduces) of PARP

20) Confidence 0.33 Published 2010 Journal Crit Care Section Body Doc Link PMC2887157 Disease Relevance 0.84 Pain Relevance 0.03

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