Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerase-1 (PARP-1) is involved in DNA repair, but its overactivation can induce cell death. Our aim was to investigate the role of PARP-1 in activation of programmed cell death processes in the brain during systemic inflammation. Our data indicated that lipopolysaccharide (1mg/kgb.w., i.p.)-evoked systemic inflammation enhanced PARP-1 activity in the mouse brain, leading to the lowering of beta-NAD(+) concentration, to translocation of apoptosis inducing factor from mitochondria to the nucleus, and to enhanced lipid peroxidation. Inhibitor of PARP-1, 3-aminobenzamide (30 mg/kgb.w., i.p.), protected the brain against prooxidative and cell death processes, suggesting involvement of PARP-1 in systemic inflammation-related processes in the brain.
...
PMID:Poly(ADP-ribose) polymerase-1 inhibition protects the brain against systemic inflammation. 1690 42

The mechanisms responsible for microbially induced epithelial apoptosis and increased intestinal permeability remain unclear. This study assessed whether purified bacterial lipopolysaccharide (LPS) increases epithelial apoptosis and permeability and whether these changes are dependent on caspase-3 activation. In nontumorigenic epithelial monolayers, Escherichia coli O26:B6 LPS increased apoptosis, as shown by nuclear breakdown, caspase-3 activation, and PARP cleavage, and induced disruption of tight junctional ZO-1. Apical, but not basolateral, exposure to LPS increased epithelial permeability. Addition of a caspase-3 inhibitor abolished the effects of LPS. The findings describe a novel mechanism whereby apical LPS may disrupt epithelial tight junctional ZO-1 and barrier function in a caspase-3-dependent fashion.
...
PMID:The role of caspase-3 in lipopolysaccharide-mediated disruption of intestinal epithelial tight junctions. 1721 70

Inflammation contributes to many pathologies, but the mechanisms by which inflammation induces cell death are unclear. We investigated interactions between inducible nitric oxide synthase (iNOS), phagocytic NADPH oxidase (PHOX) and arachidonate in inducing cell death in a J774 macrophage cell line. Little or no cell death was induced by: (i) induction of iNOS with lipopolysaccharide (LPS) and interferon-gamma (INFgamma), (ii) activation of PHOX with phorbol-12-myristate-13-acetate (PMA), or (iii) addition of arachidonate. However, when iNOS activation was combined with PHOX activation by PMA or with arachidonate, there was extensive necrotic death of macrophages. In both cases death was accompanied by peroxynitrite production, and was blocked by removal of peroxynitrite (by FeTPPS), removal of superoxide (by superoxide dismutase), inhibition of iNOS (by 1400W) or inhibition of PARP (by IsoQ or DPQ). However, when iNOS induction was combined with PMA, death was blocked by a PHOX inhibitor (apocynin). Whereas when iNOS induction was combined with arachidonate, death was not blocked by apocynin, but was blocked by a cyclooxygenase (COX) inhibitor (ibuprofen), suggesting that the source of superoxide contributing to cell death differs in these two conditions.
...
PMID:Arachidonate and NADPH oxidase synergise with iNOS to induce death in macrophages: mechanisms of inflammatory degeneration. 1733 78

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.
...
PMID:Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age-related changes in rat hippocampus. 1762 47

The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) which was initially known for its role in the repair of oxidative stress-induced DNA damage, has also been reported to play a mediating role in the inflammatory response. Studies with PARP-1 knockout models have shown that PARP-1 is a co-activator of Nuclear Factor-kappa B (NF-kappaB), although this appears not to require its enzyme activity. In addition, drug-induced inhibition of the enzyme activity of PARP-1 was observed to reduce the production of pro-inflammatory mediators. In this study, the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of PARP-1. Further evaluation of flavone in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD(+) levels, as well as the formation of PAR-polymers was dose-dependently attenuated by flavone. In addition, flavone was found to reduce the lipopolysaccharide (LPS)-induced interleukin (IL)-8 production in pulmonary epithelial cells, which was confirmed by transcription analysis. Furthermore, the transcription Inhibitor kappa B alpha (of IkappaBalpha) was significantly increased by flavone. The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases. PARP-1 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease (COPD) and diabetes, by preservation of cellular NAD(+) levels and attenuating inflammatory conditions.
...
PMID:Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. 1764 14

Poly (ADP-ribose) synthabse (PARS) or polymerase (PARP) is a cytotoxic enzyme causing cellular damage. Niacinamide inhibits PARS or PARP. The present experiment tests the effects of niacinamide (NCA) on organ dysfunction and acute lung injury (ALI) following lipopolysaccharide (LPS). LPS was administered to anesthetized rats and to isolated rat lungs. In anesthetized rats, LPS caused systemic hypotension and increased biochemical factors, nitrate/nitrite (NOx), methyl guanidine (MG), tumor necrosis factoralpha (TNFalpha), and interleukin-1beta (IL-1beta). In isolated lungs, LPS increased lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, and capillary permeability. The insult also increased NOx, MG, TNFalpha, and IL-1beta in lung perfusate, while decreased adenosine triphosphate (ATP) content with an increase in PARP activity in lung tissue. Pathological examination revealed pulmonary edema with inflammatory cell infiltration. These changes were abrogated by posttreatment (30 min after LPS) with NCA. Following LPS, the inducible NO synthase (iNOS) mRNA expression was increased. NCA reduced the iNOS expression. Niacinamide exerts protective effects on the organ dysfunction and ALI caused by endotoxin. The mechanisms may be mediated through the inhibition on the PARP activity, iNOS expression and the subsequent suppression of NO, free radicals, and proinflammatory cytokines with restoration of ATP.
...
PMID:Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin. 1787 64

In critically ill patients various conditions may lead to the activation of poly(ADP-ribose) polymerase (PARP). By promoting cellular energetic dysfunction, and by enhancing pro-inflammatory gene expression, PARP activation significantly contributes to the pathogenesis of shock. PARP activation is usually triggered by DNA strand breakage, which is typically the result of the overproduction of various reactive oxidant species. One of the pathophysiological conditions associated with PARP activation is hyperglycemia, where the reactive species are produced from the mitochondria and other cellular sources. In the present study we tested whether endotoxin-induced PARP activation and pro-inflammatory mediator production can be modified by insulin therapy. Rats subjected to bacterial lipopolysaccharide (LPS) with or without insulin co-treatment were studied. LPS-induced PARP activation in circulating lymphocytes was measured by flow cytometry, tumor necrosis factor alpha (TNF-alpha) production was measured by ELISA. The direct effect of insulin on the PARP activity of mononuclear leukocytes and human umbilical vein endothelial cells (HUVEC) in elevated glucose conditions was tested in vitro. LPS-induced significant hyperglycemic response activated PARP in circulating lymphocytes and induced TNF-alpha production. Insulin treatment prevented LPS-induced hyperglycemic response, blocked PARP activation and blunted LPS-induced TNF-alpha response. Insulin treatment caused a slight reduction in the PARP activity of mononuclear cells and HUVECs in vitro. We demonstrate that insulin treatment blocks LPS-induced PARP activation in vivo. We propose that this effect is mainly indirect, and occurs due to the prevention of stress induced hyperglycemia, with a direct cellular effect of insulin playing a potential minor supplemental role. The current findings may have significant implications in the context of the emerging concept of tight glycemic control and insulin treatment for critically ill patients.
...
PMID:Treatment with insulin inhibits poly(ADP-ribose)polymerase activation in a rat model of endotoxemia. 1807 60

Recent studies have clearly reported that there is a relationship between endotoxemia and acute renal injury. The aim of this study was to investigate whether treatment with the new potent PARP inhibitor PJ34 could prevent the acute renal injury induced by lipopolysaccharide (LPS). Endotoxemia was induced by LPS injection (10 mg/kg, i.v.). LPS increased blood urea nitrogen (BUN) levels from 22 +/- 0.54 mg/dL to 45.7 +/- 5.79 mg/dL (p < 0.05). The plasma creatinine levels were 0.38 +/- 0.02 mg/dL and 0.47 +/- 0.03 mg/dL for the control and LPS groups, respectively. In addition, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular damage) was increased after LPS injection. By light microscopy, structural renal damage was observed in the LPS-treated group. However, PJ34 treatment (10 mg/kg, i.p.) attenuated LPS-induced renal injury, as indicated by plasma BUN and creatinine levels, urinary NAG excretion, and renal histology. These results indicated that the overactivation of the PARP pathway may have a role in LPS-induced renal impairment. Hence, pharmacological inhibition of this pathway might be an effective intervention to prevent endotoxin-induced acute renal injury.
...
PMID:Poly (ADP-ribose) polymerase as a potential target for the treatment of acute renal injury caused by lipopolysaccharide. 1819 52

The enzyme poly(ADP-ribose)polymerase (PARP) has a leader role in the DNA damage survey mechanisms by its nick-sensor function, but it is also involved in the early events of the programmed cell death, particularly during inflammatory injury, as a coactivator of NF-kB. In the present study, we evaluated the PARP involvement in the mechanisms of protection and/or cell death in rat astroglial cell cultures during the early phase of proinflammatory commitment after lipopolysaccharide and interferon gamma treatment. According with the recent findings that PARP-1 phosphorylation by MAPK/ERK-2 pathway seems to modulate PARP activation, in time course experiments we demonstrated that a very early PARP activation and expression is able to trigger a cell death pathway, DNA damage independent, during strong proinflammatory insults, maintaining its role of guardian of the genome stability only during the normal cell cycling.
...
PMID:Parp and cell death or protection in rat primary astroglial cell cultures under LPS/IFNgamma induced proinflammatory conditions. 1875 54

Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 +/- 5% (fisetin) and -29 +/- 6% (tricetin); P < or = 0.001]. Moreover, LPS-induced changes in TNFalpha and IL-6 concentrations were positively correlated with the extent of reduction by fisetin and tricetin. The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.
...
PMID:Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes. 1932 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---