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

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

We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-kappa B was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of I kappa B alpha, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of I kappa B alpha and inhibition of NF-kappa B DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF-alpha-mediated activation of a transfected NF-kappa B-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination.
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PMID:Suppression of NF-kappa B survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL. 3178 79

Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern. Increased expression of adhesion molecules, prominent neutrophil accumulation, and increased production of nitric oxide are characteristics of this disorder. Moreover, histamine and proteases are supposed to participate in the pathogenesis of psoriasis. Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-alpha production, nicotinamide produces a mild TH2 bias. Nicotinamide is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release. It inhibits nitric oxide synthase mRNA induction and suppresses antigen-induced lymphocyte transformation. Nicotinamide increases the biosynthesis of ceramides, which upon degradation produce sphingosine. Sphingosine inhibits protein kinase C (PKC) and decreases basal cell proliferation dependent on PKC. Taken together, it can be reasoned that nicotinamide could be a useful addition to anti-psoriatic armamentarium. The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen-induced arthritis. Nicotinamide decreased the methotrexate-induced hepatotoxicity. The above combinations may prove to have a powerful anti-psoriatic effect as well. As PARP inhibitors could exert anti-retroviral effect, nicotinamide could also be of special value in the treatment of HIV-infected psoriatics.
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PMID:Nicotinamide: a potential addition to the anti-psoriatic weaponry. 1289 Jun 90

Although the bubonic plague or "Black Death" is notorious for the toll it took on the population of Europe in the middle ages, another epidemic, the "White Death" of tuberculosis is responsible for millions of deaths worldwide over the past 300 years. With one in four deaths due to tuberculosis in Western Europe and the United States in the 19th century, this disease undoubtedly acted as a powerful genetic selective force. The epidemiology of modern day rheumatoid arthritis (RA) is strikingly similar to the epidemiology of tuberculosis 100-200 years ago, suggesting the possibility that genetic factors that enhanced survival in tuberculosis epidemics are now influencing susceptibility to RA. Recent advances in the analysis of genetic polymorphisms associated with disease have identified several genes linked to RA susceptibility that encode proteins involved in the immune response to Mycobacterium tuberculosis infection, including TNF-alpha, NRAMP1, PARP-1, HLA-DRB1, and PADI4. These results suggest that rheumatoid arthritis, and possibly other autoimmune diseases, are modern day manifestations of the genetic selective pressure exerted by tuberculosis epidemics of the recent past.
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PMID:Is rheumatoid arthritis a consequence of natural selection for enhanced tuberculosis resistance? 1508 17

1. NCX-1000, (3alpha, 5beta, 7beta)-3,7-dihydroxycholan-24oic acid[2-methoxy-4-[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ester, is a nitric oxide (NO)-derivative of ursodeoxyxholic acid (UDCA) that selectively release NO in the liver. 2. Here, we demonstrated that administering mice with 40 micromol kg(-1) NCX-1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 micromol kg(-1) APAP from 60 to 25% (P<0.01). Administration of NCX-1000, in a therapeutic manner, that is, 2 h after acetaminophen (APAP) intoxication reduced mortality, improved liver histopathology and prevented liver IFN-gamma, TNF-alpha, Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP. 3. In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 mm, resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Deltapsi(m)) hyperpolarization followed by depolarization and cytochrome c translocation from mitochondria to cytosol. APAP-induced apoptosis associated with procaspase-3 and -9 cleavage, appearance of truncated Bid and activation of poly(ADP-ribose) polymerase (PARP). 4. Treating primary culture of hepatocytes with 5 microm cyclosporine and 10 microm trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Deltapsim was mechanistically involved in apoptosis induced by APAP in vitro. 5. NCX-1000, but not UDCA, concentration-dependently (ED(50)=16 microm) protected against Deltapsi(m) depolarization and reduced transition from apoptosis to necrosis caused by 6.6 mm APAP. 6. Treating primary cultures of hepatocytes with the NO-donor DETA-NO, 100 microm, reduced apoptosis induced by APAP and prevented caspase activation. 7. In conclusion, NCX-1000 is effective in protecting against APAP-induced hepatotoxicity when administered in a therapeutic manner. This protection may involve the inhibition of apoptosis and the maintenance of mitochondrial integrity.
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PMID:Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice. 1933 74

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. WY 14643 is a potent PPAR-alpha ligand that modulates the transcription of target genes. The aim of this study was to investigate the effect of WY 14643 on the tissue injury caused by ischemia-reperfusion (I/R) of the gut. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp, allowing reperfusion for 2 h or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 20% of the animals survived for the entire 4-h reperfusion period. Surviving animals were sacrificed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity, significant increases in plasma tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels, and marked injury to the distal ileum. Increased immunoreactivity to nitrotyrosine and polyadenosine diphosphate [ADP]-ribose (PAR) was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody or with anti-P-selectin antibody resulted in diffuse staining. Administration of WY 14643 (1 mg/kg i.v.) 30 min before the onset of gut ischemia significantly reduced the (a) fall in mean arterial blood pressure, (b) mortality rate, (c) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (d) production of proinflammatory cytokines (TNF-alpha and IL-1beta), and (e) histological evidence of gut injury. Administration of WY 14643 also markedly reduced the nitrotyrosine formation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) activation, up-regulation of ICAM-1, and expression of P-selectin during reperfusion. These results demonstrate that the PPAR-alpha agonist WY 14643 significantly reduces I/R injury of the intestine.
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PMID:WY 14643, a potent exogenous PPAR-alpha ligand, reduces intestinal injury associated with splanchnic artery occlusion shock. 1537 89

The Notch signaling pathway plays an important role in the regulation of self-renewal and differentiation of hematopoietic progenitors. Tumor necrosis factor (TNF)-alpha induces apoptosis through activation of caspase pathway. A monoblastic leukemia cell line, U937, undergoes apoptosis following stimulation with TNF-alpha. We found that Notch activation induced by a recombinant Notch ligand, Delta-1, reduced the TNF-alpha-induced growth suppression and apoptosis in U937 cells. As the molecular mechanism involved, we showed Delta-1 stimulation partially suppressed the sequential activation of caspase-8, caspase-3, and, PARP induced by TNF-alpha. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK), p38, and NF-kappaB was not affected by Delta-1 stimulation. The cells needed to be exposed to Delta-1 prior to TNF-alpha stimulation to reduce the suppressive effect of TNF-alpha. Therefore, we thought that Delta-1 stimulation might reduce the expression of TNF-receptor (R) 1 and proteins to modulate the activation of caspases such as FLIP and XIAP. However, Delta-1 stimulation did not affect their expression. The precise mechanism by which Notch signaling suppresses caspase activation has yet to be determined. This is the first report to show the relationship between Notch activation and TNF-R1 signaling. The findings suggest possible mechanisms by which Notch activation supports cell survival.
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PMID:The Notch ligand, Delta-1, reduces TNF-alpha-induced growth suppression and apoptosis by decreasing activation of caspases in U937 cells. 1549 57

Increased generation of reactive oxygen species (ROS) and the subsequent DNA damage and excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in the pathogenesis of ischemic injury. We previously demonstrated that pharmacological inhibition of PARP protects against ischemic renal injury (IRI) in rats (Martin DR, Lewington AJ, Hammerman MR, and Padanilam BJ. Am J Physiol Regul Integr Comp Physiol 279: R1834-R1840, 2000). To further define the role of PARP-1 in IRI, we tested whether genetic ablation of PARP-1 attenuates tissue injury after renal ischemia. Twenty-four hours after reperfusion following 37 min of bilateral renal pedicle occlusion, the effects of the injury on renal functions in PARP-/- and PARP+/+ mice were assessed by determining glomerular filtration rate (GFR) and the plasma levels of creatinine. The levels of plasma creatinine were decreased and GFR was augmented in PARP-/- mice. Morphological evaluation of the kidney tissues showed that the extent of damage due to the injury in PARP-/- mice was less compared with their wild-type counterparts. The levels of ROS and DNA damage were comparable in the injured kidneys of PARP+/+ and PARP-/- mice. PARP activity was induced in ischemic kidneys of PARP+/+ mice at 6-24 h postinjury. At 6, 12, and 24 h after injury, ATP levels in the PARP+/+ mice kidney declined to 28, 26, and 43%, respectively, whereas it was preserved close to normal levels in PARP-/- mice. The inflammatory cascade was attenuated in PARP-/- mice as evidenced by decreased neutrophil infiltration and attenuated expression of inflammatory molecules such as TNF-alpha, IL-1beta, and intercellular adhesion molecule-1. At 12 h postinjury, no apoptotic cell death was observed in PARP-/- mice kidneys. However, by 24 h postinjury, a comparable number of cells underwent apoptosis in both PARP-/- and PARP+/+ mice kidneys. Thus activation of PARP post-IRI contributes to cell death most likely by ATP depletion and augmentation of the inflammatory cascade in the mouse model. PARP ablation preserved ATP levels, renal functions, and attenuated inflammatory response in the setting of IRI in the mouse model. PARP inhibition may have clinical efficacy in preventing the progression of acute renal failure complications.
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PMID:Poly(ADP-ribose) polymerase-1 gene ablation protects mice from ischemic renal injury. 1549 43

The proliferative and apoptotic response to TNF-alpha and anti-Fas antibody (CH-11) in human colon adenocarcinoma HT-29 cells was modulated by pretreatment with arachidonic (AA, 20:4, n-6) or docosahexaenoic (DHA, 22:6, n-3) fatty acids, which alone increased reactive oxygen species production and lipid peroxidation, and decreased the S-phase of the cell cycle. The higher amount of floating cells, subG0/G1 population and apoptotic cells detected in pre-treated cells was potentiated by cycloheximide. The effects of CH-11 were associated with activation of caspase-8, -9, and -3, cleavage of poly(ADP-ribose)polymerase-PARP, and decreased mitochondrial membrane potential (MMP), but these parameters were not significantly changed after PUFA pretreatment.
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PMID:Polyunsaturated fatty acids sensitize human colon adenocarcinoma HT-29 cells to death receptor-mediated apoptosis. 1563 38

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a critical role in endothelial cell dysfunction associated with various pathophysiological conditions. To elucidate PARP-1 pathways involved in endothelial cell dysfunction, it is essential to establish "in vitro" experimental models using isolated endothelial cells. So far, two approaches have been used: primary endothelial cells from PARP-1-/- mice which have a limited life-span, being a major handicap if large quantities of cells are required; and pharmacological inhibition of PARP in PARP-1+/+ endothelial cell lines, which is not specific for PARP-1 and would have biological effects different that genetic inhibition. To overcome these limitations, we have established an immortalized PARP-1-/- endothelial cell line (HYKO6) by transfection of primary cells with a plasmid containing the SV40 genome and selected on the basis of morphological and phenotypical features. The HYKO6 cell line exhibited endothelial characteristics, such as constitutive expression of CD105, CD31, ICAM-2, VCAM-1, and von Willebrand factor and formation of capillary-like structures (CLS) on Matrigel surface. However, expression of ICAM-1 antigen is lost in the HYKO6 cells. After TNF-alpha treatment, HYKO6 cells exhibited increased expression of E-selectin and VCAM-1. Likewise, NF-kappaB-dependent transcriptional activation was increased in the HYKO6 cell line in response to TNF-alpha at a level similar to that found for primary PARP-1-/- cells. This cell line should provide, for the first time, a valuable tool to study PARP-1 pathways in endothelial cell dysfunction.
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PMID:Establishment of an immortalized PARP-1-/- murine endothelial cell line: a new tool to study PARP-1 mediated endothelial cell dysfunction. 1569 77

Activated microglia contribute to cell death in ischemic and neurodegenerative disorders of the CNS. Microglial activation is regulated in part by NF-kappaB, and the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) enhances NF-kappaB binding to DNA. In this study, the role of PARP-1 in microglia-mediated neurotoxicity was assessed using microglia from wild-type (wt) and PARP-1-/- mice. Cultured microglia were incubated with TNF-alpha, a cytokine that is up-regulated in many neurological disorders. When stimulated with TNF-alpha, wt microglia proliferated, underwent morphological changes characteristic of activation, and killed neurons placed in coculture. The effects of TNF-alpha were markedly attenuated both in PARP-1-/- microglia and in wt microglia treated with the PARP enzymatic inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. These effects were also blocked by (E)-3-(4-methylphenylsulfonyl)-2-propenenenitrile, which inhibits translocation of NF-kappaB to the nucleus. TNF-alpha also up-regulated microglial release of matrix metalloproteinase-9 (MMP-9), an enzyme with potential neurotoxic properties that is transcriptionally regulated by NF-kappaB. This up-regulation was blocked in PARP-1-/- microglia and in wt microglia by the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone. Microglia from MMP-9-/- mice were used to evaluate the contribution of MMP-9 to microglial neurotoxicity. MMP-9-/- microglia treated with TNF-alpha showed substantially reduced neurotoxicity relative to the wt microglia. TNF-alpha-stimulated wt microglia treated with the MMP inhibitor ilomastat also showed reduced neurotoxicity. These findings suggest that PARP-1 activation is required for both TNF-alpha-induced microglial activation and the neurotoxicity resulting from TNF-alpha-induced MMP-9 release.
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PMID:Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. 1569 64


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