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)

The effects of the hyperforin (HF), a natural phloroglucinol purified from Hypericum perforatum, were investigated ex vivo on leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL). HF was found to promote apoptosis of B-CLL cells, as shown by time- and dose-dependent stimulation of phosphatidylserine externalization and DNA fragmentation, by disruption of the mitochondrial transmembrane potential, caspase-3 activation and cleavage of the caspase substrate PARP-1. Moreover, HF-induced downregulation of Bcl-2 and Mcl-1, two antiapoptotic proteins that control mitochondrial permeability. HF also downregulated two proteins which are overexpressed by B-CLL patients' cells, the cell cycle inhibitor p27kip1 through caspase-dependent cleavage into a p23 form, and the nitric oxid (NO) synthase of type 2 (inducible NO synthase). This latter was accompanied by reduction in the production of NO known to be antiapoptotic in B-CLL cells. Preventing effects of the general caspase inhibitor z-VAD-fmk indicated that HF-promoted apoptosis of B-CLL cells was mostly caspase dependent. Furthermore, normal B lymphocytes purified from healthy donors appeared less sensitive to HF-induced apoptosis than B-CLL cells. These results indicate that HF may be of interest in the development of new therapies for B-CLL based on the induction of apoptosis and combination with cell cycle-dependent antitumor drugs.
...
PMID:Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia. 1642 68

There is accumulating evidence implicating the involvement of nitric oxide (NO) in spinal central sensitization. The long-term potentiation (LTP) of spinal C-fiber-evoked field potentials is considered as a fundamental mechanism of sensitization of nociceptive neurons in the spinal cord. The present study examined the roles of soluble guanylate cyclase (sGC) or ADP-ribosyltransferase (ADPRT), two potential NO targets, in spinal LTP. The results showed that (1) administration of sGC inhibitors, methyl blue (MB, 4mM, 20 microl) or 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one (ODQ, 10 microM, 20 microl) before tetanic stimulation, significantly inhibited the induction of spinal LTP, and this was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog. However, the maintenance of spinal LTP was not changed when application of ODQ 2h after tetanic stimulation. (2) Although our previous experiments have identified a key role for NO in the induction of spinal LTP, NO synthase (NOS) inhibitor, L-NAME (1mM, 20 microl) or hemoglobin (2mg/ml, 20 microl), a scavenger of NO, had no effect on established spinal LTP when applied 2h after the induction of spinal LTP. (3) The mono-ADPRT inhibitor, nicotinamide (10mM, 20 microl), had no effect on the induction and maintenance of spinal LTP. However, the poly-ADPRT inhibitor, benzamide (100 microM, 20 microl), inhibited its maintenance, but not its induction. The results suggest that NO-stimulated guanylyl cyclase activity plays a critical role in the induction of LTP of C-fiber-evoked field potentials in the spinal cord, whereas NO-related poly-ADPRT activity contributes to the maintenance of spinal LTP.
...
PMID:Different roles of two nitric oxide activated pathways in spinal long-term potentiation of C-fiber-evoked field potentials. 1642 64

Nitric oxide (NO) participates in a variety of physiologic and pathophysiologic processes in diverse tissues, including the kidney. Although mechanisms for cytokine induction of inducible nitric-oxide synthase (iNOS) have been increasingly clarified, the controls for termination of NO production remain unclear. Because excessive NO production can be cytotoxic to host cells, feedback inhibition of iNOS transcription would represent a means of cytoprotection. Many of the cGMP-independent functions of NO are mediated by S-nitrosylation of cysteine thiols of target proteins. We hypothesized that NO-mediated S-nitrosylation of transcription factors might serve to feedback inhibit their trans-activation potential and deactivate iNOS gene transcription. Transient transfection of murine mesangial cells with iNOS promoter deletion-luciferase constructs revealed the region -915 to -849 to be NO sensitive with respect to IL-1beta-induced promoter activity. In vitro DNase I footprinting identified a footprint at -865/-842 in the absence of NO, but not in the presence of endogenous or exogenously delivered NO. Southwestern blotting using this probe coupled with partial peptide sequencing of the protein bands revealed that poly(ADP-ribose) polymerase isoform 1 (PARP-1) bound the probe in a sequence-specific manner. Gel shift/supershift experiments and chromatin immunoprecipitation assay analysis confirmed this binding in vitro and in vivo. Functionally, mutation of the -859/-850 site to prevent PARP-1 binding or PARP-1 knockdown by RNA interference relieved the inhibitory effects of NO on iNOS promoter activity. Biotin-switch assays and co-immunoprecipitation with an anti-nitrocysteine antibody indicated that PARP-1 was S-nitrosylated. We conclude that NO feedback inhibits iNOS gene transcription by S-nitrosylating the trans-activator PARP-1 and decreasing its binding and/or action at the iNOS promoter.
...
PMID:Nitric oxide-dependent negative feedback of PARP-1 trans-activation of the inducible nitric-oxide synthase gene. 1646 59

Human umbilical vein endothelial cells (HUVECs) undergo apoptosis in response to serum deprivation. We show that the nonspecific mineralocorticoid receptor antagonist, spironolactone, protects from caspase-3 activation induced by serum deprivation in contrast to the selective mineralocorticoid receptor antagonist, eplerenone, that is nonprotective. We also demonstrate that progesterone, hydrocortisone, and dexamethasone all protect HUVECs from serum-deprivation-induced caspase-3 activation, whereas aldosterone and dihydrotestosterone have no effect. Spironolactone has been demonstrated to display agonist activity only to the progesterone receptor (PR), and we additionally show that spironolactone and progesterone, but not eplerenone, inhibit mitochondrial cytochrome c release and cleavage of nuclear poly (ADP-ribose) polymerase (PARP) and increase cell viability. Additionally, the PR antagonist mifepristone (RU486) partially blocked the inhibitory effect of both spironolactone and progesterone on caspase-3 activation, cytochrome c release, and nuclear PARP cleavage. Nitric oxide (NO) protects HUVECs from apoptosis in response to various stimuli including serum-deprivation; however, the NO synthase inhibitor N-monomethyl-l-arginine, did not abolish inhibition of caspase-3 activation or PARP cleavage by spironolactone. Thus, we demonstrate that spironolactone protects HUVECs from serum-deprivation-induced apoptosis by inhibition of caspase-3 activity, cytochrome c release and PARP cleavage by a NO-independent mechanism; further, this effect is likely mediated by the agonist properties of spironolactone toward the PR.
...
PMID:Protective effect of spironolactone on endothelial cell apoptosis. 1649 8

Following stimulation of NMDA receptors, neurons transiently synthesize nitric oxide (NO) in a calcium/calmodulin-dependent manner through the activation of neuronal NO synthase. Nitric oxide acts as a messenger, activating soluble guanylyl cyclase and participating in the transduction signalling pathways involving cyclic GMP. Nitric oxide also binds to cytochrome c oxidase, and is able to inhibit cell respiration in a process that is reversible and in competition with oxygen. This action can also lead to the release of superoxide anion from the mitochondrial respiratory chain. Here, we discuss recent evidence that this mitochondrial interaction represents a molecular switch for cell signalling pathways involved in the control of physiological functions. These include superoxide- or oxygen-dependent modulation of gene transcription, calcium-dependent cell signalling responses, changes in the mitochondrial membrane potential or AMP-activated protein kinase-dependent control of glycolysis. In pathophysiological conditions, such as brain ischaemia or neurological disorders, NO is formed excessively by NMDA receptor over-activation in neurons, or by inducible NO synthase from neighbouring glia (microglial cells and astrocytes). Elevated NO concentrations can then interact with superoxide anion, generated by the mitochondria or by other mechanisms, leading to the formation of the powerful oxidant species peroxynitrite. During pathological conditions activation of the NAD(+)-consuming enzyme poly(APD-ribose) polymerase-1 (PARP-1) is also a likely mechanism for NO-mediated energy failure and neurotoxicity. Activation of PARP-1 is, however, a repair process, which in milder forms of oxidative stress protects neurons from death. Thus, whilst NO plays a physiological role in neuronal cell signalling, its over-production may cause neuronal energy compromise leading to neurodegeneration.
...
PMID:Nitric oxide, cell bioenergetics and neurodegeneration. 1680 76

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

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that, once activated by genotoxic agents, modulates the activity of several nuclear proteins including itself. Previous studies have established that PARP-1 inhibition may provide benefit in the treatment of different diseases, particularly those involving a hypoxic situation, in which an increased oxidative and nitrosative stress occurs. One of the most important transcription factors involved in the response to the hypoxic situation is the hypoxia-inducible factor-1 (HIF-1). The activity of HIF-1 is determined by the accumulation of its alpha subunit which is regulated, in part, by oxidative stress (ROS) and nitric oxide (NO), both of them highly dependent on PARP-1. Besides, HIF-1alpha can be induced by iron chelators such as deferoxamine (DFO). In this sense, the therapeutical use of DFO to strengthen the post-hypoxic response has recently been proposed. Taking into account the increasing interest and potential clinical applications of PARP inhibition and DFO treatment, we have evaluated the impact of PARP-1 on HIF-1alpha accumulation induced by treatment with DFO. Our results show that, in DFO treated cells, PARP-1 gene deletion or inhibition decreases HIF-1alpha accumulation. This lower HIF-1alpha stabilization is parallel to a decreased inducible NO synthase induction and NO production, a higher response of some antioxidant enzymes (particularly glutathione peroxidase and glutathione reductase) and a lower ROS level. Taken together, these results suggest that the absence of PARP-1 modulates HIF-1 accumulation by reducing both NO and oxidative stress.
...
PMID:PARP-1 modulates deferoxamine-induced HIF-1alpha accumulation through the regulation of nitric oxide and oxidative stress. 1845 42

Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3-phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
...
PMID:Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. 1921 Jul 48

Icariside II (IS) isolated from the roots of Epimedium koreanum Nakai was known to have antioxidant activity and inhibit melanogenesis and hypoxia inducible factor. We report here for the first time that IS induces apoptosis through its anti-inflammatory effects in PC-3 prostate cancer cells. IS exerted cytotoxicity against PC-3 cells with IC(50) of approximately 20 microM. IS suppressed both constitutive and arachidonic acid (AA)-induced cyclooxygenase-2 (COX-2) expression as well as reduced prostaglandin E2 (PGE2) levels in PC-3 cells even at a low concentrations (5 and 10 microM). Additionally, IS increased sub G1 apoptotic portion and exhibited terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL)-positive apoptotic bodies in PC-3 cells at higher concentrations (20 and 40 microM). Furthermore, IS attenuated the mitochondrial membrane potential, released cytochrome C into cytosol, activated caspase-9, -8, and -3 expressions and cleaved poly (ADP-ribose) polymerase (PARP) in PC-3 cells. Consistently, COX-2, inducible NO synthase (iNOS), and vascular endothelial growth factor (VEGF) expressions were suppressed while in parallel inducing apoptosis in hormone-independent prostate carcinoma cells PC-3. Moreover, exogeneous PGE2 inhibited IS induced PARP cleavage in PC-3 cells and also knockdown of COX-2 by siRNA potentiated IS induced PARP cleavage, thereby implicating the critical role of COX-2 pathway in IS induced apoptosis. Taken together, these findings demonstrate that IS initiates the inhibition of COX-2/PGE(2) pathway and then induces apoptosis mainly via mitochondrial dependent pathway in PC-3 prostate cancer cells as a potent cancer chemotherapeutic agent.
...
PMID:Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells. 1928 54

The role of NF-kappaB in the expression of inflammatory genes and its participation in the overall inflammatory process of chronic diseases and acute tissue injury are well established. We and others have demonstrated a critical involvement of poly(ADP-ribose) polymerase (PARP)-1 during inflammation, in part, through its relationship with NF-kappaB. However, the mechanism by which PARP-1 affects NF-kappaB activation has been elusive. In this study, we show that PARP-1 inhibition by gene knockout, knockdown, or pharmacologic blockade prevented p65 NF-kappaB nuclear translocation in smooth muscle cells upon TLR4 stimulation, NF-kappaB DNA-binding activity, and subsequent inducible NO synthase and ICAM-1 expression. Such defects were reversed by reconstitution of PARP-1 expression. PARP-1 was dispensable for LPS-induced IkappaBalpha phosphorylation and subsequent degradation but was required for p65 NF-kappaB phosphorylation. A perinuclear p65 NF-kappaB localization in LPS-treated PARP-1(-/-) cells was associated with an export rather an import defect. Indeed, whereas PARP-1 deficiency did not alter expression of importin alpha3 and importin alpha4 and their cytosolic localization, the cytosolic levels of exportin (Crm)-1 were increased. Crm1 inhibition promoted p65 NF-kappaB nuclear accumulation as well as reversed LPS-induced p65 NF-kappaB phosphorylation and inducible NO synthase and ICAM-1 expression. Interestingly, p65 NF-kappaB poly(ADP-ribosyl)ation decreased its interaction with Crm1 in vitro. Pharmacologic inhibition of PARP-1 increased p65 NF-kappaB-Crm1 interaction in LPS-treated smooth muscle cells. These results suggest that p65 NF-kappaB poly(ADP-ribosyl)ation may be a critical determinant for the interaction with Crm1 and its nuclear retention upon TLR4 stimulation. These results provide novel insights into the mechanism by which PARP-1 promotes NF-kappaB nuclear retention, which ultimately can influence NF-kappaB-dependent gene regulation.
...
PMID:Poly(ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation. 2061 Jun 52


<< Previous 1 2 3 4 5 Next >>

---