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)

Using in vitro model for studying the induction and inhibition of spontaneous apoptosis in human first trimester placental villi, mediated by the free radical scavenger SOD, we have examined the expression of bcl-xL, bax, Caspase-3 and PARP (Poly ADP-ribosyl). An increase in apoptosis was associated with activation of PARP and an increase and activation of Caspase-3. There was no significant change in bcl-x or bax. Therefore bcl-x and bax do not appear to have a significant role in apoptosis in the first trimester in vitro. Cleavage of Caspase-3 rather than transcriptional regulation appears to be the main determinant of Caspase-3 activity in first trimester placental villi.
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PMID:The expression of apoptosis related genes in the first trimester human placenta using a short term in vitro model. 1571 29

Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3-kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3beta-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3beta inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3beta inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3beta. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3beta and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3beta-mediated cell death mechanism is important in G93A and A4V cell death.
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PMID:Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. 1604 83

Activation of both poly (ADP-ribose) polymerase (PARP) and inducible nitric oxide synthase (NOS-2) have been implicated in the pathogenesis of various forms of inflammation, therefore compounds which may simultaneously inhibit both pathways are of potential therapeutic interest. We tested the influence of potent inhibitor of PARP, 1, 5-isoquinolinediol (ISO), on NOS-2 induction in model of mouse macrophages (cell line J774.2) stimulated with lipopolysaccharide (1 microg/ml). Pretreatment with ISO (1-300 microM) resulted in dose-dependent inhibition of accumulation of NOS-2-derived nitrite in culture medium (IC(50) = 9,3 microM) as well as inhibition of NOS-2 protein induction in cultured J774.2 cells; ISO given 10 hours after LPS did not influence activity of NOS-2. Interestingly, another PARP inhibitor, 3-aminobenzamide (3-AB, 10-3000 microM), did not influence 24-hr nitrite accumulation in J774.2 cell culture, either administered 15 minutes prior to LPS or 10 hrs after LPS. Scavenging of reactive oxygen species by use of mixture of SOD and catalase (SOD/Cat, 100/300 - 1000/3000 U/ml) as well as cell permeable SOD-mimetic [Mn(III)TBAP, 1- 100 microM], did not influence NOS-2 induction in J774.2 cells. In summary, we identified 1, 5-isoquinoline as potent inhibitor of induction of NOS-2 in LPS-treated mouse macrophages. The exact mechanism of inhibitory action of this compound on NOS-2 induction requires further investigation.
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PMID:Inhibition of NOS-2 induction in LPS-stimulated J774.2 cells by 1, 5-isoquinolinediol, an inhibitor of PARP. 1660 19

This study was aimed to examine the effects of homocysteine (Hcy) on vascular responsiveness of guinea-pig isolated pulmonary arteries and to investigate possible underlying mechanisms. In order to evaluate vascular reactivity, isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). Incubation of pulmonary artery rings with Hcy (10(-3)M, 180min) resulted in significant inhibition of response to ACh (an endothelium-dependent vasodilator)(E(max): 55.3+/-6.7 vs. 13.1+/-2.0(*), P<0.05) while SNP (an endothelium-independent vasodilator)-induced relaxation was not changed significantly. Furthermore, Hcy enhanced KCl- and Phe-induced contraction of pulmonary artery rings (E(max): 1568+/-81 vs. 2101+/-145(*)mg for KCl and 1081+/-101 vs. 1544+/-117(*)mg for Phe, P<0.05). Pulmonary artery ring contractions induced by stepwise addition to Ca(2+) to high KCl solution with no Ca(2+) were also significantly augmented by Hcy incubation (E(max): 1750+/-121 vs. 2295+/-134(*)mg, P<0.05). To investigate mechanisms of Hcy action, additional sets of experiments involving rings incubation with Hcy alone or with addition of Tiron (an intracellular superoxide anion scavenger, 10(-2)M), PJ34 (an inhibitor of polyADP-ribose polymerase, 3x10(-6)M), and combination of two antioxidant enzymes superoxide dismutase (SOD, 100U/ml) and catalase (CAT, 120U/ml) for 180min. The findings of our study clearly show that all these co-treatments significantly prevented the development of endothelial dysfunction induced by Hcy. Furthermore, the effect of Hcy on KCl- and Phe-induced contraction was significantly inhibited by the concomitant incubation with either SOD plus CAT, Tiron or PJ34. This study demonstrates that Hcy causes a significant alteration in vascular reactivity of pulmonary arteries, and this alteration seems to be via oxidative stress in pulmonary artery endothelium with subsequent DNA damage and activation of poly(ADP-ribose) polymerase (PARP) pathway.
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PMID:Homocysteine-induced changes in vascular reactivity of guinea-pig pulmonary arteries: role of the oxidative stress and poly (ADP-ribose) polymerase activation. 1662 37

Pyrogallol as a catechin compound has been employed as an O(2)(*-) generator and often used to investigate the role of ROS in the biological system. Here, we investigated the in vitro effect of pyrogallol on cell growth, cell cycle and apoptosis in As4.1 juxtaglomerular cells. Dose-dependent inhibition of cell growth was observed with IC(50) of about 60 microM for 48 h using MTT assay. Pyrogallol (100 microM) did not alter intracellular H(2)O(2) level and catalase activity, but increased the intracellular O(2)(-) level and decreased SOD activity in As4.1 cells. DNA flow cytometric analysis indicated that 50 and 100 microM pyrogallol significantly increased G2 phase cells as compared with those of pyrogallol-untreated cells. Also, pyrogallol induced apoptosis as evidenced by flow cytometric detection of sub-G1 DNA content, annexin V binding assay and DAPI staining. This apoptosis process was accompanied with the loss of mitochondrial transmembrane potential (DeltaPsi(m)), Bcl-2 decrease, caspase-3 activation and PARP cleavage. Pan caspase inhibitor (Z-VAD) could significantly rescue As4.1 cells from pyrogallol-induced cell death. But, the inhibitors of caspase-3, caspase-8, and caspase-9 did not prevent apoptotic events in pyrogallol-treated As4.1 cells. Taken together, we have demonstrated that an ROS inducer, pyrogallol inhibits the growth of As4.1 JG cells via cell cycle arrest and apoptosis, and suggest that the compound exhibits an anti-proliferative efficacy on these cells.
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PMID:Pyrogallol, ROS generator inhibits As4.1 juxtaglomerular cells via cell cycle arrest of G2 phase and apoptosis. 1744 75

We have previously shown that intrastriatal injection of Delta RR, the growth-compromised herpes simplex virus type 2 (HSV-2) vector for the antiapoptotic protein ICP10PK, prevents apoptosis caused by the excitotoxin N-methyl-D-aspartate (NMDA) in a mouse model of glutamatergic neuronal cell death (Golembewski et al. [2007] Exp. Neurol. 203:381-393). Because apoptosis regulation is stimulus and cell type specific, our studies were designed to examine the mechanism of Delta RR-mediated neuroprotection in striatal neurons. Organotypic striatal cultures (OSC) that retain much of the synaptic circuitry of the intact striatum were infected with Delta RR or a growth-compromised HSV-2 vector that lacks ICP10PK (Delta PK) and examined for neuroprotection-associated signaling. The mutated ICP10 proteins (p175 and p95) were expressed in 70-80% of neurons from Delta RR- and Delta PK-infected cultures, respectively, as determined by double-immunofluorescent staining with antibodies to ICP10 and NeuN or GAD65. Delta RR- but not Delta PK-treated OSC were protected from NMDA-induced apoptosis, as verified by ethidium homodimer staining, TUNEL, caspase-3 activation, and poly(AD-ribose) polymerase (PARP) cleavage. Neuroprotection was through ICP10PK-mediated activation of the survival pathways MEK/ERK and PI3-K/Akt, up-regulation of the antiapoptotic proteins Bag-1 and Bcl-2, and phosphorylation (inactivation) of the proapoptotic protein Bad. It was blocked by the MEK inhibitor U0126 or the PI3-K inhibitor LY294002, suggesting that either pathway can prevent NMDA-induced apoptosis. The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death.
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PMID:Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades. 1789 11

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme with multiple cellular functions, including DNA repair, transcriptional regulation, and cell signaling. PARP-1 has a modular architecture with six independent domains comprising the 113-kDa polypeptide. Two zinc finger domains at the N terminus of PARP-1 bind to DNA and thereby activate the catalytic domain situated at the C terminus of the enzyme. The tight coupling of DNA binding and catalytic activities is critical to the cellular regulation of PARP-1 function; however, the mechanism for coordinating these activities remains an unsolved problem. Here, we demonstrate using spectroscopic and crystallographic analysis that human PARP-1 has a third zinc-binding domain. Biochemical mutagenesis and deletion analysis indicate that this region mediates interdomain contacts important for DNA-dependent enzyme activation. The crystal structure of the third zinc-binding domain reveals a zinc ribbon fold and suggests conserved residues that could form interdomain contacts. The new zinc-binding domain self-associates in the crystal lattice to form a homodimer with a head-totail arrangement. The structure of the homodimer provides a scaffold for assembling the activated state of PARP-1 and suggests a mechanism for coupling the DNA binding and catalytic functions of PARP-1.
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PMID:A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation. 1805 53

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.
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PMID:Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. 1843 68

Our previous studies have shown that bee venom (BV) can induce apoptosis in human cervical cancer Ca Ski cells, but it can also affect human breast cancer cells, though its molecular mechanisms are not precisely known. In this study, the molecular mechanisms of apoptosis induced by BV in human breast cancer MCF7 cells were investigated. BV induced morphological changes (examined by phase-contrast microscopy) and inhibited the proliferation (examined by MTT assay) of MCF7 cells; both effects occurred in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BV induced the production of reactive oxygen species (ROS) and dysfunction of the mitochondrial membrane potential (Azm), and led to cytochrome c release, an increase in the levels of caspase-9 and Poly (ADP-ribose) polymerase (PARP) and then apoptosis. It also showed that BV induced S-phase arrest in MCF7 cells which may occur through the promotion of p53, p21, p27 and the exhibition of Cdk2. Western blotting demonstrated that BV reduced Bcl-2 and increased Bax protein levels which may have caused the changes of delta psi m. BV treatment led to ROS production up to but after treatment led to a decrease in the levels of ROS, which may be associated with the observations of BVaffecting glutathion S-transferase (GST), Zn-superoxide dismutase (Zn-SOD), Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and catalase. The Comet assay also showed that BV induced DNA damage while DAPI staining also confirmed that BV induced apoptosis in examined MCF7 cells. Our results also showed that BV increased the levels of AIF and EndoG in MCF7 cells. In conclusion, our data demonstrated that BV induced apoptosis via a mitochondria-dependent pathway based on the changes of delta psi m, AIF and EndoG release in MCF7 cells.
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PMID:The role of mitochondria in bee venom-induced apoptosis in human breast cancer MCF7 cells. 1846 9

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Some nutritional factors (zinc, niacin, selenium) may remodel these changes leading to a possible escaping of diseases, with the consequence of healthy ageing, because they are involved in improving immune functions, metabolic homeostasis and antioxidant defence. Experiments performed "in vitro" (human lymphocytes exposed to endotoxins) and "in vivo" (old mice or young mice with low zinc dietary intake) show that zinc is important for immune efficiency (both innate and adaptive), metabolic homeostasis (energy utilization and hormone turnover) and antioxidant activity (SOD enzyme). Niacin is a precursor of NAD+, the substrate for the activity of DNA repair enzyme PARP-1 and, consequently, may contribute to maintaining genomic stability. Selenium provokes zinc release by Metallothioneins (MT), via reduction of glutathione peroxidase. This fact is crucial in ageing because high MT may be unable to release zinc with subsequent low intracellular free zinc ion availability for immune efficiency, metabolic harmony and antioxidant activity. Taking into account the existence of zinc transporters (ZnT and ZIP family) for cellular zinc efflux and influx, respectively, the association between zinc transporters and MT is crucial in maintaining satisfactory intracellular zinc homeostasis in ageing. Improved immune performance, metabolic homeostasis, antioxidant defence occur in elderly after physiological zinc supplementation, which also induces prolonged survival in old, nude and neonatal thymectomized mice. The association "zinc plus selenium" improves humoral immunity in old subjects after influenza vaccination. The association "zinc plus niacin" in elderly is actually in progress.
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PMID:Zinc, metallothioneins and longevity: interrelationships with niacin and selenium. 1899 91


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