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)

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen species in tumor initiation and promotion. Caloric restriction (CR) or energy restriction retards age-associated increases in mitochondrial free-radical production and reduces the accumulation of oxidatively damaged cell components. CR has also been shown to slow down age-related declines in various repair capabilities, including some types of DNA repair. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the effects of CR in model systems. The objective is to lower mitochondrial free-radical production by decreasing the fraction of electron carriers in the reduced state. In addition to a variety of other effects, CR has been shown to increase the rate of apoptosis, particularly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular communication (GJIC). Tumor promoters like phorbol esters have the opposite effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a central role in apoptosis, in a manner that has been highly conserved in evolution. There is good evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would require the removal of this polymer from the endonuclease, and, most likely, its removal from topoisomerase II and histone H1 as well. The role of poly (ADP-ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol, etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1 beta converting enzyme (ICE)-like protease). Also, it would be of interest to determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors potentially important in these processes.
...
PMID:The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. 865 88

Recently, we demonstrated the hepatoprotective effects of nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) on mice suffering from acetaminophen (AAP)-hepatitis, suggesting that the AAP-induced liver injury involves a step which depends on adenoribosylation. The present study investigates the effects of a diet free of precursors of NAD, the substrate on which PARP acts, in female NMRI mice with AAP hepatitis and evaluates the influence of simultaneous ethanol consumption in these animals. Liver injuries were quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). While AAP caused a 117-fold elevation of serum transaminase activities in mice kept on a standard laboratory diet, which was significantly exacerbated by ethanol and inhibited by nicotinic acid amide (NAA), adverse effects were noted in animals fed a diet free of precursors of NAD. In these animals, only minor increases of serum transaminase activities were measured in the presence of AAP, and unlike the exacerbation caused by ethanol in mice on a standard diet, the liver damage was inhibited by 50% by ethanol. A further 64% reduction of hepatitis was observed, when NAA was given to ethanol/AAP-mice. Our results provide evidence that the AAP-induced hepatitis and its exacerbation by ethanol can either be reduced by end-product inhibition of PARP by NAA or by dietary depletion of the enzyme's substrate NAD. We see the main application of NAA as for the combinational use in pharmaceutical preparations of acetaminophen in order to avoid hepatic damage in patients treated with this widely used analgesic.
...
PMID:Influence of diet free of NAD-precursors on acetaminophen hepatotoxicity in mice. 874 98

ADP-ribosylation is a posttranslational protein modification catalyzed by two classes of enzymes: mono-ADP-ribosyltransferase and poly-ADP-ribose polymerases. We previously demonstrated that long-term alcohol intake remarkably enhanced an endogenous ADP-ribosylation of a 58 kDa protein in rat liver and also identified the 58 kDa protein as phosphoglucomutase (PGM). To assess biological significance of this phenomenon, we tested the effects of long-term alcohol intake on PGM activities in connection with posttranslational modification of the protein. ADP-ribosylation of PGM was mono- rather than poly-ADP-ribosylation. Also, nonenzymatic binding of ADP-ribose was excluded. It was of note that ADP-ribosylation of exogenous PGM was remarkably increased by adding rat liver plasma membranes, and that the extent of the increase was greater in alcohol-fed rats than in pair-fed controls. Furthermore, PGM activities were significantly increased after long-term alcohol intake concomitant with increased ADP-ribosyltransferase activities toward PGM. In view of the variety of roles of PGM in the liver, such as carbohydrate metabolism and Ca2+ homeostasis, it is tempting to speculate that increased ADP-ribosylation of PGM may play a role in long-term alcohol effects on hepatocytes.
Alcohol Clin Exp Res 1998 05
PMID:Long-term alcohol effects on hepatic phosphoglucomutase activities in relation to posttranslational modification of the protein. 962 87

Transient expression of the tumor suppressor gene p53 via adenoviral-mediated gene transfer induces apoptosis in glioma cells expressing mutant p53, while causing cell cycle arrest in cells with wild-type p53. To determine whether a change in p53 status of a wild-type p53-expressing cell line such as U-87 MG would alter its apoptotic resistant phenotype in response to Ad-p53 infection, we generated cell lines U-87-175.4 and U-87-175.13 via retroviral-mediated gene transfer of the p53 (175H) mutant into the U-87 MG parental line. Control cell lines U-87-Lux.6 and U-87-Lux.8 were also generated and express the reporter gene luciferase. Both U-87-175.4 and U-87-175.13, but not control cell lines, exhibited morphology characteristic of apoptosis after Ad-p53 infection. Furthermore, expression of other p53 mutants (248W, 273H) in U-87 MG also sensitized cells to Ad-p53-induced apoptosis. Apoptosis was confirmed by TUNEL and cell cycle analysis. Several p53 response genes were examined in cells infected with Ad-p53, and among these, BCL2, p21WAF1/CIP1, CPP32/caspase 3, and PARP showed differences in expression between U87-175 and U87-Lux cell lines. Taken together, our data demonstrate that the introduction of p53 mutants in U-87 MG promotes an apoptotic response in association with adenoviral-mediated wild-type p53 gene transfer. These results underscore the importance of glioma p53 genotype for predicting tumor response to p53-based gene therapy.
...
PMID:Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis. 1129 82

The poly(ADP-ribose) polymerase (PARP-1), a 113 kDa nuclear enzyme, is cleaved in fragments of 89 and 24 kDa during apoptosis. This cleavage has become a useful hallmark of apoptosis and has been shown to be done by DEVD-ase caspases, a family of proteases activated during apoptosis. Interestingly, PARP-1 is also processed during necrosis but a major fragment of 50 kDa is observed. This event is not inhibited by zVAD-fmk, a broad spectrum caspase inhibitor, suggesting that these proteases are not implicated in the necrotic cleavage of PARP-1. Since lysosomes release their content into the cytosol during necrosis, the proteases liberated could produce the cleavage of PARP-1. We therefore isolated lysosomal rich-fractions from Jurkat T cells. Our results reveal that the in vitro lysosomal proteolytic cleavage of affinity purified bovine PARP-1 is composed of fragments corresponding, in apparent molecular weight and function, to those found in Jurkat T cells treated with necrotic inducers like 0.1% H2O2, 10% EtOH or 100 microM HgCl2. Moreover, we used purified lysosomal proteases (cathepsins B, D and G) in an in vitro cleavage assay and found that cathepsins B and G cleaved PARP-1 in fragments also found with the lysosomal rich-fractions. These findings suggest that the necrotic cleavage of PARP-1 is caused in part or in totality by lysosomal proteases released during necrosis.
...
PMID:Characterization of the necrotic cleavage of poly(ADP-ribose) polymerase (PARP-1): implication of lysosomal proteases. 1153 9

Cnidii monnieri Fructus [CmF; Cnidium monnieri (L.) Cusson] is used as a tonic agent in traditional Chinese medicine. In a previous Chinese herb-cytotoxicity screening test, the ethanol extract of CmF exhibited strong effects on human leukemia (HL-60), cervical carcinoma (HeLa) and colorectal carcinoma (CoLo 205) cells. Then, the CmF extract was subjected to silica gel column chromatography and recrystallization to give five coumarins: osthol, imperatorin, bergapten, isopimpinellin, and xanthotoxin. Among these compounds, osthol showed the strongest cytotoxic activity on tumor cell lines. The structure-activity relationship established from the results indicated that the prenyl group has an important role in the cytotoxic effects. However, imperatorin showed the highest sensitivity to HL-60 cells and the least cytotoxicity to normal PBMCs. Osthol and imperatorin both caused apoptotic bodies, DNA fragmentation, and enhanced PARP degradation in HL-60 cells by biochemical analysis. These results indicate that osthol and imperatorin can induce apoptosis in HL-60 cells. Therefore, osthol and imperatorin are cytotoxic marker substances in the fruits of Cnidium monnieri.
...
PMID:Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines. 1475 23

Hepatic steatosis may have a generally benign prognosis, either because most hepatocytes are not significantly injured or mechanisms to replace damaged hepatocytes are induced. To determine the relative importance of these mechanisms, we compared hepatocyte damage and replication in ethanol-fed and ob/ob mice with very indolent fatty liver disease to that of healthy control mice and PARP-1(-/-) mice with targeted disruption of the DNA repair enzyme, poly(ADP-ribose) polymerase. Compared to the healthy controls, both groups with fatty livers had significantly higher serum alanine aminotransferase values, hepatic mitochondrial H(2)O(2) production, and hepatocyte oxidative DNA damage. A significantly smaller proportion of the hepatocytes from fatty livers entered S phase when cultured with mitogens. Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice. Hepatocytes from PARP1(-/-) mice also had more DNA damage and reduced DNA synthesis in response to mitogens. However, neither mice with fatty livers nor PARP-1-deficient mice had atrophic livers. All of the mice with senescent mature hepatocytes exhibited hepatic accumulation of liver progenitor (oval) cells and oval cell numbers increased with the demand for hepatocyte replacement. Therefore, although hepatic oxidant production and damage are generally increased in fatty livers, expansion of hepatic progenitor cell populations helps to compensate for the increased turnover of damaged mature hepatocytes. In conclusion, these results demonstrate that induction of mechanisms to replace damaged hepatocytes is important for limiting the progression of fatty liver disease.
...
PMID:Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease. 1476 93

Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), also termed as poly(ADP-ribose) synthetase, is a key enzyme in the recognition and repair of damaged DNA. Several conditions (e.g., ischemia-reperfusion or chemical-induced injury) have been shown to overactivate PARP-1, causing neurodegeneration and necrotic or apoptotic cell death from NAD+ and ATP depletion. In contrast, inhibitors of PARP-1 have been shown to have a neuroprotective effect by ameliorating this response. The purpose of this study was to determine the effects of three routinely used organic solvents (ethanol, methanol, and dimethyl sulfoxide (DMSO)) on the activity of purified PARP-1. A dose-response was examined with each of these solvents. A 112% and 82% increase in PARP-1 activity was observed with 15% ethanol and 20% methanol, respectively. In contrast, a near 20% decrease in the activity was observed with 4% DMSO. Kinetic analysis revealed that the maximal velocity remained unchanged with increasing concentrations of DMSO up to 20%, indicating that DMSO is a competitive inhibitor of PARP-1. Thus, PARP-1 inhibition by DMSO depends on NAD+ concentration and in some pathological processes might be significant even at low DMSO concentrations. Our findings suggest that the interpretation of data from dose-response studies obtained when using common organic solvents may be dramatically skewed, either exaggerating the inherent toxicity of the compound or masking its potential for damage.
...
PMID:The effects of organic solvents on poly(ADP-ribose) polymerase-1 activity: implications for neurotoxicity. 1558 63

Rigorous and systematic pre-clinical studies are necessary and essential to establish the efficacy and safety of Oriental herbs and formulas in order to transform traditional herbal practices into evidence-based medicine. Here we evaluated the anti-cancer activities of the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT), a formula of ten Oriental herbs, with a battery of in vitro and in vivo mechanism-based biomarkers involving angiogenesis, apoptosis and metastasis. The results show that KMKKT suppressed the vascular endothelial responses by inhibiting basic fibroblast growth factor (bFGF)-induced ERK1/2 phosphorylation, cell migration as well as tube formation in the human umbilical vein endothelial cell model, and decreased the hypoxia-induced HIF1alpha and vascular epithelial growth factor (VEGF) expression in the mouse Lewis lung carcinoma (LLC) cells in vitro, and inhibited the bFGF-induced angiogenesis in chick chorioallantoic membrane model, and in the Matrigel plugs in mice. Intraperitoneal delivery of KMKKT potently inhibited the growth of the subcutaneously inoculated LLC cells in syngenic mice. In addition, KMKKT inhibited the invasion ability of the mouse colon 26-L5 cancer cells in vitro and decreased their formation of liver metastasis when intraportally inoculated in syngenic mice. Furthermore, KMKKT suppressed the growth of the human PC-3 prostate cancer xenografts in athymic nude mice and averted the cancer-related body weight loss. The in vivo cancer growth suppression was associated with a decreased microvessel density and VEGF abundance as well as an increased PARP cleavage and the TUNEL-positive apoptosis. Together, our data support broad-spectra in vivo anti-cancer activities of KMKKT targeting angiogenesis, apoptosis and metastasis without any adverse effect on the body weight. This formula merits serious consideration for further evaluation for the chemoprevention and treatment of cancers of multiple organ sites.
...
PMID:An oriental herbal cocktail, ka-mi-kae-kyuk-tang, exerts anti-cancer activities by targeting angiogenesis, apoptosis and metastasis. 1677 83

Botanical preparations are widely used by patient with cancer in Korea, Japan and China. Rhus verniciflua Stokes (RVS) has traditionally been used as a medicinal ingredient for the therapy of stomach and uterine cancer. In this study, we showed that exposure to an ethanol extract of RVS (50 microg/ml) resulted in a synergistic inhibitory effect on cell growth in AGS cells. Growth inhibition was related with the inhibition of proliferation and induction of apoptosis. The extract induces G1-cell cycle arrest through the regulation of cyclins, the induction of p27Kip1, and decrease the CDK2 kinase activity. The upregulated p27Kip1 level is caused by protein stability increment by the reduction of Skp2, a key molecule related with p27Kip1 ubiquitination and degradation, and de novo protein synthesis. RVS extract induces apoptosis through the expression of Bax, poly(ADP-ribose) polymerase (PARP) and activation of caspase-3. RVS extract induces G1-cell cycle arrest via accumulation of p27Kip1 controlled by Skp2 reduction and apoptosis passing through an intrinsic pathway in human gastric cancer cells but not in normal cells, therefore we suggest that this extract could be a candidate medicine or compound for the development of novel class of anti-cancer drugs.
...
PMID:Inhibition of cell cycle progression via p27Kip1 upregulation and apoptosis induction by an ethanol extract of Rhus verniciflua Stokes in AGS gastric cancer cells. 1678 74


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

---