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)

The poor prognosis of glioblastoma multiforme and lack of effective therapy have necessitated the identification of new treatment strategies. We have previously reported that elevation of oxidative stress induces apoptosis of glioma cells. Because the farnesyltransferase inhibitor manumycin is known to induce reactive oxygen species (ROS) generation, we evaluated the effects of manumycin on glioma cells. Manumycin induced glioma cell apoptosis by elevating ROS generation. Treatment with the ROS inhibitor N-acetylcysteine blocked manumycin-induced apoptosis, caspase-3 activity, and PARP expression, indicating the involvement of increased ROS in the proapoptotic activity of manumycin. This heightened ROS level was accompanied by a concurrent decrease in antioxidants such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). SOD-1 overexpression protects glioma cells from manumycin-induced apoptosis. In addition, small interfering RNA-mediated knockdown of SOD-1 and TRX-1 expression also increased ROS generation and sensitivity of glioma cells to manumycin-induced cell death. Interestingly, suppressing ROS generation prevented manumycin-induced Ras inhibition. This study reports for the first time that Ras inhibition by manumycin is due to heightened ROS levels. We also report for the first time that manumycin inhibits the phosphorylation of signal transducer and activator of transcription 3 and telomerase activity in a ROS-dependent manner, which plays a crucial role in glioma resistance to apoptosis. In addition manumycin (i) induced the DNA-damage repair response, (ii) affected cell-cycle-regulatory molecules, and (iii) impaired the colony-forming ability of glioma cells in a ROS-dependent manner.
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PMID:Manumycin inhibits STAT3, telomerase activity, and growth of glioma cells by elevating intracellular reactive oxygen species generation. 1940 83

We reported previously that complete spinal cord transection (SCT) results in depression of mitochondrial respiratory chain enzyme activity that triggers apoptosis via sequential activations of apoptosis-inducing factor (AIF)- and caspase-dependent cascades in the injured spinal cord. This study tested the hypothesis that nitric oxide (NO) and superoxide anion (O(2)(.-)) serve as the interposing signals between SCT and impaired mitochondrial respiratory functions. Adult Sprague-Dawley rats manifested a significant increase in NO or O(2)(.-) level in the injured spinal cord during the first 3 days after SCT. The augmented O(2)(.-) production, along with concomitant reduction in mitochondrial respiratory chain enzyme activity or ATP level, nuclear translocation of AIF, cytosolic release of cytochrome c, and DNA fragmentation were reversed by osmotic minipump infusion of a NO trapping agent, carboxy-PTIO, or a superoxide dismutase mimetic, tempol, into the epicenter of the transected spinal cord. Intriguingly, carboxy-PTIO significantly suppressed upregulation of poly(ADP-ribose) polymerase-1 (PARP-1) in the nucleus, attenuated nuclear translocation of AIF, inhibited mitochondrial translocation of Bax and antagonized mitochondrial release of cytochrome c; whereas tempol only inhibited the later two cellular events after SCT. We conclude that overproduction of NO and O(2)(.-) in the injured spinal cord promulgates mitochondrial dysfunction and triggers AIF- and caspase-dependent apoptotic signaling cascades via differential upregulation of nuclear PARP-1 and mitochondrial translocation of Bax.
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PMID:Nitric oxide and superoxide anion differentially activate poly(ADP-ribose) polymerase-1 and Bax to induce nuclear translocation of apoptosis-inducing factor and mitochondrial release of cytochrome c after spinal cord injury. 1947 58

1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor kappaB (NF-kappaB) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappaB activity. A confocal microscope showed that emodin induced NF-kappaB translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER- and mitochondria-induced apoptosis of C6 cells.
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PMID:Emodin has cytotoxic and protective effects in rat C6 glioma cells: roles of Mdr1a and nuclear factor kappaB in cell survival. 1954 30

The antiproliferative effects of a Gingko biloba leaf extract to cells from tissues of the human oral cavity were studied. Toxicity to carcinoma HSC-2 cells was correlated with the prooxidative nature of the extract. G. biloba leaf extract generated reactive oxygen species (ROS) in cell culture medium and, albeit to a lesser extent, in buffer, with higher levels detected at alkaline pH. Lowered levels of ROS were detected in culture medium coamended with the extract and with either catalase or superoxide dismutase, indicating the generation of hydrogen peroxide and superoxide anion, respectively. Biological activity of the extract was through oxidative stress. Toxicity to the HSC-2 cells was lessened by the ROS scavengers, divalent cobalt and pyruvate, by catalase, and by the antioxidant, N-acetyl-L-cysteine, and was potentiated by the glutathione depleters, DL-buthionine-[S,R]-sulfoximine, 1-chloro-2,4-dinitrobenzene, and bis(2-chloroethyl)-N-nitrosourea. G. biloba reacted directly with authentic glutathione and lowered the intracellular glutathione content in HSC-2 cells. Induction of apoptosis upon exposure of HSC-2 cells to G. biloba extract was noted by apoptotic cell morphologies, by TUNEL staining, and by PARP cleavage. The data strongly suggest that the prooxidative nature of the G. biloba extract was the cause of apoptotic cell death.
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PMID:Gingko biloba leaf extract induces oxidative stress in carcinoma HSC-2 cells. 1956 May 34

The detrimental effects of persistent stimulation with hCG were investigated in rat Leydig cells in vitro. Significant rise in lipid peroxidation and reactive oxygen species (ROS) with concomitant attenuation in the activities of antioxidant enzymes: superoxide dismutase, catalase, and glutathione-S-transferase was observed. Transcripts for catalase and superoxide dismutase were also depleted. Subsequent to each hCG challenge, the total antioxidant capacity in the target cells also declined significantly (P < 0.05). There was an increase in cell apoptosis (23%), which was associated with a rise in caspase-3 activity, PARP cleavage, and Fas, FasL, caspase-8 expression. While Bax and Caspase-9 expression remained unchanged, Bcl-2 demonstrated a marked decline. Taken together, the above data indicate that persistent hCG stimulation of Leydig cells induced adverse effects leading to oxidative stress and apoptosis which was channeled primarily through the extrinsic pathway.
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PMID:Adverse effects associated with persistent stimulation of Leydig cells with hCG in vitro. 1957 91

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T(3)) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T(3) (100 microg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T(3)-4h) or 24-hour (groups C-24h and T(3)-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H(2)O(2)]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T(3)-treated group (4.63 +/- 1.9 vs 9.27 +/- 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H(2)O(2) (50.57 +/- 1.17 vs 71.16 +/- 1.14 micromol/100 g body weight). The T(3) treatment was associated with lower postischemia GSH concentrations (3.82 +/- 1.16 vs 4.89 +/- 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 +/- 0.86 vs 9.92 +/- 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P <or= .05). These findings suggested that preconditioning with T(3) reduced proteinuria, improved lipid peroxidation biomarkers, and increased antioxidant enzyme levels in renal I/R injury.
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PMID:Effect of preconditioning with triiodothyronine on renal ischemia/reperfusion injury and poly(ADP-ribose) polymerase expression in rats. 1971 35

CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety of cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with the induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-kappaB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase-1 (SOD-1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-kappaB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in the induction of apoptosis by CDDO-Me in prostate cancer cells.
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PMID:Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. 1978 51

The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST), the incidence of DNA damage, the activation of poly (ADP-ribose) polymerase-1 (PARP-1), a marker of DNA repair, and connective tissue growth factor (CTGF), a marker of tissue fibrosis, were examined in the hearts of rats for 16 weeks after diabetes induction by streptozotocin (STZ) administration. A 150% increase in CAT activity was detected at the end of the 2nd week post-STZ administration, and CAT activity remained 80% above the control level throughout 16 weeks. While total SOD and CuZn-SOD exhibited progressively decreasing activities, those of Mn-SOD and GST were elevated. Neither DNA strand breaks (apoptosis or necrosis) nor changes in PARP-1 activity and in CTGF levels (fibrosis) were observed in the diabetic heart. The absence of cardiomyopathy is accompanied with increased activities of CAT, MnSOD and GST.
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PMID:The absence of cardiomyopathy is accompanied by increased activities of CAT, MnSOD and GST in long-term diabetes in rats. 2042 35

The pro-oxidant hydrogen peroxide (H(2)O(2)) is converted to a reactive oxygen species by transition metals like iron. Since mutations in the p53 tumor suppressor gene contribute to drug resistance, we used genetically-matched human C8161 melanoma harbouring wt or DN-R175H mutant p53, to investigate the influence of p53 status on the potentiation of H(2)O(2) toxicity by: (a) intact sodium nitroprusside or nitroferricyanide (SNP), (b) its light-exhausted NO-depleted form (lex-SNP), (c) potassium ferricyanide, or (d) ferric ammonium sulphate. Whereas single treatments with SNP or H(2)O(2) were partly cytotoxic, preferentially potentiation of H(2)O(2) toxicity was evidenced with intact or lex-SNP. No comparable increase of H(2)O(2) toxicity was induced by ferricyanide, ferric ammonium sulphate or S-nitroso-N-acetyl penicillamine (SNAP), a known NO donor lacking iron. Immune blotting revealed apoptosis-associated PARP cleavage induced by [SNP+H(2)O(2)] irrespective of p53 status. This correlated with an eightfold induction of [Mn-SOD; SOD2] in wt p53 melanoma cells, and with a super-induction of the same enzyme reciprocal with loss of [Cu,Zn-SOD; SOD1], in mutant p53 cells. All these changes were antagonized by the anti-oxidant N-acetylcysteine or the iron chelator o-phenanthroline. We hypothesize that superoxide dismutase imbalance and iron-dependent redox changes involving OH species generated from a Fenton reaction between [SNP+H(2)O(2)], may be important in this anti-tumor activity. Although tumor drug resistance is frequently associated with DN-p53 mutations, our data shows for the first time the preferential ability of SNP to enhance H(2)O(2) toxicity, irrespective of p53 status.
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PMID:H(2)O(2) preferentially synergizes with nitroprusside to induce apoptosis associated with superoxide dismutase dysregulation in human melanoma irrespective of p53 status: Antagonism by o-phenanthroline. 2067 59

Adverse effects, nephrotoxicity and hepatotoxicity, of anticancer drugs such as cisplatin have limited the usage for cancer therapy. Therefore, development or identification of supplement agents in anticancer drugs is attractive to reduce side effects and enhance antitumor activity. Here, we found that decursin isolated from Angelica gigas showed protective effects of cisplatin-induced damage in normal human primary renal epithelial cells (HRCs). We found that decursin significantly blocked cisplatin-induced cytotoxicity by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in HRCs. Further, we found that decursin inhibited sub-G1 and cell death by suppression of cleavage of caspase-3, -9 and poly(ADP-ribose) polymerase (PARP) induced by cisplatin treatment in HRCs. Importantly, decursin effectively restored the activities of Cu/Zn superoxide dismutase (SOD), catalase and glutathione peroxidase in cisplatin-treated HRCs. Taken together, our findings demonstrate that decurcin prevents cisplatin-induced cytotoxicity and apoptosis through the activation of antioxidant enzymes in HRCs and suggest further that combination of decursin might suppressed adverse effects of anticancer drugs in cancer patients.
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PMID:Decursin prevents cisplatin-induced apoptosis via the enhancement of antioxidant enzymes in human renal epithelial cells. 2068 19


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