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)

In this study, the protective effects of water extracts from pine needle (WEPN) against DNA damage and apoptosis induced by hydroxyl radical were investigated in non-cellular and cellular system. WEPN exhibited strong scavenging action on hydroxyl radical and intracellular ROS, and chelating action of Fe(2+) ion. WEPN inhibited oxidative DNA damage by hydroxyl radical. Also, WEPN prevented the cells from oxidative damage through lowering p21 and BAX protein expression, blocking the cleavage of PARP and increasing Bcl-2 protein, which was confirmed by Hoechst 33342 staining. These data indicate that WEPN possesses a spectrum of antioxidant and DNA-protective properties common to cancer chemopreventive agents.
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PMID:Effect of extracts from pine needle against oxidative DNA damage and apoptosis induced by hydroxyl radical via antioxidant activity. 1950 Jun 37

The root of Panax notoginseng is highly valued and commonly used in Oriental medicine. Although recent experimental data have revealed the proapoptotic potency of P. notoginseng extracts, the underlying molecular mechanisms of this apoptotic activity have not yet been studied in detail. In the present study, the effects of the water extract of P. notoginseng (WEPN) on the growth of human lung carcinoma cells were investigated. It was found that the exposure of A549 and NIC-H460 cells to WEPN resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. The WEPN treatment induced the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 expression and loss of mitochondrial membrane potential (MMP), which was associated with the proteolytic activation of caspases and the concomitant degradation of poly(ADP ribose) polymerase (PARP) protein. However, the caspase-3-specific inhibitor z-DEVD-fmk blocked PARP degradation and increased the survival rate of WEPN-treated cells. Moreover, the activity of Akt was downregulated in WEPN-treated cells and the phosphatidylinositol-3 kinase (PI3K)/Akt inhibitor LY294002 sensitized the cells to WEPN-induced apoptosis through enhancing the activation of caspase-3 and loss of MMP. The results indicated that the major regulators of WEPN-induced apoptosis in human lung carcinoma cells are the Bcl-2 family and caspase-3, which are associated with mitochondrial dysfunction and dephosphorylation of the Akt signaling pathway.
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PMID:Induction of apoptosis in human lung carcinoma cells by the water extract of Panax notoginseng is associated with the activation of caspase-3 through downregulation of Akt. 1951 59

The purpose of this study was to evaluate the effects of the water extract of Samultang (SMT), a Chinese herb, on apoptotic cell death by H(2)O(2)-induced oxidative stress in SK-N-MC cells. A nuclear fragmentation was observed via fluorescence imaging 12 h after exposure to 30 microM H(2)O(2) and DNA laddering was detected via agarose electrophoresis gel. In addition, increases in sub-G1 phase and cleavage of the PARP protein were observed. However, treatment with SMT for 2 h prior to H(2)O(2) exposure significantly reduced apoptotic cell death induced by incubation with 30 microM H(2)O(2) in SK-N-MC cells. Pre-incubation with water extract of SMT for 2 h prevented the H(2)O(2)-induced decrease in mitochondrial transmembrane potential. SMT also attenuated the increase in caspase-3 activity and the breakdown of PARP protein caused by H(2)O(2)-induced oxidative stress. These results suggest that the water extract of SMT provides inhibition of apoptotic cell death against oxidative injury in SK-N-MC cells.
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PMID:Water extract of samultang reduces apoptotic cell death by h(2)o(2)-induced oxidative injury in sk-N-mc cells. 1988 29

Constitutive activation of phosphoinositide 3-kinase (PI3K)-Akt pathway transmits growth-regulatory signals that play a central role in promoting survival, proliferation, and angiogenesis in human prostate cancer cells. Here, we assessed the efficacy of inositol hexaphosphate (IP6) against invasive human prostate cancer PC-3 and C4-2B cells and regulation of PI3K-Akt pathway. IP6 treatment of cells suppressed proliferation, induced apoptosis along with caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and inhibited constitutive activation of Akt and its upstream regulators PI3K, phosphoinositide-dependent kinase-1 and integrin-linked kinase-1 (ILK1). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3alpha/beta at Ser(21/9) and consequently reduced cyclin D1 expression. Efficacy studies employing PC-3 tumor xenograft growth in nude mice showed that 2% (w/v) IP6 feeding in drinking water inhibits tumor growth and weight by 52% to 59% (P < 0.001). Immunohistochemical analysis of xenografts showed that IP6 significantly reduces the expression of molecules associated with cell survival/proliferation (ILK1, phosphorylated Akt, cyclin D1, and proliferating cell nuclear antigen) and angiogenesis (platelet endothelial cell adhesion molecule-1 or CD31, vascular endothelial growth factor, endothelial nitric oxide synthase, and hypoxia-inducible factor-1alpha) together with an increase in apoptotic markers (cleaved caspase-3 and PARP). These findings suggest that, by targeting the PI3K-ILK1-Akt pathway, IP6 suppresses cell survival, proliferation, and angiogenesis but induces death in prostate cancer cells, which might have translational potential in preventing and controlling the growth of advanced and aggressive prostate cancer for which conventional chemotherapy is not effective.
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PMID:Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. 1992 Jan 84

Arsenite is an environmental pollutant. Exposure to inorganic arsenic in drinking water is associated with elevated cancer risk, especially in skin. Arsenite alone does not cause skin cancer in animals, but arsenite can enhance the carcinogenicity of solar UV. Arsenite is not a significant mutagen at non-toxic concentrations, but it enhances the mutagenicity of other carcinogens. The tumor suppressor protein P53 and nuclear enzyme PARP-1 are both key players in DNA damage response. This laboratory demonstrated earlier that in cells treated with arsenite, the P53-dependent increase in p21(WAF1/CIP1) expression, normally a block to cell cycle progression after DNA damage, is deficient. Here we show that although long-term exposure of human keratinocytes (HaCaT) to a nontoxic concentration (0.1 microM) of arsenite decreases the level of global protein poly(ADP-ribosyl)ation, it increases poly(ADP-ribosyl)ation of P53 protein and PARP-1 protein abundance. We also demonstrate that exposure to 0.1 microM arsenite depresses the constitutive expression of p21 mRNA and P21 protein in HaCaT cells. Poly(ADP-ribosyl)ation of P53 is reported to block its activation, DNA binding and its functioning as a transcription factor. Our results suggest that arsenite's interference with activation of P53 via poly(ADP-ribosyl)ation may play a role in the comutagenic and cocarcinogenic effects of arsenite.
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PMID:Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure. 2003 71

Our previous data demonstrated that systemic inflammation evoked by intraperitoneal injection of lipopolysaccharide (LPS; 1 mg/kg b.w.) induces morphological and biochemical changes in the brain, including alterations of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression of several genes. In this study, the effect of systemic inflammatory response (SIR) on glutathione redox state and on cognition, spatial memory and locomotor activity was evaluated by using spectrophotometric method, object recognition test, Morris water-maze and open-field tests, respectively. The effect of PARP-1 inhibitor was included in this study. Our data indicated that SIR significantly decreases reduced glutathione (GSH) level, enhances its disulfide form (GSSG) and decreases glutathione reductase activity. Moreover, SIR affects the object recognition and locomotor activity but has negligible effect on spatial memory. PARP-1 inhibitor protects against LPS-evoked recognition impairment and significantly improves spatial memory in LPS-treated mice. The effect of PARP-1 inhibitor could be in part connected with lowering of PARP-1 involvement in regulation of transcription of several pro-inflammatory genes. Moreover, PARP-1 inhibitors may modulate glutamatergic receptor signaling that plays an important role in learning and memory.
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PMID:Systemic administration of lipopolysaccharide impairs glutathione redox state and object recognition in male mice. The effect of PARP-1 inhibitor. 2005 84

Previous studies suggest that the n-3 polyunsaturated fatty acids (PUFAs) eicosapenteinoic acid (EPA) and docosahexaenoic acid (DHA), constituents of fish oil, exert chemopreventive activity in colon cancer. One of the mechanisms involved is the facilitation of apoptosis. While a pro-apoptotic potential of n-3 PUFAs has been suggested, it is still unclear whether additional consumption of fish will also lead to comparable results. The aim of this study was to assess EPA- and DHA-mediated effects on endpoints of apoptosis and to use a novel biomarker-approach to measure modulation of apoptosis by consumption of fish. LT97 human colon adenoma and HT29 human colon adenocarcinoma cells were used to investigate modulation of apoptosis by EPA, DHA or linoleic acid (LA) using a set of endpoints, namely phosphatidylserine staining with Annexin-V (flow cytometry), Bcl-2 expression (Real-time RT-PCR), and Bid, caspase 3, 8 and 9 expression as well as PARP cleavage (Western Blot). Furthermore, faecal water (FW) of volunteers (n = 89) from a human trial intervening with fish was used to investigate changes in apoptosis by flow cytometry. DHA was more effective at inducing apoptosis than EPA. LT97 cells were more prone to DHA and EPA induced apoptosis than HT29 cells. Treatment of LT97 cells with FW from volunteers consuming fish did not result in any changes in apoptosis. Taken together, our results show that adenoma cells are highly susceptible to n-3 PUFA-induced apoptosis. By using a biomarker-approach (FW) to measure apoptosis-induction ex vivo no change in apoptosis after additional fish consumption was detectable.
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PMID:Fish fatty acids alter markers of apoptosis in colorectal adenoma and adenocarcinoma cell lines but fish consumption has no impact on apoptosis-induction ex vivo. 2010

Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.
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PMID:Synthesis and evaluation of tricyclic derivatives containing a non-aromatic amide as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). 2018 85

Recent evidence supports a crucial role for matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) disruption and vasogenic edema formation after traumatic brain injury (TBI). Although the exact causes of MMP-9 upregulation after TBI are not fully understood, several arguments suggest a contribution of the enzyme poly(ADP-ribose)polymerase (PARP) in the neuroinflammatory response leading to MMP-9 activation. The objectives of this study were to evaluate the effect of PARP inhibition by 3-aminobenzamide (3-AB) (1) on MMP-9 upregulation and BBB integrity, (2) on edema formation as assessed by magnetic resonance imaging (MRI), (3) on neuron survival as assessed by (1)H magnetic resonance spectroscopy ((1)H-MRS), and (4) on neurological deficits at the acute phase of TBI. Western blots and zymograms showed blunting of MMP-9 upregulation 6 h after TBI. BBB permeability was decreased at the same time point in 3-AB-treated rats compared to vehicle-treated rats. Cerebral MRI showed less "free" water in 3-AB-treated than in vehicle-treated rats 6 h after TBI. MRI findings 24 h after TBI indicated predominant cytotoxic edema, and at this time point no significant differences were found between 3-AB- and vehicle-treated rats with regard to MMP-9 upregulation, BBB permeability, or MRI changes. At both 6 and 24 h, neurological function was better in the 3-AB-treated than in the vehicle-treated rats. These data suggest that PARP inhibition by 3-AB protected the BBB against hyperpermeability induced by MMP-9 upregulation, thereby decreasing vasogenic edema formation 6 h after TBI. Furthermore, our data confirm the neuroprotective effect of 3-AB at the very acute phase of TBI.
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PMID:Effect of acute poly(ADP-ribose) polymerase inhibition by 3-AB on blood-brain barrier permeability and edema formation after focal traumatic brain injury in rats. 2038 May 52

A new water-soluble phthalocyanine derivative, 2,3,9,10,16,17,23,24-octakis(3-aminopropyloxy) phthalocyaninato zinc II (PoII) was studied as a photosensitizer for photodynamic therapy (PDT) in MCF-7c3 cells. We report here that PoII and red light induces apoptosis. However, the precise mechanism appears to differ from that induced by PDT with other known phthalocyanines. The present study provides evidence that in the case of PoII, caspases do not participate in the apoptotic response. PoII-PDT-treated cells exhibited chromatin condensation and phosphatidylserine (PS) externalization. In the absence of light activation, PoII had no detectable cytotoxic effect. An early event upon PoII-PDT was photodamage to lysosomes, suggesting that they are the primary sites of action. Moreover, the treatment induces Bid activation, mitochondrial swelling and translocation of apoptosis-inducing factor (AIF) to the nucleus. An atypical proteolysis of poly(ADP-ribose) polymerase (PARP) indicative of calpain-like activation was observed. These data support the notion that an alternative mechanism of caspase-independent apoptosis was found in PoII-photosensitized cells.
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PMID:Caspase-independent apoptosis, in human MCF-7c3 breast cancer cells, following photodynamic therapy, with a novel water-soluble phthalocyanine. 2038 57


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