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)

Cells exposed to high ambient glucose concentrations are subject to increases in intracellular calcium ([Ca(2+)](i)). We therefore considered it likely that the calcium-dependent cysteine protease calpain would play a role in the development of high glucose-induced cell injury. After 3 and 24 h, high glucose concentrations (25 mM D-glucose) produced almost identical increases in the degree of necrotic cell death in kidney proximal tubular epithelial cells (LLC-PK(1)) compared to cells treated with control glucose (5 mM D-glucose). Necrotic cell death could be restricted by inhibiting the activity of calpain. High glucose-treated LLC-PK(1) cells were found to have significantly elevated [Ca(2+)](i) concentrations within 1 h, and elevated calpain activity within 2 h compared to control treated cells. The DNA nick sensor poly(ADP-ribose) polymerase (PARP) has previously been shown to be an important driver of high glucose-induced cell death, but here we found that although PARP activity was increased after 24 h, it was unaltered after 3 h. Furthermore, PARP inhibition with PJ-34 did not restrict early high glucose-induced necrosis. Using a gene knockdown strategy with small interference RNA, we found that silencing calpain was effective in reducing the degree of early high glucose-induced necrosis. We conclude that high glucose concentrations evoke an early, calpain-mediated necrosis in cultured proximal tubular cells that is PARP-independent, and precedes the previously recognized activation of apoptosis.
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PMID:High glucose initiates calpain-induced necrosis before apoptosis in LLC-PK1 cells. 1729 Feb 96

The anti-neoplastic drug taxol binds to beta-tubulin to prevent tumor cell division, promoting cell death. However, high dose taxol treatment may induce cell death in normal cells too. The anti-apoptotic molecule Bcl-2 is upregulated in many cancer cells to protect them from apoptosis. In the current study, we knocked down Bcl-2 expression using cognate siRNA during low-dose taxol treatment to induce apoptosis in two human glioblastoma U138MG and U251MG cell lines. The cells were treated with either 100 nM taxol or 100 nM Bcl-2 siRNA or both for 72 h. Immunofluorescent stainings for calpain and active caspase-3 showed increases in expression and co-localization of these proteases in apoptotic cells. Fluorometric assays demonstrated increases in intracellular free [Ca(2+)], calpain, and caspase-3 indicating augmentation of apoptosis. Western blotting demonstrated dramatic increases in the levels of Bax, Bak, tBid, active caspases, DNA fragmentation factor-40 (DFF40), cleaved fragments of lamin, fodrin, and poly(ADP-ribose) polymerase (PARP) during apoptosis. The events related to apoptosis were prominent more in combination therapy than in either treatment alone. Our current study demonstrated that Bcl-2 siRNA significantly augmented taxol mediated apoptosis in different human glioblastoma cells through induction of calpain and caspase proteolytic activities. Thus, combination of taxol and Bcl-2 siRNA offers a novel therapeutic strategy for controlling the malignant growth of human glioblastoma cells.
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PMID:Bcl-2 siRNA augments taxol mediated apoptotic death in human glioblastoma U138MG and U251MG cells. 1835 21

We investigated the response of alphaB-crystallin to oxidative stress and calpain inhibition in an attempt to elucidate the signalling pathways mediating its phosphorylation. Given the high expression levels of alphaB-crystallin in cardiac muscle one can evaluate the significance of its participation in preservation of homeostasis under adverse conditions. H9c2 cardiac myoblasts were used as our experimental model since their response reflects the signal transduction pathways activated by stress conditions in the myocardium. Thus, in H9c2 cells treated with H2O2 the mechanism regulating alphaB-crystallin phosphorylation was found to involve p38-MAPK/MSK1 as well as intracellular free calcium levels. Our immunocytochemical experiments demonstrated phosphorylated alphaB-crystallin to be co-localized with tubulin, potentially preserving cytoskeletal architecture under these interventions. In H9c2 cells treated with calpain inhibitors (ALLN, ALLM) alphaB-crystallin exhibited a p38-MAPK- and [Ca 2+](i)-dependent phosphorylation pattern since the latter was ablated in the presence of the selective p38-MAPK inhibitor SB203580 and calcium chelator BAPTA-AM. Calpain activity repression ultimately led to apoptosis confirmed by PARP fragmentation and chromatin condensation. However, the apoptotic pathway activated by ALLM and ALLN differed, underlying the diverse transduction mechanisms stimulated. In addition to this, an anti-apoptotic role for phospho-alphaB-crystallin was verified by confirmation of its interaction with pro-caspase 3, hindering its cleavage and subsequent activation. Collectively, our findings underline alphaB-crystallin crucial role as a participant of cardiac cells early response to stressful stimuli compromising their survival.
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PMID:Oxidative stress and calpain inhibition induce alpha B-crystallin phosphorylation via p38-MAPK and calcium signalling pathways in H9c2 cells. 1842 Mar 82

Amyloid beta peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD). The peptide is toxic to neurons, possibly by causing initial synaptic dysfunction and neuronal membrane dystrophy, promoted by increased cellular Ca(2+). Calpain (Ca(2+)-dependent protease) and caspase have also been implicated in AD. There is little information on communication between the two proteases or on the involvement of calpastatin (the specific calpain inhibitor) in Abeta toxicity. We studied the effects of Abeta25-35 (sAbeta) on calpain, calpastatin, and caspase in neuronal-like differentiated PC12 cells. sAbeta-treated cells exhibited primarily cell membrane damage (varicosities along neurites, enhanced membrane permeability to propidium iodide, without apparent nuclear changes of apoptosis, and little poly (ADP-ribose) polymerase [PARP] degradation). The sAbeta-induced membrane damage is in contrast with staurosporine-induced damage (nuclear apoptotic changes, PARP degradation, without membrane propidium iodide permeability). sAbeta led to activation of caspase-8 and calpain, promotion of calpastatin degradation (by caspase-8 and by calpain), and enhanced degradation of fodrin (mainly by calpain). The results support the idea that Abeta causes primarily neuronal membrane dysfunction, and point to cross-talk between calpain and caspase (protease activation and degradation of calpastatin) in Abeta toxicity. Increased expression of calpastatin and/or decrease in calpain and caspase-8 may serve as means for ameliorating early symptoms of AD.
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PMID:Amyloid beta peptide toxicity in differentiated PC12 cells: calpain-calpastatin, caspase, and membrane damage. 1843 16

Calpain, calcium-dependent cysteine protease, is reported here to impose the crucial influence on oridonin-induced L929 cell apoptosis and autophagy. We found that inhibition of calpain increased oridonin-induced Bax activation, cytochrome c release and PARP cleavage, indicating that calpain plays an anti-apoptotic role in oridonin-induced L929 cell apoptosis. To explore this potential anti-apoptotic mechanism, we inhibited calpain and proteasome activity in oridonin-induced L929 cell apoptosis, and discovered that the inducible IkappaBalpha proteolysis was partially blocked by the inhibition of either calpain or proteasome, but completely blocked by the inhibition of both. It demonstrated that calpain and proteasome were two distinct pathways participating in IkappaBalpha degradation. To further study the role of calpain in oridonin-induced L929 cell autophagy, we discovered that calpain inhibitor decreased oridonin-induced autophagy, as well as Beclin 1 activation and the conversion from LC3-I to LC3-II. Moreover, Inhibition of autophagy by 3-MA increased oridonin-induced apoptosis. In conclusion, besides suppressing apoptosis, calpain promotes autophagy in oridonin-induced L929 cell death, and inhibition of autophagy might contribute to up-regulation of apoptosis.
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PMID:Apoptosis-suppressing and autophagy-promoting effects of calpain on oridonin-induced L929 cell death. 1846 6

Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O(2) resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O(2) (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1beta) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O(2) resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O(2) treatment for neonatal HI should be reevaluated.
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PMID:Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. 1865 97

Photoreceptor cell death is the major hallmark of a group of human inherited retinal degenerations commonly referred to as retinitis pigmentosa (RP). Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Previous research work has focused on apoptosis, but recent evidence suggests that photoreceptor cell death may result primarily from non-apoptotic mechanisms independently of AP1 or p53 transcription factor activity, Bcl proteins, caspases, or cytochrome c release. This review briefly describes some animal models used for studies of retinal degeneration, with particular focus on the rd1 mouse. After outlining the major features of different cell death mechanisms in general, we then compare them with results obtained in retinal degeneration models, where photoreceptor cell death appears to be governed by, among other things, changes in cyclic nucleotide metabolism, downregulation of the transcription factor CREB, and excessive activation of calpain and PARP. Based on recent experimental evidence, we propose a putative non-apoptotic molecular pathway for photoreceptor cell death in the rd1 retina. The notion that inherited photoreceptor cell death is driven by non-apoptotic mechanisms may provide new ideas for future treatment of RP.
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PMID:Photoreceptor cell death mechanisms in inherited retinal degeneration. 1898 59

Growth hormone (GH) is found in the retina and vitreous of the chick embryo, where it appears to act as a growth and differentiation factor, having neuroprotective effects on retinal ganglion cells (RGCs). Here, we review the molecular mechanisms of the anti-apoptotic effect of GH in chick RGCs. GH treatment of RGCs reduces Akt levels, while raising Akt-phos levels, consistent with a role for Akt signaling pathways in the GH neuroprotective action. The induction of apoptosis by immunoneutralization with GH antiserum is accompanied by an increase in caspase-3 and caspase-9 activation, and also PARP-1 cleavage. Calpain activation also appears to be a major caspase-independent pathway to PARP-1 cleavage and apoptosis in these cells, supporting the view that caspase and calpain inhibitors are major neuroprotective agents for RGCs, and that pathways that activate both caspases and calpains are important for the anti-apoptotic actions of GH in these cells. These pathways involve the activation of cytosolic tyrosine kinases (Trks) and extracellular-signal-related kinases (ERKs). Occupation of the GH receptor by GH involves downstream intracellular Trk pathways. The Akt and Trk pathways appear to converge on the activation of cAMP response element binding protein (CREB), which is able to initiate transcription of pro- or anti-apoptotic genes. These results indicate that the action of GH in the neuroprotection of embryonic RGCs involves pathways common to with other neurotrophins, and that GH can be considered to be a growth and differentiation factor in the development of the embryonic retina. We have also investigated the relationship between the overlapping anti-apoptotic effects of GH and insulin-like growth factor-1 (IGF-1), two functionally closely related factors. We find that simultaneous immunoneutralization of GH and IGF-1 does not increase the level of apoptosis in the cultures above that achieved by immunoneutralization of GH alone. We therefore conclude that the neuroprotective actions of GH in the developing retina are likely mediated in large part through the action of IGF-1.
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PMID:Signaling mechanisms mediating local GH action in the neural retina of the chick embryo. 1934 64

Recent discoveries show that caspase-independent cell death pathways are a pervasive mechanism in neurodegenerative diseases, and apoptosis-inducing factor (AIF) is an important effector of this mode of neuronal death. There are currently two known mechanisms underlying AIF release following excitotoxic stress, PARP-1 and calpain. To test whether there is an interaction between PARP-1 and calpain in triggering AIF release, we used the NMDA toxicity model in rat primary cortical neurons. Exposure to NMDA resulted in AIF truncation and nuclear translocation, and shRNA-mediated knockdown of AIF resulted in neuroprotection. Both calpain and PARP-1 are involved with AIF processing as AIF truncation, nuclear translocation and neuronal death were attenuated by calpain inhibition using adeno-associated virus-mediated overexpression of the endogenous calpain inhibitor, calpastatin, or treatment with the PARP-1 inhibitor 3-ABA. Activation of PARP-1 is necessary for calpain activation as PARP-1 inhibition blocked mitochondrial calpain activation. Finally, NMDA toxicity induces mitochondrial Ca(2+) dysregulation in a PARP-1 dependent manner. Thus, PARP-1 and mitochondrial calpain activation are linked via PARP-1-induced alterations in mitochondrial Ca(2+) homeostasis. Collectively, these findings link the two seemingly independent mechanisms triggering AIF-induced neuronal death.
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PMID:Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways. 1942 6

Apoptosis-inducing factor (AIF) is critical for poly(ADP-ribose) polymerase-1 (PARP-1)-dependent cell death (parthanatos). The molecular mechanism of mitochondrial AIF release to the nucleus remains obscure, although a possible role of calpain I has been suggested. Here we show that calpain is not required for mitochondrial AIF release in parthanatos. Although calpain I cleaved recombinant AIF in a cell-free system in intact cells under conditions where endogenous calpain was activated by either NMDA or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) administration, AIF was not cleaved, and it was released from mitochondria to the nucleus in its 62-kDa uncleaved form. Moreover, NMDA administration under conditions that failed to activate calpain still robustly induced AIF nuclear translocation. Inhibition of calpain with calpastatin or genetic knockout of the regulatory subunit of calpain failed to prevent NMDA- or MNNG-induced AIF nuclear translocation and subsequent cell death, respectively, which was markedly prevented by the PARP-1 inhibitor, 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-iso-quinolinone. Our study clearly shows that calpain activation is not required for AIF release during parthanatos, suggesting that other mechanisms rather than calpain are involved in mitochondrial AIF release in parthanatos.
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PMID:Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). 1945 82


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