Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraquat (PQ, 1,1'-dimethyl-4,4'-bipyridinium), a widely-used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson's disease. In recent years, many studies have focused on the mechanism(s) of PQ neurotoxicity. In this study, we examined the neuroprotective effect of manganese (III) meso-tetrakis (N,N'-diethylimidazolium) porphyrin (MnTDM), a superoxide dismutase/catalase mimetic, on PQ-induced oxidative stress and apoptosis in 1RB3AN27 (N27) cells, a dopaminergic neuronal cell line. The results indicated that MnTDM significantly attenuated PQ-induced loss of cell viability, glutathione depletion, and reactive oxygen species production. MnTDM also ameliorated PQ-induced morphological nuclear changes of apoptosis and increased rates of apoptosis. In addition, our data provide direct evidence that MnTDM suppressed PQ-induced caspase-3 cleavage, possibly a key event of PQ neurotoxicity. These observations suggested that oxidative stress and apoptosis are implicated in PQ-induced neurotoxicity and this toxicity could be prevented by MnTDM. These findings also proposed a novel therapeutic approach for Parkinson's disease and other disorders associated with oxidative stress.
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PMID:Protective effects of a new metalloporphyrin on paraquat-induced oxidative stress and apoptosis in N27 cells. 1823 74

A hallmark of cancer cells is their ability to evade apoptosis and mitochondria play a critical role in this process. Delineating mitochondrial differences between normal and cancer cells has proven challenging due to the lack of matched cell lines. Here, we compare two matched liver progenitor cell (LPC) lines, one non-tumorigenic [p53-immortalized liver (PIL) 4] and the other tumorigenic (PIL2). Analysis of these cell lines and a p53 wild-type non-tumorigenic cell line [bipotential murine oval liver (BMOL)] revealed an increase in expression of genes encoding the antiapoptotic proteins cellular inhibitor of apoptosis protein (cIAP) 1 and yes associate protein in the PIL2 cells, which resulted in an increase in the protein encoded by these genes. PIL2 cells have higher mitochondrial membrane potential (Deltapsi(m)) compared with PIL4 and BMOL and had greater levels of reactive oxygen species, despite the fact that the mitochondrial antioxidant enzyme, manganese superoxide disumutase, was elevated at transcript and protein levels. Taken together, these results may account for the observed resistance of PIL2 cells to apoptotic stimuli compared with PIL4. We tested a new gold compound to show that hyperpolarized Deltapsi(m) led to its increased accumulation in mitochondria of PIL2 cells. This compound selectively induces apoptosis in PIL2 cells but not in PIL4 or BMOL. The gold compound depolarized the Deltapsi(m), depleted the adenosine triphosphate pool and activated caspase-3 and caspase-9, suggesting that apoptosis was mediated via mitochondria. This investigation shows that the non-tumorigenic and tumorigenic LPCs are useful models to delineate the role of mitochondrial dysfunction in tumorigenesis and for the future development of mitochondria-targeted chemotherapeutics that selectively target tumor cells.
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PMID:Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound. 1841 65

Chemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin- and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer.
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PMID:Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2. 1859 23

Oxidative stress and apoptosis are important factors in the etiology of renal ischemia-reperfusion (I/R) injury. The present study tested the hypothesis that the cell-permeant SOD mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) protects the kidney from I/R-mediated oxidative stress and apoptosis in vivo. Male Sprague-Dawley rats (175-220 g) underwent renal I/R by bilateral clamping of the renal arteries for 45 min followed by reperfusion for 24 h. To examine the role of reactive oxygen species (ROS) in renal I/R injury, a subset of animals were treated with either saline vehicle (I/R Veh) or MnTMPyP (I/R Mn) (5 mg/kg ip) 30 min before and 6 h after surgery. MnTMPyP significantly attenuated the I/R-mediated increase in serum creatinine levels and decreased tubular epithelial cell damage following I/R. MnTMPyP also decreased TNF-alpha levels, gp(91phox), and lipid peroxidation after I/R. Furthermore, MnTMPyP inhibited the I/R-mediated increase in apoptosis and caspase-3 activation. Interestingly, although MnTMPyP did not increase expression of the antiapoptotic protein Bcl-2, it decreased the expression of the proapoptotic genes Bax and FasL. These results suggest that MnTMPyP is effective in reducing apoptosis associated with renal I/R injury and that multiple signaling mechanisms are involved in ROS-mediated cell death following renal I/R injury.
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PMID:MnTMPyP, a cell-permeant SOD mimetic, reduces oxidative stress and apoptosis following renal ischemia-reperfusion. 1909 87

Hypoxic-ischemic injury (HI) to the neonatal brain results in delayed neuronal death with accompanying inflammation for days after the initial insult. The aim of this study was to depict delayed neuronal death after HI using Manganese-enhanced MRI (MEMRI) and to evaluate the specificity of MEMRI in detection of cells related to injury by comparison with histology and immunohistochemistry. 7-day-old Wistar rat pups were subjected to HI (occlusion of right carotid artery and 8% O(2) for 75 min). 16 HI (HI+Mn) and 6 sham operated (Sham+Mn) pups were injected with MnCl(2) (100 mM, 40 mg/kg) and 10 HI-pups (HI+Vehicle) received NaCl i.p. 6 h after HI. 3D T(1)-weighted images (FLASH) and 2D T(2)-maps (MSME) were acquired at 7 T 1, 3 and 7 days after HI. Pups were sacrificed after MR-scanning and brain slices were cut and stained for CD68, GFAP, MAP-2, Caspase-3 and Fluorojade B. No increased manganese-enhancement (ME) was detectable in the injured hemisphere on day 1 or 3 when immunohistochemistry showed massive ongoing neuronal death. 7 days after HI, increased ME was seen on T(1)-w images in parts of the injured cortex, hippocampus and thalamus among HI+Mn pups, but not among HI+Vehicle or Sham+Mn pups. Comparison with immunohistochemistry showed delayed neuronal death and inflammation in these areas with late ME. Areas with increased ME corresponded best with areas with high concentrations of activated microglia. Thus, late manganese-enhancement seems to be related to accumulation of manganese in activated microglia in areas of neuronal death rather than depicting neuronal death per se.
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PMID:Manganese-enhanced magnetic resonance imaging of hypoxic-ischemic brain injury in the neonatal rat. 1913 50

In order to explore the apoptotic and anti-tumor activities of metallo-salens, we synthesized several Mn(III)-salen derivatives (compds. 1-9) and analyzed their effects on cultured human cancer and non-cancer cells. Our results demonstrated that Mn(III)-salen derivatives affect cell viability, induce nuclear condensation and fragmentation in breast cancer cells (MCF7). Mn(III)-salen derivatives also induced caspase-3/7 activation and release of cytochrome-c from the mitochondria to cytosol suggesting that Mn(III)-salen derivatives induce apoptosis in human cells via mitochondrial pathway. Importantly, the nature of the substituent and the bridging spacer between diimino groups on the salen ligand play critical roles in determining the apoptotic activities of Mn(III)-salen derivatives. The IC(50) values for the active Mn(III)-salen derivatives lie within the range of 11-40microM in MCF7 cells. Most importantly, several Mn(III)-salen derivatives showed preferential cytotoxicity (2- to 5-fold) toward malignant breast cells (MCF7) over a non-malignant breast epithelial cell line (MCF10). Notably, the level of cytotoxicity and selectivity of the Mn(III)-salen derivatives towards MCF7 and MCF10 cells are very similar to cisplatin which indicate that Mn(III)-salens are potential novel anti-tumor agent.
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PMID:Manganese(III)-salens induce tumor selective apoptosis in human cells. 1929 27

Parkinson's disease is characterized by degeneration of dopaminergic neurones in the substantia nigra. Chronic manganese poisoning shares many features of Parkinson's disease, and also induces extrapyramidal syndromes that resemble those of Parkinson's disease due to dopamine depletion in the central nervous system. This study was undertaken to develop novel neuroprotective drugs via the identification of compounds that inhibit manganese-induced apoptosis. Here, we report that (arylthio)cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, prevent manganese-induced apoptosis in PC12 cells. A highly sensitive assay of caspase-3/7 activity was used for screening newly synthesized prostaglandin analogs. The results showed that some cyclopentenone derivatives (GIF-0642, GIF-0643, GIF-0644, GIF-0745, and GIF-0747) inhibit manganese-induced caspase-3/7 activation in a concentration-dependent manner. Effective compounds all have an arylthio group, indicating that this structure plays an important role in the anti-apoptotic effects of (arylthio)cyclopentenone derivatives. The anti-apoptotic effects of these compounds were confirmed by verifying their ability to inhibit the DNA fragmentation and caspase-9 activation induced by manganese. Furthermore, GIF-0747 prevented manganese-induced cytochrome c release from mitochondria. These results suggest that (arylthio)cyclopentenone derivatives may be good candidates for treating neurodegenerative diseases.
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PMID:Neuroprotective effects of (arylthio)cyclopentenone derivatives on manganese-induced apoptosis in PC12 cells. 1964 96

Manganese, an essential trace nutrient in human beings, has been widely used in the steel industry to improve hardness, stiffness, and strength. With the increased applications of manganese compounds, discharge into the environment has rapidly increased and may exert adverse effects on human health. In this study, manganese toxicity was investigated using cultured T98G cells, which are derived from human glioblasts with the ability to differentiate into several different types of neuroglia. Cytotoxicity was shown in manganese-treated groups (100, 200, 400, and 800microM of MnCl(2)), and cell viability was decreased to 58.8% of the control group at 2days after treatment with 800microM of MnCl(2). When cells were treated with manganese for 24h, ROS dose-dependently increased while antioxidant intracellular GSH decreased. With the generation of ROS, the increased activity of caspase-3 was shown, and was followed by chromatin condensation and breakage, which is an indication of the cellular apoptotic process. ROS also triggered pro-inflammatory responses in cultured T98G cells, which were demonstrated by the increased gene expression and protein levels of IL-6 and IL-8.
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PMID:Induction of oxidative stress and inflammatory cytokines by manganese chloride in cultured T98G cells, human brain glioblastoma cell line. 1981 61

Chronic inorganic manganese (Mn) exposure has been known to induce neurological disorders similar to Parkinson's disease (PD). Apoptosis has been shown to be involved in manganese-induced neurotoxicity. However, the up-stream molecular mechanisms for cell apoptosis are not established. alpha-Synuclein (alpha-syn) is a major component of intracellular inclusions in PD, Alzheimer's disease (AD), and other neurodegenerative disorders. We investigated the role of alpha-syn in manganese chloride (MnCl(2))-induced apoptosis. Results show that MnCl(2) enhanced transcriptional and translational alpha-syn overexpression, and apoptosis as measured by caspase-3 activity and flow cytometry. Overexpressing alpha-syn exacerbated manganese-induced apoptosis, whereas antisense alpha-syn treatment significantly reversed MnCl(2)-induced apoptosis in human neuroblastoma SH-SY5Y cells. In conclusion, our results imply that intracellular alpha-syn overexpression may be responsible for MnCl(2)-induced apoptosis.
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PMID:alpha-Synuclein overexpression during manganese-induced apoptosis in SH-SY5Y neuroblastoma cells. 1993 57

Water-soluble iron, and manganese(III) complexes of corroles and porphyrins were examined with regard to their neuroprotective/neurorescue activities by using various neuronal cytotoxic models of oxidative and nitrative stress. The present study demonstrates that the metallocorroles significantly protect human neuroblastoma SH-SY5Y and mouse motor neuron-neuroblastoma fusion NSC-34 cell lines against neurotoxicity induced by either the peroxynitrite donor 3-morpholinosydnonimine or the parkinsonism-related neurotoxin 6-hydroxydopamine. The neuronal survival effect is further reflected by the prevention of 3-morpholinosydnonimine-induced protein nitration, inhibition of caspase 3 activation, as well as attenuation of 6-hydroxydopamine-mediated decrease in growth associated protein-43 levels. The iron(III) corrole, but not manganese (III) corrole, also significantly promotes neuronal survival of hydrogen peroxide (H(2)O(2))-impaired SH-SY5Y and NSC-34 cells. A substantial superiority of the metallocorroles relative to the corresponding porphyrin complexes is revealed in all examined aspects. These results highlight the large potential of corrole complexes as novel agents for therapeutic approaches in degenerative disorders of the central and peripheral nervous systems, where oxidative and nitrative stresses are involved.
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PMID:Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration. 2009 90


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