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)

Green tea, owing to its beneficial effect on health, is becoming more and more popular worldwide. (-)-Epigallocatechin-3-gallate (EGCG), the main ingredient of green tea polyphenols, is a known protective effect on injured neurons in neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. Paraquat (PQ) is a widely used herbicide that possesses a similar structure to MPP(+) and is toxic to mesencephalic dopaminergic neurons. In the present study, PQ-injured PC12 cells were chosen as an in vitro cell model of Parkinson's disease and the neuroprotective effects of EGCG were investigated. The results showed that EGCG attenuated apoptosis of PC12 cells induced by PQ. The possible mechanism may be associated with maintaining mitochondrial membrane potential, inhibiting caspase-3 activity and downregulating the expression of pro-apoptotic protein Smac in cytosol. The present study supports the notion that EGCG could be used as a neuroprotective agent for treatment of neurodegenerative diseases.
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PMID:Neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) on paraquat-induced apoptosis in PC12 cells. 1793 47

Parkinson's disease is characterized by the progressive degeneration of midbrain dopaminergic neurons. Buddleia lindleyana is a traditional Chinese herb, commonly called Zui Yu Cao. The purification and identification of pedicularioside A and other phenylethanoid glycosides from this plant have been reported. However, their neuroprotective effects on the 1-methyl-4-phenylpyridinium ion (MPP(+))-induced death of rat mesencephalic neuron primary cultures and the precise mechanism of this protection remains unclear. We used the 3-(4, 5-dimethylthiozol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay for cellular growth to examine the effects of five phenylethanoid glycosides isolated from B. lindleyana, including pedicularioside A, leucosceptoside A, isoacteoside, acteoside, and arenariside, on the viability of mesencephalic neurons treated with MPP(+). Of the compounds tested, pedicularioside A exhibited the greatest degree of protection from MPP(+)-induced cell death. We also observed a marked increase in the number of tyrosine hydroxylase immunoreactive neurons. Pedicularioside A inhibited expression of the caspase-3 gene and cleavage of poly (ADP-ribose) polymerase (PARP) in cultures exposed to MPP(+). Our results suggest that pedicularioside A has a neuroprotective effect to improve the survival of mesencephalic neurons (dopaminergic neurons and non-dopaminergic neurons). The mode of action appears to be the inhibition of caspase-3 gene expression, thereby protecting mesencephalic neurons from MPP(+)-induced cell death.
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PMID:Pedicularioside A from Buddleia lindleyana inhibits cell death induced by 1-methyl-4-phenylpyridinium ions (MPP+) in primary cultures of rat mesencephalic neurons. 1803 49

Apoptosis has been identified as one of the important mechanisms involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Our previous study showed increased iron levels in the substantia nigra as well as loss of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse models. 1-Methyl-4-phenylpyridinium (MPP(+)) is commonly used to establish a cellular model of PD. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular mechanism linking increased iron and MPP(+)-induced neurodegeneration is largely unknown. In the present study, we investigate the involvement of divalent metal transporter 1 (DMT1) that accounts for the ferrous iron transport in MPP(+)-treated MES23.5 cells. In the treated cells, a significant influx of ferrous iron was observed. This resulted in a decreased mitochondrial membrane potential. Additionally, an elevated level of ROS production and activation of caspase-3 were also detected, as well as the subsequent cell apoptosis. These effects could be fully abolished by iron chelator desferal (DFO). Increased DMT1 (-IRE) expression but not DMT1 (+IRE) accounted for the increased iron influx. However, there were no changes for iron regulatory protein 1 (IRP1), despite decreased expression of IRP2. Iron itself had no effect on IRP1 and IRP2 expression. Our data suggest that although DMT1 mRNA contains an iron responsive element, its expression is not totally controlled by this. MPP(+) could up-regulate the expression of DMT1 (-IRE) in an IRE/IRP-independent manner. Our findings also show that MPP(+)-induced apoptosis in MES23.5 cells involves DMT1-dependent iron influx and mitochondria dysfunction.
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PMID:Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. 1819 77

Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease (PD) patients. Because excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons in PD, we determined the protective effect of a naturally occurring iron chelator, phytic acid (IP6), on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in immortalized rat mesencephalic/dopaminergic cells. Cell death was induced with MPP(+) in normal and iron-excess conditions and cytotoxicity was measured by thiazolyl blue tetrazolium bromide (MTT assay) and trypan blue staining. Apoptotic cell death was also measured with caspase-3 activity, DNA fragmentation, and Hoechst nuclear staining. Compared to MPP(+) treatment, IP6 (30 micromol/L) increased cell viability by 19% (P<0.05) and decreased cell death by 22% (P<0.05). A threefold increase in caspase-3 activity (P<0.001) and a twofold increase in DNA fragmentation (P<0.05) with MPP(+) treatment was decreased by 55% (P<0.01) and 52% (P<0.05), respectively with IP6. Cell survival was increased by 18% (P<0.05) and 42% (P<0.001) with 30 and 100 micromol/L of IP6, respectively in iron-excess conditions. A 40% and 52% (P<0.001) protection was observed in caspase-3 activity with 30 and 100 micromol/L IP6, respectively in iron-excess condition. Similarly, a 45% reduction (P<0.001) in DNA fragmentation was found with 100 micromol/L IP6. In addition, Hoechst nuclear staining results confirmed the protective effect of IP6 against apoptosis. Similar protection was also observed with the differentiated cells. Collectively, our results demonstrate a significant neuroprotective effect of phytate in a cell culture model of PD.
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PMID:Neuroprotective effect of the natural iron chelator, phytic acid in a cell culture model of Parkinson's disease. 1825 13

PF9601N [N-(2-propynyl) 2-(5-benzyloxyindol) methylamine] is a non-amphetamine type MAO-B inhibitor that has shown neuroprotective properties in vivo using different experimental models of Parkinson's disease. The mechanisms underlying its neuroprotective effects are poorly understood, but appear to be independent of MAO-B inhibition. We have studied its neuroprotective properties using the human SH-SY5Y dopaminergic cell line exposed to 1-methyl-4-phenylpyridinium (MPP(+)), a cellular model of Parkinson's disease. PF9601N pre-treatment significantly reduced MPP(+)-induced cell death and decreased the activation of one of the main executioner caspases, caspase-3. MPP(+) induced stabilization of transcription factor p53, which led to increased levels of this transcription factor, its nuclear translocation and transactivation of p53 response elements. PF9601N prevented this increase, thus reducing its transcriptional activity. Additional results showed that p53 may mediate its pro-apoptotic actions through caspase-2 under our experimental conditions. PUMA-alpha may also contribute to the p53-induced cell death. Since PF9601N significantly reduced MPP(+)-induced caspase-2 activity and PUMA-alpha levels, this reduction may lead to increased cell survival. Thus, PF9601N is a novel molecule with an apparently novel mechanism of action which has a promising potential as a therapeutic agent in the treatment of neurodegenerative diseases.
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PMID:Anti-apoptotic effect of Mao-B inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is mediated by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic cells. 1833 75

Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson's disease (PD). MPP(+), a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD, such as cytotoxicity, resulting in apoptosis. Undifferentiated human SH-SY5Y neuroblastoma cells had been used as an in vitro model of Parkinson's disease. We investigated if extracellular guanosine affected MPP(+)-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP(+) (10 muM-5 mM for 24-72 h) induced DNA fragmentation in a time-dependent manner (p < 0.05). Administration of guanosine (100 muM) before, concomitantly with or, importantly, after the addition of MPP(+) abolished MPP(+)-induced DNA fragmentation. Addition of MPP(+) (500 muM) to cells increased caspase-3 activity over 72 h (p < 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP(+) eliminated the anti-apoptotic effect of guanosine, indicating that this effect is dependent on a Gi protein-coupled receptor, most likely the putative guanosine receptor. The protection by guanosine was also abolished by the selective inhibitor of the enzyme PI-3-K/Akt/PKB (LY294002), confirming that this pathway plays a decisive role in this effect of guanosine. Neither MPP(+) nor guanosine had any significant effect on alpha-synuclein expression. Thus, guanosine antagonizes and reverses MPP(+)-induced cytotoxicity of neuroblastoma cells via activation of the cell survival pathway, PI-3-K/Akt/PKB. Our results suggest that guanosine may be an effective pharmacological intervention in PD.
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PMID:MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine. 1840 53

Defects in mitochondrial function have been shown to participate in the induction of neuronal cell injury. The present study assessed the preventive effect of a prostaglandin E(1) analogue misoprostol against the toxicity of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) with respect to the mitochondria-mediated cell death process and oxidative stress. MPP(+) induced the nuclear damage, the changes in the mitochondrial membrane permeability, the formation of reactive oxygen species and the depletion of GSH, which leads to cell death in differentiated PC12 cells. Misoprostol prevented the toxic effect of MPP(+). Treatment with misoprostol significantly attenuated the MPP(+)-induced mitochondrial membrane permeability change that leads to the increase in pro-apoptotic Bax and Cytochrome c levels, and subsequent caspase-3 activation. The protective effect of misoprostol may be supported by the inhibitory effect of prostaglandin E(1) on the MPP(+) toxicity. Misoprostol significantly attenuated another parkinsonian neurotoxin rotenone-induced cell death. The results show that misoprostol may prevent the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to the Cytochrome c release and caspase-3 activation. The preventive effect seems to be ascribed to the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.
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PMID:Prostaglandin analogue misoprostol attenuates neurotoxin 1-methyl-4-phenylpyridinium-induced mitochondrial damage and cell death in differentiated PC12 cells. 1860 72

It has been well documented that dysfunction of ubiquitin proteasome system (UPS) in the neuron exacerbated the Parkinson's disease (PD). However, whether or not UPS is involved in the protective effect of Puerarin on 1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine (MPP(+))-elicited cell death is yet to be elucidated. In this study, treatment of SH-SY5Y cells with 1mM MPP(+)-elicited a characteristic apoptotic cell death and pretreatment with Puerarin protected cells against MPP(+)-induced apoptosis as evidenced by promoting cell viability, improving morphological changes and reducing apoptotic rate. To further explore the potential protective mechanism of Puerarin in MPP(+)-induced SH-SY5Y cell death, UPS activity, mitochondria-dependent apoptosis and caspase-3 activity were measured. Puerarin pretreatment attenuated MPP(+)-induced dysfunction of protease activity, thereby reducing accumulation of ubiquitin-conjugated proteins. Meanwhile, caspase-3 activity was remarkably attenuated by Puerarin. In addition, the ratio of bcl-2/bax was increased by Puerarin in comparison with MPP(+)-treated group. Taken together, these results suggest that Puerarin could protect MPP(+)-induced SH-SY5Y cells from apoptosis by regulating the function of UPS.
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PMID:Involvement of ubiquitin proteasome system in protective mechanisms of Puerarin to MPP(+)-elicited apoptosis. 1902 6

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) acting to stimulate growth hormone release. In the previous study, we have observed the neuroprotective effects of ghrelin on dopaminergic neurons in vivo in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine -treated Parkinson's disease mice. In order to illustrate the underlying mechanisms, in the present study, we conducted our experiment in vitro in 1-methyl-4-phenylpyridinium (MPP(+))-treated MES23.5 cells that could express GHS-R1a. Ten- to 1,000-micromol/L MPP(+) treatment caused decreased cell viability, with increased lactate dehydrogenase leakage. A 200-micromol/L MPP(+) treatment was chosen to do the further experiments. MES23.5 cells treated with 200 micromol/L MPP(+) showed decreased mitochondrial transmembrane potential, an elevated level of reactive oxidative species production and activation of caspase-3. Additionally, these cells also showed apoptotic morphological changes. Pretreatment with different doses of ghrelin (10(-12)-10(-7) mol/L) could abolish the MPP(+)-induced apoptotic changes in a dose-dependent manner. These results suggested that ghrelin could antagonize MPP(+)-induced apoptosis in MES23.5 cells. The protective effects of ghrelin involved the restoration of mitochondria function.
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PMID:Ghrelin antagonized 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. 1905 22

Treatment of depression may ameliorate the cognitive disability and motor slowness in Parkinson's disease. It has been shown that antidepressants, including fluoxetine, may attenuate or exacerbate neuronal cell death. The present study assessed the effect of antidepressants (amitriptyline, tranylcypromine and fluoxetine) against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in relation to the mitochondria-mediated cell death process in differentiated PC12 cells. Amitriptyline and tranylcypromine attenuated the MPP(+)-induced cell death that may be associated with mitochondrial membrane permeability change and oxidative stress. Both compounds prevented the loss of the mitochondrial transmembrane potential, over-expression of Bax, reduction in Bcl-2 level, cytochrome c release, caspase-3 activation, formation of reactive oxygen species and depletion of GSH. The inhibitory effect of tranylcypromine was greater than that of amitriptyline on the basis of concentration. In contrast, fluoxetine revealed a toxic effect and exhibited an additive effect against the toxicity of MPP(+). Results show that amitriptyline and tranylcypromine may attenuate the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and subsequent caspase-3 activation. The effects seem to be associated with the inhibitory action on the formation of reactive oxygen species and the depletion of GSH. In contrast, fluoxetine seems to exert an additive toxic effect against neuronal cell damage by increasing mitochondrial damage and oxidative stress.
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PMID:Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells. 1913 49


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