Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have revealed that endoplasmic reticulum (ER) disturbance is involved in the pathophysiology of neurodegenerative disorders, contributing to the activation of the ER stress-mediated apoptotic pathway. Therefore, we investigated here the molecular mechanisms underlying the ER-mitochondria axis, focusing on calcium as a potential mediator of cell death signals. Using NT2 cells treated with brefeldin A or tunicamycin, we observed that ER stress induces changes in the mitochondrial function, impairing mitochondrial membrane potential and distressing mitochondrial respiratory chain complex Moreover, stress stimuli at ER level evoked calcium fluxes between ER and mitochondria. Under these conditions, ER stress activated the unfolded protein response by an overexpression of GRP78, and also caspase-4 and-2, both involved upstream of caspase-9. Our findings show that ER and mitochondria interconnection plays a prominent role in the induction of neuronal cell death under particular stress circumstances.
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PMID:ER-mediated stress induces mitochondrial-dependent caspases activation in NT2 neuron-like cells. 1994 12

The present study focused on the early stages of acute glutamate (L-Glu)-induced neurotoxic mechanisms, both biochemical, e.g. intracellular reactive oxygen species (ROS) and associated parameters as well as gene expression of cell survival/death pathways, i.e. Bcl-2 and caspases. Stereotactic intracortical injections of L-Glu (1micromol/1microl) resulted in decreased size of pyramidal neurons in rat after 1h. We also observed that intracellular ROS, calcium (Ca(2+)) and peroxynitrite (ONOO(-)) production were significantly elevated, whereas, mitochondrial transmembrane potential (DeltaPsim) and total glutathione were significantly decreased by L-Glu bolus. The Bcl-2/Bax ratio in the L-Glu-injected rats was found to be significantly lower than the controls. Moreover, acute L-Glu significantly induced mRNA expression of nNOS, iNOS, caspase-3 and caspase-9. It may be concluded from the present study that acute L-Glu administration, at an early stage, increases intracellular ROS accumulation, Ca(2+) levels and peroxynitrite production and decreases glutathione pool. Furthermore, it appears that decreased mitochondrial Bcl-2/Bax ratio might have upregulated the mRNA expression of caspase-3 and caspase-9 which launch cell death cascade. Regarding the chronology of the events, we presume that acute L-Glu increases ROS and decreases DeltaPsim and glutathione rapidly and it is more likely that these events precede gene expression changes, ultimately resulting in neuronal damage/death.
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PMID:Cell death mechanisms in the early stages of acute glutamate neurotoxicity. 1994 20

The common inhalation anesthetic isoflurane has been shown to induce apoptosis, which then leads to accumulation of beta-amyloid protein, the hallmark feature of Alzheimer disease neuropathogenesis. The underlying molecular mechanism of the isoflurane-induced apoptosis is largely unknown. We, therefore, set out to assess whether isoflurane can induce apoptosis by regulating Bcl-2 family proteins, enhancing reactive oxygen species (ROS) accumulation, and activating the mitochondrial pathway of apoptosis. We performed these studies in cultured cells, primary neurons, and mice. Here we show for the first time that treatment with 2% isoflurane for 6 h can increase pro-apoptotic factor Bax levels, decrease anti-apoptotic factor Bcl-2 levels, increase ROS accumulation, facilitate cytochrome c release from the mitochondria to the cytosol, induce activation of caspase-9 and caspase-3, and finally cause apoptosis as compared with the control condition. We have further found that isoflurane can increase the mRNA levels of Bax and reduce the mRNA levels of Bcl-2. The isoflurane-induced ROS accumulation can be attenuated by the intracellular calcium chelator BAPTA. Finally, the anesthetic desflurane does not induce activation of mitochondrial pathway of apoptosis. These results suggest that isoflurane may induce apoptosis through Bcl-2 family proteins- and ROS-associated mitochondrial pathway of apoptosis. These findings, which have identified at least partially the molecular mechanism by which isoflurane induces apoptosis, will promote more studies aimed at studying the potential neurotoxic effects of anesthetics.
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PMID:The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. 2000 10

Excessive stimulation of the NMDA receptor induces neuronal cell death and is implicated in the development of several neurodegenerative diseases. While EGCG suppresses apoptosis induced by NMDA receptor-mediated excitotoxicity, the mechanisms underlying this process have yet to be completely determined. This study was designed to investigate whether (-)-epigallocatechin-3-gallate (EGCG) plays a neuroprotective role by inhibiting nitric oxide (NO) production and activating cellular signaling mechanisms including MAP kinase, PI3K, and GSK-3beta and acting on the antiapoptotic and the proapoptotic genes in N18D3 neural cells. The cells were pretreated with EGCG for 2 h and then exposed to quinolinic acid (QUIN), a NMDA receptor agonist, 30 mM for 24 h. MTT assay and DAPI staining were used to identify cell viability and apoptosis, respectively, and demonstrated that EGCG significantly increased cell viability and protected the cells from apoptotic death. In addition, EGCG had a capacity to reduce QUIN-induced excitotoxic cell death not only by blocking increase of intracellular calcium levels but also by inhibiting NO production. Gene expression analysis revealed that EGCG prevented the QUIN-induced expression of the proapoptotic gene, caspase-9, and increased that of the antiapoptotic genes, Bcl-XL, Bcl-2, and Bcl-w. Further examination about potential cell signaling candidate involved in this neuroprotective effect showed that immunoreacitivity of PI3K was significantly increased in the cells treated with EGCG. These results suggest that the neuroprotective mechanism of EGCG against QUIN-induced excitotoxic cell death includes regulation of PI3K and modulation of cell survival and death genes through decreasing of intracellular calcium levels and controlling of NO production.
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PMID:Neuroprotective effects of (-)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. 2002 54

Organismal stress responses to oxidative stress are relevant to ageing and disease and involve key cell-/tissue-specific signal transduction mechanisms. Using Drosophila, an established in vivo model for stress studies, we show that cell-specific inositol phosphate signalling specifically via inositol 1,4,5 trisphosphate 3-kinase (InsP(3) 3-K, IP(3)K), negatively regulates organismal responses to oxidative stress. We demonstrate that the Drosophila Malpighian tubule (equivalent to vertebrate kidney and liver) is a key epithelial sensor for organismal oxidative stress responses: precise targeting of either gain-of-function constructs of Drosophila IP(3)Ks (IP(3)K-1 and IP(3)K-2), or loss-of-function (RNAi) constructs to only one cell type in tubule reversibly modulates survival of stress-challenged adult flies. In vivo, targeted IP(3)K-1 directly increases H(2)O(2) production, pro-apoptotic caspase-9 activity and mitochondrial membrane potential. The mitochondrial calcium load in tubule principal cells-assessed by luminescent and fluorescent genetically-encoded mitochondrial calcium reporters-is significantly increased by IP(3)K-1 under oxidative stress conditions, leading to apoptosis. The Drosophila orthologues of human apoptotic bcl-2 genes include debcl and buffy. Oxidative stress challenge does not modulate gene expression of either debcl or buffy in tubules; and altered debcl expression does not influence survival rates under oxidative stress challenge. Finally, targeted over-expression of either debcl or buffy to tubule principal cells does not impact on tubule caspase-9 activity. Thus, IP(3)K-1 modulates epithelial cell apoptosis without involvement of bcl-2-type proteins.
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PMID:Cell-specific inositol 1,4,5 trisphosphate 3-kinase mediates epithelial cell apoptosis in response to oxidative stress in Drosophila. 2006 Aug 94

We have evaluated the effect of melatonin on apoptosis evoked by increases in [Ca(2+)]( c ) in human leukocytes. Our results show that treatment of neutrophils with the calcium mobilizing agonist FMLP or the specific inhibitor of calcium reuptake thapsigargin induced a transient increase in [Ca(2+)]( c ). Our results also show that FMLP and thapsigargin increased caspase-9 and -3 activities and the active forms of both caspases. The effect of FMLP and thapsigargin on caspase activation was time-dependent. Similar results were obtained when lymphocytes were stimulated with thapsigargin. This stimulatory effect was accompanied by induction of mPTP, activation of the proapoptotic protein Bax and release of cytochrome c. However, when leukocytes were pretreated with melatonin, all of the apoptotic features indicated above were significantly reversed. Our results suggest that melatonin reduces caspase-9 and -3 activities induced by increases in [Ca(2+)]( c ) in human leukocytes, which are produced through the inhibition of both mPTP and Bax activation.
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PMID:Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. 2013 Aug 48

Amyloid-beta (Abeta) peptide plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previously we found that Abeta induces both mitochondrial and endoplasmic reticulum (ER) dysfunction leading to apoptosis, and now we address the relevance of ER-mitochondria crosstalk in apoptotic cell death triggered by Abeta peptide. Using mitochondrial DNA-depleted rho0 cells derived from the human NT2 teratocarcinoma cell line, characterized by the absence of functional mitochondria, and the parental rho+ cells, we report here that treatment with the synthetic Abeta1-40 peptide, or the classical ER stressors thapsigargin or brefeldin A, increases GRP78 expression levels and caspase activity, two ER stress markers, and also depletes ER calcium stores. Significantly, we show that the presence of functional mitochondria is required for ER stress-mediated apoptotic cell death triggered by toxic insults such as Abeta. We found that the increase in the levels of the pro-apoptotic transcription factor GADD153/CHOP, which mediates ER stress-induced cell death, as well as caspase-9 and -3 activation and increased number of TUNEL-positive cells, occurs in treated parental rho+ cells but is abolished in rho0 cells. Our results strongly support the close communication between ER and mitochondria during apoptotic cell death induced by the Abeta peptide and provide insights into the molecular cascade of cell death in AD.
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PMID:ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria. 2018 29

The role of vitamin D3 in cancer prevention and its potential as an anticancer therapeutic agent have been researched and are well established. However, the clinical use of the natural vitamin D3 metabolite, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] is limited by a possible cause of hypercalcemia and hypercalciuria. A new 24-chloro calcipotriene-based vitamin D3 analog (BGP-15) was synthesized and examined for antiproliferative activity in the androgen-dependent cell lines of prostate cancer (LNCaP) and breast cancer (MCF-7). The new analog led to significant decrease in cell viability in cultured LNCaP and MCF-7 cell lines compared with calcipotriene and 1,25(OH)2D3. We observed elevated vitamin D receptor protein levels in both LNCaP and MCF-7 cells, which were treated with 5 micromol/l of 1,25(OH)2D3, calcipotriene or BGP-15 for 20 h, indicating vitamin D receptor-binding ability. Treatments of LNCaP and MCF-7 cells with 5 micromol/l BGP-15 and calcipotriene for 20 h generated procaspase-3 cleavage and therefore, apoptosis. Interestingly, BGP-15, and to a lesser extent calcipotriene, but not 1,25(OH)2D3, activated caspase-3 in MCF-7 cells, a cell line that normally lacks this specific caspase (and procaspase). It is presumed that management of MCF-7 with BGP-15 modulates procaspase-3 expression and cleavage, and a subsequent activation of caspase-3. Similar treatments of LNCaP cells induced procaspase-9 cleavage and therefore caspase-9 activation, whereas similar treatments of MCF-7 cells failed to induce caspase-9 activation. Cytochrome c release was, however, detected in both cell lines, LNCaP and MCF-7. In-vivo results suggested that BGP-15 (similar to its parent drug) did not cause calcium-related toxic side effects after chronic treatment.
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PMID:Induction of apoptosis and inhibition of prostate and breast cancer growth by BGP-15, a new calcipotriene-derived vitamin D3 analog. 2033 94

The molecular mechanism and possible signaling pathway of apigenin-induced cytotoxicity and apoptosis in human lung cancer cells has not been reported. We investigated the role of ROS, Ca2+, caspases and Bax proteins and mitochondria membrane potential in apigenin-induced apoptosis in A549 cells. Cells were incubated with different concentrations of apigenin then cell morphological changes, DNA damage, cell viability and apoptosis were determined by Comet assay, and flow cytometric analysis. Sub-G1 phase was also examined. Western blot analysis was used to determined the levels of Bax and Bcl-2 and apoptosis associated proteins, and confocal laser microscope for examining the translocation of associated protein after exposed to apigenin. The results indicated that apigenin induced morphological changes, decreased percentage of viable cells and induced apoptosis dose- and time-dependently. DAPI staining and Comet assay also confirmed that apigenin-induced DNA condensation and damage. The levels of caspase-3, -8 and -9 involved in apigenin-induced apoptosis indicating caspase-dependent pathway was induced by apigenin. Western blotting showed that apigenin promoted cytochrome c levels and also induced dysfunction of mitochondria leading to the release of cytochrome c, AIF and Endo G, causing the activation of caspase-9 and -3, then apoptosis in A549 cells.
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PMID:Apigenin induces caspase-dependent apoptosis in human lung cancer A549 cells through Bax- and Bcl-2-triggered mitochondrial pathway. 2042 72

Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variable periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as reperfusion injury. At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Studies in animal models of ventricular fibrillation have shown that limiting myocardial cytosolic Na+ overload attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation, which is the main bioenergetic function of mitochondria. This effect is associated with functional myocardial benefits such as preservation of myocardial compliance during chest compression and attenuation of myocardial dysfunction after return of spontaneous circulation. Additional studies in similar animal models of ventricular fibrillation have shown that mitochondrial injury leads to activation of the mitochondrial apoptotic pathway, characterized by the release of cytochrome c to the cytosol, reduction of caspase-9 levels, and activation of caspase-3 coincident with marked reduction in left ventricular function. Cytochrome c also "leaks" into the bloodstream attaining levels that are inversely proportional to survival. These data indicate that mitochondria play a key role during cardiac resuscitation by modulating energy metabolism and signaling apoptotic cascades and that targeting mitochondria could represent a promising strategy for cardiac resuscitation.
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PMID:Targeting mitochondria for resuscitation from cardiac arrest. 2044 8


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