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)

The present study was designed to assess the preventive effect of licorice compounds glycyrrhizin and 18beta-glycyrrhetinic acid against mitochondrial damage and cell death in lung epithelial cells exposed to 3-morpholinosydnonime, a donor of nitric oxide and superoxide. Treatment of lung epithelial cells with 3-morpholinosydnonime resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species and depletion of GSH. Treatment of glycyrrhizin and 18beta-glycyrrhetinic acid attenuated the 3-morpholinosydnonime-induced mitochondrial damage, formation of reactive oxygen species and GSH depletion and revealed a maximal inhibitory effect at 10 and 1 muM, respectively; beyond these concentrations the inhibitory effect declined. Melatonin, carboxy-PTIO, rutin and uric acid reduced the 3-morpholinosydnonime-induced cell death. The results show that glycyrrhizin and 18beta-glycyrrhetinic acid seem to prevent the toxic effect of 3-morpholinosydnonime against lung epithelial cells by suppressing the mitochondrial permeability transition that leads to the release of cytochrome c and activation of caspase-3. The preventive effect may be ascribed to the inhibitory action on the formation of reactive oxygen species and depletion of GSH. The findings suggest that licorice compounds seem to prevent the nitrogen species-mediated lung cell damage.
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PMID:Glycyrrhizin protection against 3-morpholinosydnonime-induced mitochondrial dysfunction and cell death in lung epithelial cells. 1734 52

Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in preventing the renal mitochondrial damage caused by cisplatin. These results strongly suggest that protection of mitochondria by hydroxyl radical scavengers may be an interesting approach to prevent the kidney tissue damage caused by cisplatin-chemotherapy.
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PMID:Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. 1739 64

Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (FAAH(-/-)) mice and their wild-type (FAAH(+/+)) littermates. Additionally, we have explored the effects of anandamide on TNF-alpha-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2- to 3-mo-old (young) FAAH(-/-) and FAAH(+/+) mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-alpha, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose)polymerase cleavage and caspase-3/9 activity, observed in 28- to 31-mo-old (aging) FAAH(+/+) mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB(1) and CB(2) receptor gene expression between young and aging FAAH(-/-) and FAAH(+/+) mice. Anandamide dose dependently attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression, NF-kappaB activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB(1)- and CB(2)-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis.
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PMID:Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. 1743 80

3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a psychoactive and hallucinogenic drug of abuse. MDMA has been shown to produce neurotoxicity both in animals and humans. MDMA and other amphetamines induce serotonergic and dopaminergic terminal neurotoxicity and also neurodegeneration in areas including the cortex, hippocampus, striatum and thalamus. Herein, we investigated the mechanisms involved in MDMA-induced neurotoxicity to neuronal serum free cultures from rat cortex. The hyperthermic effect produced by MDMA has been shown to be a clinically relevant aspect for the neurotoxic events. Thus, MDMA-induced toxicity to cortical neurons was evaluated both under normothermic (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings showed that MDMA produced neuronal apoptosis, accompanied by activation of caspase 3, in a concentration dependent manner. MDMA neurotoxicity was completely prevented by pre-treatment with a 5-HT(2A)-receptor antibody, which acted as an "irreversible non-competitive antagonist" of this receptor. Furthermore, MDMA depleted intracellular glutathione (GSH) levels in a concentration dependent manner, an effect that was attenuated by Ketanserin, a competitive 5-HT(2A)-receptor antagonist. Accordingly, N-acetylcysteine, an antioxidant and GSH precursor, also reduced MDMA-induced toxicity. Specific inhibitors of the inducible and neuronal nitric oxide synthase (NOS) partially prevented MDMA neurotoxicity, ascertaining the involvement of reactive nitrogen species, in the toxic effect. In conclusion, direct MDMA 5-HT(2A)-receptor stimulation produces intracellular oxidative stress that leads to neuronal apoptosis accompanied by caspase 3 activation.
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PMID:Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons. 1757 1

Liver ischemia/reperfusion has been shown to result in injury of remote organs such as the heart and lungs. Whether or not acute liver injury also results in kidney injury has so far not been adequately addressed. In anesthetized Wistar rats, partial (70%) normothermic hepatic ischemia was applied for 75 min. After 24 h of reperfusion, renal injury was assessed by histology, creatinine and blood urea nitrogen (BUN) serum concentrations, renal expression of proinflammatory genes [quantitative real-time polymerase chain reaction (qRT-PCR)], caspase-3 activation (Western blot), and neutrophil accumulation (myeloperoxidase assay). Twenty-four hours after hepatic ischemia, creatinine (0.57+/-0.06 vs. 0.32+/-0.04 mg/dL) and BUN (40.7+/-15.3 vs. 14.3+/-2.0 mg/dL) were increased when compared to sham. qRT-PCR revealed higher renal intercellular adhesion molecule-1 gene expression following hepatic ischemia (166+/-45% when compared to sham) but no differences in renal monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and inducible NO synthase expression. In both groups, kidneys showed no morphological damage and no increase in caspase-3 and myeloperoxidase activity. Severe hepatic ischemia results in a moderate impairment of renal function in rats but does not trigger an inflammatory response in the kidney and does not result in morphological damage of the kidney.
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PMID:Remote renal injury following partial hepatic ischemia/reperfusion injury in rats. 1770 Oct 74

There is mounting evidence implicating the accumulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on hydrogen-peroxide- and peroxynitrite-induced oxidative cell death. PC12 rat pheochromocytoma (PC12) cells treated with hydrogen peroxide or SIN-1 (a peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of poly(ADP-ribose)polymerase (PARP). Piceatannol treatment attenuated hydrogen-peroxide- and peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of caspase-3 and -8, which were also inhibited by piceatannol treatment. Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the c-Jun-N-terminal kinase (JNK), which was inhibited by piceatannol treatment. Moreover, SP600125 (a JNK inhibitor) significantly inhibited hydrogen-peroxide- and peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.
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PMID:Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK. 1786 87

A successful pathogen manipulates its host for its own benefit. After ingestion, on reaching the intestine Salmonella encounters the resident tissue macrophages. Rather than being destroyed by these professional phagocytes after internalization, Salmonella survives intracellularly. Invasive Salmonella has been reported to induce apoptosis of macrophages as a part of its infection process, which may allow it to avoid detection by the innate immune system. However, the induction of apoptosis under different host environments, including the anaerobic stress encountered by the pathogen in the gut, remains to be examined. The present study is aimed at investigating the apoptotic potential of S. enterica serovar Typhi (S. typhi) grown under anaerobic conditions simulating the in vivo situation encountered by the pathogen. Apoptotic cell death was determined by assessment of nucleosomal DNA and flow cytometric analysis. Evaluation of the data revealed that anaerobically grown S. typhi could induce apoptosis in significantly more number of macrophages compared to the bacterial cells grown under aerobic conditions. A significantly enhanced generation of reactive nitrogen intermediates and caspase-3 activity during macrophage apoptosis induced by anaerobic S. typhi correlated with the increased generation of tumour necrosis factor-alpha, interleukin (IL)-1alpha and IL-6. The results indicate that reactive nitrogen intermediates and monokines induce caspase-3 mediated apoptosis of macrophages by S. typhi under anaerobic conditions. These findings may be relevant for clearer understanding of the Salmonella-macrophage interactions and may be of clinical importance in the development of preventive intervention against the infection.
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PMID:Reactive nitrogen intermediates and monokines induce caspase-3 mediated macrophage apoptosis by anaerobically stressed Salmonella typhi. 1788 27

Lignin is a durable aromatic network polymer that is second only to cellulose in natural abundance. Lig-8, a lignophenol derivative from bamboo lignin, is a highly potent neuroprotectant. It protects human neuroblastoma cells (SH-SY5Y) from hydrogen peroxide (H2O2)-induced apoptosis by preventing caspase-3 activation via either caspase-8 or caspase-9. It exerts this antiapoptotic effect by protecting mitochondrial membrane permeability from damage by H2O2 or the peripheral benzodiazepine receptor ligand PK11195. Lig-8 has been also shown to scavenge the reactive oxygen or nitrogen species in vitro. Furthermore, lig-8 suppresses apoptosis induced by oxygen-glucose deprivation, tunicamycin (endoplasmic reticulum [ER]-stress inducer), or proteasome inhibitor in pheochromocytoma cells. In addition, in vivo, lig-8 reduced intravitreal N-methyl-D-aspartate-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness) in mice. Lig-8 prevents neuronal damage partly by inhibiting excessive endoplasmic reticulum stress. In this article, we review the protective effects of lig-8 against apoptosis induced by various stimuli. Apoptosis is an active, energy-dependent process through which living cells initiate their own death. It can be induced by a variety of physiological and pharmacological stimuli. Apoptotic cell death is associated with neurodegenerative disorders such as Alzheimer, Parkinson, or Huntington disease as well as glaucoma. We believe that the elucidation of the mechanism of antiapoptotic action of lig-8 may help in finding new approaches to the treatment of neurodegenerative disorders.
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PMID:Lig-8, a highly bioactive lignophenol derivative from bamboo lignin, exhibits multifaceted neuroprotective activity. 1789 46

Nephrotoxicity is a frequent complication of cisplatin-based chemotherapy often limiting its use. In this study, we attempted to the role of the phosphoinositide-3 kinase (PI3K)-gamma-Akt pathway in this form of acute kidney injury. Using PI3K-gamma knockout mice, we found that a conventional dose of cisplatin was more lethal in the knockout mice where the blood urea nitrogen and serum creatinine were significantly higher in them than in wild-type mice. Phosphorylation of Akt in the renal tubules was abrogated in the knockout mice with the severity of renal dysfunction and numbers of TUNEL (terminal deoxynucleotidyl transferase (TdT) mediated nick-end labeling)-positive renal tubule cells being higher in the knockout than in wild-type mice. Cisplatin treatment significantly increased. Caspase-3 activity, histone-associated DNA fragments, and number of annexin V-positive cells was significantly higher in cisplatin-treated primary cultured renal tubular epithelial cells of knockout mice. Transfection of dominant-active forms of Akt and PI3K-gamma ameliorated apoptosis of the tubule epithelial cells derived from the knockout mice. Our results suggest that the PI3K-gamma-Akt pathway lessens apoptosis and plays a critical role in the maintenance of renal function in cisplatin-induced acute kidney injury.
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PMID:The phosphoinositide-3 kinase gamma-Akt pathway mediates renal tubular injury in cisplatin nephrotoxicity. 1804 17

Renal ischemia was induced in the rat by constriction of the renal artery for 45 min, and the ability of the ATP-sensitive K(+) (K(ATP)) channel opener diazoxide (DZ) to ameliorate renal ischemia-reperfusion (I/R) injury was evaluated. In this model, blood urea nitrogen and creatinine were elevated 2 days after I/R injury but returned closer to normal levels by 7 days after reperfusion. Histological staining for reactive oxygen species (ROS) was clearly positive and oxidized DNA, detected by the presence of the stable adduct 8-hydroxy-2'-deoxyguanosine, was clearly present in the cytoplasm of tubular cells after 1 h of reperfusion and declined 7 days after reperfusion. This finding was confirmed by ELISA, which detected 8-hydroxy-2'-deoxyguanosine in the mitochondrial fraction of kidney homogenates. Despite evidence of improved function measured by blood urea nitrogen and creatinine 7 days after reperfusion, the early changes in tubules were alarming. Mitochondrial DNA showed the common deletion, and the number of TdT-mediated dUTP nick-end label-positive tubular cells increased. Activation of caspase-3 continued, and abnormal levels of ROS were found in the mitochondrial fraction of cellular homogenates. Treatment with DZ before ischemia reduced or prevented the acute and subacute deleterious effects associated with renal I/R injury. We conclude that excess production of ROS by mitochondria on reperfusion is a major upstream event in renal reperfusion injury and that DZ functioned by preventing ROS accumulation in the mitochondria after I/R injury, thereby reducing oxidative stress as measured by the presence of oxidized mitochondrial DNA and features of apoptosis.
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PMID:Amelioration of oxidative mitochondrial DNA damage and deletion after renal ischemic injury by the KATP channel opener diazoxide. 1816 Jun 22


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