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)

Beta-elemene is an active component of herb medicine Curcuma Wenyujin and N-(beta-elemene-13-yl)tryptophan methyl ester (ETME) was synthesized for increasing its antitumor activity. ETME induced apoptosis in human leukemia HL-60 and NB4 cells at concentrations less than 40 microM. The apoptosis induction ability of ETME was associated with the production of hydrogen peroxide (H(2)O(2)), the decrease of mitochondrial membrane potential, and the activation of caspase-3 that was blocked by catalase. ETME in combination with arsenic trioxide (As(2)O(3)), an agent used to treat acute promyelocytic leukemia, synergistically induced apoptosis in both cell lines by enhanced production of H(2)O(2). These data suggest that ETME induces apoptosis and synergizes with As(2)O(3) in leukemia cells through a H(2)O(2)-dependent pathway.
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PMID:N-(beta-Elemene-13-yl)tryptophan methyl ester induces apoptosis in human leukemia cells and synergizes with arsenic trioxide through a hydrogen peroxide dependent pathway. 1853 21

The essential amino acid tryptophan is primarily metabolised through the kynurenine pathway, some components of which may be neurotoxic. We have now examined the potential toxicity of several kynurenine metabolites in relation to the generation of oxidative stress and activation of cell death signalling pathways in cultured cerebellar granule neurons. 3-Hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA) and 5-hydroxyanthranilic acid (5HAA) induced cell death which increased with exposure time and compound concentration. The neurotoxic effects of 3HK, 3HAA and 5HAA were prevented by catalase, but not by superoxide dismutase. In addition, Western blot analysis demonstrated p38 activation due to 3HK or 5HAA treatment, although caspase-3 activation was not evident in either case. The results indicate that kynurenine metabolites can be neurotoxic via a caspase-3 independent mechanism, and that the minor metabolite 5HAA is as potent a toxin as the better documented compounds 3HK and 3HAA.
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PMID:5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones. 1938 64

Free radicals are involved in pathophysiology of ischemia/reperfusion injury (IRI). Melatonin is a potent scavenger of reactive oxygen and nitrogen species. Thus, this study was designed to elucidate its effects in a model of rat kidney transplantation. Twenty Lewis rats were randomly divided into 2 groups (n = 10 animals each). Melatonin (50 mg/kg BW) dissolved in 5 mL milk was given to one group via gavage 2 hr before left donor nephrectomy. Controls were given the same volume of milk only. Kidney grafts were then transplanted into bilaterally nephrectomized syngeneic recipients after 24 hr of cold storage in Histidine-Tryptophan-Ketoglutarate solution. Both graft function and injury were assessed after transplantation through serum levels of blood urea nitrogen (BUN), creatinine, transaminases, and lactate dehydrogenase (LDH). Biopsies were taken to evaluate tubular damage, the enzymatic activity of superoxide dismutase (SOD) and lipid hydroperoxide (LPO), and the expression of NF-kBp65, inducible nitric oxide synthase (iNOS), caspase-3 as indices of oxidative stress, necrosis, and apoptosis, respectively. Melatonin improved survival (P < 0.01) while decreasing BUN, creatinine, transaminases, and LDH values up to 39-71% (P < 0.05). Melatonin significantly reduced the histological index for tubular damage, induced tissue enzymatic activity of SOD while reducing LPO. At the same time, melatonin down-regulated the expression of NF-kBp65, iNOS, and caspase-3. In conclusion, donor preconditioning with melatonin protected kidney donor grafts from IRI-induced renal dysfunction and tubular injury most likely through its anti-oxidative, anti-apoptotic and NF-kB inhibitory capacity.
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PMID:Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. 1955 59

The continuous shortage of organs necessitates the use of marginal organs from donors with various diseases, including arrhythmia-associated cardiac failure. One of the most frequently used anti-arrhythmic drugs is amiodarone (AM), which is given in particular in emergency situations. Apart from its anti-arrhythmic actions, AM provides anti-oxidative properties in cardiomyocytes. Thus, we were interested in whether AM donor pretreatment affects the organ quality and function of livers procured for preservation and transplantation. Donor rats were pretreated with AM (5 mg/kg of body weight) 10 minutes before flush-out of the liver with a cold (4 degrees C) histidine-tryptophan-ketoglutarate solution (n = 8). Livers were then stored for 24 hours at 4 degrees C before ex situ reperfusion with a 37 degrees C Krebs-Henseleit solution for 60 minutes in a nonrecirculating system. At the end of reperfusion, tissue samples were taken for histology and Western blot analysis. Animals with vehicle only (0.9% NaCl) served as ischemia/reperfusion controls (n = 8). Additionally, livers of untreated animals (n = 8) not subjected to 24 hours of cold ischemia served as sham controls. AM pretreatment effectively attenuated lipid peroxidation, stress protein expression, and apoptotic cell death. This was indicated by an AM-mediated reduction of malondialdehyde, heme oxygenase-1, and caspase-3 activation. However, AM treatment also induced mitochondrial damage and hepatocellular excretory dysfunction, as indicated by a significantly increased glutamate dehydrogenase concentration in the effluate and decreased bile production. In conclusion, AM donor pretreatment exerts anti-oxidative actions in liver preservation and reperfusion. However, these protective AM actions are counteracted by an induction of mitochondrial damage and hepatocellular dysfunction. Accordingly, AM pretreatment of donors for anti-arrhythmic therapy should be performed with caution.
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PMID:Amiodarone pretreatment of organ donors exerts anti-oxidative protection but induces excretory dysfunction in liver preservation and reperfusion. 1956 10

Fatty livers are particularly susceptible to mitochondrial alterations after cold preservation. We thus aimed to improve graft integrity by brief hypothermic oxygenation prior to warm reperfusion. Macrovesicular steatosis was induced in rat livers by fasting and subsequent feeding of a fat-free diet enriched with carbohydrates. Fatty livers were retrieved and stored ischemically at 4 degrees C for 20 hours in histidine-tryptophan-ketoglutarate solution. Hypothermic reconditioning (HR) was performed in some livers by insufflation of gaseous oxygen via the caval vein during the last 90 minutes of preservation. Viability was assessed upon isolated reperfusion. HR resulted in a significant (approximately 5-fold) reduction of parenchymal (alanine aminotransferase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzyme release. Functional recovery (bile production, oxygen consumption, and tissue levels of adenosine triphosphate) was significantly improved by HR. In untreated grafts, cellular autophagy (cleavage of LC3B and protein expression of beclin-1) was significantly impaired (<50% of baseline) after preservation/reperfusion but was restored to normal values by HR. HR also increased cleavage of caspase 9 (P < 0.5) and caspase 3 enzyme activity (by a factor of 1.5). In contrast, histological signs of tissue necrosis were abundant after reperfusion in untreated livers and largely abrogated in reconditioned livers. In conclusion, HR limits mitochondrial defects and restores basal rates of cellular autophagy. This may represent a rescue mechanism for maintaining cellular homeostasis and tissue survival.
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PMID:Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning. 1956 17

Delayed graft function still represents a major complication in clinical kidney transplantation. Here we tested the possibility to improve functional outcome of cold stored kidneys a posteriori by short-term hypothermic machine perfusion immediately prior to reperfusion. A total of 18 kidneys from female German Landrace pigs was flushed with Histidine-Tryptophan-Ketoglutarate solution and cold-stored for 18 h (control). Some grafts were subsequently subjected to 90 min of hypothermic reconditioning by hypothermic machine perfusion with (HR+O(2)) or without (HR-O(2)) oxygenation of the perfusate. Early graft function of all kidneys was assessed thereafter by warm reperfusion in vitro (n = 6, respectively). Renal function upon reperfusion was significantly enhanced by HR+O(2) with more than threefold increase in renal clearances of creatinine and urea. HR+O(2) also led to significantly higher urinary flow rates and abrogated the activation of caspase 3. By contrast, HR-O(2) was far less effective and only resulted in minor differences compared to control. It is derived from the present data that initial graft function can be significantly improved by 2 h of oxygenated machine perfusion after arrival of the preserved organ in the transplantation clinic.
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PMID:Hypothermic reconditioning after cold storage improves postischemic graft function in isolated porcine kidneys. 1995 72

5-Hydroxyindole (5HI), a metabolite of tryptophan, is involved in learning and memory, central neuron system regulation, and anti-oxidant activity. However, its protective action in mitochondrial function is not clear. Here, we tested whether 5HI protects against tert-butylhydroperoxide (t-BHP)-induced oxidative damage and mitochondrial dysfunction in human fibroblast cells. 5HI significantly suppressed t-BHP-induced cytotoxicity as determined by intracellular reactive species generation, lipid peroxidation, glutathione depletion, and peroxynitrite (ONOO(-)) generation. In addition, 5HI reduced t-BHP-induced DNA condensation. Pretreatment with 5HI significantly restored mitochondrial membrane potential (Deltapsim), suggesting that it protected cells against t-BHP-induced apoptosis. Western blot analysis also revealed that 5HI markedly inhibited cytochrome c release and caspase-3 activation, but not caspase-9 activation. Our data suggest that 5HI protects cells by attenuating oxidative stress and consequently protects against mitochondrial dysfunction.
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PMID:The anti-apoptotic action of 5-hydroxyindole: protection of mitochondrial integrity. 2041 May 84

Interferon-gamma (IFN-gamma) is known to cause apoptosis of lens epithelial cells and cataract formation, but the molecular mechanisms underlying these effects are unknown. IFN-gamma induces the expression of indoleamine 2,3-dioxygenase (IDO) and thereby enhances the production of kynurenines from l-tryptophan. The present study was designed to investigate the role of IDO and kynurenines in the IFN-gamma-mediated apoptosis of lens epithelial cells and to determine the signaling pathways involved. IFN-gamma stimulated the synthesis of IDO and activated the JAK-STAT1 signaling pathway in human lens epithelial cells (HLE-B3) in a dose-dependent manner. Meanwhile, fludarabine, an inhibitor of STAT1 activation, blocked IFN-gamma-mediated IDO expression. N-Formylkynurenine, kynurenine (Kyn) and 3-hydroxykynurenine (3OHKyn) were detected in cells, with 3OHKyn concentrations being higher than those of the other kynurenines. The intracellular production of kynurenines was completely blocked by 1-methyl-DL-tryptophan (MT), an inhibitor of IDO. Kyn- and 3OHKyn-modified proteins were detected in IFN-gamma-treated cells. The induction of IDO by IFN-gamma in HLE-B3 cells caused increases in intracellular ROS, cytosolic cytochrome c and caspase-3 activity, along with a decrease in protein-free thiol content. These changes were accompanied by apoptosis. At equimolar concentrations, 3OHKyn caused higher levels of apoptosis than the other kynurenines in HLE-B3 cells. MT and a kynurenine 3-hydroxylase inhibitor (Ro61-8048) effectively inhibited IFN-gamma-mediated apoptosis in HLE-B3 cells. Our results show that the induction of IDO by IFN-gamma is JAK-STAT1 pathway-dependent and that this induction causes 3OHKyn-mediated apoptosis in HLE-B3 cells. These data suggest that IDO-mediated kynurenine formation could play a role in cataract formation related to chronic inflammation.
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PMID:Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human lens epithelial cells: apoptosis through the formation of 3-hydroxykynurenine. 2043 58

Recent studies have shown that indoleamine 2,3-dioxygenase (IDO) plays a pivotal role in the modulation of immune response against tumor and virus infection. Here we demonstrate the pro-apoptotic effect of L-kynurenine, a tryptophan catabolite of IDO, on human NK cell line, NK92 MI. Treatment with L-kynurenine dose-dependently induced growth inhibition and apoptosis in NK92 MI cells. Treatment with the antioxidant NAC completely protected cells from L-kynurenine-induced apoptosis. Moreover, we found that treatment with Z-VAD-fmk and ZB4 slightly inhibited L-kynurenine-induced apoptosis, suggesting that L-kynurenine-induced apoptosis in NK cells occurs primarily through an ROS mediated pathway. We observed that the presence of NAC blocks cytochrome c release and activation of caspase-3 during L-kynurenine-induced apoptosis. Overall, we conclude that L-kynurenine resulting from IDO can cause cell death via ROS pathway in NK cells. Our findings provide a new insight into the interaction between NK cells and IDO positive cancer cells in regulating immune responses.
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PMID:L-kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species. 2135 63

Various apoptotic signals can activate caspases 3 and 7 by triggering the L2 loop cleavage of their proenzymes. These two enzymes have highly similar structures and functions, and serve as apoptotic executioners. The structures of caspase 7 and procaspase 7 differ significantly in the conformation of the loops constituting the active site, indicating that the enzyme undergoes a large structural change during activation. To define the role of the leucine residue on the L2 loop, which shows the largest movement during enzyme activation but has not yet been studied, Leu168 of caspase 3 and Leu191 of caspase 7 were mutated. Kinetic analysis indicated that the mutation of the leucine residues sometimes improved the Km but also greatly decreased the kcat, resulting in an overall decrease in enzyme activity. The tryptophan fluorescence change at excitation/emission = 280/350 nm upon L2-L2' loop cleavage was found to be higher in catalytically active mutants, including the corresponding wild-type caspase, than in the inactive mutants. The crystal structures of the caspase 3 mutants were solved and compared with that of wild-type. Significant alterations in the conformations of the L1 and L4 loops were found. These results indicate that the leucine residue on the L2 loop has an important role in maintaining the catalytic activity of caspases 3 and 7.
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PMID:Molecular insight into the role of the leucine residue on the L2 loop in the catalytic activity of caspases 3 and 7. 2230 5


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