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

Sudden death syndrome (SDS) in fast growing broiler chickens has been recognized as a patho-physiological entity for four decades, but its pathogenesis still remains unknown. More recent investigations provided evidence that link SDS to cardiac arrhythmia, but the mechanism triggering arrhythmogenesis and factors responsible for fatal outcome are poorly understood. In order to understand the chain of events leading to SDS in broilers, the present study focused on putative mechanisms that trigger arrhythmia and mechanisms that predispose the myocardium to fatal arrhythmia. Susceptibility of broilers to cardiac arrhythmia under stress conditions was evaluated using a simulated stress test with epinephrine. Detailed histopathological evaluation of the broiler heart was undertaken to identify structural features that may predispose the myocardium to fatal arrhythmia. The simulated stress challenge revealed that many broilers are highly susceptible to stress induced cardiac arrhythmia. In some broilers the stress challenge induced severe ventricular arrhythmia, and the life threatening nature of this arrhythmia was evidenced by the fact that several birds showing the most severe arrhythmic responses, died suddenly within several days after the stress challenge. Examination of hearts of broilers that died of SDS revealed microscopic lesions in the cardiomyocytes, and widespread changes in the sub-endocardial and mural His-Purkinje system (HPS). Immune staining for Caspase-3 confirmed that numerous Purkinje cells in the left ventricular myocardium from broiler chickens that died of SDS were undergoing apoptosis. The observed lesions suggest that the electrical stability of the myocardium was compromised. Taken together, our findings indicate that stress is a most likely trigger of cardiac arrhythmia in broilers, whereas the pathological changes seen in the myocardium and in the HPS in fast growing broilers provide a very conducive milieu for sustained ventricular arrhythmia. In cases where the electrical stability of the myocardium is compromised, even an episodic arrhythmic event may readily degenerate to catastrophic ventricular fibrillation and sudden death. We conclude that the combination of stress and changes in the cardiomyocytes and HPS are the key requisite features in the pathogenesis of SDS.
 ...
PMID:A study on pathogenesis of sudden death syndrome in broiler chickens. 1790 71

(2S)-1-(4-Amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate (SUN N8075) is a novel antioxidant with neuroprotective properties. We examined whether SUN N8075 inhibited the neuronal damage resulting from permanent focal cerebral ischemia, and examined its neuroprotective properties in vivo and in vitro mechanism. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice, and the resulting infarction, brain swelling, and neurological deficits were evaluated after 24 h or 72 h. Brain damage was assessed histochemically using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and antibody recognizing 4-hydroxynonenal histidine adduct (4-HNE). In the in vitro study, we examined the effects of SUN N8075 on 1) lipid peroxidation in mouse brain homogenates and 2) cell viability and caspase-3 protease activity under a hypoxic insult or FeSO(4) in rat cultured cerebrocortical neurons. SUN N8075 administered either 10 min before or at 1 h after the occlusion reduced both infarction size and neurological deficits. SUN N8075 reduced brain swelling when administered 10 min before, 1 h, or 3 h after occlusion. Furthermore, only pretreatment (administered 10 min before) decreased infarct volume and brain swelling at 72 h after middle cerebral artery occlusion. SUN N8075 reduced the number of TUNEL-positive cells and decreased the level of oxidative damage, as assessed by immunopositive staining to 4-HNE. SUN N8075 inhibited lipid peroxidation, leakage of lactate dehydrogenase, caspase-3 activation induced by in vitro hypoxia, and the neuronal damage induced by in vitro FeSO(4) exposure. These findings indicate that SUN N8075 has neuroprotective effects against acute ischemic neuronal damage in mice and may prove promising as a therapeutic drug for stroke.
 ...
PMID:Prevention of in vitro and in vivo acute ischemic neuronal damage by (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate (SUN N8075), a novel neuroprotective agent with antioxidant properties. 1794 33

In this study, we investigated the induction of apoptosis by ultrasound in the presence of a photochemically active chlorin, mono-l-aspartyl chlorin e6 (NPe6). HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of NPe6, and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Cells treated with 80 microM NPe6 and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound alone, at the same intensity, or NPe6 alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and NPe6 but not in cells treated with ultrasound or NPe6 alone. In addition, NPe6 substantially enhanced nitroxide generation by ultrasound in the same acoustical arrangement. Sonodynamically-induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. These results suggest that the combination of ultrasound and NPe6 sonochemically induces apoptosis as well as necrosis in HL-60 cells. They further suggest that some ultrasonically-generated active species, deactivatable by histidine, are the major mediators to induce the observed apoptosis.
 ...
PMID:Sonodynamically-induced apoptosis, necrosis, and active oxygen generation by mono-l-aspartyl chlorin e6. 1797 Jul 84

Recently, the endoplasmic reticulum (ER) has been disclosed as subcellular target reactive to ischaemia/reperfusion and possibly influenced by hypothermic machine preservation. Here, the respective role of perfusate, perfusion itself, and the effect of continuous oxygenation to trigger ER-stress in the graft should be investigated. Livers were retrieved 30 min after cardiac arrest of male Wistar rats and preserved by cold storage (CS) in histidine-tryptophan-ketoglutarate (HTK) for 18 h at 4 degrees C. Other organs were subjected to aerobic conditions either by oxygenated machine perfusion with HTK (MP-HTK) or Belzer solution (MP-Belzer) at 4 degrees C or by venous insufflation of gaseous oxygen during cold storage (VSOP). Viability of livers was evaluated upon reperfusion in vitro according to previously validated techniques for 120 min at 37 degrees C. Oxygenation during preservation (MP-HTK, MP-Belzer or VSOP) concordantly improved functional recovery (bile flow, ammonia clearance), reduced parenchymal enzyme leakage and histological signs of necrosis and significantly attenuated mitochondrial induction of apoptosis (cleavage of caspase 9) compared to CS. However, MP with either medium produced about 500% elevated protein expression of CHOP/GADD153, suggesting pro-apoptotic ER-stress responses, paralleled by a significant elevation of caspase-12 enzyme activity compared to CS or VSOP. Although MP also promoted a slight (20%) induction of the cytoprotective ER-protein Bax inhibitor protein (BI-1), prevailing of proapoptotic reactions was seen by increased cleavage of caspase-3 and poly (ADP-Ribase)-polymerase (PARP) in both MP-groups. Endoplasmic stress activation is conjectured a specific side effect of long-term machine preservation irrespective of the medium, actually promoting cellular apoptosis via activation of caspase-12. The simple insufflation of gaseous O2 may be considered a feasible alternative, apparently indifferent to the endoplasmic reticulum.
 ...
PMID:Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver. 1800 84

Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of L-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of L-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery (n=18), surgical brain injury without treatment (SBI) (n=33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI+H) (n=29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. L-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI+H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood-brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI+H groups, similar histological outcomes between SBI and SBI+H, and similar qualitative staining for cleaved caspase 3. SBI+H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.
 ...
PMID:Role of histamine in brain protection in surgical brain injury in mice. 1834 55

Oxidative glutamate toxicity in HT22 murine hippocampal cells is a model for neuronal death by oxidative stress. We have investigated the role of proteases in HT22 cell oxidative glutamate toxicity. L-glutamate-induced toxicity was characterized by cell and nuclear shrinkage and chromatin condensation, yet occurred in the absence of either DNA fragmentation or mitochondrial cytochrome c release. Pretreatment with the selective caspase inhibitors either benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (pan-caspase), N-acetyl-Leu-Glu-His-Asp-aldehyde (caspase 9) or N-acetyl-Ile-Glu-Thr-Asp-aldehyde (caspase 8), significantly increased L-glutamate-induced cell death with a corresponding increase in observed nuclear shrinkage and chromatin condensation. This enhancement of glutamate toxicity correlated with an increase in L-glutamate-dependent production of reactive oxygen species (ROS) as a result of caspase inhibition. Pretreating the cells with N-acetyl-L-cysteine prevented ROS production, cell shrinkage and cell death from L-glutamate as well as that associated with the presence of the pan-caspase inhibitor. In contrast, the caspase-3/-7 inhibitor N-acetyl-Asp-Glu-Val-Asp aldehyde was without significant effect. However, pretreating the cells with the calpain inhibitor N-acetyl-Leu-Leu-Nle-CHO, but not the cathepsin B inhibitor CA-074, prevented cell death. The cytotoxic role of calpains was confirmed further by: 1) cytotoxic dependency on intracellular Ca(2+) increase, 2) increased cleavage of the calpain substrate Suc-Leu-Leu-Val-Tyr-AMC and 3) immunoblot detection of the calpain-selective 145 kDa alpha-fodrin cleavage fragment. We conclude that oxidative L-glutamate toxicity in HT22 cells is mediated via calpain activation, whereas inhibition of caspases-8 and -9 may exacerbate L-glutamate-induced oxidative neuronal damage through increased oxidative stress.
 ...
PMID:Opposing roles for caspase and calpain death proteases in L-glutamate-induced oxidative neurotoxicity. 1868 50

Danshen (DS) is used for treatment of various ischemic events in the traditional Chinese medicine. Hence, this study was designed to investigate its effect on ischemia/reperfusion injury (IRI) after experimental kidney transplantation (eKTx). Nephrectomized Sprague-Dawley rats underwent eKTx. Some animals were infused with 1.5 ml DS 10 min before surgery. Kidney grafts were transplanted after cold storage for 20 h in Histidine-Tryptophane-Ketoglutarate solution. After reperfusion blood samples were collected for blood urinary nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and alanine transaminase. Further, tissue was assessed for morphologic and pathophysiologic changes. Donor preconditioning with DS (DS-d) significantly decreased BUN, creatinine, LDH, and aspartate aminotransferase to 65-97% of controls while preconditioning of the recipient (DS-r) decreased values to 58-82% (P < 0.05). Tubular damage and caspase-3 decreased significantly in both DS-d and DS-r (DS-d: 96% and 67%, DS-r: 83% and 75% of controls) while heat shock protein 72 and superoxide dismutase increased significantly (DS-d: 143% and 173%, DS-r: 166% and 194% of controls). Further, inducible nitric oxide synthase and tumor necrosis factor-alpha decreased (DS-d: 84% and 61%, DS-r: 79% and 67% of controls) after DS. Preconditioning of both donors and recipients with DS significantly reduces IRI and thus improves graft function after eKTx.
 ...
PMID:Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation. 1895 74

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.
 ...
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.
 ...
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.
 ...
PMID:Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning. 1956 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>