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)

A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 related peripheral neuropathic pain.
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PMID:Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. 1743 46

Organ dysfunction secondary to ischemia-reperfusion (I/R) injury still represents a major problem in liver transplantation. Apoptosis has been observed in hepatocytes and sinusoidal endothelial cell, following I/R injury and it has been postulated as a contributing factor in ischemia-reperfusion graft dysfunction, involving a complex series of events, as changes of protein tyrosine-kinase phosphorylation. We evaluated hepatic purine metabolites, protein tyrosine phosphatases (PTPs), nitrate plus nitrite levels (NOx), caspase-3 (C-3) activity and DNA fragmentation in the time course of twelve pig orthotopic liver transplantation. Biopsies were taken before explantation (t0), after cold ischemic storage (t1) and 30 min from reperfusion (t2). During the ischemic period we observed a reduction of high energy phosphates and an increase of purine bases; PTP activity was largely increased. At t2 high energy phosphates showed a tendency to increase with respect to t1, with a partial restoration of phosphorylation potential, measured as ATP/ADT ratio. PTP activity was significantly reduced, with a concomitant increase of NOx production and C-3 activity; in a considerable number of cases we observed a sustained DNA fragmentation. We speculate that NOx production could be related to nitrosative stress, which in turn leads to dynamic alteration in PTP balance and cell signalling, regulating the activity of a number of proteins implicated in apoptotic cell death. These findings could be of interest in new potential strategy to prevent and treat I/R injury.
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PMID:Nitric oxide generation is associated with an unbalance of protein tyrosine phosphatases during liver transplantation. 1746 55

Successive bouts of endurance exercise are associated with both increased cardiac levels of heat shock protein-72 (HSP-72) and improved cardioprotection against ischemia-reperfusion (I/R)-induced cardiac cell death. Although overexpression of HSP-72 has been shown to be cardioprotective in transgenic animals, it is unclear whether increased levels of HSP-72 are essential for exercise-induced cardioprotection against I/R-mediated cell death. We tested the hypothesis that exercise-induced increases in myocardial levels of HSP-72 are required to achieve exercise-mediated protection against I/R-induced cardiac cell death. To test this postulate, we investigated the effect of preventing the exercise-induced increase in cardiac HSP-72 on myocardial infarction and apoptosis after 50 min of in vivo ischemia and 120 min of reperfusion. Adult male rats remained sedentary or performed successive bouts of endurance exercise in cold (8 degrees C) or warm (22 degrees C) environments. We found that, compared with sedentary control animals, exercise in a warm environment significantly increased myocardial HSP-72 content. In contrast, exercise in the cold environment prevented the exercise-induced increase in myocardial HSP-72 levels. After in vivo myocardial I/R, infarct size was reduced in both exercised groups compared with sedentary animals. Furthermore, compared with sedentary rats, I/R-induced myocardial apoptosis (as indicated by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive nuclei and caspase-3 activity) was attenuated in both groups of exercised animals. Therefore, although HSP-72 has cardioprotective properties, our results reveal that increased myocardial levels of HSP-72 (above control) are not essential for exercise-induced protection against I/R-induced myocardial infarction and apoptosis.
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PMID:Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis. 1756 68

The herpes simplex virus type 1 (HSV-1) latency associated transcript (LAT) gene's anti-apoptosis activity plays a central, but not fully elucidated, role in enhancing the virus's reactivation phenotype. In transient transfection experiments, LAT increases cell survival following an apoptotic insult in the absence of other HSV-1 genes. However, the high background of untransfected cells has made it difficult to demonstrate that LAT inhibits specific apoptotic factors such as caspases. Here we report that, in mouse neuroblastoma cell lines (C1300) stably expressing high levels of LAT, cold shock induced apoptosis was blocked as judged by increased survival, protection against DNA fragmentation (by DNA ladder assay), and inhibition of caspase 3 cleavage and activation (Western blots). To our knowledge, this is the first report providing direct evidence that LAT blocks two biochemical hallmarks of apoptosis, caspase 3 cleavage and DNA laddering, in the absence of other HSV-1 gene products.
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PMID:Stable cell lines expressing high levels of the herpes simplex virus type 1 LAT are refractory to caspase 3 activation and DNA laddering following cold shock induced apoptosis. 1772 10

Ischemia/reperfusion injury (IRI) remains an important problem in clinical transplantation. Following ischemia, phosphatidylserine (PS) translocates to surfaces of endothelial cells (ECs) and promotes the early attachment of leukocytes/platelets, impairing microvascular blood flow. Diannexin, a 73 KD homodimer of human annexin V, binds to PS, prevents attachment of leukocytes/platelets to EC, and maintains sinusoidal blood flow. This study analyzes whether Diannexin treatment can prevent cold IRI in liver transplantation. Rat livers were stored at 4 degrees C in UW solution for 24 h, and then transplanted orthotopically (OLT) into syngeneic recipients. Diannexin (200 microg/kg) was infused into: (i) donor livers after recovering and before reperfusion, (ii) OLT recipients at reperfusion and day +2. Controls consisted of untreated OLTs. Both Diannexin regimens increased OLT survival from 40% to 100%, depressed sALT levels, and decreased hepatic histological injury. Diannexin treatment decreased TNF-alpha, IL-1beta, IP-10 expression, diminished expression of P-selectin, endothelial ICAM-1, and attenuated OLT infiltration by macrophages, CD4 cells and PMNs. Diannexin increased expression of HO-1/Bcl-2/Bcl-xl, and reduced Caspase-3/TUNEL+ apoptotic cells. Thus, by modulating leukocyte/platelet trafficking and EC activation in OLTs, Diannexin suppressed vascular inflammatory responses and decreased apoptosis. Diannexin deserves further exploration as a novel agent to attenuate IRI, and thereby improve OLT function/increase organ donor pool.
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PMID:Diannexin, a novel annexin V homodimer, protects rat liver transplants against cold ischemia-reperfusion injury. 1786 64

Andrographolide (Andro) is a potentially anti-inflammatory diterpenoid lactone isolated from the traditional herbal medicine ANDROGRAPHIS PANICULATA, which has been effectively used for the treatment of infection, inflammation, cold, fever and diarrhea in China for centuries. In the current study, we found that Andro significantly decreased the number of surviving hepatoma-derived Hep3B cells in the MTT assay and induced cell apoptosis. Further study showed that Andro induced activation of mitogen-activated protein kinases (MAPKs) including p38 kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-related kinases (ERK1/2), but had no significant effect on caspase-3, Bcl-xL and Bcl-2, which are apoptosis-related proteins. Moreover, inhibition of JNK activation partially rescued the toxic effect of Andro on Hep3B cells. Therefore, our results indicate that the JNK signaling pathway plays an important role in the toxic effect of Andro on Hep3B cells.
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PMID:Andrographolide inhibits human hepatoma-derived Hep3B cell growth through the activation of c-Jun N-terminal kinase. 1791 40

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.
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PMID:Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver. 1800 84

Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 +/- 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4 degrees C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F(2)alpha, and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p = .03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p = .001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p = .003) in the placebo group, but decreased in the NAC group (p = .004). In both groups staining for 8-isoprostaglandin-F(2)alpha showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.
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PMID:Pneumocyte apoptosis induction during cardiopulmonary bypass: effective prevention by radical scavenging using N-acetylcysteine. 1809 76

Goldfish and crucian carp at low temperature exhibit plasticity in gill morphology during exposure to hypoxia to enhance gas exchange. Hypoxia-induced changes in gill morphology and cellular ultrastructure of the high altitude scaleless carp from Lake Qinghai, China, were investigated to determine whether this is a general characteristic of cold water carp species. Fish were exposed to acute hypoxia (0.3 mg O2 l(-1)) for 24 h followed by 12 h recovery in normoxic water (6 mg O2 l(-1) at 3200 m altitude), with no mortality. Dramatic alterations in gill structure were initiated within 8 h of hypoxia and almost complete by 24 h, and included a gradual reduction of filament epithelial thickness (>50%), elongation of respiratory lamellae, expansion of lamellar respiratory surface area (>60%) and reduction in epithelial water-blood diffusion distance (<50%). An increase in caspase 3 activity in gills occurred following 24 h exposure to hypoxia, indicating possible involvement of apoptosis in gill remodeling. Extensive gill mucous production during hypoxia may have been part of a general stress response or may have played a role in ion exchange and water balance. The large increase in lamellar surface area and reduction in diffusion distance presumably enhances gas transfer during hypoxia (especially in the presence of increased mucous production) but comes with an ionoregulatory cost, as indicated by a 10 and 15% reduction in plasma [Na+] and [Cl-], respectively, within 12-24 h of hypoxia. Within 12 h of hypoxia exposure, ;wavy-convex'-mitochondria rich cells (MRCs) with large apical crypts and numerous branched microvilli were transformed into small ;shallow-basin' cells with a flattened surface. As the apical membrane of MRCs is the site for active ion uptake from the water, a reduction in apical crypt surface area may have contributed to the progressive reduction in plasma [Na+] and [Cl-] observed during hypoxia. The changes in the macro- and ultra-structure of fish gills, and plasma [Na+] and [Cl-] during hypoxia were reversible, showing partial recovery by 12 h following return to normoxia. Although the large morphological changes in the gill observed in the scaleless carp support the hypothesis that gill remodeling during hypoxia is a general characteristic of cold water carp species, the reduced magnitude of the response in scaleless carp relative to goldfish and crucian carp may be a reflection of their more active lifestyle or because they reside in a moderately hypoxic environment at altitude.
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PMID:The effect of hypoxia on gill morphology and ionoregulatory status in the Lake Qinghai scaleless carp, Gymnocypris przewalskii. 1834 80

The essential oil of Tanacetum gracile (Accession no. AT-01 termed AT-01 in the manuscript), a cold desert alpine highly aromatic herb, has 40 constituents including lavendulol (21.5 %), lavendulol acetate (1.7 %), alpha-pinene (11.2 %), 1,8-cineole (15.2 %), CIS-beta-ocimene (6.9 %), borneol (6.1 %), limonene (5.1 %) and chamazulene (3.7 %). AT-01 was evaluated for its anticancer activity. It inhibited HL-60 cell proliferation with an IC (50) of 27 microg/mL. Furthermore, AT-01 induced apoptosis in human leukemia HL-60 cells as measured by several biological end points. AT-01 induced apoptotic body formation, enhanced annexinV-FITC binding of the cells, increased sub-G (0) DNA fraction, loss of mitochondrial membrane potential (Deltapsi (mt)) and release of cytochrome c from mitochondria, activated caspase-9 as well as caspase-3, and increased cleavage of PARP in HL-60 cells. Thus, AT-01 induced apoptosis through the mitochondrial dependent pathway in HL-60 cells.
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PMID:Induction of mitochondrial-dependent apoptosis by an essential oil from Tanacetum gracile. 1840 43


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