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)

D-myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumor necrosis factor-alpha/interferon-gamma. At a concentration of 100 muM AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitin-proteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn(2+). The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several catabolic conditions.
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PMID:Mechanism of attenuation of protein loss in murine C2C12 myotubes by D-myo-inositol 1,2,6-triphosphate. 1971 18

Achyranthes bidentata polypeptides (ABPP), the important constituents separated from the aqueous extract of Achyranthes bidentata, have been shown to attenuate N-methyl-D-aspartate (NMDA)-induced cell apoptosis in cultured hippocampal neurons through differential modulation of NR2A- and NR2B-containing NMDA receptors. The present study sought to investigate the possible mechanism underlying the neuroprotective effect of ABPP on NMDA-induced cell death. Western blot analysis and colorimetric enzymatic assay demonstrated that ABPP pretreatment inhibited NMDA-induced increase of Bax protein expression or caspase-3 activity in cultured hippocampal neurons. Fluorescence measurements after staining with 2,7-dichlorofluorescin diacetate and rhodamine 123 showed that ABPP treatment also reversed NMDA-induced intracellular radical oxygen species (ROS) elevation and mitochondrial membrane potential depression in cultured hippocampal neurons. Furthermore, the in vivo effects of ABPP on cerebral neuronal damage during focal ischemia-reperfusion were also investigated. In rat middle cerebral artery occlusion (MCAO) model, ABPP attenuated the increase in the neurological deficit and cerebral infarction induced by focal ischemia-reperfusion, showing in vivo neuroprotective effects. The results collectively suggest that ABPP might exert neuroprotective actions through inhibiting Bax protein expression, caspase-3 activity, ROS production, and mitochondrial dysfunction that are all caused by overstimulation of NMDA receptors.
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PMID:Achyranthes bidentata polypeptides confer neuroprotection through inhibition of reactive oxygen species production, Bax expression, and mitochondrial dysfunction induced by overstimulation of N-methyl-D-aspartate receptors. 1977 71

1. Cisplatin is a potent chemotherapeutic agent with broad-spectrum antineoplastic activity against various types of tumours. However, a major factor limiting treatment with cisplatin is its acute and cumulative cardiotoxicity. The aim of the present study was to explore the effect of cisplatin on myocardial contractile function and the possible underlying cellular mechanisms. 2. C57 mice were treated with cisplatin (10 mg/kg per day, i.v.) or vehicle (0.9% NaCl) for 1 week and myocardial function was assessed using the Langendorff and cardiomyocyte edge-detection systems. Transmission electron microscopy, mitochondrial membrane potential, indices of endoplasmic reticulum (ER) stress and caspase 3 activity were evaluated. 3. Cisplatin-treated mice developed myocardial contractile dysfunction, as evidenced by a reduction in left ventricular developed pressure (LVDP) and the first derivative of LVDP (+/-dP/dt). Cisplatin treatment significantly prolonged time to 90% relengthening, depressed peak shortening, maximal velocity of shortening/relengthening (+/-dL/dt) and augmented the frequency-elicited depression in peak shortening. The JC-1 fluorescent assay demonstrated that cispatin-induced cardiac dysfunction was associated with mitochondrial membrane depolarization. Transmission electron microscopy revealed that cisplatin induces ultrastructural abnormalities of the mitochondria. Following cisplatin treatment, cardiomyocytes show activation of the ER stress response, increased caspase 3 activity and increased terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining. 4. The data indicate that cisplatin is cardiotoxic and may lead to left ventricular dysfunction and depressed cardiomyocyte contraction associated with mitochondrial abnormalities, enhanced ER stress and apoptosis. This work should shed some light on the management of cisplatin-induced cardiac injury.
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PMID:Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. 1987 17

We evaluated the effects of nicotine on cell and oxidative damage caused by olfactory bulbectomy (OBX). The rats were divided into seven groups as follows: i) control; ii) vehicle (6% ethanol); iii) treated with nicotine; iv) sham operated; v) olfactory bulbectomy (OBX); vi) OBX+vehicle; and vii) OBX+Nic. The OBX was performed using the trepanation of frontal bone. The olfactory bulbs were cut and removed without damage to the frontal cortex. Two weeks after surgery nicotine was administered chronically once daily for 14 days, intraperitoneally (i.p.) in doses of 1.5 mg/kg, two weeks after surgery. OBX caused an increase in lipid peroxidation products and caspase-3 but prompted a reduction in reduced glutathione (GSH) content and antioxidative enzyme activity. All these changes were reverted by treatment of nicotine (14 days). In conclusions: i) OBX induces oxidative stress and cell death by apoptosis; and ii) nicotine presents antidepressant and antioxidant effect. All these findings suggest that nicotine would be a therapeutic tool for depression, although more studies are needed in this area to define the appropriate treatment regime.
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PMID:Protective effect of nicotine on oxidative and cell damage in rats with depression induced by olfactory bulbectomy. 1988 66

Vitamin A exerts a wide range of physiological roles from embryonic to adulthood stages of the mammalian life. However, there is a great concern regarding the deleterious effects of vitamin A use even therapeutically. It was shown that vitamin A induces behavioral impairments, for instance, anxiety-like behavior and depression, in experimental animals and humans. Caspases are enzymes associated with cell death; however, there is a role for such enzymes also in synaptic plasticity. Then, based on previously published data, we have investigated the effects of vitamin A supplementation at clinical doses (1000-9000 IU/kg/day) for 28 days on caspase-3 and caspase-8 activities in adult rat cerebral cortex, cerebellum, striatum, and hippocampus. Furthermore, we have quantified TNF-alpha levels, a pro-inflammatory cytokine that, besides other biological roles, trigger the extrinsic apoptotic pathway in several cellular types, in those rat brain regions. Interestingly, we found increased caspase-3 activity only in rat cerebral cortex. In all the other regions caspase-3 and caspase-8 activities did not change, as well as the levels of TNF-alpha. The presented results, herein, indicate that more caution is needed regarding vitamin A clinical use and, also importantly, the consumption of vitamin A-fortified foods, which are not exclusively distributed among vitamin A-deficient subjects.
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PMID:Pharmacological doses of vitamin A increase caspase-3 activity selectively in cerebral cortex. 1988 26

Severe malarial anemia is the most common syndrome of severe malaria in endemic areas. The pathophysiology of chronic malaria is characterised by a striking degree of abnormal development of erythroid precursors (dyserythropoiesis) and an inadequate erythropoietic response in spite of elevated levels of erythropoietin. The cause of dyserythropoiesis is unclear although it has been suggested that bone-marrow macrophages release cytokines, chemokines or lipo-peroxides after exposure to hemozoin, a crystalloid form of undigested heme moieties from malarial infected erythrocytes, and so inhibit erythropoiesis. However, we have previously shown that hemozoin may directly inhibit erythroid development in vitro and the levels of hemozoin in plasma from patients with malarial anemia and hemozoin within the bone marrow was associated with reduced reticulocyte response. We hypothesized that macrophages may reduce, not enhance, the inhibitory effect of hemozoin on erythropoiesis. In an in vitro model of erythropoiesis, we now show that inhibition of erythroid cell development by hemozoin isolated from P. falciparum is characterised by delayed expression of the erythroid markers and increased apoptosis of progenitor cells. Crucially, macrophages appear to protect erythroid cells from hemozoin, consistent with a direct contribution of hemozoin to the depression of reticulocyte output from the bone marrow in children with malarial anemia. Moreover, hemozoin isolated from P. falciparum in vitro inhibits erythroid development independently of inflammatory mediators by inducing apoptotic pathways that not only involve activation of caspase 8 and cleavage of caspase 3 but also loss of mitochondrial potential. Taken together these data are consistent with a direct effect of hemozoin in inducing apoptosis in developing erythroid cells in malarial anemia. Accumulation of hemozoin in the bone marrow could therefore result in inadequate reticulocytosis in children that have adequate levels of circulating erythropoietin.
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PMID:Hemozoin (malarial pigment) directly promotes apoptosis of erythroid precursors. 2004 Nov 81

The role of Ca(2+) in the activation of PKR (double-stranded-RNA-dependent protein kinase), which leads to skeletal muscle atrophy, has been investigated in murine myotubes using the cell-permeable Ca(2+) chelator BAPTA/AM (1,2-bis (o-aminphenoxy) ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester). BAPTA/AM effectively attenuated both the increase in total protein degradation, through the ubiquitin-proteasome pathway, and the depression of protein synthesis, induced by both proteolysis-inducing factor (PIF) and angiotensin II (Ang II). Since both protein synthesis and degradation were attenuated this suggests the involvement of PKR. Indeed BAPTA/AM attenuated both the activation (autophosphorylation) of PKR and the subsequent phosphorylation of eIF2alpha (eukaryotic initiation factor 2alpha) in the presence of PIF, suggesting the involvement of Ca(2+) in this process. PIF also induced an increase in the activity of both caspases-3 and -8, which was attenuated by BAPTA/AM. The increase in caspase-3 and -8 activity was shown to be responsible for the activation of PKR, since the latter was completely attenuated by the specific caspase-3 and -8 inhibitors. These results suggest that Ca(2+) is involved in the increase in protein degradation and decrease in protein synthesis by PIF and Ang II through activation of PKR by caspases-3 and -8.
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PMID:Mechanism of activation of dsRNA-dependent protein kinase (PKR) in muscle atrophy. 2007 39

Dormancy in vertebrates may expose cells to acidosis, hypoxia/anoxia, oxidative damage, and extremes in temperature. All of these insults are known to be pro-apoptotic in typical vertebrate cells, especially mammals. Since dormancy is presumably the result of a need for energy conservation, the inherent energetic demand of replenishing cells that underwent apoptosis seems at odds with this strategy. This review will discuss processes to mitigate apoptosis and how these processes might be regulated in stress-tolerant vertebrates such as mammalian hibernators. As data directly addressing such issues are scarce and often conflicting, an apparently complex regulation of apoptosis seems to be at work. For example, apoptosis is mitigated during dormancy, key signaling events including the activation of caspase-3 may still occur. However, both passive, temperature-induced depression of apoptotic signaling as well as active suppression of apoptosis appear to work in synergy in these systems. In many instances cell death is prevented by simply avoiding the cellular triggers (e.g. leakage of proteins from the mitochondria or increases in intracellular calcium) that initiate apoptotic signaling. In this review we discuss what is known about programmed cell death in these under-studied models and highlight features of their physiology that likely support survival in the face of conditions that would induce cell death in typical vertebrate cells.
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PMID:Vertebrate cell death in energy-limited conditions and how to avoid it: what we might learn from mammalian hibernators and other stress-tolerant vertebrates. 2012 73

BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.
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PMID:The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. 2068 30

The epaulette shark (Hemiscyllium ocellatum) represents an ancestral vertebrate model of episodic hypoxia and anoxia tolerance at tropical temperatures. We used two-dimensional gel electrophoresis and mass spectrometry-based proteomics approaches, combined with a suite of physiological measures, to characterize this species' responses to 1) one episode of anoxia plus normoxic recovery, 2) one episode of severe hypoxia plus recovery, or 3) two episodes of severe hypoxia plus recovery. We examined these responses in the cerebellum and rectal gland, two tissues with high ATP requirements. Sharks maintained plasma ionic homeostasis following all treatments, and activities of Na(+)/K(+)-ATPase and caspase 3/7 in both tissues were unchanged. Oxygen lack and reoxygenation elicited subtle adjustments in the proteome. Hypoxia led to more extensive proteome responses than anoxia in both tissues. The cerebellum and rectal gland exhibited treatment-specific responses to oxygen limitation consistent with one or more of several strategies: 1) neurotransmitter and receptor downregulation in cerebellum to prevent excitotoxicity, 2) cytoskeletal/membrane reorganization, 3) metabolic reorganization and more efficient intracellular energy shuttling that are more consistent with sustained ATP turnover than with long-term metabolic depression, 4) detoxification of metabolic byproducts and oxidative stress in light of continued metabolic activity, particularly following hypoxia in rectal gland, and 5) activation of prosurvival signaling. We hypothesize that neuronal morphological changes facilitate prolonged protection from excitotoxicity via dendritic spine remodeling in cerebellum (i.e., synaptic structural plasticity). These results recapitulate several highly conserved themes in the anoxia and hypoxia tolerance, preconditioning, and oxidative stress literature in a single system. In addition, several of the identified pathways and proteins suggest potentially novel mechanisms for enhancing anoxia or hypoxia tolerance in vertebrates. Overall, our data show that episodic hypoxic or anoxic exposure and recovery in the epaulette shark amplifies a constitutive suite of compensatory mechanisms that further prepares them for subsequent insults.
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PMID:Compensatory proteome adjustments imply tissue-specific structural and metabolic reorganization following episodic hypoxia or anoxia in the epaulette shark (Hemiscyllium ocellatum). 2037 47


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