UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
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The aim of this study was to prepare buoyant (B) melatonin (MT)-loaded chitosan microcapsules having favourable sustained release characteristics (in simulated gastric fluid (SGF), pH 1.2) in comparison with non-buoyant (NB) chitosan particles. The new buoyant microcapsules were prepared by the ionotropic gelation method using sodium lauryl sulfate (NaLS) for coagulation. The microcapsule characteristics were affected by the initial drug and NaLS concentrations, as well as the presence of sodium dioctyl sulfosuccinate (DOS) or pectin with NaLS in the external phase. In general, spherical microcapsules with 36.90-56.23% encapsulation efficiencies, hollow core and satisfactory release properties were produced. The best sustained release profiles (t(50%): 5h) with near zero-order kinetics were observed with the higher theoretical payload microcapsules prepared with both NaLS and DOS in a 1:2 ratio. In vivo studies were also carried out to exploit the protective effect of the MT-loaded NaLS-DOS microcapsules against aflatoxin B1 (AFB1)-induced toxicity (liver apoptosis) in male rats. The results implied that apoptotic rate was significantly reduced when MT or its microcapsules formulation was co-administered with AFB1. The levels of the oxidative stress indices (malondialdehyde (MDA), a lipid peroxidation product and nitric oxide (NO)) in liver tissues were significantly reduced, while the levels of the hepatic antioxidants (glutathione (GSH) and zinc (Zn), as well as the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST)) which act as antiapoptosis were significantly increased as compared to AFB1 group (without MT). MT microcapsules appeared more effective in reduction of apoptotic rate than free MT as indicated by the decline of caspase-3 activities (an apoptotic marker) and confirmed by histopathology.
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PMID:Novel B melatonin-loaded chitosan microcapsules: in vitro characterization and antiapoptosis efficacy for aflatoxin B1-induced apoptosis in rat liver. 1281 6

Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1 mmol kg(-1), i.p.) and exposed to 1.5 mg l(-1) (the 96-h LC85) of dichlorvos for 96 h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and gamma-glutamyl transferase (gammaGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96 h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.
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PMID:Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine. 1456 51

Several pieces of evidence have demonstrated the importance of reduction/oxidation (redox) signaling in biological processes, including sensitivity toward apoptosis. In parallel, it was recently reported that growth factors induce the generation of reactive oxygen species (ROS). Therefore, we tested the hypothesis that the anti-apoptotic effect of epidermal growth factor (EGF) was mediated by changes in the redox state of hepatocytes through changes in GSH stocks. Isolated mouse hepatocytes were cultured and exposed to anti-Fas stimulation in order to induce apoptosis. Cell death by apoptosis was assessed by Hoechst 33258 staining and by measuring caspase-3 proteolysis activity. Cell treatment with EGF significantly decreased total (GSx) and reduced (GSH) glutathione levels in the presence and the absence of anti-Fas. Furthermore, glutathione reductase activity was lower in EGF-treated cultures (by 28%) as compared to untreated cultures which lead to a significant decline in GSH/GSx ratio. These effects were found to be EGF-receptor tyrosine kinase activity dependent. Co-stimulation of cells with anti-Fas and EGF attenuated caspase-3 activation and cell death by apoptosis by 70%. GSH monoethylester (GSHmee) significantly attenuated the effect of EGF on GSH and GSH/GSx ratio. It caused an increase in caspase-3 activation and in the percentage of apoptotic cells in anti-Fas + EGF-treated cells, thus resulting in a 53% decline in the protective effect of EGF. In conclusion, EGF induces a significant and specific depletion and oxidization of intracellular GSH, paralleled by a protection against Fas-induced apoptosis. GSH repenishment partly counteracted these effects suggesting that GSH depletion contributed to the protective effect of EGF against caspase-3 activation and cell death by apoptosis.
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PMID:EGF mediates protection against Fas-induced apoptosis by depleting and oxidizing intracellular GSH stocks. 1458 45

In the present study, caspase-3 enzyme activity (apoptotic marker) and heat shock protein-70 (HSP70) expression in male rat liver after aflatoxin B1 (AFB1) treatment and the effect of melatonin (MEL) were investigated. Four groups of 20 rats each were used: controls, MEL-treated rats (MEL dose, 5 mg/kg body wt), AFB1-treated rats (50 microg/kg body wt) and MEL+AFB1-treated rats. After 8 weeks of daily treatment, biochemical assays in liver homogenates were done. The caspase-3 enzyme activity was measured using colorimetric method while the level of HSP70 expression was determined using dot blot analysis. In addition, the tissue levels of lipid peroxides (LPO), nitric oxide (NO), glutathione (GSH) and the enzyme activities of glutathione reductase (GR) and glutathione peroxidase (GSPx) were determined using colorimetric methods. The levels of caspase-3 activities and HSP70 level in AFB1 group were significantly higher than control group. Concomitantly, the levels of oxidative stress indices, LPO and NO, were significantly increased while the levels of antioxidants, GSH, GSPx and GR in AFB1 group were significantly decreased compared to their levels in controls. Caspase-3 activity was positively correlated with LPO while negatively correlated with GSH in rat livers treated with AFB1. The levels of caspase-3 activity, LPO, NO and HSP70 expression were significantly lower while the levels of GSH, GSPx and GR activities were significantly higher in MEL+AFB1 group than AFB1 group. In conclusion, higher levels of caspase-3 activity and HSP70 expression were associated with oxidative stress in rat liver treated with AFB1. The increased HSP70 expression in liver of AFB1 group may be due to a compensatory defense mechanism. MEL may effectively normalize the impaired antioxidants status, which consequently reduce both expression of HSP70 and apoptotic dysregulation in the liver. Thus, clinical application of MEL as therapy may benefit in cases of aflatoxicosis.
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PMID:Caspase-3 and heat shock protein-70 in rat liver treated with aflatoxin B1: effect of melatonin. 1503 34

Sodium butyrate (NaBu), a potent histone deacetylase inhibitor, modulates the expression of a large number of genes. The purpose of this study was to determine whether this dietary agent could induce apoptosis in MCF-7 cells, a breast cancer cell line that lacks caspase-3 activity, and to identify the mechanisms that underlie NaBu toxicity in these cells. Cell viability assessed by the activity of mitochondrial succinate dehydrogenase (MTT assay) revealed a dose-dependent reduction of MCF-7 cellular growth in response to NaBu treatment. Restoring caspase-3 function by transfection did not modify NaBu toxicity in these cells. Following a 24-h exposure, NaBu-induced cell growth arrest in G2/M phase in a dose-dependent fashion in association with stable expression of CDC25A, a G1-specific regulator of the cell cycle. The anti-proliferative effects of NaBu were accompanied by diminished expression of p53. Similarly, mRNA encoding c-Myc, a well-known regulator of p53, was decreased in NaBu-treated cells, while p21(Waf1/Cip1) mRNA was increased. Furthermore, bax mRNA level was up-regulated whereas a decline in Bcl-2 both protein and mRNA levels were detected in NaBu-treated cells. Apoptosis was observed following a treatment with 2 mM NaBu, reflected by Annexin-V staining and by the cleavage of poly(ADP-ribose) polymerase, whereas DNA laddering was absent. Apoptosis was associated with a pronounced depletion of intracellular glutathione levels. Finally, NaBu treatment significantly increased the activities of several antioxidant enzymes, including glutathione reductase, glutathione peroxidase, and catalase. Together, these data suggest that the pro-apoptotic effects of NaBu observed in MCF-7 cells are associated with oxidative stress.
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PMID:The histone deacetylase inhibitor sodium butyrate induces breast cancer cell apoptosis through diverse cytotoxic actions including glutathione depletion and oxidative stress. 1554 8

We have investigated whether maternal obstructive cholestasis during pregnancy (OCP) causes oxidative stress and apoptosis in rat placenta and whether treatment with ursodeoxycholic acid (UDCA, i.g., 60 microg/100 g b.wt./day, following complete biliary obstruction on day 14 of pregnancy) has protective effects on this organ. In rats with OCP, increased (15-fold) serum bile acid concentrations (BAs) together with signs of placental oxidative stress (lipid peroxidation and protein carbonylation) were found. The latter were partly prevented by UDCA, even though hypercholanemia was not corrected. Some elements of the antioxidant system (total glutathione content, GSH/GSSG ratio and catalase, glutathione peroxidase, and glutathione-S-transferase--but not glutathione reductase--activities) were impaired in placentas from the OCP group. UDCA treatment partly prevented changes in the antioxidant system. OCP induced an increase in Bax-alpha/Bcl-2 mRNA ratio, as determined by real-time quantitative PCR, suggesting enhanced susceptibility to apoptosis activation through the mitochondria-mediated pathway. Accordingly, the activity of caspase-3, but not caspase-8, was increased in OCP placentas, in which DNA-ladder analysis and TUNEL confirmed the existence of apoptosis. UDCA prevented changes in the Bax-alpha/Bcl-2 mRNA ratio and caspase-3 activity. In conclusion, OCP causes oxidative stress and apoptosis in rat placenta, which can be prevented by treatment with UDCA.
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PMID:Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. 1631 35

Arsenic is a well established human carcinogen and is ubiquitous in the environment. The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats. Sodium arsenite was administered orally at doses of 6.3 mg/kg, 10.5 mg/kg and 12.6 mg/kg of body weight on the basis of a lethal dose 50% (LD50) for 24 hr. After administration of arsenites, liver and brain were analyzed for various parameters of oxidative stress, histopathological changes and caspase-3 activity. Glutathione levels were decreased significantly in the liver at all doses. In liver the following biochemical changes were observed, a significant lipid peroxidation and cytochrome-P450 induction along with significant decrease in catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione peroxidase was increased significantly at all doses. In brain, no significant change was observed at 6.3 mg/kg. However, a significant increase in lipid peroxidation and glutathione peroxidase activity along with significant decrease in the activity of glutathione, catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione-S-transferase was decreased significantly in both liver and brain at 10.5 and 12.6 mg/kg. No significant alteration in the activity of glucose-6-phosphate dehydrogenase and glutathione reductase was observed in either liver or brain at any dose. Dose-dependent histopathological changes, observed in both liver and brain are also described. A significant increase in caspase-3 activity was observed at all doses in liver and at 10.5 and 12.6 mg/kg in brain. Sodium arsenite caused DNA cleavage into fragments and manifested as "DNA laddering", a hallmark of apoptosis.
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PMID:Arsenic-induced cell death in liver and brain of experimental rats. 1643 89

Bis(2-hydroxybenzylidene)acetone is a potent inducer of the phase 2 response through the Keap1-Nrf2-ARE pathway. This double Michael reaction acceptor reacts directly with Keap1, the sensor protein for inducers, leading to enhanced transcription of phase 2 genes and protection against oxidant and electrophile toxicities. In our efforts to identify potent chemoprotective agents, we found that in rapidly growing murine leukemia cells (L1210) low concentrations (in the submicromolar range) of bis(2-hydroxybenzylidene)acetone markedly increased the activities of NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) and glutathione reductase, and the levels of total glutathione, three markers of the phase 2 response. In contrast, at high concentrations (in the micromolar range) the same compound caused G2/M cell cycle arrest and apoptosis. Importantly, a mutant L1210 cell line (Y8), selected for resistance to deoxyadenosine and lacking expression of p53 protein, was considerably more sensitive to the apoptotic effects of bis(2-hydroxybenzylidene)acetone. When caspase activities were evaluated in cell-free extracts prepared from treated wild type or mutant L1210 cells, the activities of caspase-3, the terminal caspase in the cascade leading to apoptosis, and caspase-10 were found to be markedly elevated. The activities of other caspases measured, caspase-1, -6 and -8, were not appreciably affected. Thus, both induction of the phase 2 response and p53-independent, caspase-3-mediated apoptosis could act cooperatively in chemoprotection. The concentration-dependent differential effects on these two pathways should be carefully considered in mechanistic explanations and strategic designs.
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PMID:Bis(2-hydroxybenzylidene)acetone, a potent inducer of the phase 2 response, causes apoptosis in mouse leukemia cells through a p53-independent, caspase-mediated pathway. 1651 63

Free radical production and, consequently, oxidative stress play an important role in the pathogenesis of AIDS and cause damage to lipids, proteins, and DNA. In our previous study, the HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 have been found to induce oxidative stress in an immortalized endothelial cell line from rat brain capillaries, RBE4 (in vitro model of the blood-brain barrier). Here, we have determined the effects of a novel antioxidant, N-acetylcysteine amide (NACA), on gp120- and Tat-induced oxidative stress. Various oxidative stress parameters, including reduced glutathione (GSH), oxidized glutathione (GSSG), catalase (CAT) activity, and glutathione reductase (GR) activity, as well as malondialdehyde (MDA) levels, were used as measures of oxidative stress. NACA significantly increased the levels of intracellular GSH, CAT, and GR and decreased the levels of MDA in RBE4 cells, showing that oxidatively challenged cells were protected. Gp120- and Tat-induced increases in intracellular reactive oxygen species (ROS) were observed by using the 2',7'-DCF assay; the ROS scavenger, NACA, blocked ROS generation. A well-known apoptosis indicator, caspase-3 activity, was measured and was also found to have been returned to its control levels by NACA. Treatment of RBE4 cells with gp120 and Tat caused an increase in toxicity, as measured by lactate dehydrogenase (LDH) and tetrazolium reduction (MTS) assays. HIV-1 protein-induced toxicity in these cells was blocked by treatment with NACA. These studies show that NACA reverses gp120- and Tat-induced oxidative stress in immortalized endothelial cells.
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PMID:A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. 1675 May 28

Ethanol is able to cross the placenta, which may cause teratogenicity. Here we investigated whether ethanol consumption during pregnancy (ECDP), even at doses unable to cause malformation, might increase the susceptibility of fetal rat liver to oxidative insults. Since cholestasis is a common condition in alcoholic liver disease and pregnancy, exposure to glycochenodeoxycholic acid (GCDCA) has been used here as the oxidative insult. The mothers received drinking water without or with ethanol from 4 weeks before mating until term, when placenta, maternal liver, and fetal liver were used. Ethanol induced a decreased GSH/GSSG ratio in these organs, together with enhanced gamma-glutamylcysteine synthetase and glutathione reductase activities in both placenta and fetal liver. Lipid peroxidation in placenta and fetal liver was enhanced by ethanol, although it had no effect on caspase-3 activity. Although the basal production of reactive oxygen species (ROS) was higher by fetal (FHs) than by maternal (AHs) hepatocytes in short-term cultures, the production of ROS in response to the presence of varying GCDCA concentrations was higher in AHs and was further increased by ECDP, which was associated to a more marked impairment in mitochondrial function. Moreover, GCDCA-induced apoptosis was increased by ECDP, as revealed by enhanced Bax-alpha/Bcl-2 ratio (both in AHs and FHs) and the activity of caspase-8 (only in AHs) and caspase-3. In sum, our results indicate that although AHs are more prone than FHs to producing ROS, at doses unable to cause maternal liver damage ethanol consumption causes oxidative stress and apoptosis in fetal liver.
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PMID:Maternal ethanol consumption during pregnancy enhances bile acid-induced oxidative stress and apoptosis in fetal rat liver. 1682 60

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