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)

We examined the effect of daily melatonin supplementation on liver apoptosis induced by aging in rats. Young (3-month-old) and aged (24-month-old) Wistar rats were supplemented daily with melatonin in their drinking water (20 mg/L) for 4 weeks. Aged rats showed increases in the liver concentration of thiobarbituric acid-reactive substances and in the oxidized/reduced glutathione ratio. These increases were accompanied by apoptotic ultrastructural alterations and increases in cytochrome c mitochondrial release, Bax to Bcl-2 relative expression, and activity of caspase-3. No significant changes were observed in Fas-ligand (Fas-L) expression and caspase-8 activity. Melatonin administration was able to abrogate changes detected in aged rats. Data suggest that liver apoptotic cell death is induced by reactive oxygen species, via the intrinsic signalling pathway, and that the antiapoptotic action provided by melatonin is related to its antioxidant effect, with reduction of cytochrome c release by the modulation of Bcl-2 and Bax genes.
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PMID:Melatonin is able to reduce the apoptotic liver changes induced by aging via inhibition of the intrinsic pathway of apoptosis. 1763 14

Maternal cholestasis is usually a benign condition for the mother but induces profound placental damage and may be lethal for the fetus. The aim of this study was to investigate the protective effects in rat maternal and fetal livers as also the placenta of melatonin or silymarin against the oxidative stress and apoptosis induced by maternal obstructive cholestasis during the last third of pregnancy (OCP). Melatonin or silymarin administration (i.e. 5 mg/100 g bw/day after ligation of the maternal common bile duct on day 14 of pregnancy) reduced OCP-induced lipid peroxidation, and prevented decreases in total glutathione levels. However, the protective effect on OCP-induced impairment in the GSH/GSSG ratio was mild in the placenta and fetal liver, while absent in maternal liver. Melatonin or silymarin also reduced OCP-induced signs of apoptosis (increased caspase-3 activity and Bax-alpha upregulation) in all the organs assayed. Moreover, melatonin (but not silymarin) upregulated several proteins involved in the cellular protection against the oxidative stress in rats with OCP. These included, biliverdin-IX alpha reductase and the sodium-dependent vitamin C transport proteins SVCT1 and SVCT2, whose expression levels were enhanced in maternal and fetal liver by melatonin treatment. In contrast, in placenta only biliverdin-IX alpha reductase and SVCT2 were upregulated. These results indicate that whereas the treatment of cholestatic pregnant rats with melatonin or silymarin affords a direct protective antioxidant activity, only melatonin has dual beneficial effects against OCP-induced oxidative challenge in that it stimulates the expression of some components of the endogenous cellular antioxidant defense.
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PMID:Multiple protective effects of melatonin against maternal cholestasis-induced oxidative stress and apoptosis in the rat fetal liver-placenta-maternal liver trio. 1764 91

In the present study, the protective effect of melatonin on sodium arsenite (arsenite)-induced apoptosis was investigated. Local infusion of arsenite elevated lipid peroxidation and depleted glutathione content in the infused substantia nigra (SN), as well as reduced striatal dopamine content. Systemic administration of melatonin diminished arsenite-induced oxidative injury. Furthermore, melatonin attenuated arsenite-induced increases in heat shock protein 70 and heme oxygenase-1 as well as phosphorylation of p38 mitogen-activated protein kinase and elevations in cyclooxygenase II and inducible nitric oxide synthase expression. Inhibition by melatonin of arsenite-induced apoptosis was determined by its attenuation of DNA fragmentation and terminal deoxytransferase-mediated dUTP-nick end labeling's positive cells in the infused SN of melatonin-treated rats. Melatonin reduced arsenite-induced apoptosis through mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, systemic melatonin inhibited arsenite-induced elevations in Bcl-2 and cytosolic cytochrome c as well as arsenite-induced reductions in procaspase-3 levels and elevations in active caspase-3 levels in the infused SN. Regarding the ER pathway, melatonin attenuated arsenite-induced elevations in activating transcription factor-4, CCAAT/enhancer binding protein (C/EBP) homologues protein, X-bon binding protein (XBP-1) and cytosolic immunoglobulin binding protein (BIP) as well as reductions in procaspase 12 levels. Moreover, aggregation of alpha-synuclein was reduced in the arsenite-infused SN of melatonin-treated rats. Our in vitro data showed that melatonin ameliorated arsenite-induced lipid peroxidation. Taken together, our data suggest that melatonin is neuroprotective against arsenite-induced oxidative injury in the nigrostriatal dopaminergic system of rat brain. Furthermore, the neuroprotective effects by melatonin on arsenite-induced apoptosis were mediated via inhibiting both mitochondrial and ER pathways. Accordingly, melatonin may be therapeutically useful for the treatment of arsenite-induced apoptosis in central nervous system.
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PMID:Melatonin attenuates arsenite-induced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of alpha-synuclein. 1764 94

We showed earlier that malarial infection significantly induces liver apoptosis mediated by oxidative stress mechanisms. Thus, a nontoxic antioxidant-antiapoptotic molecule may be beneficial for hepatoprotection. Melatonin remarkably prevents hepatocyte apoptosis in mice induced during malaria as indicated by caspase 3 and TUNEL assays as well as transmission electron microscopy (TEM) of the liver tissue. The mitochondrial apoptotic pathway, which plays a critical role in liver cell death during malarial infection, was almost completely suppressed by melatonin as it corrects both the overexpression of Bax and down-regulation of bcl-2 as revealed by semiquantitative RT-PCR. Fluorometric studies using JC-1 documented that melatonin also restores mitochondrial transmembrane potential (DeltaPsim) in malaria-infected mice liver. The antiapoptotic effect of melatonin is associated with its antioxidant role because melatonin protects liver from oxidative stress induced during malaria by scavenging the hydroxyl radicals, preventing the depletion of reduced glutathione, inhibiting lipid peroxidation and protein carbonyl formation. The effective antioxidant dose of melatonin to protect liver from oxidative stress during malaria is 20 times lower than that of known antioxidants, vitamin C and vitamin E. Apoptosis of hepatocytes during malarial infection is well correlated with dysfunction of the liver while melatonin offers hepatoprotective effects as indicated by different liver function tests. Thus, melatonin may well be effective in combating oxidative stress-induced apoptosis and liver damage during malaria infection.
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PMID:Melatonin inhibits free radical-mediated mitochondrial-dependent hepatocyte apoptosis and liver damage induced during malarial infection. 1791 Jun 6

Melatonin protects against organ ischemia; this effect has mainly been attributed to the antioxidant properties of the indoleamine. This study examined the cytoprotective properties of melatonin against injury to the liver caused by ischemia/reperfusion (I/R). Rats were subjected to 60 min of ischemia followed by 5 hr of reperfusion. Melatonin (10 mg/kg) or the vehicle was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. The serum aminotransferase activity and lipid peroxidation levels were increased markedly by hepatic I/R, which were suppressed significantly by melatonin. In contrast, the glutathione content, which is an index of the cellular redox state, and mitochondrial glutamate dehydrogenase activity, which is a maker of the mitochondrial membrane integrity, were lower in the I/R rats. These decreases were attenuated by melatonin. The rate of mitochondrial swelling, which reflects the extent of the mitochondrial permeability transition, was higher after 5 hr of reperfusion but was attenuated by melatonin. Melatonin limited the release of cytochrome c into the cytosol and the activation of caspase-3 observed in the I/R rats. The melatonin-treated rats showed markedly fewer apoptotic (TUNEL positive) cells and DNA fragmentation than did the I/R rats. These results suggest that melatonin ameliorates I/R-induced hepatocytes damage by inhibiting the level of oxidative stress and the apoptotic pathway. Consequently, melatonin may provide a new pharmacological intervention strategy for hepatic I/R injuries.
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PMID:Cytoprotective effects of melatonin against necrosis and apoptosis induced by ischemia/reperfusion injury in rat liver. 1828 68

To preserve the central nervous system (CNS) function after a traumatic injury, therapeutic agents must be administered to protect neurons as well as glial cells. Cell death in CNS injuries and diseases are attributed to many factors including glutamate toxicity and oxidative stress. We examined whether melatonin, a potent anti-oxidant and free radical scavenger, would attenuate apoptotic death of rat C6 astroglial cells under glutamate excitotoxicity and oxidative stress. Exposure of C6 cells to 500 microM L-glutamic acid (LGA) and 100 microm hydrogen peroxide (H(2)O(2)) for 24 hr caused significant increases in apoptosis. Apoptosis was evaluated by Wright staining and ApopTag assay. Melatonin receptor 1 appeared to be involved in the protection of these cells from excitotoxic and oxidative damage. Cells undergoing excitotoxic and oxidative stress for 15 min were then treated with 150 nM melatonin, which prevented Ca(2+)influx and cell death. Western blot analyses showed alterations in Bax and Bcl-2 expression resulting in increased Bax:Bcl-2 ratio during apoptosis. Western blot analyses also showed increases in calpain and caspase-3 activities, which cleaved 270 kD alpha-spectrin at specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. However, 15-min post-treatment of C6 cells with melatonin dramatically reduced Bax:Bcl-2 ratio and proteolytic activities, decreasing LGA or H(2)O(2)-induced apoptosis. Our data showed that melatonin prevented proteolysis and apoptosis in C6 astroglial cells. The results suggest that melatonin may be an effective cytoprotective agent against glutamate excitotoxicity and oxidative stress in CNS injuries and diseases.
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PMID:Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stress. 1837 57

Melatonin reduces proliferation in many different cancer cell lines. However, studies on the oncostatic effects of melatonin in the treatment of hepatocarcinoma are limited. In this study, we examined the effect of melatonin administration on HepG2 human hepatocarcinoma cells, analyzing cell cycle arrest, apoptosis and mitogen-activated protein kinase (MAPK) signalling pathways. Melatonin was dissolved in the cell culture media in 0.2% dimethyl sulfoxide and administered at different concentrations for 2, 4, 6, 8 and 10 days. Melatonin at concentrations 1000-10,000 microM caused a dose- and time-dependent reduction in cell number. Furthermore, melatonin treatment induced apoptosis with increased caspase-3 activity and poly(ADP-ribose) polymerase proteolysis. Proapoptotic effects of melatonin were related to cytosolic cytochrome c release, upregulation of Bax and induction of caspase-9 activity. Melatonin treatment also resulted in increased caspase-8 activity, although no significant change was observed in Fas-L expression. In addition, JNK 1,-2 and -3 and p38, members of the MAPK family, were upregulated by melatonin treatment. Growth inhibition by melatonin altered the percentage or cells in G0-G1 and G2/M phases indicating cell cycle arrest in the G2/M phase. The reduced cell proliferation and alterations of cell cycle were coincident with a significant increase in the expression of p53 and p21 proteins. These novel findings show that melatonin, by inducing cell death and cell cycle arrest, might be useful as adjuvant in hepatocarcinoma therapy.
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PMID:Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. 1901 62

Melatonin prevents neuronal cell death in ischemic brain injury. This study investigated whether melatonin inhibits the apoptotic signal through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad. Adult male rats were treated with melatonin (5 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 hr after MCAO. We confirmed that melatonin significantly decreases the number of TUNEL positive cells in the cerebral cortex. Western blot analysis showed that levels of Raf-1, MEK1/2, and ERK1/2 phosphorylation decrease in vehicle-treated animals. Melatonin prevents the injury-induced decrease of Raf-1, MEK1/2, and ERK1/2 phosphorylation. Also, it inhibits the injury-induced decrease of p90RSK and Bad phosphorylation. Recently, we reported that melatonin prevents the injury-induced reduction of interaction between pBad and 14-3-3 and inhibits the activation of caspase-3. Subsequently, melatonin prevents the injury-induced an increase of cleaved PARP levels. Taken together, these results suggest that melatonin prevents cell death resulting from ischemic brain injury, and that its neuroprotective effects are mediated by the activation of Raf/MEK/ERK/p90RSK cascade.
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PMID:Melatonin attenuates the cerebral ischemic injury via the MEK/ERK/p90RSK/bad signaling cascade. 1905 41

2-Bromopropane (2-BP) was used as an alternative for ozone-depleting solvents, which caused reproductive disorders in male workers and laboratory animals. A recent study indicated that 2-BP impaired antioxidant cellular defences and enhanced lipid peroxidation (LPO). Melatonin is a powerful endogenous antioxidant. We hypothesized that reactive oxygen species (ROS) and lipid peroxidation are involved in 2-BP-induced testicular toxicities. To test the hypothesis, we investigated the effects of melatonin on 2-BP-induced testicular toxicities. Rats were intraperitoneally injected with 2-BP (1g/kg) with or without melatonin (5mg/kg), then sacrificed on 7th day after 2-BP injection. Epididymal and testicular tissues were examined for biochemical and histopathological changes. Apoptotic cells in testis were detected by TUNEL staining and immunohistochemistry for active caspase-3. Exposure to 2-BP significantly decreased epididymal sperm count and morphological normal sperms. 2-BP also induced vacuolation and atrophy of the seminiferous tubules, reduction of spermatogonia and apoptosis of germ cells. 2-BP significantly increased TBARS levels in plasma and epididymis, and decreased GSH content in testis and epididymis. Pretreatment with melatonin counteracted 2-BP-induced oxidative stress, ameliorated apoptosis in testis and attenuated histopathological damage in testis. In addition, pretreatment with melatonin significantly attenuated 2-BP-induced sperm morphological changes. We conclude that pretreatment with melatonin attenuates 2-BP-induced testicular toxicity through its ROS scavenging and anti-apoptotic effects.
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PMID:Melatonin pretreatment attenuates 2-bromopropane-induced testicular toxicity in rats. 1906 34

We studied the effect of age and melatonin on cell death processes in brain aging. Senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 5 and 10 months of age were used as models of the study. Melatonin (10 mg/kg) or its vehicle (ethanol at 0.066%) was administered in the drinking water from 1 to 9 months of age. Neurodegeneration, previously shown in the aged brain of SAMP8 and SAMR1 at 10 months of age, may be due to a drop in age-related proteolytic activities (cathepsin D, calpains, and caspase-3). Likewise, lack of apoptotic and macroautophagic processes were found, without apparent modification by melatonin. However, the caspase-independent cell death, owing to high p53 and apoptosis-inducing factor (AIF) levels, might be an alternative pathway of cell death in the aged brain. The main effects of melatonin treatment were observed in the aged SAMR1 mice; in this strain we observed a marked increase in antioxidant activity (catalase and superoxide dismutase). Likewise, a key antioxidant role of apoptosis-related proteins, Bcl-2 and AIF, was suggested in the aged brain of SAM mice, which was clearly influenced by melatonin. Moreover, the age-related increase of lysosomal activity of cathepsin B and a lysosomal membrane-associated protein 2 supports the possibility of the maintenance of lysosomal viability in addition to age-related impairments of the proteolytic or macroautophagic activities. The effectiveness of melatonin against the oxidative stress-related impairments and apoptosis during the aging process is, once more, corroborated in this article.
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PMID:Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. 1909 Sep 13


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