Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been linked with apoptosis in germ cells and with male infertility. However, the molecular mechanism of oxidative-stress-mediated apoptosis in germ cells has not been clearly defined so far. Because of the involvement of CDC2 and cyclin B1 in cell cycle regulation and their plausible role in apoptosis, the present study aimed to investigate the possibility that selenium (Se)-induced oxidative-stress-mediated modulations of these cell cycle regulators cause DNA damage and apoptosis in germ cells. To create different Se status (deficient, adequate and excess), male Balb/c mice were fed yeast-based Se-deficient diet (Group I) and a deficient diet supplemented with Se as sodium selenite (0.2 and 1 ppm Se in Groups II and III, respectively) for a period of 8 weeks. After the completion of the diet feeding schedule, a significant decrease in Se levels and glutathione peroxidase activity was observed in the Se-deficient group (Group I), whereas the Se-excess group (Group III) demonstrated an increase in Se levels. Increased levels of lipid peroxidation were seen in both Groups I and III when compared to Group II, indicating oxidative stress. The mRNA and protein expressions of both CDC2 and cyclin B1 were found to be significantly decreased in Groups I and III. A decrease in the immunohistochemical localization of these proteins was also observed in spermatogenic cells. The mRNA expressions of apoptotic factors such as Bcl-2, Bax, caspase-3 and caspase-9 were found to be increased in Groups I and III. A decrease in CDC2 kinase activity was also seen in these groups. Increased apoptosis was observed in Group I and Group III animals by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay indicating oxidative-stress-mediated DNA damage. These findings suggest the effect of Se-induced oxidative stress on the cell cycle regulators and apoptotic activity of germ cells, thus providing new dimensions to molecular mechanisms underlying male infertility.
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PMID:Dietary selenium variation-induced oxidative stress modulates CDC2/cyclin B1 expression and apoptosis of germ cells in mice testis. 1732 Mar 65

During cerebral ischemic cascade, a unifying factor which leads to mitochondrial dysfunctions is lack of oxygen followed by decrease in ATP production. The present study demonstrates the effect of selenium pretreatment (0.1 mg/kg as sodium selenite, i.p, 7 days) on cerebral ischemia-induced altered levels of mitochondrial ATP content, intracellular calcium (Ca(i)(2+)) in synaptosomes, expression of heat stress protein (Hsp70) and caspase-3 activity in hippocampus followed by neurobehavioral deficits and histopathological changes in Wistar rats. Cerebral ischemia was induced for 2 h followed by reperfusion for 22 h. It was observed that levels of (Ca(i)(2+)), Hsp70 and caspase-3 activity were significantly (p<0.01-0.001) higher with a marked decrease in ATP level in hippocampus of ischemic group as compared to sham values. Subsequently, a marked change was observed in neurobehavioral activities in ischemic animals as compared to control one. As a result of selenium pretreatment, a significant (p<0.05-0.001) trend of restoration was observed in the level of ATP, (Ca(i)(2+)), Hsp70, caspase-3 and behavioral outputs as compared to ischemic group. Histopathological analysis confirmed the protective effect of selenium against cerebral ischemia induced histological alterations as evidenced by lesser edema formation and separation of cells with minimal microglial cell infiltration in selenium pretreated group as compared to ischemic animals. The present study suggests that selenium may be able to salvage the ischemic penumbral zone neurons, thereby limiting ischemic cell death.
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PMID:Selenium plays a modulatory role against cerebral ischemia-induced neuronal damage in rat hippocampus. 1737 11

Extensive studies have indicated that the apoptosis pathway appears to be associated with intracellular reactive oxygen species (ROS) production in cadmium-induced nephrotoxicity, however, the precise cellular mechanism remains unclear. The purpose of this study was to determine the relationships between the activation of phosphorylated c-jun N-terminal kinase (JNK) and cadmium-induced apoptosis, and assess the possible cytoprotective mechanism of selenium. Our study clearly revealed cadmium treatment caused apoptosis in LLC-PK1 cells, which was partially suppressed by pretreatment with selenium, an antioxidant nutrient. Further studies found the phosphorylation of JNK kinase increased with exposure to cadmium for 3 h, even remained elevated at 9 h in the time course study, and the activation of phosphorylated JNK was detected in a dose-dependent manner. In addition, a concomitant time-dependent increase in caspase-3 activities was observed by cadmium treatment. During the process, selenium played the same role as N-acetyl-L-cysteine (NAC), a free radical scavenger. Pretreatment of cells with selenium partially suppressed of the phosphorylation of JNK, coupled with caspase-3 activation involved in cadmium-induced apoptosis. In conclusion, our studies provided a molecular linkage between the phosphorylation of JNK and cadmium-induced LLC-PK1 cells apoptosis, and demonstrated selenium also contributed a potentially protection to prevent cadmium-cytotoxicity.
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PMID:Cytoprotective effects of selenium on cadmium-induced LLC-PK1 cells apoptosis by activating JNK pathway. 1738 51

The present study was designed to evaluate the apoptotic efficacy of selenium (Se) under glutathione-deprived conditions. Testicular cells were used as a model to assess the above. For the study, cells were maintained for 4 h under various treatments; control (media only), selenium (0.5 microM and 1.5 microM), BSO (20 nM), selenium + BSO (0.5 microM Se + 20 nM BSO and 1.5 microM Se + 20 nM BSO). The treated cells were harvested for various estimations viz. viability, GSH, GSSG, redox ratio, ROS generation and integrity of DNA. mRNA was extracted for RT-PCR analysis of JNK, p38, caspase 3 and Bcl-2. It was observed that the cell viability decreased concomitant with the decrease in GSH levels, increase in GSSG levels and increase in the generation of ROS in the combined treatment group in comparison to control and individual treatments. Also, there was an increase in the mRNA expression of JNK and p38 MAPK along with an increase in caspase 3 expression and decrease in Bcl-2 expression. The integrity of DNA was also found to be altered in the combined treatment. Thus, the results presented in this work agree with those earlier reports in a notion that sodium selenite causes apoptosis and the toxicity of selenite is mediated by increase of intracellular ROS. Also, reduction in endogenous GSH along with selenite treatment is associated with increased apoptosis, increased expression of p38 and JNK MAPK, decreased Bcl-2 expression, and increase in caspase-3 expression. Our data indicates that GSH participates in apoptosis in testicular cells and that depletion of this molecule may be critical in predisposing these cells to apoptotic cell death.
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PMID:Decreased glutathione levels potentiate the apoptotic efficacy of selenium: possible involvement of p38 and JNK MAPKs--in vitro studies. 1798 39

Methylselenol has been implicated as an active anticancer selenium (Se) metabolite. However, its in vivo efficacy against prostate cancer (PCa) has yet to be established. Here, we evaluated the growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human PCa xenografts in athymic nude mice. Each Se was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed serum, liver and tumor Se content to confirm supplementation status and apoptosis indices and tumor microvessel density for association with antitumor efficacy. Furthermore, we analyzed lymphocyte DNA integrity to detect genotoxic effect of Se treatments. The data show that MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor Se retention than in the SeMet-treated mice. Selenite treatment increased DNA single-strand breaks in peripheral lymphocytes, whereas the other Se forms did not. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and cleaved caspase-3 indices (apoptosis) from MSeC-treated tumors were higher than tumors from control mice or MSeA-treated mice, whereas the microvessel density index was lower in tumors from MSeA-treated mice. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body wt. In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite.
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PMID:Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite. 1831 93

D-Galactosamine (D-GaIN) is a highly selective hepatotoxin that causes liver injury similar to human viral hepatitis via depletion of uridine nucleotides, which subsequently diminishes synthesis of RNA and proteins. The aim of this study was to investigate the role of selenium, ascorbic acid, beta-carotene, and alpha-tocopherol on D-GaIN-induced liver injury of rats by morphological and immunohistochemical means. In this study, Sprague-Dawley female rats were divided into four groups. Group I consists of rats injected physiologic saline solution intraperitoneally. Group II consists of rats given selenium (0.2 mg/kg per day), ascorbic acid (100 mg/kg per day), beta-carotene (15 mg/kg per day), and alpha-tocopherol (100 mg/kg per day) for 3 days via gavage method. Group III consists of the single dose of D-GaIN (500 mg/kg)-injected animals. Group IV are the D-GaIN-injected animals given the same antioxidant combination. In situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) assay was applied to determine apoptosis for paraffin sections of the liver samples. Moreover, caspase-3 and proliferating cell nuclear antigen antibody were applied for paraffin sections. In the group given D-GaIN, apoptotic cells with TUNEL assays and caspase-3 activity, which are liver injury markers induced by D-GaIN, the hepatocyte proliferation with cell proliferation assay increased. However, selenium and other three antioxidants combination clearly suppressed an increase in apoptotic cells with TUNEL assay and caspase-3 activity. In addition, it suppressed D-GaIN-induced cell proliferation in the liver. As a result, these results indicate that selenium and three naturally occurring antioxidants shows a protective effect against liver injury induced by D-GaIN. These results suggest that supplementation with the combination of selenium, ascorbic acid, beta-carotene, and alpha-tocopherol may help prevent the development of liver injury.
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PMID:Combination of selenium and three naturally occurring antioxidants administration protects D-galactosamine-induced liver injury in rats. 1837 31

Selenium (Se) is an essential micronutrient as well as a toxic trace element in animal and human nutrition. The effects of Se in the immune system and some diseases are well documented. The objective of the present study was to examine the role of Se in reducing the hypoxia induced apoptosis in neuroblastoma cell line. Hypoxia showed an enhanced cytotoxicity, increased free radical production and apoptosis (p<0.001) which was measured in terms of DNA break down by comet assay. Hypoxia has decreased reduced Glutathione (GSH) content, Glutathione Reductase (GR), Glutathione peroxidase (GPx) and Superoxide Dismutase (SOD) activities as compared to control cells. During hypoxic condition the expression of cytochrome C, pro and active caspase-3 levels were enhanced significantly followed by nonsignificant upregulation of Bcl-2. But, the Se supplementation inhibited the cytotoxicity, free radical generation and stabilized the HIF-1alpha accumulation in cells under hypoxia. The GSH content, GR, GPx and SOD activities increased significantly in Se-treated hypoxic cells, as compared to control. Further there was an appreciable inhibition of apoptosis by upregulation of Bcl-2 proteins, in the presence of Se under hypoxia. Selenium supplementation to cells significantly inhibited the hypoxia induced DNA fragmentation and restored the antioxidant status back to control levels. This study suggests that Se supplementation prevented the cells from hypoxia induced apoptosis by triggering upregulation of Bcl-2 protein and reducing the oxidative stress.
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PMID:Selenium protects the hypoxia induced apoptosis in neuroblastoma cells through upregulation of Bcl-2. 1840 86

Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
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PMID:PBISe, a novel selenium-containing drug for the treatment of malignant melanoma. 1848 17

It is known that the brain tissue is extremely sensitive to ischemia-reperfusion (IR) injury and therefore, brain ischemia and consecutive reperfusion result in neural damage and apoptosis. The proinflammatory cytokines such as tumor necrosis factor alfa (TNF-alpha) and interleukin-1 beta (IL-1beta) are produced during neurological disorders including cerebral ischemia. On the other hand, nerve growth factor (NGF), which is essential for the differentiation, survival and functions of neuronal cells in the central nervous system, regulate neuronal development through cell survival and cell death signaling. In the present study, we aimed to investigate the effect of selenium (Se) on prefrontal cortex and hippocampal damage in rats subjected to cerebral IR injury. Selenium was injected intraperitoneally at the doses of 0.625 mg/(kg day) after induction of IR injury. Prefrontal cortex and hippocampal damage was examined by cresyl-violet staining. Apostain and caspase-3 immune staining were used to detect apoptosis. TNF-alpha, IL-1beta and NGF levels were also evaluated. Histopathological evaluation showed that treatment with selenium after ischemia significantly attenuated IR-induced neuronal death in prefrontal cortex and hippocampal CA1 regions of rats. Apoptotic cells stained with apostain and caspase-3 were significantly decreased in treatment group when compared with the IR group. Additionally, treatment with selenium decreased the TNF-alpha and IL-1beta levels and increased the NGF levels in prefrontal cortex and hippocampal tissue of animals subjected to IR. The present results suggest that selenium is potentially a beneficial agent in treating IR-induced brain injury in rats.
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PMID:The effects of selenium against cerebral ischemia-reperfusion injury in rats. 1849 Jan 6

Apoptosis, also known as programmed cell death is a highly regulated and crucial process found in all multicellular organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases, i.e. inflammation, malignancy, autoimmunity and neurodegeneration. A variety of toxins can induce apoptosis. Carcinogenic transition metals, viz. cadmium, chromium and nickel promote apoptosis along with DNA base modifications, strand breaks and rearrangements. Generation of reactive oxygen species, accumulation of Ca(2+), upregulation of caspase-3, down regulation of bcl-2, and deficiency of p-53 lead to arsenic-induced apoptosis. In the case of cadmium, metallothionein expression determines the choice between apoptosis and necrosis. Reactive oxygen species (ROS) and p53 contribute in apoptosis caused by chromium. Immuno suppressive mechanisms contribute in lead-induced apoptosis whereas in the case of mercury, p38 mediated caspase activation regulate apoptosis. Nickel kills the cells by apoptotic pathways. Copper induces apoptosis by p53 dependent and independent pathways. Beryllium stimulates the formation of ROS that play a role in Be-induced macrophage apoptosis. Selenium induces apoptosis by producing superoxide that activates p53. Thus, disorders of apoptosis may play a critical role in some of the most debilitating metal-induced afflictions including hepatotoxicity, renal toxicity, neurotoxicity, autoimmunity and carcinogenesis. An understanding of metal-induced apoptosis will be helpful in the development of preventive molecular strategies.
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PMID:Metals and apoptosis: recent developments. 1901 55


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