Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological evidence indicates several health benefits of the consumption of broccoli, especially related to chemoprevention. Because broccoli contains high amounts of selenium and glucosinolates (particularly glucoraphanin and isothiocyanate sulforaphane), which can produce redox-regulated cardioprotective protein thioredoxin (Trx), it was reasoned that consumption of broccoli could be beneficial to the heart. To test this hypothesis, a group of rats were fed broccoli (slurry made with water) through gavaging; control animals were gavaged water only. After 30 days, the rats were sacrificed; isolated hearts perfused via working mode were made ischemic for 30 min followed by 2 h of reperfusion. The results demonstrated significant cardioprotection with broccoli as evidenced by improved postischemic ventricular function, reduced myocardial infarct size, and decreased cardiomyocyte apoptosis accompanied by reduced cytochrome c release and increased pro-caspase 3 activities. Ischemia/reperfusion reduced both RNA transcripts and protein levels of the thioredoxin superfamily including Trx1, Trx2, glutaredoxin Grx1, Grx2, and peroxiredoxin (Prdx), which were either restored or enhanced with broccoli. Broccoli enhanced the expression of Nrf2, a cytosolic suppressor of Keap1, suggesting a role of antioxidant response element (ARE) in the induction of Trx. Additionally, broccoli induced the expression of another cardioprotective protein, heme oxygenase (HO)-1, which could be transactivated during the activation of Trx. Examination of the survival signal revealed that broccoli caused the phosphorylation of Akt and the induction of Bcl2 in concert with the activation of redox-sensitive transcription factor NF kappa B and Src kinase, indicating a role of Akt, Bcl2, and cSrc in the generation of survival signal. Taken together, the results of the present study indicate that the consumption of broccoli triggers cardioprotection by generating a survival signal through the activation of several survival proteins and by redox cycling of thioredoxins.
 ...
PMID:Broccoli: a unique vegetable that protects mammalian hearts through the redox cycling of the thioredoxin superfamily. 2241 31

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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
PMID:The effects of selenium against cerebral ischemia-reperfusion injury in rats. 1849 Jan 6

Quantum dots (QDs) are being investigated as novel in vivo imaging agents. The leaching of toxic metals from these QDs in biological systems is of great concern. This study compared the cytotoxic mechanisms of two QD species made of different core materials (cadmium selenide [CdSe] vs. indium gallium phosphide [InGaP]) but similar core sizes (5.1 vs. 3.7 nm) and surface compositions (both ZnS capped, lipid-coated and pegylated). The CdSe QD was found to be 10-fold more toxic to porcine renal proximal tubule cells (LLC-PK1) than the InGaP QD on a molar basis, as determined by MTT assay (48 h IC(50) 10nM for CdSe vs. 100nM for InGaP). Neither of the QD species induced appreciable oxidative stress, as determined by lipid peroxide and reduced glutathione content, suggesting that toxicity was not metal associated. In agreement, treatment of cells with CdSe QDs was not associated with changes in metallothionein-IA (MT-IA) gene expression or Cd-associated caspase 3 enzyme activation. By contrast, incubation of the LLC-PK1 cells with the InGaP QD resulted in a dramatic increase in MT-IA expression by 21- and 43-fold, at 8 and 24 h, respectively. The most remarkable finding was evidence of extensive autophagy in QD-treated cells, as determined by Lysotracker Red dye uptake, TEM, and LC3 immunobloting. Autophagy induction has also been described for other nanomaterials and may represent a common cellular response. These data suggest that QD cytotoxicity is dependent upon properties of the particle as a whole, and not exclusively the metal core materials.
 ...
PMID:Induction of autophagy in porcine kidney cells by quantum dots: a common cellular response to nanomaterials? 1863 27

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.
 ...
PMID:Metals and apoptosis: recent developments. 1901 55

The purpose of this study was to determine the inhibitory effect of selenocystamine coated intraocular lenses (IOLs) on the formation of posterior capsule opacification (PCO) in an ex vivo canine lens capsular bag assay. Selenocystamine was covalently bound to the surface of poly(2-hydroxyethyl methacrylate) (poly(HEMA)) discs. Three groups of canine lens capsules (6 coated IOLs (SeIOLs), 7 non-coated control IOLs and 8 empty capsules) were cultured for 10 days. During the culture period PCO was scored based on visual inspection of the capsules using phase contrast microscopy. On day 10 all the capsules were prepared for light microscopic examination and lens epithelial cells (LECs) were quantified. Proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and cleaved caspase-3 were examined by immunohistochemistry. Additionally, cell viability assays were performed on LECs cultured in tissue culture medium pre-incubated with either a SeIOL or control IOL. The viability assays demonstrated that no detectable cytotoxic leachables were associated with the functionalized IOLs. The central posterior capsule was free of cells underneath all SeIOLs, although large numbers of LECs populated the capsular periphery. Apoptotic cells were observed underneath the periphery of some SeIOLs. Both the PCO scores and LEC counts of SeIOL containing capsules were significantly lower than those of control group capsules (p < 0.01 and p = 0.0004, respectively). The use of selenium functionalized IOLs resulted in a significant reduction of PCO in this ex vivo model. Binding of selenocystamine to a foldable IOL may provide an effective method to prevent population of the central posterior capsule with LECs.
 ...
PMID:Selenium functionalized intraocular lenses inhibit posterior capsule opacification in an ex vivo canine lens capsular bag assay. 1958 56

Selenium is an essential micronutrient to freshwater fish, but can be very toxic at slightly above the threshold level. The liver is known to be the major site of selenium accumulation and metabolism in fish. Recent evidence from mammalian systems suggests that oxidative damage is an important mechanism of selenium toxicity; however this phenomenon has not been investigated in-depth in fish, either in vivo or in vitro. Therefore, the present study was designed to investigate whether selenium (as selenite) exposure causes cytotoxicity in fish by inducing oxidative stress. We used isolated hepatocytes in primary culture from freshwater rainbow trout (Oncorhynchus mykiss) as the model in vitro experimental system. The 24h LD(50) of selenite to trout hepatocytes was found to be 587 microM. In order to evaluate the dose-dependent response patterns of various oxidative stress parameters, the trout hepatocytes were exposed to three different doses of selenite [50, 100 and 200 microM (corresponding to approximately 10%, 20% and 35% of 24h LD(50))] in addition to control (0 microM of selenite) for 24h. We observed an induction of catalase (CAT) and superoxide dismutase (SOD) activities at 50 and 100 microM of selenite exposure, but not at 200 microM, relative to the control. In contrast, the induction of glutathione peroxidase (GPx) activity was recorded at 100 and 200 microM exposure doses, but not at 50 microM. We also demonstrated that selenite exposure (100-200 microM) increased intracellular ROS formation at an early stage (2h). The reduced to oxidized glutathione ratio (GSH:GSSG) decreased sharply with increasing selenite dose, indicating the loss of cellular reducing capacity. The cellular lipid peroxidation tended to increase with increasing selenite exposure dose, indicating the occurrence of membrane damage. A 20-40% decrease in cell viability was observed at 100 and 200 microM of selenite exposure. The increase in cell death was associated with a significant increase of caspase-3/7 activity, suggesting the induction of apoptosis. Overall, the present study suggests that selenite exposure at high level causes oxidative damage to trout hepatocytes, probably by inducing the imbalance of intracellular glutathione (GSH) redox.
 ...
PMID:Selenite causes cytotoxicity in rainbow trout (Oncorhynchus mykiss) hepatocytes by inducing oxidative stress. 1965 Dec 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>