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

Advanced glycation endproducts (AGEs) are implicated in the complications of diabetes and ageing, affecting several tissues, including bone. Metformin, an insulin-sensitizer drug, reduces the risk of life-threatening macrovascular complications. We have evaluated the hypothesis that metformin can abrogate AGE-induced deleterious effects in osteoblastic cells in culture. In two osteoblast-like cell lines (UMR106 and MC3T3E1), AGE-modified albumin induced cell death, caspase-3 activity, altered intracellular oxidative stress and inhibited alkaline phosphatase activity. Metformin-treatment of osteoblastic cells prevented these AGE-induced alterations. We also assessed the expression of AGE receptors as a possible mechanism by which metformin could modulate the action of AGEs. AGEs-treatment of osteoblast-like cells enhanced RAGE protein expression, and this up-regulation was prevented in the presence of metformin. Although the precise mechanisms involved in metformin signaling are still elusive, our data implicate the AGE-RAGE interaction in the modulation of growth and differentiation of osteoblastic cells.
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PMID:Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. 1827 53

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl(4) significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl(4)-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl(4)-induced Fas/FasL protein expression levels and, in turn, attenuated CCl(4)-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl(4)-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl(4)-induced acute liver injury may involve its ability to block CYP2El-mediated CCl(4) bioactivation and to protect against Fas/FasL-mediated apoptosis.
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PMID:Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. 1843 64

The purpose of this study was to determine the differential effects of therapeutic X-radiation on constituent bone cells relative to the pediatric tumor cells: Ewing's sarcoma of bone and rhabdomyosarcoma. In addition, the radioprotectant drugs amifostine and sodium selenite were administered to constituent bone cells and the two tumor cells to determine if the radioprotectants differentially protect bone cells while not benefiting the tumor cells. These studies are a necessary first step in determining the potential clinical benefit of radioprotective therapy. An established in vitro cell culture model employing both constituent bone cells (osteoblasts, primary bone marrow monocytes, osteoclasts chondrocytes, and endothelial cells) and the tumor cells lines (Ewing's sarcoma of bone and rhabdomyosarcoma) were exposed to irradiation, amifostine, and sodium selenite. Cells were then assayed for changes in cell number, cytotoxicity, mineralization, bone resorption, cell attachment, osteocalcin, caspase-3 expression, clonogenic survival, and alkaline phosphatase expression. Radiation therapy differentially decreased cell number; with osteoblasts being shown to be the least sensitive to irradiation, the tumor cells had an intermediate sensitivity and monocytes were the most sensitive. Both amifostine and sodium selenite protected chondrocytes and osteoblasts from the negative effects of irradiation, while not protecting the tumor cells. The pediatric tumor cell lines were generally more radiosensitive than the bone cells examined. The radioprotectant drugs amifostine and sodium selenite provided significant radioprotection to constituent bone cells while not protecting the tumor cells. Finally, amifostine and sodium selenite therapy provided an additional benefit beyond radioprotection by increasing cytotoxicity in nonirradiated and irradiated tumor cells.
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PMID:The differential effects of the radioprotectant drugs amifostine and sodium selenite treatment in combination with radiation therapy on constituent bone cells, Ewing's sarcoma of bone tumor cells, and rhabdomyosarcoma tumor cells in vitro. 1847 85

The present study was undertaken to validate a battery of cytotoxicity assays performed in a multiplex format to screen pharmaceutical compounds at an early stage of drug development. Two experiments were performed on HepG2 cells and the parameters were measured in 96-well plates. Biological and technical triplicates were performed to evaluate the reproducibility of the assay. In the first experiment, HepG2 cells were exposed to tamoxifen, staurosporine, phenobarbital and triton X-100 for 2 and 24h. The following nine cytotoxicity parameters were analyzed, cell viability, lactate dehydrogenase (LDH), adenosine triphosphate (ATP), caspase-3/7, aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and alpha-glutathione-S-transferase (alpha-GST). In the second experiment, HepG2 cells were exposed to doxorubicin, t-butyl hydroperoxide, ferrous sulfate and sulfamoxole for 2 and 24h. Based on the results of the first experiment, six cytotoxicity parameters were selected for further evaluation (cell viability, ATP, LDH, caspase, AST and GLDH). ALT (activity always below detection limit), ALP (no response to drug treatment) and alpha-GST (too labor intensive and not possible to multiplex) were eliminated. The analysis of the data revealed that the reproducibility of the assays was accurate according to principal component analysis. Our data also clearly indicated that the potential of this battery of selected assays measured in a multiplex format not only made it possible to rank and select the most promising drug candidates based on their cytotoxic potential, but also to gather information that may help to understand some of the toxic events occurring in the cells.
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PMID:Selection of cytotoxicity markers for the screening of new chemical entities in a pharmaceutical context: a preliminary study using a multiplexing approach. 1911 50

Ghrelin is a 28-residue peptide identified in the stomach as an endogenous ligand of the growth hormone secretagogue receptor that is expressed in a variety of peripheral tissues, as well as in the brain. In previous studies, ghrelin has been shown to stimulate both adipogenic differentiation from preadipocytes and osteogenic differentiation from preosteoblasts or primary osteoblasts. This study was undertaken to investigate the direct effect of ghrelin on the lineage allocation of mesenchymal stem cells (MSCs). We identified ghrelin receptor mRNA in C3H10T1/2 cells, and we found the levels of this mRNA to be attenuated during osteogenic differentiation. Treatment of cells with ghrelin resulted in both proliferation and inhibition of caspase-3 activity. In addition, ghrelin decreased serum deprivation-induced bax protein expression and release of cytochrome c from the mitochondria, whereas it increased bcl-2 protein expression. Moreover, ghrelin inhibited early osteogenic differentiation, as shown by alkaline phosphatase activity and staining, and inhibited osteoblast-specific genes expression by altering Runx2, PPARgamma, and C/EBPalpha protein expression.
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PMID:Ghrelin inhibits early osteogenic differentiation of C3H10T1/2 cells by suppressing Runx2 expression and enhancing PPARgamma and C/EBPalpha expression. 1916 Apr 22

Growth plate cartilage is responsible for long bone growth in children and adolescents and is regulated by vitamin D metabolites in a cell zone-specific manner. Resting zone chondrocytes (RC cells) are regulated by 24,25-dihydroxyvitamin D3 via a phospholipase D-dependent pathway, suggesting downstream phospholipid metabolites are involved. In this study, we showed that 24R,25(OH)2D3 stimulates rat costochondral RC chondrocytes to release lysophosphatidic acid (LPA) and, therefore sought to determine the role of LPA signaling in these cells. RC cells expressed the G-protein coupled receptors LPA1-5 and peroxisome proliferator-activated receptor gamma (PPAR-gamma). LPA and the LPA1/3 selective agonist OMPT increased proliferation and two maturation markers, alkaline phosphatase activity and [35S]-sulfate incorporation. LPA and 24R,25(OH)2D3's effects were inhibited by the LPA1/3 selective antagonist VPC32183(S). Furthermore, apoptosis induced by either inorganic phosphate or chelerythrine was attenuated by LPA, based on DNA fragmentation, TUNEL staining, caspase-3 activity, and Bcl-2:Bax protein ratio. LPA prevented apoptotic signaling by decreasing the abundance, nuclear localization, and transcriptional activity of the tumor-suppressor p53. LPA treatment also regulated the expression of the p53-target genes Bcl-2 and Bax to enhance cell survival. Collectively, these data suggest that LPA promotes differentiation and survival in RC chondrocytes, demonstrating a novel physiological function of LPA-signaling.
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PMID:Lysophosphatidic acid signaling promotes proliferation, differentiation, and cell survival in rat growth plate chondrocytes. 1923 32

Chondrogenic ATDC5 cells were used as a model of in vitro endochondral maturation to study the role of inorganic phosphate (Pi) in the regulation of growth plate chondrocytes by vitamin D3 metabolites. ATDC5 cells that were cultured for 10 days post-confluence in differentiation media and then treated for 24 h with Pi produced a type II collagen matrix based on immunohistochemistry and expressed mRNAs for several chondrocytic markers, including aggrecan, collagen types II and X, cartilage oligomeric matrix protein, and SOX9. Pi also caused a decrease in [(35)S]-sulfate incorporation and stimulated apoptosis, as evidenced by increased DNA fragmentation and caspase-3 activity. In addition, treatment with Pi induced sensitivity to 24,25-dihydroxyvitamin D3 and this effect was both dose-dependent and was blocked by phosphonoformic acid (PFA), a specific inhibitor of sodium dependent type III Pi transporters. Treatment with 24R,25(OH)(2)D(3) reduced cell number and increased alkaline phosphatase specific activity in a dose-dependent manner. Moreover, 24R,25(OH)(2)D(3) reversed the Pi-induced decrease in incorporation of [(3)H]-thymidine and [(35)S]-sulfate incorporation, as well as the Pi-induced increase in apoptosis. These results suggest that Pi acts as an early chondrogenic differentiation factor, inducing response to 24R,25(OH)(2)D(3); treatment of committed chondrocytes with Pi induces apoptosis, but 24R,25(OH)(2)D(3) mitigates these effects, indicating a possible inhibitory feedback loop.
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PMID:Inorganic phosphate modulates responsiveness to 24,25(OH)2D3 in chondrogenic ATDC5 cells. 1928 98

The effects of simulated orthodontic forces such as centrifugal force or water pressure on sodium fluoride (NaF)-induced cytotoxicity against mouse osteoblast-like cells MC3T3-E1 were investigated. Loading with centrifugal force (44.5 g/cm2) or water pressure (5 g/cm2) slightly reduced the cell proliferation and additively enhanced the cytotoxic activity of millimolar concentrations of NaF. NaF induced the appearance of phosphatidylserine at outer cell membrane (detected by Annexin staining) but failed to induce caspase-3 activation even under the water pressure. On the other hand, NaF induced autophagic phenotype characterized by the formation of acidic organelles (detected by acridine orange staining). NaF did not increase, but rather dose-dependently reduced the alkaline phosphatase activity, with or without the loading of water pressure. The present study demonstrates that centrifugal force and water pressure partially enhanced the caspase-independent cytotoxicity of NaF against osteoblasts. These simulated orthodontic forces may be a new factor that affects the physiological activity of NaF.
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PMID:Effect of simulated orthodontic forces on fluoride-induced cytotoxicity in MC3T3-E1 osteoblast-like cells. 1941 11

ABSTRACT The present study was carried out to assess the antitumor effect of venomous peptide from the cephalopod Octopus aegina on Ehrlich's ascites carcinoma (EAC). Male albino Swiss mice were used in the present study. Four groups of animals were treated with three doses of the sublethal dose of venom, 15, 75, and 150 mug/kg body weight (intraperitoneal injection), along with the standard drug 5-fluorouracil (20 mg/kg b.w.). After 10 days of treatment, six animals from each group were sacrificed for the biochemical analysis and the rest were left to calculate the mean survival time. In EAC-bearing mice, mean lifespan, tumor volume, hemoglobin, red blood cells, and lymphocytes were significantly decreased when compared to the normal animals. While body weight, neutrophils, and viable tumor cell count were increased in the EAC-bearing mice, these changes were brought back to near normal levels in different treatment groups. The macromolecule concentration of peritoneal cells, such as DNA, RNA, and protein, were altered in the EAC-bearing mice and observed to be near normal in the treatment groups. The caspase-3 activity was significantly increased in the peritoneal cells of the treatment groups when compared to the EAC-bearing mice. The role of apoptotic cascade in EAC cell death was confirmed by the DNA fragmentation on agarose gel. Apart from the antitumor effect, octopus venom reduced the tumor burden on the liver and altered the changes in the activities of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Therefore, the venom from O. aegina has a potential antitumor effect on the EAC-bearing mice.
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PMID:PGE from Octopus aegina Induces Apoptosis in Ehrlich's Ascites Carcinoma of Mice. 2002 Aug 71

Endotoxemia caused by lipopolysaccharide (LPS) produced an inflammatory condition contributing to multiple organ failure. This study was carried out to investigate the effects of thymoquinone (TQ), the main constituent of Nigella sativa seeds, against LPS-induced hepatotoxicity. The obtained data revealed that LPS markedly depleted liver reduced glutathione (GSH) and significantly increased the level of malondialdehyde (MDA) and the activity of caspase-3 enzyme in the liver. Serum tumour necrosis factor-alpha (TNF-alpha) and bilirubin levels and the activities of alkaline phosphatase (ALP) and gamma-glutamyl transferase (gamma-GT) enzymes were markedly increased in LPS-treated rats. TQ supplementation resulted in normalization of liver GSH and decreases in the levels of MDA and caspase-3 activity in the liver with reduction of serum TNF-alpha, serum total bilirubin and the activities of ALP and gamma-GTenzymes. Histopathological examination revealed that TQ administration improved LPS-induced pathological abnormalities in liver tissues. The present study conclude that TQ reduced acute endoxemia-induced liver dysfunction at least in part by its anti-inflammatory, antiapoptotic and antioxidant activities.
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PMID:Thymoquinone supplementation ameliorates acute endotoxemia-induced liver dysfunction in rats. 2036 88


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