Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of methods devoted to the identification of apoptotic cells and the analysis of the morphological, biochemical, and molecular changes that take place during this universal biological process have been developed. Apoptotic cells are recognized on the basis of their reduced DNA content and morphological changes that include nuclear condensation and which can be detected by flow cytometry (sub-G1 DNA content), Trypan Blue, or Hoechst staining. Changes in plasma membrane composition and function are detected by the appearance of phosphatidylserine on the plasma membrane, which reacts with Annexin V-fluorochrome conjugates. Combined with propidium iodide (PI) staining, this method can distinguish between the early and late apoptotic events. The best-recognized biochemical hallmarks of apoptosis are the activation of cysteine proteases (caspases), condensation of chromatin, and fragmentation of genomic DNA into nucleosomal fragments. Recognized by a variety of assays, activated caspases cleave many cellular proteins and the resulting fragments may serve as apoptosis markers. Finally, the mitochondria and the Bcl-2 family proteins play an important role in this process that can be recognized by translocation of apoptogenic factors, such as Bax and cytochrome c, in and out of mitochondria.
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PMID:Apoptosis assays. 1708 18

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; (S)-HPMPC] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir also possesses potent activity against human papillomavirus-induced tumors in animal models and patients. We have recently shown that cidofovir inhibits the development of vascular tumors induced by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE) in mice. Here, we demonstrate that the inhibitory activity of cidofovir in FGF2-T-MAE cells may result from the specific induction of apoptosis. Cell cycle analysis revealed that cidofovir induces accumulation of cells in the S phase and, upon prolonged treatment, a significant increase in sub-G1 cells, exhibiting a subdiploid DNA content. Moreover, annexin V binding, an early event in apoptosis induction, was increased in cidofovir-treated FGF2-T-MAE cells. Cidofovir also caused nuclear fragmentation and the activation of caspase-3-like proteases, as evidenced by the cleavage of poly(ADP-ribose)polymerase. In addition, cidofovir treatment of FGF2-T-MAE cells resulted in a pronounced up-regulation of the tumor suppressor protein p53. However, the expression of Bax and Bcl-2 remained unchanged, and cidofovir did not induce the release of cytochrome c from the mitochondria. In addition, cidofovir did not suppress the phosphorylation of protein kinase B/Akt, a transmitter of antiapoptotic survival signals, or its downstream regulator Bad, indicating that the Akt pathway is not affected by cidofovir in FGF2-T-MAE cells. However, the compound inhibited the expression of FGF2 and FGF2 signaling through Erk42/44, as shown by Western blot analysis. Our results indicate that cidofovir inhibits the growth of FGF2-T-MAE cells via inhibition of FGF2 expression and signaling and via the induction of apoptosis. These findings suggest that the clinical use of cidofovir might be expanded to tumors that are not induced by oncogenic viruses.
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PMID:The nucleotide analog cidofovir suppresses basic fibroblast growth factor (FGF2) expression and signaling and induces apoptosis in FGF2-overexpressing endothelial cells. 1715

Cisplatin [cis-diamminedichloroplatinum (II)]-treated murine peritoneal macrophages interact with L929 cells in vitro in a sequential manner, resulting in the formation of contact between the two cells. This interaction leads to the death of L929 cells by the process of apoptosis. The detailed investigations have suggested the involvement of two different pathways in macrophage-mediated L929 cell apoptosis. It is observed that the induction of apoptosis in L929 cells by cisplatin-treated macrophages is contact dependent and is mediated through Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1 pathways. This conclusion was based on the Western blot and immunoprecipitation analysis of Fas-Fas ligand, tumor necrosis factor-tumor necrosis factor receptor 1, Fas-associated death domain and tumor necrosis factor receptor-associated death domain. The Fas-Fas ligand interaction between macrophages and L929 cells increased the expression of Fas-associated death domain, and tumor necrosis factor-tumor necrosis factor receptor 1 interaction between macrophages and L929 cells increased the expression of tumor necrosis factor receptor-associated death domain in L929 cells. The induction of apoptosis in L929 cells was investigated by DNA fragmentation, Annexin V staining and Western blot analysis of Bax, Bcl-2, Bid, cytochrome c, poly(ADP ribose) polymerase, CAD, caspase-8 and caspase-3.
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PMID:Cisplatin-treated murine peritoneal macrophages induce apoptosis in L929 cells: role of Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1. 1715 5

Using K562 and HL60 cell lines, we have investigated the anti-tumoral activity of d-limonene, a monocyclic monoterpene, in human leukemia cells. Apoptosis was evaluated by Hoechst staining and by the annexin V/propidium iodide binding assay. d-Limonene induced apoptosis in a dose- and time-dependent manner in both cell lines. Our findings and data, demonstrating an increase in Bax protein expression, the release of cytochrome c from mitochondria, and an increase in caspase-9 and cleaved caspase-3, but not caspase-8, after the treatment of d-limonene, all suggest that the mitochondrial death pathway is primarily involved in the development of d-limonene-induced apoptosis.
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PMID:Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells. 2709 93

Strategies to enhance skeletal myoblast (SkM) survival after transplantation in the ischemic heart have achieved little success. We posit that preconditioned (PC) SkMs show improved survival and promote repair of the infarcted myocardium via paracrine signaling after transplantation. SkMs from male Fischer-344 rats (rSkMs) were PC for 30 minutes with 200 micromol/L diazoxide. Treatment of PC rSkMs with 100 micromol/L H(2)O(2) for 2 hours resulted in significantly reduced cell injury, as shown by lactate dehydrogenase-release assay, and prevented apoptosis, as demonstrated by cytochrome c translocation, TUNEL, annexin V staining, and preservation of mitochondrial membrane potential. PC rSkMs expressed elevated phospho-Akt (1.85-fold), basic fibroblast growth factor (1.44-fold), hepatocyte growth factor (2.26-fold), and cyclooxygenase-2 (1.33-fold) as compared with non-PC rSkMs. For in vivo studies, female Fischer-344 rats after permanent coronary artery ligation were grouped (n=12/group) to receive 80 microL of basal medium without rSkMs (group 1) or containing 1.5 x 10(6) non-PC (group 2) or PC (group 3) rSkMs. Real-time PCR for sry gene 4 days after transplantation (n=4/group) showed 1.93-fold higher survival of rSkMs in group 3 as compared with group 2. Four weeks later, echocardiography revealed improved indices of left ventricular function, including ejection fraction and fractional shortening in group 3 (P<0.02) as compared with groups 1 and 2. Blood vessel count per surface area (at x400 magnification) was highest in scar and periscar areas in group 3 as compared with the other groups (P<0.05). We conclude that activation of signaling pathways of preconditioning in SkMs promoted their survival by release of paracrine factors to promote angiomyogenesis in the infarcted heart. Transplantation of PC SkMs for heart cell therapy is an innovative approach in the clinical perspective.
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PMID:Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart. 1733 34

There is substantial interest in identifying agents that differentially activate keratinocyte differentiation versus apoptosis. Okadaic acid (OA) is a tumor promoter in mouse skin that also stimulates apoptosis of murine keratinocytes. OA also enhances human keratinocyte differentiation; however, the impact of OA treatment on apoptosis in these cells has not been examined. We show that OA promotes normal human keratinocyte apoptosis as evidenced by increased accumulation of cells having sub-G1/S DNA content, decreased mitochondrial integrity, increased annexin V binding, increased cytoplasmic cytochrome c level, and increased procaspase 3 and PARP cleavage. Cyclin A, cyclin D1, cdk2, cdk4, p53 and p21 levels are reduced. These changes are associated with release of the PKCdelta catalytic domain and increased phosphorylation of PKCdelta-T(505)-responses consistent with PKCdelta activation. In contrast, phosphorylation of PKCdelta-Y(311) is not increased. The apoptotic response is enhanced in OA treated cells in the presence of p38delta, a PKCdelta target. OA treatment selectively activated p38delta, and OA-dependent apoptosis is not inhibited by treatment with the p38alpha/beta inhibitor, SB203580. These findings are consistent with the idea that the response is mediated by p38delta. Our data indicate that OA is an agent that regulates both keratinocyte differentiation and apoptosis, and that this regulation is mediated via activation of a PKCdelta/p38delta signaling cascade.
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PMID:Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. 1725 48

Different rigidities of adhesive collagen substrate affect cellular functions with unclear mechanisms. Here, we cultured a renal epithelial cell line (LLC-PK1) and a tumor cell line (HeLa) on substrates of different rigidities and compared the cell type-specific responses. The culture dish was coated with a very thin layer of collagen gel (control group) or overlaid with collagen gel (soft substrate). LLC-PK1 cells contracted as they grew on collagen gel and the apoptotic bodies obviously appeared with time. The protein levels of procaspase-12 and its downstream target procaspase-3 were decreased when LLC-PK1 cells cultured on collagen gel. Mu-calpain was activated on collagen gel. Collage gel also induced the cleavage of alpha-spectrin which resulted in the disorganization of actin cytoskeleton. In contrast, there was no significant change in cytochrome c revelation, mitochondrial membrane potential, and the protein levels of procaspase-8 and procaspase-9. Moreover, soft substrate caused elevated cytosolic Ca(2+), Ca(2+) overload in ER and upregulation of capacitative calcium entry. Ca(2+) chelator or channel blocker partially rescued the collagen-gel induced apoptosis by inhibiting mu-calpain activation. In contrast, for HeLa cells cultured either on collagen gel or on gel-coated dish, there was no significant change in positive Annexin V staining, no activation of procaspase-12 and no cleavage of mu-calpain. Thus, soft substrate induces apoptosis in LLC-PK1 cells by the disturbance of Ca(2+) homeostasis.
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PMID:Soft substrate induces apoptosis by the disturbance of Ca2+ homeostasis in renal epithelial LLC-PK1 cells. 1731 Dec 96

Glioblastomas are high-risk primary brain tumors that are generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus novel therapeutic strategies and agents are urgently needed to treat these incurable cancers. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional Asian medicine as anti-inflammatory and anti-cancer agents. Recently, synthetic oleanolic acid triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives have been shown to exhibit potent antitumor activity against diverse types of tumor cell lines, including leukemia, multiple myeloma, osteosarcoma, breast, lung, and pancreatic cancer cell lines; however, the anticancer activity of these agents for brain tumors has not been reported. In the present study, we investigated the apoptosis-inducing activity of CDDOs in glioblastoma (U87MG, U251MG) and neuroblastoma (SK-N-MC) cell lines. Cell growth/viability (MTS) and cytotoxicity (LDH release) assays demonstrated that glioblastoma cell lines are least sensitive to CDDO, but are highly sensitive to CDDO-Me and CDDO-Im at concentrations of 2.5-10 muM. CDDO-Im and CDDO-Me were equipotenent in their growth inhibitory activity. The primary mode of tumor cell destruction was apoptosis as demonstrated by significant increase in the number of hypo-diploid (sub-G0) cells and annexin V-FITC binding. Induction of apoptosis was associated with the activation of procaspases-3, -8, and -9, mitochondrial depolarization and the release of cytochrome c from mitochondria. Furthermore, CDDO-Me inhibited the levels of anti-apoptotic and prosurvival p-Akt, NF-kappaB (p65) and Notch1 signaling molecules. These studies provide rationale for clinical evaluation of these novel agents for the management of lethal brain neoplasms.
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PMID:Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. 1736 29

tert-Butylhydroperoxide has been reported to inhibit growth and induce apoptosis in number of cell types, but little is known about the molecular mechanism mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with t-BOOH. The cells were exposed to different concentrations of t-BOOH (100-750 microM) for 1-4 h and various parameters such as cytotoxicity, ROS (reactive oxygen species) generation, MMP (mitochondrial membrane potential), intracellular Ca++ levels and expression of various proteins involved in apoptosis were determined. Exposure of U-937 cells to t-BOOH induced cytotoxicity in a time dependent manner with about 50% toxicity at 400 microM t-BOOH in 4h. t-BOOH treatment resulted in a time dependent increase in reactive oxygen species levels, Ca++ influx and annexin V positive cells. There was a significant fall in MMP following exposure to t-BOOH with time. t-BOOH treatment of U-937 cells leads to apoptosis, which is accompanied by activation of caspase-3. The caspase-3 inhibitor (Ac-DEVD-CHO) inhibits the cytotoxicity induced by t-BOOH, indicating a direct link between caspase-3 activation and cell death. This activation of apoptosis is accompanied by release of cytochrome c, down regulation of anti-apoptotic protein Bcl-2 levels with concurrent increase in pro-apoptotic proteins Bax and Bad levels. These observations indicate that t-BOOH induces cell death in U-937 macrophages by apoptosis, which is mediated through mitochondrial pathway.
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PMID:Mechanism of tert-butylhydroperoxide induced cytotoxicity in U-937 macrophages by alteration of mitochondrial function and generation of ROS. 1741

Alterations in lipid metabolism play an integral role in neuronal death in cerebral ischemia. Here we used an in vitro model, oxygen-glucose deprivation (OGD) of rat pheochromocytoma (PC12) cells, and analyzed changes in phosphatidylcholine (PC) and sphingomyelin (SM) metabolism. OGD (4-8 h) of PC12 cells triggered a dramatic reduction in PC and SM levels, and a significant increase in ceramide. OGD also caused increases in phosphatidylcholine-phospholipase C (PC-PLC) and phospholipase D (PLD) activities and PLD2 protein expression, and reduction in cytidine triphosphate:phosphocholine cytidylyltransferase-alpha (CCTalpha, the rate-limiting enzyme in PC synthesis) protein expression and activity. Phospholipase A2 activity and expression were unaltered during OGD. Increased neutral sphingomyelinase activity during OGD could account for SM loss and increased ceramide. Surprisingly, treatment with PC-PLC inhibitor tricyclodecan-9-yl potassium xanthate (D609) aggravated cell death in PC12 cells during OGD. D609 was cytotoxic only during OGD; cell death could be prevented by inclusion of sera, glucose or oxygen. During OGD, D609 caused further loss of PC and SM, depletion of 1,2-diacylglycerol (DAG), increase in ceramide and free fatty acids (FFA), cytochrome c release from mitochondria, increases in intracellular Ca2+ ([Ca2+]i), poly-ADP ribose polymerase (PARP) cleavage and phosphatidylserine externalization, indicative of apoptotic cell death. Exogenous PC during OGD in PC12 cells with D609 attenuated PC, SM loss, restored DAG, attenuated ceramide levels, decreased cytochrome c release, PARP cleavage, annexin V binding, attenuated the increase in [Ca2+]i, FFA release, and significantly increased cell viability. Exogenous PC may have elicited these effects by restoring membrane PC levels. A tentative scheme depicting the mechanism of action of D609 (inhibiting PC-PLC, SM synthase, PC synthesis at the CDP-choline-1,2-diacylglycerol phosphocholine transferase (CPT) step and causing mitochondrial dysfunction) has been proposed based on our observations and literature.
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PMID:Effect of tricyclodecan-9-yl potassium xanthate (D609) on phospholipid metabolism and cell death during oxygen-glucose deprivation in PC12 cells. 1743 80


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