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)

Fibroblast growth factors interact with appropriate endothelial cell (EC) surface receptors and initiate intracellular signal cascades, which participate in modulating blood vessel growth. EC, upon exposure to basic fibroblast growth factors (bFGFs) undergo profound functional alterations, which depend on their actual sensitivity and involve gene expression and de novo protein synthesis. We investigated the effects of bFGF on signaling pathways of EA.hy926 cells in different environments. EC were cultured under normal gravity (1 g) and simulated microgravity (micro g) using a three-dimensional (3D) clinostat. Microgravity induced early and late apoptosis, extracellular matrix proteins, endothelin-1 (ET-1) and TGF-beta(1) expression. Microgravity reduced eNOS mRNA within 24 h. Moreover, a six- to eightfold higher amount of IL-6 and IL-8 was secreted within 24 h micro g. In addition, microgravity induced a duplication of NF-kappaB p50, while p65 was quadrupled. At 1 g, bFGF application (4 h) reduced ET-1, TGF-beta(1) and eNOS gene expression. After 24 h, bFGF enhanced fibronectin, VEGF, Flk-1, Flt-1, the release of IL-6, IL-8, and TGF-beta(1). Furthermore, bFGF promoted apoptosis, reduced NFkB p50, but enhanced NFkB p65. After 4 h micro g, bFGF decreased TGF-beta(1), eNOS, and ET-1 gene expression. After 24 h micro g, bFGF elevated fibronectin, Flk-1 and Flt-1 protein, and reduced IL-6 and IL-8 compared with vehicle treated micro g cultures. In micro g, bFGF enhanced NF-KappaB p50 by 50%, Bax by 25% and attenuated p65, activation of caspase-3 and annexin V-positive cells. bFGF differently changes intracellular signals in ECs depending whether it is applied under microgravity or normal gravity conditions. In microgravity, bFGF contributes to protect the EC from apoptosis.
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PMID:Effects of basic fibroblast growth factor on endothelial cells under conditions of simulated microgravity. 1825 36

We have previously shown that prothrombin, a blood coagulation factor, can cause an inhibition of DNA synthesis in normal rat hepatocytes. To explore the mechanisms of this prothrombin action, we examined its effects on the activation of fibronectin receptor integrin alpha5, since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures. We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor (EGFR), leading to EGFR tyrosine phosphorylation at tyrosine residues Tyr-845 and Tyr-1173. EGFR tyrosine phosphorylation triggered phosphorylation of its down-stream target Shc and the activation of the c-Jun N-terminal kinase (JNK) pathway. Prothrombin also induced hepatocyte apoptosis, a change in cell shape and activation of caspase 3 pathway. The JNK pathway is most likely involved in prothrombin-induced hepatocyte apoptosis, because pre-treatment of hepatocytes with JNK kinase inhibitor II (SP600125) antagonized these prothrombin actions. The data suggest that integrin-related EGFR activation by prothrombin can induce cell growth inhibition and apoptosis via an EGFR-JNK signaling pathway.
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PMID:Integrin alpha5-induced EGFR activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway. 1833 Aug 91

Islet transplantation is associated with an elevated rate of early graft failure. The isolation process leads to structural and functional abnormalities. The reestablishment of the cell-matrix relationship is important to modulate the survival and function of islets. Thus, we evaluated the effect of human fibronectin (hFN) and self-assembling peptide nanofiber (SAPNF) in the ability to support islet function in vitro and after transplantation into streptozotocin (STZ)-induced diabetic severe combined immunodeficiency (SCID) mice. Human isolated islets were cultured with hFN or SAPNF for 7 days. Their ability to maintain insulin production/glucose responsiveness over time was evaluated. Islets embedded in hFN, SAPNF, or alone were transplanted into STZ-induced diabetic SCID mice. Islet grafts were removed after 14 days to evaluate insulin content, insulin expression, and apoptosis. SAPNF-entrapped islets maintained satisfactory morphology/viability and capability of glucose-dependent insulin secretion for over 7 days, whereas islets cultured in hFN underwent widespread deterioration. In vivo grafts containing human islets in SAPNF showed remarkably higher insulin content and expression when compared with human islets in hFn or alone. RT-PCR revealed lower caspase-3 expression in SAPNF islets grafts. These studies indicate that the reestablishment of the cell-matrix interactions by a synthetic matrix in the immediate postisolation period is a useful tool to maintain islet functions in vitro and in vivo.
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PMID:Reestablishment of microenvironment is necessary to maintain in vitro and in vivo human islet function. 1846 41

Previous in vitro studies suggest that the p38 MAPK pathway may be involved in the pathogenesis of diabetic nephropathy, but the consequences of the inhibition of the p38 MAPK pathway have not been well elucidated in diabetic (DM) glomeruli. This study was undertaken to investigate the effect of p38 MAPK inhibitor, FR167653, on fibronectin expression and apoptosis in DM glomeruli and in high-glucose-stimulated mesangial cells (MC). In vivo, 32 Sprague-Dawley rats were injected with diluent (control, N = 16) or streptozotocin intraperitoneally (DM, N = 16). Eight rats from each group were treated with FR167653 for 3 mo. In vitro, rat MC were exposed to medium containing 5.6 mM glucose or 30 mM glucose [high glucose (HG)] with or without 10(-6) M FR167653 for 24 h. Fibronectin mRNA and protein expression were determined by real-time PCR and Western blot, respectively. Western blot for apoptosis-related molecules, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, and Hoechst 33342 staining were performed to determine apoptosis. FR167653 ameliorated the increases in fibronectin-to-GAPDH mRNA ratio and protein expression in DM glomeruli by 89 and 79% and in HG-stimulated MC by 70 and 91%, respectively (P < 0.05). Under diabetic conditions, Bcl-2 protein expression was decreased, whereas cleaved caspase-3 protein expression was increased (P < 0.05), and these changes were inhibited by FR167653 treatment. Apoptotic cells were also significantly increased in DM glomeruli and in HG-stimulated MC (P < 0.05), and FR167653 ameliorated these increases in apoptotic cells, both in vivo and in vitro. In conclusion, these findings suggest that the inhibition of the p38 MAPK pathway has a beneficial effect on the development of diabetic nephropathy by inhibiting the increase in fibronectin expression and apoptosis.
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PMID:FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells. 1852 57

Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE, or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27(Kip1), collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells.
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PMID:Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells. 1883 96

Matrix Metalloproteinase-9 (MMP-9) consists of a prodomain, catalytic domain with 3 fibronectin-like type II modules and C-terminal hemopexin-like (PEX) domain. These domains play distinct roles in terms of proteolytic activity, substrate binding and interaction with inhibitors and receptors. To assess the potential of the MMP-9-PEX domain to interfere with tumor progression, we stably transfected human glioblastoma cells with an expression vector containing a cDNA sequence of the MMP-9-PEX. The selected clones exhibited decreased MMP-9 activity and reduced invasive capacity. We assessed how secretion of MMP-9-PEX by glioblastoma cells affects angiogenic capabilities of human microvascular endothelial cells (HMECs) in vitro. MMP-9-PEX conditioned medium treatment caused a reduction in migration of HMECs and inhibited capillary-like structure formation in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level. The suppression of HMECs survival by conditioned medium from MMP-9-PEX stable transfectants was associated with apoptosis induction characterized by an increase in cells with a sub-G0/G1 content, fragmentation of DNA, caspase-3, -8 and -9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. A significant tumor growth inhibition was observed in intracranial implants of MMP-9-PEX stable transfectants in nude mice with attenuation of CD31 and MMP-9 protein expression. These results demonstrate that MMP-9-PEX inhibits angiogenic features of endothelial cells and retards intracranial glioblastoma growth.
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PMID:The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude mice. 1894 17

Fumonisins are mycotoxins produced by Fusarium verticillioides. The toxic effects of fumonisin B(1) (FB(1)) at the cellular level consist of a mixture of both necrosis and apoptosis. We studied the effect of FB(1) in human lung fibroblasts (NHLF) and human kidney epithelial cells (RPTEC) in primary culture. Apoptotic and necrotic cell death, collagen and fibronectin secretion were determined mainly after 14 days' exposure. The protein content of NHLF and RPTEC cells was slightly increased after 14 days' exposure to low FB(1) concentrations (0.1 or 1 microm). Caspase-3 activity tended to increase in NHLF and to decrease in RPTEC cells with higher FB(1) concentrations after 14 days' exposure. LDH release was slightly decreased in both cell types after 14 days. Collagen I and III secretion was enhanced in NHLF cells. Collagen III was decreased in RPTEC. Collagen IV was not changed in both cell types. Fibronectin secretion was uninfluenced in RPTEC and interim increased in NHLF. Furthermore LC-MS/MS studies did not give any hints for a metabolism of FB(1). Therefore, the main risk of prolonged FB(1) exposure seems to be altered collagen secretion pattern.
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PMID:Effects of the mycotoxin fumonisin B(1) on cell death in human kidney cells and human lung fibroblasts in primary culture. 1898 66

Ochratoxin A (OTA) is a mycotoxin produced by several fungi growing on food source material. The main target of OTA is the kidney. So far, mainly cell lines of different origin have been used to study OTA toxicity. Yet all of them derived from tubule segments and therefore only limited information is available on glomerular effects of OTA. We exposed human mesangial cells in primary culture to OTA in nanomolar concentrations for up to 14 days. Necrotic and apoptotic cell death as well as fibrotic changes were studied. Protein content decreased only when unusual high OTA concentrations were used (1 microM). By contrast, an increase of caspase-3 activity or LDH release was observed after five days already at 10 nM OTA. A decrease of collagen I secretion was accompanied by a virtually unchanged collagen III and fibronectin secretion. Collagen IV secretion was slightly increased at low OTA concentrations (0.3-10 nM). We conclude that OTA has only a minor effect on human mesangial cells in primary culture. OTA did not influence collagen homeostasis substantially. Based on the data presented here, a risk of mesangial damage by OTA exposure is unlikely.
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PMID:Effect of ochratoxin A on cell survival and collagen homeostasis in human mesangial cells in primary culture. 1903 72

Sulforaphane (SUL) is an isothiocyanate naturally present in widely consumed vegetables, particularly in broccoli. SUL has recently been focused as a result of its inhibitory effects on tumor cell growth in vitro and in vivo. We used endothelial progenitor cells (EPCs) as an in vitro model to investigate the effect of SUL on the various steps of vasculogenesis and angiogenesis. Peripheral blood mononuclear cells from blood of normal human volunteers were plated on fibronectin-coated 100 mm dishes and incubated for 7 days. The viability of EPCs, treated with SUL at different doses, was assessed by MTS assay. Cell apoptosis was analyzed by flow cytometry. To determine the relative contributions of caspase-8 and caspase-9 pathways to SUL-induced apoptosis, the effect of caspase inhibitors was determined. The expression of apoptosis-related proteins (Bax, Bcl-2) was investigated by Western blot test. Finally, the effect of SUL on the ability of EPCs to form vascular-like structures on Matrigel was investigated. We clearly demonstrated that SUL induced the dose-dependent inhibition of EPCs' viability by induction of apoptosis. All caspases (caspase-3, -8, and -9) were activated during apoptosis induction by SUL, but the effect of caspase-9 was more prominent than that of caspase-8. Also, the expression of Bax was upregulated by SUL treatment. In addition to apoptosis induction, SUL dose-dependently inhibited the tube-like formation by EPCs on Matrigel. The present results demonstrate the antivasculogenic/antiangiogenic activity of SUL in vitro and open premise for the use of SUL as a multipotent anticancer agent that targets both cancer cells and the angiogenic endothelium.
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PMID:Sulforaphane stimulates activation of proapoptotic protein bax leading to apoptosis of endothelial progenitor cells. 1903 79

Synthetic phosphothioated (PTO) oligodeoxynucleotide (ODN) sequences are commonly used for a variety of applications that benefit from nuclease protection. The PTO modification is implemented mainly in antisense ODN, but also in ODN that were shown to activate members of the toll-like receptor (TLR) family such as TLR3 (poly-I:C), TLR8 (ssRNA), and TLR9 (CpG). Neurons are routinely plated on surfaces coated with either cationic substances such as poly-L-ornithine (PLO), polyethylenimine (PEI), poly-L-lysine or ECM components such as laminin, collagen, or fibronectin. We found that PTO-ODN aimed at activating TLR9 induces a non-TLR9-specific detachment phenotype in cortical neurons plated on either laminin or PEI, but not on PLO. This phenotype was correlated with decreased viability and was partially inhibited when caspase-3 was inhibited with Ac-DEVD-CMK. This finding suggests that the use of PTO-ODN can cause nonspecific effects on cell adhesion that could compromise interpretation of data from experiments using PTO-ODN.
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PMID:Phosphothioated oligodeoxynucleotides induce nonspecific effects on neuronal cell adhesion in a growth substrate-dependent manner. 1915 68


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