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)

Previous studies showed that exposure to Vibrio vulnificus cytolysin (VVC) caused characteristic morphologic changes and dysfunction of vascular structures in lung. VVC showed cytotoxicity for mammalian cells in culture and acted as a vascular permeability factor. In this study, the underlying mechanisms of VVC-induced cytotoxicity was investigated on ECV304 cell, a human vascular endothelial cell line. When cells were exposed to 0.4 hemolytic units (HU) of VVC, consecutive apoptotic events were observed; the elevation of superoxide anion (O (-.)(2)), the release of cytochrome c, the activation of caspase-3, the cleavage of poly(ADP-ribose) polymerase, and the DNA fragmentation. The pretreatment with 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), O(-.) 2) scavenger, completely abolished O(-.)(2) levels and downstream apoptotic events. Moreover, pretreatment with cyclosporin A (CsA), a mitochondrial permeability transition inhibitor, was capable of attenuating O(-.)(2)-mediated cytochrome c release and caspase-3 activation, and consequent apoptosis. Apoptosis, as demonstrated by oligonucleosomal DNA fragmentation and fluorescence microscopy, was induced 24 h after VVC treatment, which was also prevented by caspase-3 inhibitor, Ac-DEVD-CHO. Caspase-1 inhibitor, Ac-YVAD-CHO, did not protect ECV 304 cells from apoptosis. These results suggest a scenario where VVC-induced apoptosis is triggered by the generation of O(-.)(2), release of cytochrome c from mitochondria, activation of caspase-3, degradation of poly(ADP-ribose) polymerase, and DNA fragmentation. The induction of apoptosis in endothelial cells by VVC may provide a pivotal mechanism for understanding the pathophysiology of septicemia.
 ...
PMID:Vibrio vulnificus cytolysin induces superoxide anion-initiated apoptotic signaling pathway in human ECV304 cells. 1159 24

Angiostatin consisting of the first four-kringle domains of the plasminogen potently inhibits angiogenesis in vitro and in vivo. However, the molecular mechanism of action whereby angiostatin mediates its inhibitory effect on proliferating endothelial cells remains elusive. We therefore used the proliferating cultured human umbilical vein endothelial cells (HUVECs) promoted by vascular endothelial growth factor A to identify the endogenous signaling elements that mediate the antiangiogenic effect of angiostatin. Treatment of HUVEC with angiostatin at a concentration known to inhibit cell proliferation and induce apoptosis resulted in induction of p53-, Bax-, and tBid-mediated release of cytochrome c into the cytosol. In addition, angiostatin also activated the Fas-mediated apoptotic pathway in part via up-regulation of FasL mRNA, down-regulation of c-Flip, and activation of caspase 3. These results suggest that the anti-angiogenic action of angiostatin is likely mediated by two distinct signaling pathways, one intrinsic mediated by p53 while the other extrinsic involved in FasL engagement and mitochondria dysfunction.
 ...
PMID:Angiostatin antagonizes the action of VEGF-A in human endothelial cells via two distinct pathways. 1455 Feb 75

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis in the mammalian eye, suggesting that loss of PEDF is implicated in the pathogenesis of proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. Since oxidative stress is thought to be involved in pericyte loss and dysfunction, one of the changes characteristic of early diabetic retinopathy, we investigated whether and how PEDF could protect cultured retinal pericyte against oxidative stress injury. High glucose (30 mM) increased intracellular reactive oxygen species (ROS) generation in pericytes, which was completely blocked by PEDF. High glucose or H2O2 was found to induce growth retardation and apoptotic cell death of pericytes. PEDF completely restored these cytopathic effects on pericytes. An increased ratio of bax to bcl-2 mRNA level with subsequent activation of caspase-3 was observed in high-glucose- or H2O2-exposed pericytes, which was also completely prevented by PEDF. PEDF significantly increased glutathione peroxidase (GPx) mRNA levels and activity in pericytes. Further, PEDF was found to completely inhibit high-glucose- or H2O2-induced increase in a mRNA ratio of angiopoietin-2 to angiopoietin-1 and up-regulation of VEGF mRNA levels in pericytes. PEDF mRNA levels themselves were down-regulated in high-glucose- or H2O2-exposed pericytes. These results demonstrate that PEDF protects against high-glucose- or H2O2-induced pericyte apoptosis and dysfunction through its anti-oxidative properties via GPx induction. Our present study suggests that substitution of PEDF proteins might be a promising therapeutic strategy for treatment of patients with early diabetic retinopathy.
 ...
PMID:Pigment epithelium-derived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes. 1579 60

A highly vascular endocrine gland, the corpus luteum (CL) is an excellent model for the study of angiogenic factors. Prokineticins (PK-1 and -2), also termed endocrine-gland-derived vascular endothelial growth factor (VEGF) and BV8 are newly identified proteins described as selective angiogenic mitogens. We previously identified PK binding sites, two closely homologous G protein-coupled receptors (PK-R1 and PK-R2) in human and bovine ovarian cells, but their function remained unknown. In this study we examined the presence and effects of PK in CL-derived endothelial and steroidogenic cell types (LEC and LSC, respectively). PK-1 mRNA was identified in CL and follicles by real-time PCR, using primers specific for the bovine PK-1 sequence (retrieved from Bos taurus whole genome shotgun database). PK were potent angiogenic mitogens for LEC; they enhanced cell proliferation, elevated [3H]thymidine incorporation, MAPK activation, and c-jun/fos mRNA expression. The effects of PK proteins on cell survival were examined by nuclear morphology (4',6-diamidino-2-phenylindole dihydrochloride staining), measurement of DNA fragmentation (terminal dUTP nucleotide end labeling assay), and caspase-3 cleavage. Results obtained by these techniques demonstrated that PK protected LEC from serum starvation-induced apoptosis. Stress conditions such as serum withdrawal, TNF-alpha, and hypoxia markedly increased PK-R2 expression, whereas mRNA levels of PK-R1 remained unchanged. These suggest that the antiapoptotic effect of PK-1 on LEC may be mediated via PK-R2. PK-1 increased VEGF mRNA expression by LSC, implying that it could also indirectly, via VEGF, affect luteal angiogenesis. Together, these findings suggest an important role for PK-1 in luteal function by acting as a mitogen and survival factor in LEC.
 ...
PMID:Prokineticins (endocrine gland-derived vascular endothelial growth factor and BV8) in the bovine ovary: expression and role as mitogens and survival factors for corpus luteum-derived endothelial cells. 1593 29

The purpose of the study was to investigate the antitumor effects of Isatin and the related mechanism. Human neuroblastoma cells (SH-SY5Y) were exposed to Isatin at different concentrations for 48 h. Apoptotic features were demonstrated by means of nuclei staining with Hoechst 33258 and flow cytometry with propidium iodide (PI). Expressions of Bcl-2, Bax and vascular endothelial growth factor (VEGF) mRNA were analyzed via RT-PCR. Expressions of Bcl-2, Bax proteins and phosphorylated extracellular signal regulated protein kinases (ERKs, p42/p44) were analyzed via Western blot. Activation of caspase-3 was assayed by flow cytometry with anti-active caspase-3-McAb-PE. VEGF protein was determined by ELISA kits. And the results showed that apoptosis of SH-SY5Y cells were induced by Isatin in a dose-dependent manner. Expressions of Bcl-2, VEGF mRNA and Bcl-2, VEGF proteins were down-regulated, while expressions of Bax mRNA and Bax protein were not changed obviously. Expression of phosphorylated ERKs decreased, but the level of activated caspase-3 increased after treatment of Isatin. These results suggest that Isatin promotes the apoptosis of neuroblastoma cells, therefore, it might be a potential candidate for the treatment of neuroblastoma.
 ...
PMID:Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. 1856 13

The use of dexamethasone (Dex) in premature infants to prevent and/or treat bronchopulmonary dysplasia can adversely affect early neurodevelopment and probably result in loss of cerebral volume. Vascular endothelial growth factor A (VEGF), specifically VEGF(164) isoform has neurotrophic, neuroprotective and neurogenesis enhancing effects. Previous studies have demonstrated that Dex usually down-regulates VEGF. In the present study we investigated the effect of Dex on brain growth and VEGF in the neonatal rat brain. The pups in each litter were divided into the vehicle (n=84) or Dex-treated (n=98) groups. Rat pups in the Dex group received one of three different regimens of i.p. Dex which included tapering doses on postnatal days 3-6 (0.5, 0.25, 0.125 and 0.06 mg/kg, respectively), or repeated doses of 0.5 or 1 mg/kg/day on postnatal days 4-6 or single dose of 0.031, 0.06, 0.125, 0.25 or 0.5 mg/kg on postnatal day 6. The total VEGF protein and mRNA expression of the three main VEGF splice variants (VEGF(120), VEGF(164), and VEGF(188)) were measured in the rat pup brain using enzyme-linked immunosorbent assay and real-time reverse transcription polymerase chain reaction, respectively. Treatment with Dex significantly decreased the gain of body and brain weight. The tapering and repeated doses of Dex significantly increased caspase-3 activity, VEGF protein and the expression of mRNA of VEGF(164) and VEGF(188) splice variants but the single dose did not. We conclude that Dex is neurodegenerative in the developing brain but also increases VEGF which may play a neurotrophic and neuroprotective role.
 ...
PMID:Dexamethasone induces neurodegeneration but also up-regulates vascular endothelial growth factor A in neonatal rat brains. 1900 63

This study investigated apoptotic mechanisms of down-expression vascular endothelial growth factor (VEGF) by short interfering RNA (siRNA) in human breast cancer MCF-7 cells. Human breast cancer cells were evaluated for the expression of VEGF and VEGF receptor 2 (VEGFR-2). siRNA targeting VEGF mRNA were chemically synthesized and transfected into cells with Lipofectamine2000. In vitro assessments were then made of the ability of anti-VEGF siRNA to knock down expression of VEGF and the subsequent effect this decreased expression had on breast cancer cell apoptosis. Growth curve construction and nude mice experimentation in vivo were performed to assess the effects of VEGF silencing on tumor growth. Those cells transfected with siRNA targeting VEGF showed a 65% knockdown in VEGF expression and a marked increase in cell apoptosis. The expression of Bcl-2 protein in MCF-7 cells was decreased, the level of Bax protein was kept the same, cytochrome c was released from mitochondria into cytosol, and the cleaved Caspase-3 protein rose after siRNA transfection. The siRNA targeting human VEGF could induce apoptosis in MCF-7 cells and the mechanism of apoptosis is possibly related with changing Bcl-2/Bax expression ratio, releasing cytochrome c from mitochondria into cytosol, and up-regulation of Caspase-3 protein, but also could suppress the growth of breast cancer cells in vivo. VEGF might be a potential therapeutic target for human breast cancer.
 ...
PMID:The mechanisms on apoptosis by inhibiting VEGF expression in human breast cancer cells. 1916 40

This study was purposed to investigate the effect of a hypoxia-inducible factor inhibitor (YC-1) on expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) as well as induction of apoptosis in leukemic cell lines. RT-PCR was used to determine the levels of HIF-1alpha mRNA and VEGF mRNA in K562, U937 and Jurkat cells. After treatment of U937 cell with 4 micromol/L YC-1, cell apoptosis was assayed by DAPI staining under fluorescent microscope and flow cytometry with Annexin V-FITC/PI staining; the expression levels of HIF-1alpha mRNA and VEGF mRNA were measured with RT-PCR; the expression levels of HIF-1alpha, VEGF, BAX, BCL-2 and caspase-3 proteins were measured by Western blot. The results showed that HIF-1alpha mRNA and VEGF mRNA were expressed in all three leukemia cell lines. After treatment of U937 cell with 4 micromol/L YC-1 for 0, 8, 16 and 24 hours, the changes of morphologic features of U937 cells could be observed under fluorescent microscope and the apoptotic rates significantly increased in time-dependent manner, they were (4.87 +/- 0.70)%, (27.27 +/- 2.00)%, (51.53 +/- 2.81) and (60.5 +/- 3.20)% respectively, the expression levels of VEGF mRNA reduced, while the expression levels of HIF-1alpha mRNA had no obviously changes.Furthermore, the expression of HIF-1alpha, VEGF and BCL-2 decreased, while the expression of BAX and caspase-3 increased, the ratio of BAX/BCL-2 increased in time-dependent manner (r = 0.973, p < 0.01). It is concluded that HIF-1alpha mRNA and VEGF mRNA are all expressed in in K562, U937 and Jurkat cells, YC-1 has significant effect on down-regulating the protein expression of HIF-1alpha and VEGF, and induces the apoptosis in U937. The mechanism of apoptosis in leukemic cells may involve in up-regulating BAX/BCL-2 ratio and expression of protein caspase-3.
 ...
PMID:[Effects of hypoxia-inducible factor inhibitor on expression of HIF-1alpha and VEGF and induction of apoptosis in leukemic cell lines]. 2013 22

Vascular endothelial growth factor A (VEGF) likely plays a role in the hypoxic preconditioning (PC) induced tolerance to subsequent hypoxic-ischemic (HI) injury to the brain. However, limited data is available concerning VEGF in the developing brain after HI following PC. Neuroprotection by VEGF involves activation of Akt which inhibits apoptotic processes that contribute significantly to the brain injury in neonatal HI. We evaluated whether PC provides neuroprotection and affects VEGF, Akt and caspase-3 following HI in the developing rat brain. Newborn rats (6 days) were subjected to normoxia (21% O(2)) or PC (8% O(2)) for 3h followed by 24h of reoxygenation. The rats then had the right carotid artery permanently ligated followed by 140 min of hypoxia (8% O(2)) (HI or PC+HI). Brains from rats at the corresponding age without any exposure to PC or HI were examined for comparison (Sham). PC significantly reduced brain damage as measured by weight loss of the right hemisphere at 22 days after HI and by gross and microscopic morphology. PC amplified and prolonged the induction of mRNA of VEGF splice variants measured by real-time RT-PCR and enhanced the increase in VEGF protein measured by ELISA in brain following HI. PC preserved the phosphorylation of Akt-Ser-473 and diminished the increase in caspase-3 activity in brain following HI. We conclude that PC provides neuroprotection and augments and preserves the increase in VEGF following HI in the newborn rat brain which may play an important role in neuroprotection.
 ...
PMID:Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor A, preserves the phosphorylation of Akt-Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic-ischemic model. 2015 36

Dexamethasone (Dex) provides neuroprotection against subsequent hypoxia ischemia (HI) in newborn rats, but the mechanism of this neuroprotection is not well understood. It is known that vascular endothelial growth factor A (VEGF) has neuroprotective effects. The objective of this study was to evaluate the role of the VEGF signaling pathway in the Dex-induced neuroprotection in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 or 160 min of hypoxia (8% oxygen). Rat pups received two i.p. injections of either saline or Dex (0.25 mg/kg) at 24 and 4 h before HI exposure. To quantify the effects of a glucocorticoid receptor (GR) blocker, on postnatal day (PD) 6 and 15 min prior to Dex treatment rat pups received s.c. vehicle or RU486 (GR blocker, 60 mg/kg). After 24 h at PD 7, all rat pups had HI as described earlier. To quantify the effects of a VEGFR 2 blocker, at 24 h after Dex/Veh treatment (PD7), SU5416, a VEGFR 2 inhibitor or vehicle was injected intracerebroventricularly in the right hemisphere at 30 min before and 2 h after HI. Dex pre-treatment reduced brain injury and enhanced the HI-induced brain VEGF protein while a GR blocker inhibited these effects. Treatment with VEGFR 2 blocker decreased Dex-induced neuroprotection also. Dex pre-treatment enhanced the HI-induced increase in mRNA expression of VEGF splice variants and decreased the HI-induced reduction of Akt phosphorylation. Additionally, it also decreased HI-induced increase of caspase-3 activity and DNA fragments in neonatal rat brain. We conclude that Dex provides robust neuroprotection against subsequent HI in newborn rats via GR likely with the partial involvement of VEGF signaling pathway.
 ...
PMID:Dexamethasone pre-treatment protects brain against hypoxic-ischemic injury partially through up-regulation of vascular endothelial growth factor A in neonatal rats. 2127 50


1 2 3 Next >>