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

The mechanisms involved in regulating mammary cell turnover during the pregnancy-lactation cycle in dairy cows are unclear. The objective of present experiment was to describe expression of genes encoding proteins known to be involved in pathways regulating mammary cell proliferation, apoptosis, differentiation, cell survival, and tissue remodeling. Mammary gland biopsies were taken 7 times during the pregnancy-lactation cycle of 10 dairy cows, and samples were analyzed by immunohistochemistry and real-time PCR. Cell proliferation was greatest during the dry period and apoptosis was high in early dry period and early lactation. Based on Fas (tumor necrosis factor receptor superfamily member 6), Fas ligand, and caspase-3, caspase-8, and caspase-9 gene expression, no indication was found of a stage-dependent shift between the extrinsic and intrinsic pathways leading to apoptosis. Gene expression of microsomal glutathione S-transferase (mGST) did not vary significantly, whereas B-cell leukemia/lymphoma 2 (Bcl-2) and BCL2-associated X protein (Bax) gene expression was greatest during the dry period and early lactation and coincided with high cell turnover. Gene expression of early response genes c-Fos, c-Jun, and c-Myc correlated to neither rate of cell proliferation nor plasma concentration of insulin-like growth factor (IGF)-I and insulin. Gene expression of nuclear factor of kappa light chain gene enhancer in B-cells (NFkappaB) and NFkappaB inhibitor alpha was greatest in the periparturient period, and NFkappaB gene expression coincided with an anticipated need for cell survival factors. Expression of transforming growth factor beta (TGF-beta) receptor 1 and 2 mRNA was greatest in early lactation, whereas TGF-beta1 did not vary significant during the pregnancy-lactation cycle. Even though our results on the TGF-beta system did not comply with other studies, the gene expression pattern of the TGF-beta receptors indicates a role in regulating apoptosis in early lactation. Signal transducer and activator of transcription 5 (STAT5) gene expression was high in the periparturient period, which suggests a role for STAT5 in regulation of mammary cell proliferation and differentiation in dairy cows. Expression of tissue-plasminogen activator, plasminogen activator inhibitor-1, and IGF binding protein 5 genes was greatest in early lactation, suggesting a role for IGF binding protein 5 in coordinating regulation of apoptosis and tissue remodeling.
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PMID:Cellular mechanisms in regulating mammary cell turnover during lactation and dry period in dairy cows. 1848 54

High energy intake and excessive body fatness impair mammogenesis in prepubertal ruminants. High energy intake and excessive fatness also increase serum leptin. Our objective was to determine if an infusion of leptin decreases proliferation of mammary epithelial cells of prepubertal heifers in vivo. Ovine leptin at 100 microg/ quarter per d with or without 10 microg of insulin-like growth factor (IGF)-I was infused via the teat canal into mammary glands of prepubertal dairy heifers; contralateral quarters were used as controls. After 7 d of treatment, bromodeoxyuridine was infused intravenously and heifers were slaughtered approximately 2 h later. Tissue from 3 regions of the mammary parenchyma was collected and immunostained for bromodeoxyuridine (BrdU), proliferating cell nuclear antigen (Ki-67), and caspase-3. Leptin decreased the number of mammary epithelial cells in the S-phase of the cell cycle by 48% in IGF-I-treated quarters and by 19% in saline-treated quarters. Leptin did not alter the number of mammary epithelial cells within the cell cycle, as indicated by Ki-67 labeling. Caspase-3 immunostaining within the mammary parenchyma was very low in these heifers, but leptin significantly increased labeling in saline-treated quarters. Leptin enhanced SOCS-3 expression in IGF-I-treated quarters but did not alter SOCS-1 or SOCS-5 expression. We conclude that a high concentration of leptin in the bovine mammary gland reduces proliferation of mammary epithelial cells. The reduced proliferation is accompanied by an increase in SOCS-3 expression, suggesting a possible mechanism for leptin inhibition of IGF-I action. Whether leptin might be a physiological regulator of mammogenesis remains to be determined.
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PMID:Intramammary infusion of leptin decreases proliferation of mammary epithelial cells in prepubertal heifers. 1865 Feb 80

Growth hormone (GH) is found in the retina and vitreous of the chick embryo, where it appears to act as a growth and differentiation factor, having neuroprotective effects on retinal ganglion cells (RGCs). Here, we review the molecular mechanisms of the anti-apoptotic effect of GH in chick RGCs. GH treatment of RGCs reduces Akt levels, while raising Akt-phos levels, consistent with a role for Akt signaling pathways in the GH neuroprotective action. The induction of apoptosis by immunoneutralization with GH antiserum is accompanied by an increase in caspase-3 and caspase-9 activation, and also PARP-1 cleavage. Calpain activation also appears to be a major caspase-independent pathway to PARP-1 cleavage and apoptosis in these cells, supporting the view that caspase and calpain inhibitors are major neuroprotective agents for RGCs, and that pathways that activate both caspases and calpains are important for the anti-apoptotic actions of GH in these cells. These pathways involve the activation of cytosolic tyrosine kinases (Trks) and extracellular-signal-related kinases (ERKs). Occupation of the GH receptor by GH involves downstream intracellular Trk pathways. The Akt and Trk pathways appear to converge on the activation of cAMP response element binding protein (CREB), which is able to initiate transcription of pro- or anti-apoptotic genes. These results indicate that the action of GH in the neuroprotection of embryonic RGCs involves pathways common to with other neurotrophins, and that GH can be considered to be a growth and differentiation factor in the development of the embryonic retina. We have also investigated the relationship between the overlapping anti-apoptotic effects of GH and insulin-like growth factor-1 (IGF-1), two functionally closely related factors. We find that simultaneous immunoneutralization of GH and IGF-1 does not increase the level of apoptosis in the cultures above that achieved by immunoneutralization of GH alone. We therefore conclude that the neuroprotective actions of GH in the developing retina are likely mediated in large part through the action of IGF-1.
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PMID:Signaling mechanisms mediating local GH action in the neural retina of the chick embryo. 1934 64

delta-Opioid receptor (DOR) agonists possess cytoprotective properties, an effect associated with activation of the "pro-survival" kinase Akt. Here we delineate the signal transduction pathway by which opioids induce Akt activation in neuroblastomaxglioma (NG108-15) hybrid cells. Exposure of the cells to both [D-Pen(2,5)]enkephalin and etorphine resulted in a time- and dose-dependent increase in Akt activity, as measured by means of an activation-specific antibody recognizing phosphoserine-473. DOR-mediated Akt signaling is blocked by the opioid antagonist naloxone and involves inhibitory G(i/o) proteins, because pre-treatment with pertussis toxin, but not over-expression of the G(q/11) scavengers EBP50 and GRK2-K220R, prevented this effect. Further studies with Wortmannin and LY294002 revealed that phophoinositol-3-kinase (PI3K) plays a central role in opioid-induced Akt activation. Opioids stimulate Akt activity through transactivation of receptor tyrosine kinases (RTK), because pre-treatment of the cells with inhibitors for neurotrophin receptor tyrosine kinases (AG879) and the insulin-like growth factor receptor IGF-1 (AG1024), but not over-expression of the Gbetagamma scavenger phosducin, abolished this effect. Activated Akt translocates to the nuclear membrane, where it promotes GSK3 phosphorylation and prevents caspase-3 cleavage, two key events mediating inhibition of cell apoptosis and enhancement of cell survival. Taken together, these results demonstrate that in NG108-15 hybrid cells DOR agonists possess cytoprotective properties mediated by activation of the RTK/PI3K/Akt signaling pathway.
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PMID:delta-Opioid receptor-stimulated Akt signaling in neuroblastoma x glioma (NG108-15) hybrid cells involves receptor tyrosine kinase-mediated PI3K activation. 1936 48

Pyrrolizidine alkaloids (PAs) are well-known natural hepatotoxins. In this study, we investigated the protection of epidermal growth factor (EGF) against the hepatotoxicity of clivorine, which is an otonecine-type PA from traditional Chinese medicine Ligularia hodgsonii Hook. Cell viability assay and cell morphology observation showed that EGF (1 ng/mL) reversed clivorine-induced cytotoxicity on human normal liver L-02 cells. EGF (1 ng/mL) also inhibited clivorine-induced DNA fragmentation and caspase-3 cleavage. Our previous study has showed that antiapoptotic Bcl-xL degradation and mitochondrial-mediated apoptosis was involved in clivorine-induced hepatotoxicity. In this study, we found that EGF (1 ng/mL) inhibited clivorine-induced antiapoptotic Bcl-xL protein decrease, caspase-9 activation, and release of cytosolic cytochrome C. We further investigated the effects of vascular epidermal growth factor, basic fibroblast growth factor, and insulin-like growth factor-1 on clivorine-induced cytotoxicity, and there is no significant protection observed. Our results suggest that EGF exerts its protective effects against clivorine-induced hepatotoxicity probably by modulating mitochondrial-mediated apoptotic signal pathway.
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PMID:Protection of epidermal growth factor against clivorine-induced mitochondrial-mediated apoptosis in hepatocytes. 1943 49

Type 1 insulin-like growth factor receptor (IGF1R) signaling in neuronal development was studied in mutant mice with blunted igf1r gene expression in nestin-expressing neuronal precursors. At birth [postnatal (P) day 0] brain weights were reduced to 37% and 56% of controls in mice homozygous (nes-igf1r(-/-)) and heterozygous (nes-igf1r(-/Wt)) for the null mutation, respectively, and this brain growth retardation persisted postnatally. Stereological analysis demonstrated that the volumes of the hippocampal formation, CA fields 1-3, dentate gyrus (DG), and DG granule cell layer (GCL) were decreased by 44-54% at P0 and further by 65-69% at P90 in nes-igf1r(-/Wt) mice. In nes-igf1r(-/-) mice, volumes were 29-31% of controls at P0 and, in the two mice that survived to P90, 6-19% of controls, although the hilus could not be identified. Neuron density did not differ among the mice at any age studied; therefore, decreased volumes were due to reduced cell number. In postnatal nes-igf1r(-/Wt) mice, the percentage of apoptotic cells, as judged by activated caspase-3 immunostaining, was increased by 3.5-5.3-fold. The total number of proliferating DG progenitors (labeled by BrdU incorporation and Ki67 staining) was reduced by approximately 50%, but the percentage of these cells was similar to the percentages in littermate controls. These findings suggest that 1) the postnatal reduction in DG size is due predominantly to cell death, pointing to the importance of the IGF1R in regulating postnatal apoptosis, 2) surviving DG progenitors remain capable of proliferation despite reduced IGF1R expression, and 3) IGF1R signaling is necessary for normal embryonic brain development.
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PMID:Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. 1943 43

Insulin-like growth factor binding protein-3 (IGFBP-3) is known to induce apoptosis in an insulin-like growth factor (IGF)-dependent and IGF-independent manner, but the mechanism underlying the IGF-independent effects remains unclear. Polypeptide N-acetylgalactosaminyltransferase 14 (GalNAc-T14) is a novel IGFBP-3 binding partner. In this paper, small interference RNA (siRNA) targeting GalNAc-T14 was used to examine whether GalNAc-T14 affects the apoptotic action of IGFBP-3. Using semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and western blot analysis, we determined that GalNAc-T14 expression was downregulated by the siRNA directed against GalNAc-T14. Apoptosis analysis of IGFBP-3-overexpressing cells treated with siRNA against GalNAc-T14 was performed to determine if GalNAc-T14 was specifically involved in IGFBP-3 signalling. The results, as determined by flow cytometric analysis and caspase-3 assay, showed that the extent of apoptosis induced by IGFBP-increased with RNA interference (RNAi) knockdown of GalNAc-T14. Our data suggest that GalNAc-T14 influences the apoptotic action of IGFBP-3 and might mediate the signalling pathway of IGFBP-3. Experiments to determine the role of GalNAc-T14 in the regulation of apoptosis induced by IGFBP-3 are under way.
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PMID:GalNAc-T14 may be involved in regulating the apoptotic action of IGFBP-3. 1980

Human peripheral blood lymphocytes have been useful as a putative model of oxidative stress-induced apoptosis for Parkinson's disease. The present work shows that rotenone, a mitochondrial complex I inhibitor, induced time- and concentration-dependent apoptosis in lymphocytes which was mediated by anion superoxide radicals (O(2)*(-))/hydrogen peroxide, depolarization of mitochondria, caspase-3 activation, concomitantly with the nuclear translocation of transcription factors such as NF-kappaB, p53, c-Jun and nuclei fragmentation. Since insulin-like growth factor-1 (IGF-1) interferes with a cell's apoptotic machinery when subjected to several stressful conditions, it is demonstrated here for the first time that IGF-1 effectively protects lymphocytes against rotenone through PI-3K/Akt activation, down-regulation of p53 and maintenance of mitochondrial membrane potential independently of ROS generation. These data might contribute to understanding the role played by IGF-1 against oxidative stress stimuli.
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PMID:Effects of insulin-like growth factor-1 on rotenone-induced apoptosis in human lymphocyte cells. 1987 89

Neutrophil elastase (NE) decreases the endothelial production of prostacyclin (PGI(2)) through the inhibition of endothelial nitric oxide synthase (NOS) activation and thereby contributes to the development of ischemia/reperfusion (I/R)-induced liver injury. We previously demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons increases the insulin-like growth factor- I (IGF-I) production and thereby reduces I/R-induced liver injury. Because PGI(2) is capable of stimulating sensory neurons, we hypothesized that NE contributes to the development of I/R-induced liver injury by decreasing IGF-I production. In the present study, we examined this hypothesis in rats subjected to hepatic I/R. Ischemia/reperfusion-induced decreases of hepatic tissue levels of CGRP and IGF-I were prevented significantly by NE inhibitors, sivelestat, and L-658, 758, and these effects of NE inhibitors were reversed completely by the nonselective cyclooxygenase inhibitor indomethacin (IM) and the nonselective NOS inhibitor L-NAME but not by the selective inducible NOS inhibitor 1400W. I/R-induced increases of hepatic tissue levels of caspase-3, myeloperoxidase and the number of apoptotic cells were inhibited by NE inhibitors, and these effects of NE inhibitors were reversed by IM and L-NAME but not by 1400W. Administration of iloprost, a stable PGI(2) analog, produced effects similar to those induced by NE inhibitors. Taken together, these observations strongly suggest that NE may play a critical role in the development of I/R-induced liver injury by decreasing the IGF-I production through the inhibition of sensory neuron stimulation, which may lead to an increase of neutrophil accumulation and hepatic apoptosis through activation of caspase-3 in rats.
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PMID:Neutrophil elastase contributes to the development of ischemia/reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats. 2047 44

This study aimed to evaluate the radiosensitizing effect of a COX-2 inhibitor, NS398, and its mechanism in radioresistant esophageal cancer Eca109R50Gy cells. NS398 enhanced radiosensitivity of Eca109R50Gy cells, characterized by redistribution of cell cycle, inhibition of DNA-dependent protein kinase catalytic subunit expression and induction of apoptosis. NS398 also reduced phospho-AKT level, upregulated expression of Bax and both procaspase-3 and active caspase-3, and downregulated Bcl-2 expression. Finally, NS398-induced radiosensitization was partly reversed by insulin-like growth factor-1, but not by prostaglandin E2. Our results suggest that NS398 may enhance radiosensitivity of Eca109R50Gy cells through blocking AKT activation and inducing apoptosis.
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PMID:Cyclooxygenase-2 inhibitor NS398 enhances radiosensitivity of radioresistant esophageal cancer cells by inhibiting AKT activation and inducing apoptosis. 2048 53


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