UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteolytic caspase cascade plays a central role in the signaling and execution steps of apoptosis. This study investigated the activation of different caspases in apoptosis induced by MAL (a folding variant of human alpha-lactalbumin) isolated from human milk. Our results show that the caspase-3-like enzymes, and to a lesser extent the caspase-6-like enzymes, were activated in Jurkat and A549 cells exposed to MAL. Activated caspases subsequently cleaved several protein substrates, including PARP, lamin B, and alpha-fodrin. A broad-range caspase inhibitor, zVAD-fmk, blocked the caspase activation, the cleavage of proteins, and DNA fragmentation, indicating an important role for caspase activation in MAL-induced apoptosis. Since an antagonistic anti-CD95 receptor antibody, ZB4, did not influence the MAL-induced killing, we conclude that this process does not involve the CD95-mediated pathway. While MAL did not directly activate caspases in the cytosol, it colocalized with mitochondria and induced the release of cytochrome c. Thus, these results demonstrate that caspases are activated and involved in apoptosis induced by MAL and that direct interaction of MAL with mitochondria leads to the release of cytochrome c, suggesting that this release is an important step in the initiation and/or amplification of the caspase cascade in these cells.
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PMID:Protease activation in apoptosis induced by MAL. 1036 25

We studied the mechanism of the cytotoxic effects of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT; induction with 1 mM ALA for 4 h followed by a blue light dose of 18 J/cm(2)) on the human promyelocytic leukemia cell line HL60 using biochemical and electron microscopy methods. The disruption of mitochondrial membrane potential, deltapsi(m), was paralleled by a decrease in ATP level, unmasking of the mitochondrial antigen 7A6, release of cytochrome c into the cytoplasm, activation of caspases 9 and 3 and cleavage of poly(ADP-ribose) polymerase (PARP). This was followed by DNA fragmentation. These data suggest that ALA-PDT activates the mitochondrial apoptotic pathway. The level of endoplasmic reticulum Ca(2+)-binding chaperones ERp57 and ERp72 and of anti-apoptotic proteins Bcl-2 and Bcl-x(L) was decreased whereas that of Ca(2+)-binding protein calmodulin and the stress protein HSP60 was elevated following ALA-PDT. Inhibition of the initiator caspase 9, execution caspase 3 and Ca(2+)-dependent protease m-calpain, did not prevent DNA fragmentation. We conclude that, in our in vitro model, ALA-based photodynamic treatment initiates several signaling processes in HL60 cells that lead to rapidly progressing apoptosis, which is followed by slow necrosis. Two apoptotic processes proceed in parallel, one representing the mitochondrial pathway, the other involving disruption of calcium homeostasis and activation of the endoplasmic reticulum stress-mediated pathway.
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PMID:Mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by 5-aminolevulinic acid-based photodynamic therapy in HL60 leukemia cells. 1263 80

Apoptosis is essential to eliminate secretory epithelial cells during the involution of the mammary gland. The environmental regulation of this process is however, poorly understood. This study tested the effect of HAMLET (human alpha-lactalbumin made lethal to tumor cells) on mammary cells. Plastic pellets containing HAMLET were implanted into the fourth inguinal mammary gland of lactating mice for 3 days. Exposure of mammary tissue to HAMLET resulted in morphological changes typical for apoptosis and in a stimulation of caspase-3 activity in alveolar epithelial cells near the HAMLET pellets but not more distant to the pellet or in contralateral glands. The effect was specific for HAMLET and no effects were observed when mammary glands were exposed to native a-lactalbumin or fatty acid alone. HAMLET also induced cell death in vitro in a mouse mammary epithelial cell line. The results suggest that HAMLET can mediate apoptotic cell death in mammary gland tissue.
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PMID:Apoptotic cell death in the lactating mammary gland is enhanced by a folding variant of alpha-lactalbumin. 1514 7

Pathogenic microorganisms invading the mammary gland induce an inflammatory reaction which includes an increase of somatic cells in milk and activation of bacteriostatic enzymes and proteins in milk. During spontaneously occurring subclinical mastitis the somatic milk cells, mainly macrophages, secrete cytokines, eicosanoids, acute phase proteins and other immunomediators. In contrast, the bacteriostatic protein lactoferrin is mainly secreted by mammary epithelial tissue, while major milk proteins like alpha-lactalbumin and kappa-casein are down-regulated already during subclinical infection. Changes of the mRNA expression of various immunomediators in the mammary tissue of cows during 12 h after induction of mastitis via intramammary administration of lipopolysaccharide (LPS) in several studies are reported. Six healthy lactating cows were injected in one quarter with 100 microg Escherichia coli-LPS (O26: B6) and the contralateral quarter with saline (9 g/l) serving as control. mRNA expression in mammary biopsy samples of various inflammatory factors and milk proteins at 0, 3, 6, 9 and 12 h after LPS administration was quantified by real-time reverse transcription-PCR. In LPS-challenged quarters tumour necrosis factor alpha and cyclooxygenase-2 mRNA expression increased to their highest values (P<0.05) at 3 h after LPS-challenge. Expression of lactoferrin, lysozyme, inducible nitric oxide synthase, and of the apoptotic factors caspase-3, caspase-7 and FAS was elevated (P<0.05) and peaked at 6 h after challenge. No significant increase in mRNA expression of platelet-activating factor acethylhydrolase, 5-lipoxygenase, and insulin-like growth factor 1 was found. None of the parameters tested did change significantly in the control quarters. mRNA expression of major milk proteins did not change significantly in response to the LPS challenge (alphaS1-casein, alphaS2-CN, beta-CN and beta-lactoglobulin) except for alpha-lactalbumin which decreased (P<0.05) in LPS-treated and control quarters and for kappa-CN which decreased in the LPS-treated quarters. In conclusion, mRNA expression of the majority albeit not all inflammatory factors changed within hours of LPS challenge. Decreased gene expression of alpha-lactalbumin and kappa-CN may reduce milk yield and suitability for cheese production.
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PMID:Gene expression of factors related to the immune reaction in response to intramammary Escherichia coli lipopolysaccharide challenge. 1618 Jul 30

This study addressed the mechanisms by which suckling regulates cell turnover and onset and maintenance of lactation of individual mammary glands of sows. The effects of no, transient (through 12 to 14 h postpartum), or regular suckling of individual glands during d 0 to 6 of lactation were studied in 5 sows. Nonsuckling was obtained by taping the glands to prevent access to the nipples. Visual scores confirmed that regularly suckled glands maintained lactation, whereas transiently suckled and nonsuckled glands regressed during lactation. Mammary gland biopsies were collected on d -5, 1, 2, 4, and 6 relative to farrowing in order to evaluate the cell turnover and to quantify the transcription of genes potentially involved in mammary cell turnover and function. The proportion of proliferating cells was greatest prepartum (13.1%). After farrowing, the proportion of proliferating cells declined in all glands, then remained low (5.6%) in nonsuckled glands and increased (P < 0.01) from an average of 7.5% on d 1 to 9.9% on d 6 in regularly suckled and transiently suckled glands. Transcriptional data were analyzed using a gamma-distributed, generalized linear mixed model. Abundance of alpha-lactalbumin mRNA (P < 0.01) increased in regularly suckled glands within the first day of lactation and remained elevated, whereas the expression in taped glands remained at the prepartum level. Prolactin receptor mRNA abundance decreased (P < 0.001), and IGFBP-5 mRNA abundance increased (P < 0.01) in nonsuckled and transiently suckled glands after parturition compared with regularly suckled glands. Mammary mRNA abundances of IGF-I, IGF-II, type I IGF receptor, and caspase 3 were minimally or inconclusively affected by the suckling regimens. In conclusion, suckling during the first 12 to 14 h postpartum is insufficient to initiate and maintain lactation until 24 to 36 h postpartum but sufficient to induce mammary cell proliferation for at least 6 d postpartum. Furthermore, a high prolactin receptor transcription and a low IGFBP-5 transcription seem important for maintaining a functional mammary gland during lactation.
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PMID:Role of suckling in regulating cell turnover and onset and maintenance of lactation in individual mammary glands of sows. 1677 52

The basic mechanism of cell death induced by 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) (ALA-PDT) in glioma cells has not been fully elucidated. In this study, the details of the cell death mechanism induced by ALA-PDT were investigated in three human glioma cell lines (U251MG, U87MG, and U118MG) in vitro. To evaluate the manner of accumulation of protoporphyrin IX (PpIX), intracellular PpIX contents were measured by flow cytometry after incubation with 5-ALA. To analyze the mechanism of cell death, U251MG cells were assayed by the terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick end-labeling (TUNEL) method, and the caspase activity was measured after ALA-PDT. Furthermore, the mitochondrial membrane potential (MMP) and the release of mitochondrial cytochrome c were determined. PpIX fluorescence reached a plateau 4 h after exposure to 5-ALA. The proportion of dead cells increased with increases in the dosage of light. These cells were confirmed by TUNEL staining to be apoptotic. Increases in the activity of both caspase-3 and -9, a decrease in MMP, and a marked increase in cytochrome c in the cytosolic fraction were found after cells were subjected to PDT. These results indicate that a dysfunction of MMP is followed by mitochondrial cytochrome c release, which triggers apoptosis through a mitochondrial pathway. ALA-PDT induces massive apoptosis due to the direct activation of a mitochondrial pathway, which is resistant to many anti-apoptotic processes, in human glioma cells. This finding implies that ALA-PDT is a promising therapy for the treatment of apoptosis-reluctant tumors such as malignant gliomas.
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PMID:Massive apoptotic cell death of human glioma cells via a mitochondrial pathway following 5-aminolevulinic acid-mediated photodynamic therapy. 1724 20

Glioblastoma is the most common astrocytic brain tumor in humans. Current therapies for this malignancy are mostly ineffective. Photodynamic therapy (PDT), an exciting treatment strategy based on activation of a photosensitizer, has not yet been extensively explored for treating glioblastoma. We used 5-aminolevulinic acid (5-ALA) as a photosensitizer for PDT to induce apoptosis in human malignant glioblastoma U87MG cells and to understand the underlying molecular mechanisms. Trypan blue dye exclusion test showed a decrease in cell viability after exposure to increasing doses of 5-ALA for 4h followed by PDT with a broad spectrum blue light (400-550 nm) at a dose of 18J/cm(2) for 1h and then incubation at 37 degrees C for 4h. Following 0.5 and 1mM 5-ALA-based PDT (5-ALA-PDT), Wright staining and ApopTag assay showed occurrence of apoptosis morphologically and biochemically, respectively. After 5-ALA-PDT, down regulation of nuclear factor kappa B (NFkappaB) and baculovirus inhibitor-of-apoptosis repeat containing-3 (BIRC-3) protein indicated inhibition of survival signals. Besides, 5-ALA-PDT caused increase in Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF). Activation of calpain, caspase-9, and caspase-3 occurred in course of apoptosis. Calpain and caspase-3 activities cleaved alpha-spectrin at specific sites generating 145kD spectrin breakdown product (SBDP) and 120kD SBDP, respectively. The results suggested that 5-ALA-PDT induced apoptosis in U87MG cells by suppression of survival signals and activation of proteolytic pathways. Thus, 5-ALA-PDT can be an effective strategy for inducing apoptosis in glioblastoma.
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PMID:5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells. 1733 70

Alpha-lactalbumin (alpha-LA), a major human milk whey protein, has been reported to exhibit bactericidal properties, immune suppressive effects, anti-proliferation and apoptosis in transformed cells; however, little is known about its anti-inflammation and related molecular mechanism. In this study we investigated the effects of alpha-LA on macrophages. We found that treatment with high concentration alpha-LA (> or = 100 microg/ml) could result in a time- and dose-dependent decrease in growth activity, morphological changes, increase in hypodiploid DNA population, and DNA fragmentation in RAW 264.7 cells. We also found that high dose alpha-LA could induce cellular apoptosis and necrosis, as determined by Annexin V binding assay. The alpha-LA could enhance the expression levels of cytochrome c, active caspase 3, active caspase 8, extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activation without changing the protein levels, but suppress the protein level of Bcl-2. The broad-spectrum caspase inhibitor, Boc-D-fmk, failed to block cell death, indicating that alpha-LA-induced cell death was modulated in a caspase-independent manner. In addition, the ERK1/2 inhibitor, PD98059, could partially rescue alpha-LA-induced cell death, while the JNK inhibitor, SP600125, could weakly protect cells from death. Our results suggested that activation of ERK1/2 might mediate alpha-LA-induced cell death in RAW 264.7 cells.
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PMID:Induction of cell death in RAW 264.7 cells by alpha-lactalbumin. 1804 62

Mammary glands are special tissue characterized by proliferation of the epithelium, during puberty and pregnancy and by programmed cell death, during involution. In this study, apoptosis was identified by TUNEL staining and then related to cell proliferation, as determined by Ki-67 staining. The apoptotic index was at its highest at 8 days of involution, whereas the proliferation index was at its highest during lactation. Caspase-3 was immunolocalised only in mast cells and along the basal membrane in the mammary tissue at -10 days from lambing, 150 days of lactation and at 8 days of involution. This finding could indicate that caspase-3 is not involved in sheep mammary gland apoptosis, but that other proteins - such as apoptosis inducing factor (AIF) - can trigger apoptosis, through the mitochondrial pathway, in a caspase-independent manner. The expression of genes involved in the regulation of lactation and apoptosis was also investigated and determined relatively to -10 days from lambing. The relative expression level of LALBA, reached its maximum during lactation, whereas the expressions of BCL2, BCL2L1, BAX, STAT5A, STAT3, IGFBP5 and FOXO3A, increased significantly during involution in correlation with apoptotic index. This work shows for the first time the turnover of mammary cells and the interaction of their signals during the complete lactation cycle in sheep. The data on gene expression can contribute to elucidate the mechanisms controlling milk production and cell turnover in this species.
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PMID:Cell turnover and gene activities in sheep mammary glands prior to lambing to involution. 1932 11

Recent studies in dairy cows have demonstrated that serotonergic ligands affect milk yield and composition. Correspondingly, serotonin (5-HT) has been demonstrated to be an important local regulator of lactational homeostasis and involution in mouse and human mammary cells. We determined the mRNA expression of bovine 5-HT receptor (HTR) subtypes in bovine mammary tissue (BMT) and used pharmacological agents to evaluate functional activities of 5-HT receptors. The mRNAs for five receptor isoforms (HTR1B, 2A, 2B, 4, and 7) were identified by conventional real-time (RT)-PCR, RT quantitative PCR, and in situ hybridization in BMT. In addition to luminal mammary epithelial cell expression, HTR4 was expressed in myoepithelium, and HTR1B, 2A, and 2B were expressed in small mammary blood vessels. Serotonin suppressed milk protein mRNA expression (alpha-lactalbumin and beta-casein mRNA) in lactogen-treated primary bovine mammary epithelial cell (BMEC) cultures. To probe the functional activities of individual receptors, caspase-3 activity and expression of alpha-lactalbumin and beta-casein were measured. Both SB22489 (1B antagonist) and ritanserin (2A antagonist) increased caspase-3 activity. Expression of alpha-lactalbumin and beta-casein mRNA levels in BMEC were stimulated by low concentrations of SB224289, ritanserin, or pimozide. These results demonstrate that there are multiple 5-HT receptor isoforms in the bovine mammary gland, and point to profound differences between serotonergic systems of the bovine mammary gland and the human and mouse mammary glands. Whereas human and mouse mammary epithelial cells express predominately the protein for the 5-HT(7) receptor, cow mammary epithelium expresses multiple receptors that have overlapping, but not identical, functional activities.
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PMID:The bovine mammary gland expresses multiple functional isoforms of serotonin receptors. 1965 43

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