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

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study tests the hypothesis that this vulnerability occurs because protective, antiapoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e., activation of caspase 3) events that occur during hepatocyte apoptosis, and various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout this period, there is negligible histological evidence of liver damage, and serum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fold greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-regulated genes. Consistent with this heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.
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PMID:Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation. 1144 19

Leptin, the Ob gene product, has emerged recently as a key regulator of bone mass. However, the mechanism mediating leptin effect remains controversial. Because the action of leptin is dependent on its receptors, we analyzed their expression in osteoblast-lineage primary human bone marrow stromal cells (hBMSC). Both the short and long forms of leptin receptors were detected in hBMSC. Leptin significantly decreased the viability of hBMSC. This cytotoxic effect was prevented by Z-Val-Ala-Asp-fluoromethylketone, a pan-caspase inhibitor, implicating that leptin-induced hBMSC death was caspase-dependent. Further investigation demonstrated that leptin activated caspase-3 and caspase-9, but not caspase-8, and increased the cleavage of poly-(ADP-ribose) polymerase and cytochrome c release into cytosol. Leptin activated ERK, but not p38 and JNK, and up-regulated cPLA2 activity; the latter was abolished by pre-treatment of cells with the MEK inhibitor (PD98059 or U0126) or cPLA2 inhibitor (AACOCF3). PD98059, U0126, and AACOCF3 also diminished the leptin-induced cytochrome c release into cytosol, cell death, and caspase-3 activation. These data indicated that leptin induced hBMSC apoptosis via ERK/cPLA2/cytochrome c pathway with activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. To our knowledge, this is the first study demonstrating the direct detrimental effect of leptin on bone cells.
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PMID:Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. 1266 5

Human term-placental culture techniques such as villous explant or dual perfusion are commonly used to study trophoblast function under control and experimentally manipulated conditions. We have compared trophoblast viability during perfusion and in explants cultured under various conditions by monitoring glucose consumption, protein synthesis and secretion, expression of differentiation-specific genes, induction of stress proteins and apoptotic cell death. The tissue was obtained from term-placentae of uncomplicated pregnancies after elective Caesarean delivery. We observed a severe loss of trophoblast viability in explants irrespective of the culture conditions used. Over 7 h of culture the amount of the differentiation specific placental hormones hCG, hPL and leptin accumulated in the medium dropped significantly. Analysis of their expression by semi-quantitative and real-time RT-PCR revealed that the down-regulation of expression occurred at the transcriptional level. This transcriptional repression was accompanied by induction of the stress-proteins RTP and BiP/GRP78. Analysis of apoptotic cell death by TUNEL assay and immunohistochemical detection of the caspase-3-specific degradation product of cytokeratin 18 revealed prominent cell death after 7 h of culture. These results are in contrast to the findings obtained in perfused placental tissue where, after 7 h of culture, hormone secretion, expression of stress proteins and cell death were similar as in native tissue. This difference between villous explant incubation and dual perfusion is also reflected by a significantly higher consumption of glucose in perfused tissue.
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PMID:Trophoblast viability in perfused term placental tissue and explant cultures limited to 7-24 hours. 1312 86

The localization of leptin and leptin receptors in the stomach and small intestine has been reported. Their function is still unknown, although leptin is a hormone that regulates appetite and fat-related metabolism. The small intestine is one of the important organs for regulating metabolism. The purpose of the present study was to investigate whether leptin regulates apoptosis in the small intestinal mucosa. Intestinal apoptosis was evaluated by percent fragmented DNA, electrophoresis, TUNEL staining, and western blotting analysis of caspase-3. Mucosal apoptosis in the rat jejunum and ileum was evaluated at 0, 3, 6, 12, and 24 hrs after injection. Rats were tested after ad libitum feeding and 24-hr fasting to exclude the anorectic effect of leptin. Leptin was injected intraperitoneally (ip) at a dose of 200 microg/rat and infused into the rat third cerebroventricle (icv) at a dose of 8 microg/rat. Leptin at a dose of 8 microg/rat significantly induced intestinal apoptosis in the small intestine at 3 and 6 hrs after icv administration in both ad libitum feeding and 24-hr fasted rats. This increase in apoptosis was not attenuated by vagotomy. Intestinal apoptosis increased 12 and 24 hrs after ip injection of leptin at a dose of 200 microg/rat. The peak of the increase in apoptosis in icv rats appeared earlier than that in ip rats. Leptin induced jejunal and ileal mucosal apoptosis in the rat, indicating that leptin might control intestinal function through the regulation of intestinal apoptosis.
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PMID:Intracerebroventricular administration of leptin-induced apoptosis in the rat small intestinal mucosa. 1461 Feb 67

Leptin, a multifunctional hormone produced predominantly by adipocytes but also identified throughout the glandular tissue of alimentary tract, including salivary glands and oral mucosa, has emerged recently as an important regulator of mucosal inflammatory responses to bacterial infection. In this study, we report that leptin prevents (up to 88.4%) the reduction in mucin synthesis evoked in mucous cells of sublingual salivary gland by LPS of periodontopathic bacterium, Porphyromonas gingivalis. The effect of leptin, moreover, was reflected in a marked decrease in the LPS-induced apoptosis, expression of TNF-alpha, caspase-3 activity, and NO generation. The impedance by leptin of the LPS inhibitory effect on mucin synthesis was blocked by wortmannin, an inhibitor of PI3K, which also obviated the inhibitory effect of leptin on the LPS-induced upregulation in apoptosis, caspase-3 activity, and NO generation. A potentiation in the impedance by leptin of the LPS-induced apoptosis, caspase-3 activity, and NO generation was, however, attained with NOS-2 inhibitor, 1400W, that also caused further enhancement in the impedance by leptin of the LPS detrimental effect on mucin synthesis. Taken together, our data are the first to demonstrate the nature of the involvement of leptin in countering the pathological consequences of P. gingivalis infection on the synthesis of salivary mucins.
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PMID:Leptin suppresses Porphyromonas gingivalis lipopolysaccharide interference with salivary mucin synthesis. 1465 85

High concentrations of glucose induce beta cell production of IL-1beta, leading to impaired beta cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1beta and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1beta and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic beta cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased beta cell production of IL-1Ra and induced IL-1beta release from the islet preparation, leading to impaired beta cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired beta cell function. Moreover, siIL-1Ra enhanced glucose-induced beta cell apoptosis. These findings demonstrate expression of IL-1Ra in the human beta cell, providing localized protection against leptin- and glucose-induced islet IL-1beta.
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PMID:Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. 1514 Oct 93

Many factors regulate nervous system development, including complex cross-talk between local neuroendocrine systems. The adipocyte-secreted hormone leptin, mainly known for its key roles in nutrition and reproductive balance, may also be involved in neuroanatomical organization, myelination processes, and neuronal/glia maturation. SK-N-SH-SY5Y neuroblastoma cells were employed as an in vitro model of human neuronal cells to determine whether leptin exerts neuroprotective activities. We show that SH-SY5Y cells express leptin, the long and short isoforms of the leptin receptor (ObRl, ObRs). In SH-SY5Y cells, leptin induced signal transducer and activator of transcription (STAT)-3 phosphorylation and suppressor of cytokine signaling-3 mRNA expression. Leptin dose-dependently increased cell number (up to 200% at 1 microm by 48 h, P < 0.01), and at 24-48 h, leptin at 100 nm increased SH-SY5Y cell number by 30-50%, respectively. SH-SY5Y cell viability was reduced in serum-free conditions at 24 h, and addition of leptin at 100 nm significantly reduced apoptosis by approximately 20% (P < 0.001). Leptin's antiapoptotic activity required Janus kinase/STAT, MAPK, and phosphatidylinositol-3-kinase activation because the antiapoptotic effects of leptin were abolished, and caspase-3 immunoreactivity increased in the presence of the specific blockers AG490, U0126, or LY294002. Gene array demonstrated that leptin inhibits apoptosis via potent down-regulation of caspase-10 and TNF-related apoptosis-inducing ligand. Our data thus demonstrate, for the first time, that leptin stimulates, in a time- and dose-dependent manner, neuroblastoma cell proliferation and that the underlying mechanisms involve suppression of apoptosis via the Janus kinase-STAT, phosphatidylinositol-3 kinase, and MAPK pathways that culminate altogether in the down-regulation of the apoptotic factors caspase-10 and TNF-related apoptosis-inducing ligand.
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PMID:Antiapoptotic effects of leptin in human neuroblastoma cells. 1516 21

A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cell (HSC) phenotype by both proliferation and inhibition of apoptosis. We provide evidence that leptin is a potent HSC mitogen and dramatically inhibits stellate cell apoptosis. Leptin proved to be as potent an HSC mitogen as platelet-derived growth factor (PDGF) as assessed by bromodeoxyuridine (BrdU) incorporation in isolated primary HSCs; data using fluorescent propidium iodide (PI) uptake revealed that leptin, like PDGF, increased HSC populations in the S- and G2/M-phases of the cell cycle. Leptin resulted in a robust increase in cyclin D1 expression. Using the chemical inhibitor of Janus kinase 2 (Jak2) activity, AG 490, and overexpression of the suppressor of cytokine signaling 3 (SOCS-3), we show that blockade of leptin receptor (Ob-Rb) phosphorylation blocks leptin-induced HSC proliferation. Leptin-associated phosphorylation of both extracellular regulated kinase (p44/p42, Erk) and Akt is also prohibited. Further, the PI-3 kinase inhibitor LY294002 and MAPK inhibitor PD98059 were found to significantly reduce leptin-induced HSC proliferation, thereby indicating that leptin induced HSC proliferation is Akt- and Erk-dependent. Akt was also protective against HSC apoptosis. Leptin abolished both cycloheximide-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, demonstrated by reduced caspase-3 activity, HSC-TUNEL staining, and DNA fragmentation. We conclude that leptin acts as a direct hepatic stellate cell survival agonist. Importantly, we have demonstrated that leptin-induced HSC proliferation and survival by Ob-Rb phosphorylation are both Erk- and Akt-dependent.
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PMID:Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. 1531 73

Leptin regulates food intake as well as metabolic, endocrine, and immune functions. It exerts proliferative and antiapoptotic activities in a variety of cell types, including T cells. Leptin also stimulates macrophages and neutrophils, and its production is increased during inflammation. In this study, we demonstrate that human neutrophils express leptin surface receptors under in vitro and in vivo conditions, and that leptin delays apoptosis of mature neutrophils in vitro. The antiapoptotic effects of leptin were concentration dependent and blocked by an anti-leptin receptor mAb. The efficacy of leptin to block neutrophil apoptosis was similar to G-CSF. Using pharmacological inhibitors, we obtained evidence that leptin initiates a signaling cascade involving PI3K- and MAPK-dependent pathways in neutrophils. Moreover, leptin delayed the cleavage of Bid and Bax, the mitochondrial release of cytochrome c and second mitochondria-derived activator of caspase, as well as the activation of both caspase-8 and caspase-3 in these cells. Taken together, leptin is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in inflammatory diseases.
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PMID:Apoptotic pathways are inhibited by leptin receptor activation in neutrophils. 1594 17

This study was designed to determine whether leptin modulates growth hormone (GH)- and insulin like growth factor-I (IGF-I)-stimulated progesterone (P4) production by corpora lutea (CL). Luteal cells were recovered from early developing (ELP) and mature (MLP) corpora lutea and cultured in defined medium with various combinations of GH, IGF-I, and leptin (0-200 ng/ml). P4 concentrations in the media were determined after 48 h of culture. During the early luteal phase, leptin at all used doses had no effect on basal P4 secretion, but it did suppress caspase-3 activity. When added in combination with GH, it had no effect on either GH-stimulated P4 secretion or apoptosis. Concomitant treatment with IGF-I and leptin decreased P4 secretion and parallelly increased the apoptosis rate. In mature corpora lutea of full secreting capacity, leptin at all doses had no effect on basal and GH-stimulated P4 secretion and caspase-3 activity. Only at the highest dose (200 ng/ml) when leptin was added with IGF-I did P4 secretion decrease with no effect on the caspase-3 activity. We conclude that the role of leptin is to restrict the stage of CL formation. During this luteal phase, leptin acts as an antiapoptotic factor and, at the same time, reverses antiapoptotic action of IGF-I, thereby protecting cells from excessive apoptosis and supporting retention of appropriate cell numbers, which is necessary for maintenance of homeostasis in developing CL.
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PMID:In vitro effect of leptin on growth hormone (GH)- and insulin-like growth factor-I (IGF-I)-stimulated progesterone secretion and apoptosis in developing and mature corpora lutea of pig ovaries. 1617 44


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