Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Early growth response (Egr)-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation, and wound healing; however, little is known about the role of Egr-1 in acute liver injury. We tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure biphasically increased hepatic egr-1 mRNA accumulation at 1 h and again at 4-5.5 h after treatment in wild-type mice. Within 4-5.5 h after GalN/LPS exposure, wild-type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma alanine aminotransferase activities. In contrast, these parameters were largely attenuated in egr-1(-/-) mice. The initial expression of tumor necrosis factor-alpha, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 mRNA or protein was equivalent between genotypes at 1 h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1(-/-) compared with wild-type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1(-/-) compared with wild-type mice 4 h after GalN/LPS. Whereas caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were detected in wild-type mice at 4 and 5.5 h after GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1(-/-) mice. Delayed development of apoptosis was associated with an extension of survival by 1 h in egr-1(-/-) compared with wild-type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis, and subsequent mortality in GalN/LPS-induced acute liver injury.
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PMID:Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice. 1791 44

The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GRalpha, and dominant negative receptor, GRbeta. Sepsis induction by LPS injection (300 mug/kg ip) decreased mRNA and protein levels of GRalpha and increased protein expression of GRbeta in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GRalpha expression but slightly affected the increase in GRbeta expression. Consequently, this led to a significant reduction in GRalpha nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-kappaB activity, as determined by NF-kappaB nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.
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PMID:Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone. 1883 31

Bacterial LPS (endotoxin) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygenase (COX)-2 in LPS-induced liver injury, we generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector and the animals produced were subjected to a standard experimental protocol of LPS-induced acute fulminant hepatic failure (i.p. injection of low dose of LPS in combination with d-galactosamine (d-GalN)). The COX-2 transgenic mice exhibited earlier mortality, higher serum aspartate aminotransferase and alanine aminotransferase levels and more prominent liver tissue damage (parenchymal hemorrhage, neutrophilic inflammation, hepatocyte apoptosis, and necrosis) than wild-type mice. Western blot analysis of the liver tissues showed that LPS/d-GalN treatment for 4 h induced much higher cleavage of poly(ADP-ribose) polymerase, caspase-3, and caspase-9 in COX-2 transgenic mice than in wild-type mice. Increased hepatic expression of JNK-2 in COX-2 transgenic mice suggest that up-regulation of JNK-2 may represent a potential mechanism for COX-2-mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP(1), prevented LPS/d-GalN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP(1) showed less LPS/d-GalN-induced liver damage and less hepatocyte apoptosis with prolonged survival when compared with the wild-type mice. These findings demonstrate that COX-2 and its downstream prostaglandin receptor EP(1) signaling pathway accelerates LPS-induced liver injury. Therefore, blocking COX-2-EP(1) pathway may represent a potential approach for amelioration of LPS-induced liver injury.
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PMID:Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure. 1901 95

Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.
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PMID:Distinct functions of activated protein C differentially attenuate acute kidney injury. 1909 24

Cytotoxic T lymphocytes and their granule components, such as perforin and granzyme, play an important role in the defense of hepatic infections caused by different pathogens. Moreover, it has been shown in vitro that hepatocytes can initiate cell death via a perforin-dependent mechanism. Although it is well known that hepatocellular apoptosis in D-galactosamine/lipopolysaccharide (D-Gal/LPS)-associated liver failure is mediated by TNF-alpha-dependent Fas/FasL cytotoxicity, there is no information on the role of perforin-mediated mechanisms in vivo. Therefore, we studied whether the cytolytic perforin/granzyme pathway contributes to the D-Gal/LPS-associated hepatotoxicity. Perforin knockout (Pko) mice showed significantly higher hepatic TNF-alpha and IL-6 mRNA expression as well as plasma TNF-alpha and IL-6 concentrations within the first hour upon D-Gal/LPS challenge compared with perforin wild-type (Pwt) mice. At 6 h upon D-Gal/LPS challenge, Pko mice further presented with higher transaminase release and onconecrotic tissue damage, whereas hepatocellular apoptosis and caspase-3 cleavage remained unaffected by the perforin deficiency. Pretreatment with a recombinant human TNF-alpha receptor fusion protein attenuated necrotic and apoptotic tissue damage and reduced plasma transaminase activities as well as cytokine release, thereby preventing acute liver failure in Pko mice as effectively as in Pwt mice. These data do not only confirm the significance of TNF-alpha as distal mediator of hepatic injury in this model but simultaneously reveal a contribution of a perforin-dependent immunoregulation, limiting the D-Gal/LPS-induced overwhelming cytokine release and onconecrotic tissue injury.
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PMID:Role of the perforin/granzyme cell death pathway in D-Gal/LPS-induced inflammatory liver injury. 1926 54

Damp building-related illnesses have caused concern for years in many countries. Although the problem is extensive, the knowledge of the immunological reactions behind damp building-related illnesses is still quite limited. Trichothecene mycotoxins form one major group of toxins, which possibly contribute to the illnesses. Stachybotrys chartarum is a well-known, but also controversial damp building mold and many strains of this mold are capable of producing trichothecenes. In this report, we have examined the effect of S. chartarum and trichothecene mycotoxins on the proinflammatory cytokine response in human macrophages. As a result, satratoxin-positive S. chartarum activated inflammasome-associated caspase-1, which is needed for proteolytic processing of IL-1beta and IL-18. Furthermore, purified trichothecene mycotoxins, roridin A, verrucarin A, and T-2 toxin activated caspase-1, and these mycotoxins also strongly enhanced LPS-dependent secretion of IL-1beta and IL-18. The satratoxin-positive strain of S. chartarum and the trichothecenes also triggered the activation of caspase-3, which is an effector caspase of apoptosis. Satratoxin-negative S. chartarum was not able to activate either caspase-1 or caspase-3. In conclusion, our results indicate that human macrophages sense trichothecene mycotoxins as a danger signal, which activates caspase-1, and further enables the secretion of IL-1beta and IL-18 from the LPS-primed cells.
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PMID:Trichothecene mycotoxins activate inflammatory response in human macrophages. 1941 95

It has been reported that catalpol, an iridoid glucoside, isolated from the root of Rehmannia glutinosa, protected cells from damage induced by a variety of toxic stimulus such as LPS, MPP(+) and rotenone. Here, we further evaluated the effect of catalpol against Abeta(1-42)-induced apoptosis in primary cortical neuron cultures. In the present study, the primary cortical neuron culture treated with Abeta(1-42) was severed as cell model of Alzheimer's disease (AD) in vitro. By exposure to Abeta(1-42) (5 microM) for 72 h in cultures, neuronal apoptosis occurred characterized by enhancement of activities of caspases and reactive oxygen species (ROS) as well as Bax increase, loss of mitochondrial membrane potential and cytochrome c release. Pretreatment with catalpol (0.5mM) for 30 min prior to Abeta(1-42) treatment attenuated neuronal apoptosis not only by reversing intracellular ROS accumulation, Bax level, mitochondrial membrane potential and, cytochrome c release to some extent, but also through regulating the activity and cleavage of caspase-3 and caspase-9. Thus, catalpol protects primary cultured cortical neurons induced by Abeta(1-42) through a mitochondrial-dependent caspase pathway.
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PMID:Catalpol protects primary cultured cortical neurons induced by Abeta(1-42) through a mitochondrial-dependent caspase pathway. 1963 Dec 47

Our goal was to investigate whether previously related antiapoptotic and anti-inflammatory effects of tacrolimus could be useful in protecting human islets cultured in the presence of several proinflammatory mediators. Human islets obtained from cadaveric donors after intraductal infusion with collagenase, mechanical digestion, and continuous Ficoll gradient purification were cultured in RPMI-1640 medium for 24 h. Escherichia coli lipopolysaccharide (10 microg/ml) or interleukin-1 (50 UI/ml) + gamma-IF (1000 UI/ml) and low-dose tacroliumus (5 ng/ml) were added. Homogenized samples (300 IE) from five different donors where assigned to four different experimental groups (control, treatment, cytokines, and cytokines + treatment). To evaluate islet damage and apoptotic response, nucleosome content, Bcl-2 protein levels, caspase-3, -8, and -9 levels, and insulin concentration were measured. Also, TNF-alpha and IL-6 levels where assessed as indicators of the inflammatory response. All proapoptotic markers, TNF-alpha, and IL-6 levels were augmented after both LPS and cytokine stimulation. Tacrolimus reduced significantly all of them and restored baseline values of nucleosome and caspase-9 in both experiments and Bcl-2 and caspase-3 when IL-1 + gamma-IF was added. Twenty-four-hour insulin concentration diminished when LPS or IL-1 + gamma-IF were present. Tacrolimus treatment restored insulin levels in both experiments. These results suggest that in vitro apoptotic events and media insulin concentration decrease after proinflammatory stimulation can be reverted using low-dose tacrolimus.
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PMID:Antiapoptotic effect of tacrolimus on cytokine-challenged human islets. 1966 Jan 76

We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.
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PMID:Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection. 1974 31

Neurological deficits in children, including cerebral palsy, are associated with prior infection during the perinatal period. Experimentally, we have shown that pre-exposure to the Gram-negative component LPS potentiates hypoxic-ischemic (HI) brain injury in newborn animals. LPS effects are mediated by binding to TLR4, which requires recruitment of the MyD88 adaptor protein or Toll/IL-1R domain-containing adapter inducing IFN-beta for signal transduction. In this study, we investigated the role of MyD88 in neonatal brain injury. MyD88 knockout (MyD88 KO) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 50 min on postnatal day 9. LPS or saline were administered i.p. at 14 h before HI. At 5 days after HI in wild-type mice, LPS in combination with HI caused a significant increase in gray and white matter tissue loss compared with the saline-HI group. By contrast, in the MyD88 KO mice there was no potentiation of brain injury with LPS-HI. MyD88 KO mice exhibited reduced NFkappaB activation and proinflammatory cytokine-chemokine expression in response to LPS. The number of microglia and caspase-3 activation was increased in the brain of MyD88 KO mice after LPS exposure. Collectively, these findings indicate that MyD88 plays an essential role in LPS-sensitized HI neonatal brain injury, which involves both inflammatory and caspase-dependent pathways.
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PMID:Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner. 1991 90


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