Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

To test the hypothesis that exogenous purified angiotensin II (ANG) might cause apoptosis of alveolar epithelial cells (AECs) and acute lung injury, male Wistar rats were intratracheally instilled with purified ANG (10 mumol/L), ANG plus the caspase inhibitor ZVAD-fmk (60 mumol/L), ANG plus the ANG receptor AT1 antagonist losartan (LOS, 100 mumol/L) or sterile phosphate-buffered saline (PBS) vehicle alone. Six or 20 h later, the lungs were lavaged in situ for determination of bronchoalveolar lavage (BAL) fluid content of hemoglobin (Hb) and fluorescent (BODIPY)-albumin, a bolus of which was injected intravenously 15 min prior to BAL. Terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) revealed that instillation of ANG, but not PBS alone, increased labeling of fragmented DNA in bronchiolar epithelial cells and in AECs (P<0.05) at 6 h post-ANG. Increased TUNEL was abrogated by concurrent instillation of ZVAD-fmk or LOS. Significant increased numbers of caspase-positive cells were observed by anti-caspase 3 immunolabeling after instillation of ANG (P<0.01); the same doses of LOS or ZVAD-fmk that blocked TUNEL also blocked the activation of caspase 3 (P<0.01). Intratracheal instillation of ANG also remarkably increased BAL BODIPY-albumin (P< 0.01) and Hb (P<0.05), both of which were eliminated by ZVAD-fmk or LOS. These data indicate that exposure of AECs to ANG in vivo is sufficient to induce apoptosis and alveolar epithelial barrier injury mediated by ANG receptor AT1.
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PMID:Apoptosis-dependent acute pulmonary injury after intratracheal instillation of angiotensin II. 1908 26

Premature infants are at risk for bilirubin-associated brain damage. In cell cultures bilirubin causes neuronal apoptosis and necrosis. Ibuprofen is used to close the ductus arteriosus, and is often given when hyperbilirubinemia is at its maximum. Ibuprofen is known to interfere with bilirubin-albumin binding. We hypothesized that bilirubin toxicity to cultured rat embryonic cortical neurons is augmented by coincubation with ibuprofen. Incubation with ibuprofen above a concentration of 125 microg/mL reduced cell viability, measured by methylthiazole tetrazolium reduction, to 68% of controls (p < 0.05). Lactate dehydrogenase (LDH) release increased from 29 to 38% (p < 0.01). The vehicle solution did not affect cell viability. Coincubation with 10 microM unconjugated bilirubin (UCB)/human serum albumin in a molar ratio of 3:1 and 250 microg/mL ibuprofen caused additional loss of cell viability and increased LDH release (p < 0.01), DNA fragmentation, and activated caspase-3. Preincubation with the pan-caspase inhibitor z-val-ala-asp-fluoromethyl ketone abolished ibuprofen- and UCB-induced DNA fragmentation. The study demonstrates that bilirubin in low concentration of 10 microM reduces neuron viability and ibuprofen increases this effect. Apoptosis is the underlying cell death mechanism.
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PMID:Ibuprofen augments bilirubin toxicity in rat cortical neuronal culture. 1912 20

Hepatic apoptosis is elevated in patients with non-alcoholic steatohepatitis and is correlated with the severity of the disease. Long-chain saturated fatty acids, such as palmitate, induce apoptosis in liver cells. The present study examined adiponectin-mediated protection against saturated fatty acid-induced apoptosis in the human hepatoma cell line, HepG2. Cells were cultured in a control media (i.e. without fatty acids) or the same media containing 250 micromol L(-1) of albumin-bound oleate or palmitate for 24 h. The adiponectin concentrations used were: 0, 1, 10 or 100 microg mL(-1) (n = 4-6 per treatment). Palmitate and thapsigargin, but not oleate, activated caspase-3 and decreased cell viability in the absence of adiponectin. Adiponectin reduced palmitate- and thapsigargin-induced activation of caspase-3 and cell death in a dose-dependent manner. Phosphatidylinositol 3-kinase and AMP-activated protein kinase inhibitors abolished the effects of adiponectin. Adiponectin-induced inhibition of palmitate- and thapsigargin-induced apoptosis was not the result of an augmentation in the unfolded protein response or the increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate and thapsigargin, but not oleate, increased c-Jun NH(2) terminal kinase phosphorylation in the absence of adiponectin. Adiponectin blocked palmitate- and thapsigargin-induced activation of c-Jun NH(2) terminal kinase and reduced apoptosis. These data suggest that adiponectin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in adiponectin-deficient individuals.
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PMID:Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase. 1929 Aug 87

Recent studies from our laboratory demonstrated the involvement of endothelial cell reactive oxygen species (ROS) formation and activation of apoptotic signaling in vascular hyperpermeability after hemorrhagic shock (HS). The objective of this study was to determine if (-)-deprenyl, an antioxidant with antiapoptotic properties, would attenuate HS-induced vascular hyperpermeability. In rats, HS was induced by withdrawing blood to reduce the MAP to 40 mmHg for 60 min followed by resuscitation for 60 min. To study hyperpermeability, we injected the rats with fluorescein isothiocyanate--albumin (50 mg/kg), and the changes in integrated optical intensity of the mesenteric postcapillary venules were obtained intravascularly and extravascularly using intravital microscopy. Mitochondrial ROS formation and mitochondrial transmembrane potential (DeltaPsim) were studied using dihydrorhodamine 123 and JC-1, respectively. Mitochondrial release of cytochrome c was determined using enzyme-linked immunosorbent assay and caspase-3 activity by a fluorometric assay. Parallel studies were performed in rat lung microvascular endothelial cells using proapoptotic BAK as inducer of hyperpermeability. Hemorrhagic shock induced vascular hyperpermeability, mitochondrial ROS formation, DeltaPsim decrease, cytochrome c release, and caspase-3 activation (P G 0.05). (-)-Deprenyl (0.15 mg/kg) attenuated all these effects (P < 0.05). Similarly in rat lung microvascular endothelial cells, (-)-deprenyl attenuated BAK peptide-induced monolayer hyperpermeability (P < 0.05), ROS formation, DeltaPsim decrease, cytochrome c release (P<0.05), and caspase-3 activation (P < 0.05). The protective effects of (-)-deprenyl on vascular barrier functions may be due to its protective effects on DeltaPsim, thereby preventing mitochondrial release of cytochrome c and caspase-3--mediated disruption of endothelial adherens junctions.
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PMID:(-)-Deprenyl inhibits vascular hyperpermeability after hemorrhagic shock. 1937 32

Many cell and tissue abnormalities in diabetes mellitus are mediated by auto- and paracrine TGFbeta which is induced by high ambient glucose and glycated proteins. In most cell types TGFbeta reduces cell proliferation and enhances apoptosis which are mediated through the TGFbeta type I receptor, Alk5. In contrast, early diabetic microangiopathy is characterized by endothelial cell proliferation. Endothelial cells are unique in expressing a second TGFbeta type I receptor, Alk1, as well as the co-receptor, endoglin which increases the affinity of the ligand to Alk1. In differentiated blood outgrowth endothelial cells from normal subjects Alk1 and endoglin are constitutively expressed. Incubation with high glucose (HG) and glycated albumin (gAlb) induces Alk5 and raises TGFbeta secretion 3-fold without affecting Alk1 or endoglin levels. This diabetic milieu accelerates cell proliferation, at least in part, through TGFbeta/Alk1-smad1/5 and probably involving VEGF as well as pro-migratory MMP2 downstream of Alk1. In contrast, HG/gAlb also increases caspase-3 activity (suggesting increased apoptosis) in part but not entirely using a TGFbeta/Alk5-smad2/3 pathway. The findings support pleiotropy of TGFbeta in endothelial cells including proliferative effects (through Alk1-smad1/5) and pro-apoptotic signals (through Alk5-smad2/3).
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PMID:Diabetes-relevant regulation of cultured blood outgrowth endothelial cells. 1953 33

Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the United States and Europe. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end ESRD. The study was designed to evaluate the impact of sesamol on renal function and renoinflammatory cascade in streptozotocin (STZ)-induced diabetes. STZ-induced diabetic rats were treated with sesamol (2, 4, and 8 mg/kg/day; po) or with vehicle from the fifth to eighth weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine, and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney were prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, nonprotein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1 beta (TGF-beta1), p65 subunit of NFkappabeta, and caspase-3. After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate, and active p65 subunit of NFkappabeta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of sesamol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-sesamol combination produced more pronounced effect on molecular parameters as compared to their respective groups. The data reveal that sesamol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation, and apoptosis and thus exerts a marked renoprotective effect.
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PMID:Attenuation of renoinflammatory cascade in experimental model of diabetic nephropathy by sesamol. 1960 60

15-Deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ(2) shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ(2) induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARgamma-dependent pathways because an irreversible PPARgamma antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor kappaB- (NF-kappaB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-kappaB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ(2) had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ(2) rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with gamma-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ(2) can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration.
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PMID:Albumin-binding and tumor vasculature determine the antitumor effect of 15-deoxy-Delta-(12,14)-prostaglandin-J(2) in vivo. 2001 43

Despite advances in treatment, age-related cardiac dysfunction still remains a leading cause of cardiovascular death. Recent data have suggested that increases in cardiomyocyte apoptosis may be involved in the pathological remodeling of heart. Here, we examine the effects of aging on cardiomyocyte apoptosis in 6-, 30-, and 36-month-old Fischer344 x Brown Norway F1 hybrid rats (F344XBN). Compared with 6-month hearts, aged hearts exhibited increased TdT-mediated dUTP nick end labeling-positive nuclei, caspase-3 activation, caspase-dependent cleavage of alpha-fodrin and diminished phosphorylation of protein kinase B/Akt (Thr 308). These age-dependent increases in cardiomyocyte apoptosis were associated with alterations in the composition of the cardiac dystrophin glycoprotein complex and elevated cytoplasmic IgG and albumin immunoreactivity. Immunohistochemical analysis confirmed these data and demonstrated qualitative differences in localization of dystrophin-glycoprotein complex (DGC) molecules with aging. Taken together, these data suggest that aging-related increases in cardiac apoptotic activity model may be due, at least in part, to age-associated changes in DGC structure.
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PMID:Possible molecular mechanisms underlying age-related cardiomyocyte apoptosis in the F344XBN rat heart. 2005 83

Cardiotonic pills (CP) is a compound Chinese medicine widely used in China, as well as other countries, for the treatment of cardiovascular disease. However, limited data are available regarding the mechanism of action of CP on myocardial function during ischemia-reperfusion (I/R) injury. In this study, we examined the effect of CP on I/R-induced coronary microcirculatory disturbance and myocardial damage. Male Sprague-Dawley rats were subjected to left coronary anterior descending branch occlusion for 30 min followed by reperfusion with or without pretreatment with CP (0.1, 0.4, or 0.8 g/kg). Coronary blood flow, vascular diameter, velocity of red blood cells, and albumin leakage were evaluated in vivo after reperfusion. Neutrophil expression of CD18, malondialdehyde, inhibitor-kappaBalpha, myocardial infarction, endothelial expression of intercellular adhesion molecule 1, apoptosis-related proteins, and histological and ultrastructural evidence of myocardial damage were assessed after reperfusion. Pretreatment with CP (0.8 g/kg) significantly attenuated the I/R-induced myocardial microcirculatory disturbance, including decreased coronary blood flow and red blood cell velocity in arterioles, increased expression of CD18 on neutrophils and intercellular adhesion molecule 1 on endothelial cells, and albumin leakage from venules. In addition, the drug significantly ameliorated the I/R-induced myocardial damage and apoptosis indicated by increased malondialdehyde, infarct size, myocardial ultrastructural changes, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive myocardial cells, inhibitor-kappaBalpha degradation, and expression of Bcl-2, Bax, and caspase-3 in myocardial tissues. The results provide evidence for the potential role of CP in preventing microcirculatory disturbance and myocardial damage following I/R injury.
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PMID:Cardiotonic pills, a compound Chinese medicine, protects ischemia-reperfusion-induced microcirculatory disturbance and myocardial damage in rats. 2011 6


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