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

Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. The aim of the current study was to assess the utility of the pan-caspase inhibitor IDN-6556 on CI/WR injury during human liver transplantation. This report is a post hoc analysis of a Phase II, multi-center, randomized, placebo-controlled, double-blinded, parallel group study. Subjects were assigned to four treatment groups: Group 1 (Organ storage/flush: Placebo-Recipient: Placebo); Group 2 (Organ storage/flush: 15 microg/mL-Recipient: Placebo); Group 3 (Organ storage/flush: 5 microg/mL-Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 microg/mL-Recipient: 0.5 mg/kg). Liver cell apoptosis was assessed by serum concentrations of the apoptosis-associated CK18Asp396 ('M30') neo-epitope, TUNEL assay and caspase 3/7 immunohistochemistry. Liver injury was assessed by serum AST/ALT determinations. Serum markers of liver cell apoptosis were reduced in all groups receiving drug as compared to placebo. However, TUNEL, caspase 3/7 positive cells and serum AST/ALT levels were only consistently reduced in Group 2 (drug exposed to organ only). This reduction in serum transaminases was significant and observed across the study. In conclusion, IDN-6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR-mediated apoptosis and injury. However, larger studies are required to confirm these observations.
 ...
PMID:Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury. 1722 70

In the present study, we investigated the hepatoprotective effects of salvianolic acid A, a novel antioxidant, against oxidative stress and acute liver injury induced by carbon tetrachloride (CCl(4)) in rats, and the mechanisms underlying its protective effects. Administration of CCl(4) to rats caused severe hepatic damage, as demonstrated by the significant increase in the levels of serum alanine aminotransferase, aspartate aminotransferase and classic histological changes including hepatocyte necrosis or apoptosis, haemorrhage, fatty degeneration, etc. Co-treatment with salvianolic acid A (20 mg/kg, intraperitoneally), a water-soluble extract from a Chinese traditional drug, Radix Salvia miltiorrhiza, significantly decreased CCl(4)-induced hepatotoxicity. Salvianolic acid A not only decreased serum alanine aminotransferase, aspartate aminotransferas levels and ameliorated histopathological manifestations in CCl(4)-treated rats, but also reduced oxidative stress, as evidenced by decreased reactive oxygen species production and malondialdehyde concentrations in the liver tissues, combined with elevated hepatic superoxide dismutase activity and gluthathione content. In addition, salvianolic acid A treatment remarkably reduced intrahepatic tumour necrosis factor-alpha concentrations and caspase-3 activities as compared with the CCl(4)-treated rats. The results suggested that treatment with salvianolic acid A provides a potent protective effect against acute hepatic damage caused by CCl(4) in rats, which may mainly be related to its antioxidative effect.
 ...
PMID:Effects of salvianolic acid a on oxidative stress and liver injury induced by carbon tetrachloride in rats. 1724 60

The antioxidant and hepatoprotective actions of Terminalia catappa L. collected from Okinawa Island were evaluated in vitro and in vivo using leaves extract and isolated antioxidants. A water extract of the leaves of T. catappa showed a strong radical scavenging action for 1,1-diphenyl-2-picrylhydrazyl and superoxide (O(2)(.-)) anion. Chebulagic acid and corilagin were isolated as the active components from T. catappa. Both antioxidants showed a strong scavenging action for O(2)(.-) and peroxyl radicals and also inhibited reactive oxygen species production from leukocytes stimulated by phorbol-12-myristate acetate. Galactosamine (GalN, 600 mg/kg, s.c.,) and lipopolysaccharide (LPS, 0.5 microg/kg, i.p.)-induced hepatotoxicity of rats as seen by an elevation of serum alanine aminotransferase, aspartate aminotransferase and glutathione S-transferase (GST) activities was significantly reduced when the herb extract or corilagin was given intraperitoneally to rats prior to GalN/LPS treatment. Increase of free radical formation and lipid peroxidation in mitochondria caused by GalN/LPS treatment were also decreased by pretreatment with the herb/corilagin. In addition, apoptotic events such as DNA fragmentation and the increase in caspase-3 activity in the liver observed with GalN/LPS treatment were prevented by the pretreatment with the herb/corilagin. These results show that the extract of T. catappa and its antioxidant, corilagin are protective against GalN/LPS-induced liver injury through suppression of oxidative stress and apoptosis.
 ...
PMID:Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. 1729 97

Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125, a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained JNK activation. Administration of SP600125 diminished JNK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha, and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FHF by downregulating Bad and inhibiting Bid cleavage.
 ...
PMID:An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. 1730 Aug 14

We studied the hepatocellular alterations induced by sub-lethal concentrations (0.50 muM) of arsenic in Indian catfish Clarias batrachus L. Sub-lethal arsenic exposure altered serum aspartate aminotransferase and alkaline phosphatase levels and brought about significant changes in different serum biochemical parameters. Arsenic exposure reduced total hepatocyte protein content and suppressed the proliferation of hepatocytes in a time-dependent manner. Routine histological studies on liver documented arsenic-induced changes characterized by dilated sinusoids, formation of intracellular edema, megalocytosis, vacuolation and appearance of hepatic cells with distorted nuclei. Transmission electron microscopy of hepatocytes further revealed hyperplasia and hypertrophy of mitochondria, development of dilated rough endoplasmic reticulum and changes in peroxisome size with duration of arsenic exposure. Degeneration of mitochondrial cristae and condensation of chromatin was also evident in arsenic-exposed hepatocytes. A significant number of hepatocytes isolated from arsenic-exposed fish stained with annexin V and demonstrated DNA ladder characteristic of apoptosis. Single-cell gel electrophoresis of exposed hepatocytes also revealed the development of comets usually seen in apoptotic cells. Using specific inhibitors it was determined that the arsenic-induced apoptosis of hepatocytes was caspase-mediated, involving the caspase 3 pathway.
 ...
PMID:Sub-lethal concentration of arsenic interferes with the proliferation of hepatocytes and induces in vivo apoptosis in Clarias batrachus L. 1733 63

We hypothesized that the hepatotoxicity that develops after the induction of oxidative stress (induced by d-galactosamine [GalN]) can be ameliorated by alpha-tocopherol (ATC) and the soy isoflavone daidzein. To test this, we ranked and assigned male Wistar rats into 6 groups, which involved pretreatment (ATC or daidzein) for 1 hour followed by treatment (GalN) for 23 hours. Histopathologic analysis showed that GalN administration induced marked necrosis (P < .001), steatosis (P < .001), both lobular and portal inflammations (P < .001), overall histopathologic score (P < .001), and activation of caspase-3 in the liver (P < .001). Immunohistochemical staining of malondialdehyde-protein adducts, a measure of oxidative stress, was increased in response to GalN (P < .001). Paradoxically, there were increases in total (P < .05) and cytosolic superoxide dismutase (P < .001) activities after GalN administration, indicative of an up-regulation of antioxidant defenses. The concentration of total protein (P < .001), albumin (P < .01), and globulin fractions (P < .001) in the plasma, as well as the activity of aspartate aminotransferase (P < .001), was significantly perturbed after GalN treatment, reflective of overall acute hepatic injury. Administration of daidzein showed a significant amelioration of the Ga1N-induced increase in malondialdehyde-protein adducts (P < .01) and cytosolic superoxide dismutase activities (P < .01) in the liver. However, all other variables were not significantly altered in response to daidzein. In response to ATC pretreatment, the total histopathologic score (P < .05), degree of necrosis (P < .05), and both lobular (P < .05) and portal (P = .05) inflammations were significantly ameliorated. To conclude, both daidzein and ATC protect the liver against oxidative damage possibly via different pathways.
 ...
PMID:The cytoprotective effect of alpha-tocopherol and daidzein against d-galactosamine-induced oxidative damage in the rat liver. 1757 Feb 44

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been shown to be induced during oxidative injury, and its induction acts as an important cellular defense mechanism against such injuries. In this study, we examined the functional roles of HO-1 induction in a rat model of d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced liver injury. We found that GalN/LPS treatment of rats produced severe hepatic injury, whereas upregulation of HO-1 by hemin pretreatment prevented rats from liver damage, as evidenced by decreased serum ALT, AST levels and ameliorated histological signs in the liver. Induction of HO-1 resulted in a significant decrease in hepatic malondialdehyde (MDA) contents, tumor necrosis factor-alpha (TNF-alpha) levels, iNOS/NO production, as well as the levels of caspase-3. In contrast, inhibition of HO activity by zinc protoporphyrin-9 (ZnPP, a specific inhibitor of HO) completely reversed HO-1-induced hepatoprotective effect. These data therefore suggested that HO-1 induction provided critical protection against GalN/LPS-induced liver injury, and the protection seemed to be mediated through the anti-oxidant, anti-inflammatory and anti-apoptotic functions.
 ...
PMID:Upregulation of heme oxygenase-1 with hemin prevents D-galactosamine and lipopolysaccharide-induced acute hepatic injury in rats. 1758 81

The potential protective effect of the natural antioxidant, carnosine was evaluated against ischemia/reperfusion liver injury in rats. Ischemia was induced by clamping the pedicle supplying the left hepatic lobe for 60 min followed by reperfusion for 2 h. Untreated rats exposed to ischemia/reperfusion showed significant elevation of serum aspartate aminotransferase and alanine aminotransferase levels, and malondialdehyde level and caspase-3 activity in liver homogenates associated with significant reduction in hepatic nitrite level, catalase and glutathione peroxidase activities as compared with sham-operated group. Pre-treatment with a single i.p. dose of carnosine (250 mg/kg), 30 min prior to the ischemic episode significantly attenuated the deterioration in the measured biochemical parameters observed with ischemia/reperfusion-induced liver injury. Also, light and electron microscopic examinations in ischemia/reperfusion untreated group revealed severe hepatic damage, such as cytoplasmic vacuolation, necrotic and apoptotic cell death, which was markedly ameliorated by pre-ischemic treatment with carnosine. These results strongly emphasize that carnosine can be useful as a prophylactic treatment to protect the liver against hypoxia-reoxygenation damage.
 ...
PMID:The hepatoprotective effect of carnosine against ischemia/reperfusion liver injury in rats. 1761 Aug 73

Most acute respiratory distress syndrome studies have been focused on the lung injury. Little is known about other organs during the development of acute respiratory distress syndrome. Herein, we investigated the injury and cell death in multiple organs after intestinal ischemia-reperfusion (IIR) in C57BL/6 mice. Terminal transferase dUTP nick end labeling staining was used as a marker of cell death. Caspase 3 and cathepsin B activation as markers of caspase-dependent and caspase-independent apoptosis, respectively, and electron microscopy for ultimate characterization of cell death were used. In comparison with control and sham-operated mice, the IIR group showed interstitial inflammatory infiltrates in the lung and significant increases of lung injury parameters and plasma lactate dehydrogenase and aspartate aminotransferase levels. Terminal transferase dUTP nick end labeling-positive cells and immunostaining for hemeoxygenase 1, an enzyme induced by inflammatory stimuli, were increased in the lung, heart, and kidney, but not in the liver. The number of hemeoxygenase 1-positive cells positively and significantly correlated to the number of terminal transferase dUTP nick end labeling-positive cells. Cell death was not associated with caspase 3 or cathepsin B activation. Electron microscopy showed morphological features compatible with oncotic rather than apoptotic cell death or necrosis, including mitochondrial swelling and cytoplasm disorganization in pulmonary and renal epithelial cells, lung and cardiac endothelial cells, and myocytes. These results indicate that, although lung injury is the most significant manifestation after IIR, oncotic cell death occurs in the lung, heart, and kidney, which may be related to ischemia and inflammation.
 ...
PMID:Intestinal ischemia-reperfusion-induced acute lung injury and oncotic cell death in multiple organs. 1766 44

Lipopolysaccharide (LPS) is implicated in the pathology of acute liver injury and can induce lethal liver failure when simultaneously administered with D-galactosamine (D-GalN). At the present time, nonlethal liver failure, the liver injury of clinical implication, is incompletely understood following challenge by low-dose LPS/D-GalN. We report here our investigation of the effects of liver injury following a nonlethal dose LPS/D-GalN and the role of apoptosis in this disorder. Blood biochemistry indexes, including those of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), had risen by 6 h post-LPS/D-GalN injection, reached a peak at 24 h and sustained high levels at 48 h. An abnormal liver appearance was found at 24 and 48 h post-injection. Histopathological changes of hepatic injuries accompanied by hepatocellular death, inflammatory infiltration and hemorrhage began to appear at 6 h and were markedly aggravated at 24 and 48 h. Cell apoptosis was significantly induced by the nonlethal dose LPS/D-GalN challenge, and the apoptotic indexes (AIs) in 24 h- and 48 h-treated rats were approximately 70%, as estimated by the terminal transferase dUTP nick end labeling (TUNEL) assay. The mRNA levels of the inflammatory cytokine IL-1beta rose markedly at 6 h and maintained high levels at 24 and 48 h; however, TNF-alpha levels were normal in the liver tissues of 6-, 24- and 48-h-treated rats. mRNA expression of the damage gene nitric oxide synthase (NOS) was also induced early by the LPS/D-GalN challenge, reaching a peak at 6 h, then gradually decreasing in a stepwise manner; conversely, high expression levels of the apoptosis-inducing gene p53 mRNA were not found in the early post-injection period (6 h) but emerged in the crest-time of liver apoptosis (24 h) and were maintained at this level until the late stage (48 h). We also observed that in 24 h-treated rats, caspase-3, -8, -9 and -12 were markedly activated by LPS/D-GalN challenge. These results suggest that a challenge with low-dose LPS in conjunction with D-GalN can induce nonlethal but marked liver failure, the main morphological feature of which is hepatic apoptosis, which may be associated with a high expression of inducible (i)NOS (early post-injection period) and p53 genes (in the mid and late stages) and at least three apoptosis pathways participate in the pathogenesis.
 ...
PMID:A role of cell apoptosis in lipopolysaccharide (LPS)-induced nonlethal liver injury in D-galactosamine (D-GalN)-sensitized rats. 1793 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>