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)

This study was designed to investigate the protective effects of the phenethyl ester of caffeic acid (CAPE) against carbon tetrachoride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CAPE prior to administration of CCl(4) significantly prevented the increases in serum alanine, aspartate aminotransferase and alkaline phosphatase activities, hepatic lipid peroxidation formation, and depletion of glutathione content. In addition, CAPE prevented CCl(4)-induced apoptosis and necrosis, as indicated by liver histopathology and DNA laddering studies. To determine whether the Fas/Fas ligand (FasL) pathway is involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3 and -8 activities were tested by western blotting and ELISA. CAPE markedly decreased CCl(4)-induced Fas/FasL protein expression levels and, in turn, attenuated CCl(4)-induced caspase-3 and -8 activities in mouse liver. Moreover, the effect of CAPE on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CAPE significantly decreased the CYP2E1-dependent hydroxylation of aniline. In addition, CAPE attenuated the CCl(4)-mediated depletion of antioxidant enzyme (catalase, superoxide dismutase and glutathione-S-transferase) activities. These findings suggest that the protective effects of CAPE against CCl(4)-induced acute liver injury may involve its ability to block CYP2El-mediated CCl(4) bioactivation and to protect against Fas/FasL-mediated apoptosis.
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PMID:Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. 1843 64

Cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) is a dipeptide isolated from Laennec, and Laennec is a hydrolyzate of human placenta. Evidence has indicated that JBP485 exhibits potent anti-hepatitis activity. In this study, we investigated the protective effect and possible mechanisms of action of JBP485 in Concanavalin A (Con A)-induced hepatotoxicity in vitro. Two in vitro models were established. Model I: primary cultured female rat hepatocytes were only incubated with Con A (50 microg/ml); model II: co-culture system of hepatocytes and autologous splenic lymphocytes, both were stimulated with Con A (20 microg/ml). JBP485 (25 microM) was pre-incubated with the two models. Our results showed that JBP485 reduced cellular aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and tumor necrosis factor alpha (TNF-alpha) leakage following the application of Con A in both of the models. Potential protective mechanisms were elucidated by measuring DNA fragmentations, immunocytochemistry and RT-PCR. We showed that DNA fragmentations in hepatocytes were attenuated in the JBP485 pre-incubated groups, and at the same time, immunocytochemistry and RT-PCR indicated that expression levels of caspase-3 protein and mRNA in the JBP485 treated groups were decreased compared with those in the untreated groups. Moreover, intercellular adhesion molecule-1 (ICAM-1) was also down-regulated by this dipeptide. The results indicate that JBP485 exhibits hepatoprotective effect through inhibition of hepatocyte apoptosis and ICAM-1 expression.
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PMID:Protective effect of JBP485 on concanavalin A-induced hepatocyte toxicity in primary cultured rat hepatocytes. 1857 Nov 56

The protective effect of salidroside (SDS) isolated from Rhodiola sachalinensis A. BOR. (Crassulaceae), was investigated in acetaminophen (APAP)-induced hepatic toxicity mouse model in comparison to N-acetylcysteine (NAC). Drug-induced hepatotoxicity was induced by an intraperitoneal (i.p.) injection of 300 mg/kg (sub-lethal dose) of APAP. SDS was given orally to mice at a dose of 50 or 100 mg/kg 2 h before the APAP administration in parallel with NAC. Mice were sacrificed 12 h after the APAP injection to determine aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-alpha) levels in serum and glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, and caspase-3 expression in liver tissues. SDS significantly protected APAP-induced hepatotoxicity for SDS improved mouse survival rates better than NAC against a lethal dose of APAP and significantly blocked not only APAP-induced increases of AST, ALT, and TNF-alpha but also APAP-induced GSH depletion and MDA accumulation. Histopathological and immunohistochemical analyses also demonstrated that SDS could reduce the appearance of necrosis regions as well as caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) expression in liver tissue. Our results indicated that SDS protected liver tissue from the APAP-induced oxidative damage via preventing or alleviating intracellular GSH depletion and oxidation damage, which suggested that SDS would be a potential antidote against APAP-induced hepatotoxicity.
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PMID:Protective effects of salidroside against acetaminophen-induced toxicity in mice. 1867 83

The natural history of pediatric nonalcoholic steatohepatitis is still unknown; however, there are differences between adult and pediatric presentation. Apoptosis may play an important role in pathophysiologic pathways involved in liver damage and progression. Our aim was to detect early apoptosis markers, activated caspase-3 and cleaved cytokeratin-18, in hepatocytes and to correlate their presence with clinical, serologic, and histologic characteristics in pediatric nonalcoholic steatohepatitis. Twenty-five pediatric nonalcoholic steatohepatitis liver biopsies were evaluated by immunohistochemistry for presence of activated caspase-3 and cleaved cytokeratin-18. Biopsy specimens were semiquantitatively graded for activity (steatosis, inflammation, and ballooning) and fibrosis. Records were reviewed for serum aspartate aminotransferase, alanine aminotransferase, cholesterol, triglycerides, and body mass index, which was elevated in 92% of cases. Serum aspartate aminotransferase and alanine aminotransferase were elevated in 32% and 68% of cases, respectively. Sixty percent of biopsies exhibited lobular steatosis grade 3, 84% lobular inflammatory activity grade 1, 72% ballooning grade 1, and 76% fibrosis stage 3. Cleaved cytokeratin-18 was associated with milder fibrosis (P = .02) and inflammation (P = .07), although there was no association with steatosis grade. Activated caspase-3 detection was also associated with low inflammatory grade (P = .03) but not with fibrosis and steatosis. This study reveals interesting differential features concerning nonalcoholic steatohepatitis histologic characteristics and apoptosis markers compared with adult cases. Because, in this pediatric series, apoptosis seemed to be an early event in the cascade of liver injury steps, it would be useful to consider caspase inhibitors as potential therapeutic strategies to prevent liver damage progression.
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PMID:Apoptosis markers in liver biopsy of nonalcoholic steatohepatitis in pediatric patients. 1871 20

Danshen (DS) is used for treatment of various ischemic events in the traditional Chinese medicine. Hence, this study was designed to investigate its effect on ischemia/reperfusion injury (IRI) after experimental kidney transplantation (eKTx). Nephrectomized Sprague-Dawley rats underwent eKTx. Some animals were infused with 1.5 ml DS 10 min before surgery. Kidney grafts were transplanted after cold storage for 20 h in Histidine-Tryptophane-Ketoglutarate solution. After reperfusion blood samples were collected for blood urinary nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and alanine transaminase. Further, tissue was assessed for morphologic and pathophysiologic changes. Donor preconditioning with DS (DS-d) significantly decreased BUN, creatinine, LDH, and aspartate aminotransferase to 65-97% of controls while preconditioning of the recipient (DS-r) decreased values to 58-82% (P < 0.05). Tubular damage and caspase-3 decreased significantly in both DS-d and DS-r (DS-d: 96% and 67%, DS-r: 83% and 75% of controls) while heat shock protein 72 and superoxide dismutase increased significantly (DS-d: 143% and 173%, DS-r: 166% and 194% of controls). Further, inducible nitric oxide synthase and tumor necrosis factor-alpha decreased (DS-d: 84% and 61%, DS-r: 79% and 67% of controls) after DS. Preconditioning of both donors and recipients with DS significantly reduces IRI and thus improves graft function after eKTx.
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PMID:Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation. 1895 74

To gain insight into the processes by which severe acute pancreatitis induced apoptosis takes place in the liver, and to observe the protective effect of resveratrol on hepatic injury, a rat model of severe acute pancreatitis was induced by administering 4% sodium taurocholate through the common biliopancreatic duct. Pancreatic and hepatic injury was assessed by histology. Serum ALT (alanine aminotransferase), AST (aspartate aminotransferase) and total bilirubin were determined by reaction rate assay, and the serum levels of TNF-alpha (tumor necrosis factor-alpha) and IL-6 (interleukin-6) were detected by ELISA (enzyme linked immunosorbent assay). We investigated cytochrome c released from mitochondria and used the RT-PCR (reverse transcription PCR), Western blot technique to evaluate Bax, Bcl-2, and caspase-3 expression levels in hepatic tissue over the time course of apoptosis. Changes in hepatic cell mitochondrial membrane potential were observed by confocal laser scanning microscopy. The majority of cytochrome c release occurred early in apoptosis from mitochondria, which undergo gradual hepatic impairment. The released cytochrome c can be reduced by resveratrol through both up-regulation of Bcl-2 and down-regulation of Bax and caspase-3. These data provide substantial evidence that apoptosis is involved in hepatic injury during the severe acute pancreatitis process and that resveratrol can ameliorate the situation, thus protecting liver function in rats with severe acute pancreatitis.
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PMID:Resveratrol ameliorates hepatic injury via the mitochondrial pathway in rats with severe acute pancreatitis. 1897 15

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

The present study was undertaken to validate a battery of cytotoxicity assays performed in a multiplex format to screen pharmaceutical compounds at an early stage of drug development. Two experiments were performed on HepG2 cells and the parameters were measured in 96-well plates. Biological and technical triplicates were performed to evaluate the reproducibility of the assay. In the first experiment, HepG2 cells were exposed to tamoxifen, staurosporine, phenobarbital and triton X-100 for 2 and 24h. The following nine cytotoxicity parameters were analyzed, cell viability, lactate dehydrogenase (LDH), adenosine triphosphate (ATP), caspase-3/7, aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and alpha-glutathione-S-transferase (alpha-GST). In the second experiment, HepG2 cells were exposed to doxorubicin, t-butyl hydroperoxide, ferrous sulfate and sulfamoxole for 2 and 24h. Based on the results of the first experiment, six cytotoxicity parameters were selected for further evaluation (cell viability, ATP, LDH, caspase, AST and GLDH). ALT (activity always below detection limit), ALP (no response to drug treatment) and alpha-GST (too labor intensive and not possible to multiplex) were eliminated. The analysis of the data revealed that the reproducibility of the assays was accurate according to principal component analysis. Our data also clearly indicated that the potential of this battery of selected assays measured in a multiplex format not only made it possible to rank and select the most promising drug candidates based on their cytotoxic potential, but also to gather information that may help to understand some of the toxic events occurring in the cells.
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PMID:Selection of cytotoxicity markers for the screening of new chemical entities in a pharmaceutical context: a preliminary study using a multiplexing approach. 1911 50

The accumulation of bile acids during obstructive cholestasis causes liver injury and fibrosis, which is at least partly mediated by the death receptors Tumor necrosis factor-related apoptosis-inducing ligand, Tumor necrosis factor-alpha, and Fas. The BH3-interacting domain death agonist Bid is a critical mediator of death receptor-induced apoptosis in hepatocytes. Our aim for this study was, therefore, to elucidate whether Bid also mediates death receptor-induced liver injury in obstructive cholestasis. Overall, survival and various aspects of liver injury were analyzed in wild-type and Bid(-/-) mice after bile duct ligation (BDL), a commonly used model to study obstructive cholestasis in mice. Liver injury was examined at 3, 7, and 14 days after BDL. Loss of Bid did not affect the number of bile infarcts, serum aspartate aminotransferase values, or animal survival. Processing of procaspase-3 and procaspase-9, and caspase-3 enzyme activities, were not detectable in either group, and Bid(-/-) mice displayed the same pattern of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive hepatocytes as wild-type controls following BDL. In contrast to Fas-receptor deficient lpr mice, hepatic fibrosis and the inflammatory response was not affected by loss of Bid. Together, these data suggest that Bid is not a downstream target of death receptors in obstructive cholestasis and does not significantly contribute to bile acid induced liver injury and fibrosis.
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PMID:The BH3-only protein bid does not mediate death-receptor-induced liver injury in obstructive cholestasis. 1966 44

This study was designed to investigate the protective effects of the active part of Artemisia sacrorum Ledeb. Extract (ASE) against acetaminophen (APAP)-induced hepatotoxicity in mice. As a result, pretreated with ASE prior to the administration of APAP significantly prevented the increases of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-alpha) levels in serum, and glutathione (GSH) depletion, malondialdehyde (MDA) accumulation in liver tissue. In addition, ASE prevented APAP-induced apoptosis and necrosis, as indicated by a liver histopathological analysis and DNA laddering. Furthermore, according to the results from Western blot analysis, ASE markedly decreased APAP-induced caspase-3 and -8 protein expressions in mouse livers. All these results suggest that the protective effects of ASE against APAP-induced liver injury may involve mechanisms associated with its inhibitive effects of lipid peroxidation and the down-regulation of TNF-alpha mediated apoptosis.
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PMID:Protective Effects of the Supernatant of Ethanol Eluate from Artemisia sacrorum Ledeb. against Acetaminophen-Induced Liver Injury in Mice [corrected]. 1980 28

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