UNIPROT:P17174 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent studies, the cytotoxic activity of NO has been investigated for its potential use in anticancer therapies. Nitrosated human serum albumin (NO-HSA) may act as a reservoir of NO in vivo. However, there are no published reports regarding the effects of NO-HSA on cancer. Therefore, the present study investigated the antitumor activity of NO-HSA. NO-HSA was prepared by incubating HSA, which had been sulfhydrylated using iminothiolane, with isopentyl nitrite (6.64 mol NO/mol HSA). Antitumor activity was examined in vitro using murine colon 26 carcinoma (C26) cells and in vivo using C26 tumor-bearing mice. Exposure to NO-HSA increased the production of reactive oxygen species in C26 cells. Flow cytometric analysis using rhodamine 123 showed that NO-HSA caused mitochondrial depolarization. Activation of caspase-3 and DNA fragmentation were observed in C26 cells after incubation with 100 muM NO-HSA for 24 h, and NO-HSA inhibited the growth of C26 cells in a concentration-dependent manner. The growth of C26 tumors in mice was significantly inhibited by administration of NO-HSA compared with saline and HSA treatment. Immunohistochemical analysis of tumor tissues demonstrated an increase in terminal deoxynucleotidyl transferase dUTP nickend labeling-positive cells in NO-HSA-treated mice, suggesting that inhibition of tumor growth by NO-HSA was mediated through induction of apoptosis. Biochemical parameters (such as serum creatinine, blood urea nitrogen, aspartate aminotransferase, and alanine aminotransferase) showed no significant differences among the three treatment groups, indicating that NO-HSA did not cause hepatic or renal damage. These results suggest that NO-HSA has the potential for chemopreventive and/or chemotherapeutic activity with few side effects.
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PMID:Design and evaluation of S-nitrosylated human serum albumin as a novel anticancer drug. 1821 31

The purpose of this study was to investigate the protective effects of the saponins isolated from the root of Platycodi Radix (Changkil saponins: CKS) on carbon tetrachloride (CCl(4))-induced hepatotoxicities in mice. Pretreatment with CKS prior to the administration of CCl(4) significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activities and hepatic lipid peroxidation formation. In addition, CKS prevented CCl(4)-induced apoptosis and necrosis, as indicated by a liver histopathologic study and DNA laddering. To determine whether Fas/Fas ligand (FasL) pathway involved in CCl(4)-induced acute liver injury, Fas and FasL proteins and caspase-3, -8 activities were tested by western blotting and ELISA. CKS markedly decreased CCl(4)-induced Fas/FasL protein expression levels and in turn attenuated CCl(4)-induced caspase-3, -8 activities in mouse livers. Additionally, CKS protected the CCl(4)-induced depletion of hepatic glutathione levels. The effect of CKS on CYP2E1, the major isozyme involved in CCl(4) bioactivation, was investigated. Treatment with CKS resulted in a significant decrease in the CYP2E1-dependent hydroxylation of aniline. In addition, CKS exhibited antioxidant effects on FeCl(2)-ascorbate induced lipid peroxidation in liver homogenates, and on superoxide radical scavenging activity. These findings suggest that the protective effects of CKS against CCl(4)-induced acute liver injury possibly involve mechanisms related to its ability to block CYP2El-mediated CCl(4) bioactivation and its free radical scavenging effects, and that is also protects against Fas/FasL pathway mediated apoptosis.
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PMID:Protective effect of saponins derived from the roots of Platycodon grandiflorum against carbon tetrachloride induced hepatotoxicity in mice. 1829 69

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

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