Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.109 (AST)
 6,066 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors for matrix metalloproteinases (MMPs) are under investigation for the treatment of various important chronic illnesses, including cancer, arthritis, and cardiovascular disease (CVD). In particular, MMP-13 is currently being probed as a potential key target in CVD and malignant disease due to its documented effects on extracellular matrix (ECM) remodeling, important in the pathophysiology of these diseases. Within the family of related mammalian MMP enzymes, MMP-13 possesses a large hydrophobic binding pocket relative to that of other MMPs. Homochiral astaxanthin (3S,3'S-AST; 3S,3'S-dihydroxy-beta,beta-carotene-4,4'-dione), an important antioxidant and anti-inflammatory xanthophyll carotenoid, is an active metabolite of several novel soft drugs in clinical development; it is also extensively used and tested as a human nutraceutical. In the current study, the prediction of the geometry and energetics of its binding to human MMP-13 was conducted with molecular modeling. The method used was found to predict the energy of binding of known ligands of MMP-13 with great precision. Blind docking using the whole protein target was then used in order to identify the possible binding site(s) of AST. AST was predicted to bind at several sites in close proximity to the active center. Subsequent analyses focused on the binding site at the atomic (i.e., amino acid sequence) level suggested that AST can bind to MMP-13 with high affinity and favorable energetics. Therefore, the modeling study predicts potential direct enzyme-inhibitory activity of AST against MMP-13, a behavior that may be exploited in mammalian systems in which pathological upregulation of MMP activity is paramount.
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PMID:Molecular modeling of non-covalent binding of homochiral (3S,3'S)-astaxanthin to matrix metalloproteinase-13 (MMP-13). 1671 95

Although dysfunctional telomeres and oncogenic or stressful stimuli are known to trigger cellular senescence in normal human diploid cells, the molecules and signaling network involved in the cellular senescence program are not fully understood. We have been trying to identify cellular senescence-inducing factors by various means. First, we screened for an extrinsic signal that can induce cellular senescence in human lung adenocarcinoma cell line A549, and identified transforming growth factor-beta (TGF-beta) as the cellular senescence-inducing factor. Cancer cells senesced by treatment with TGF-beta impaired tumorigenicity both in vitro and in vivo, suggesting that cellular senescence functions as a tumor suppression mechanism. Next, we identified 86 independent senescence-associated genes by subtractive screening using A549-derived cell lines. Thirdly, we established novel cell lines (AST cells) from A549 cells exposed to mild oxidative stress. AST cells demonstrated functional impairment of telomerase due to perturbed subcellular localization of human telomerase reverse transcriptase, suggesting that mild oxidative stress might affect the cell fate of cancer cells. These results should provide insight into the molecular basis of the cellular senescence program.
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PMID:Molecular basis for the cellular senescence program and its application to anticancer therapy. 1671 6

Exposure to certain industrial agents has been thought to have carcinogenic potential, both for employees who work closely with agents and for the general population that comes into contact with them. The objective of the present study is to evaluate the changes at the cellular level or at the level of cellular metabolism products present in the biological fluid, and to detect early stages of the carcinogenic process resulting from the exposure of industrial environmental hazards. Carcinoembryonic antigen (CEA), alpha-fetoproteins (AFP), and prostate-specific antigen (PSA) were measured in sera of workers (n = 51), who were divided into 4 groups: group I, workers exposed to phenol; group II, workers exposed to formaldehyde; group III, workers exposed to urea; and group IV, workers exposed to mixed vapor, plus a reference control healthy group (n = 15). The results showed that 75% of the workers exposed to phenol, 75% of the workers exposed to urea, 83.3% of workers exposed to formalin, and 92.3% of the workers exposed to mixed vapors had raised values of serum CEA (S-CEA) above normal value of the control group. Also, 23% of workers exposed to mixed vapors, 44% of workers exposed to formalin, 50% of workers exposed to phenol, and 62.5% of workers exposed to urea had raised values of serum AFP (S-AFP) above normal value of control group. Finally, 16.6% of workers exposed to phenol, 23% of workers exposed to mixed vapors, and 33.3% of workers exposed to formalin had raised values of serum PSA (S-PSA) above the normal value of control group; there were no raised values of S-PSA in workers exposed to urea. No significant difference was found in the activities of AST and ALT in group I, but a highly significant increase was found in the AST activities for groups II and IV and the ALT activities for groups III and IV. A significant difference was found in the activity of ALT in group II and in AST for group III. There was no significant difference in the levels of albumin in groups I, II, and III, whereas albumin levels were significantly decreased in group IV. No significant change was found in the level of urea and creatinine in all groups except for group III, where serum levels of creatinine were significantly decreased. From our findings, we concluded that S-CEA can be used as an important prognostic screening marker for early prediction for malignancy, and for management of workers with lung cancer who are exposed to the environmental hazards in industrial factories. Furthermore, S-AFP can be used also as a biomarker if it is carried out and correlated with S-CEA.
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PMID:Carcinoembryonic antigen, alpha-fetoprotein, and prostate-specific antigen in the sera of industrial workers exposed to phenol, formaldehyde, urea, and mixed vapors. 1696 4

Liver allografts declined by local transplant centers are then offered regionally or nationally as imported grafts. Most of these grafts are declined because of poor donor quality. We retrospectively reviewed the medical records of patients who underwent liver transplantation between January 2004 and December 2005. There were 102 liver transplants in 98 recipients. They were divided into two groups: imported graft recipients (n = 37) and locally procured grafts recipients (n = 61). Eighty-six percent (32 of 37) of imported grafts were obtained from extended criteria donors defined as subjects treated with high doses of ionotropes with elevated liver enzymes, donor age over 70 years, macrosteatosis above 25%, positive hepatitis C or hepatitis B core antibody serology, systemic disease, history of cancer, hypernatremia, or with infection. The remaining grafts were declined due to unavailability of suitable recipients or social history. Recipient age and etiology of liver disease were similar for both groups. The mean MELD score was 22.1 +/- .9 among the imported graft recipients and 26.1 +/- 1 for the locally procured graft recipients (P < .01). There was no difference in blood loss or postoperative complications. Postoperative mean peak total bilirubin was similar in both groups. However, imported graft recipients had significantly higher mean peak AST (2436 +/- 282 vs 1380 +/- 165 U/L, P < .001) and ALT (1098 +/- 114 vs 803 +/- 87 U/L, P < .05). Primary graft nonfunction as well as 30 day and 1-year patient and graft survivals were similar for both groups. In conclusion, imported grafts can be transplanted in selected patients with outcomes comparable to locally procured grafts.
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PMID:Outcome of imported liver allografts and impact on patient access to liver transplantation. 1717 32

The organ shortage has driven many transplant centers to accept extended donor criteria and to modify graft allocation policies. This study was designed to analyze the impact of applying extended donor criteria (EDC) in orthotopic liver transplantation (OLT). Between December 2001 and December 2004, we performed 165 primary cadaveric whole OLTs. Up to three EDC, that is, ventilation >7 days; aminotransferases (ALT or AST) >3 x normal; bilirubin >3 mg/dL; anti-HBc or HBs Ag positivity; donor age >65 years; liver steatosis >40%; donor body mass index >30; cold ischemia time >14 hours; peak serum Na(+) >165 mmol/L; history of extrahepatic malignancy; or previous drug abuse were present in 55% of all grafts. Both univariate and multivariate analysis revealed that EDC status had no effect on graft or patient survival, the necessity for retransplantation, the length of intensive care/intermediate care unit stay, mechanical ventilation, complications, or posttransplant laboratory findings. Recipient age of >/=55 years was the only independent prognostic factor for survival, regardless of EDC. These findings suggested that the use of grafts from EDC donors are safe and expand the donor pool.
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PMID:Extended donor criteria have no negative impact on early outcome after liver transplantation: a single-center multivariate analysis. 1736 74

The neural networks in the crustacean stomatogastric ganglion are modulated by neuroactive substances released locally into the neuropil of the stomatogastric ganglion and by circulating hormones released by neuroendocrine structures including the pericardial organs. Using nanoscale liquid chromatography coupled to electrospray ionization quadrupole-time-of-flight mass spectrometry, we have identified and sequenced a novel B type allatostatin (CbAST-B1), VPNDWAHFRGSWamide, present in the pericardial organs of the crabs, Cancer borealis, and Cancer productus. We describe the physiological actions of CbAST-B1 on the pyloric rhythm of the stomatogastric ganglion of the crab, Cancer borealis. CbAST-B1 reduces the pyloric network frequency in a dose-dependent manner. The effect of bath-applied CbAST-B1 depends on the preceding physiological state of the preparation. Surprisingly, despite marked amino-acid sequence dissimilarity between the novel CbAST-B1 and the A type allatostatin family of peptides (AST-A), the physiological effects of CbAST-B1 are similar to those of AST-A.
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PMID:Mass spectrometric characterization and physiological actions of VPNDWAHFRGSWamide, a novel B type allatostatin in the crab, Cancer borealis. 1739 56

Neuromodulators can change the output of neural circuits. The crustacean cardiac ganglion (CG) drives the contractions of the heart. The CG is a direct target for neurohormones that are released from the pericardial organs and other neuroendocrine sites. In this study, we have characterized for the first time the physiological actions of the peptides red pigment concentrating hormone (RPCH), Cancer borealis tachykinin-related peptide Ia (CabTRP Ia) and allatostatin III type A (AST-3) on the isolated CG of the crab, Cancer borealis. RPCH and CabTRP Ia excited the CG while AST-3 strongly inhibited its motor output. We also studied the actions of other peptides and small molecule transmitters known to be present in C. borealis. Dopamine, serotonin, proctolin, crustacean cardioactive peptide (CCAP), a number of extended FLRFamide peptides, and cholinergic agonists increased the activity of the CG, GABA inhibited the CG, while other substances had little or no significant effect on the CG motor pattern. These results demonstrate, in one species, that the CG is multiply modulated. We suggest that multiple modulators may be important to regulate and coordinate the activity of the heart and other organs in response to external stimuli or the endogenous physiological state.
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PMID:Multiple modulators act on the cardiac ganglion of the crab, Cancer borealis. 1769 Feb 36

In a group of patients (n=18) with primary (n=7) liver cancer high increase in enzyme activities (AST, ALT, AP, gama-GT, 5'NU), billirubin, alpha-1 AT, alpha- and beta-globulins and alpha-phetoprotein, and considerable decrease of albumin and cholinesterase, were established. These disturbances were duo to the weakened biofunction of the liver. All the examined biochemical parameters are of great significance in the differential diagnosis of cancer, prognosis and development of the disease.
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PMID:[Biochemistry in liver cancer]. 1797 39

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m(-2) intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m(-2) i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3-4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63-82%) obtained a >/=50% PSA decline with 15 patients (37.5%; 95% CI 20-50%) that demonstrated a >/=90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8-8.2 months) and 19.2 months (95% CI 13.9-24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.
Br J Cancer 2007 Dec 17
PMID:Phase II study of sequential chemotherapy with docetaxel-estramustine followed by mitoxantrone-prednisone in patients with advanced hormone-refractory prostate cancer. 1802 96

The present study was designated to evaluate the effect of direct current induced permanent magnetic field (DC-MF) on chemically induced rat colon carcinogenesis. Five experimental groups of male S.D. rats were injected with 1,2-dimethylhydrazine (DMH) subcutaneously, 20 mg/kg b.wt., once a week for four weeks, with exposure to 1 mT DC-MF (12 hours/day) as follows: Before (pre) the carcinogen administration (group 1), simultaneously (group 2), after (post) the carcinogen administration (group 3) and daily from the beginning to the end of the experiment after 12 weeks (group 4). Rats of group 5 served as carcinogen-only treated controls while those of group 6 were non-treated controls. There were no differences in the incidences and multiplicities of colonic aberrant crypt foci (ACF), putative preneoplastic lesions, among all groups except that large foci in group 1 were significantly fewer in numbers than those found in group 5. Proliferating cell nuclear antigen labeling indexes (PCNA-LI) in the colon epithelium were essentially the same in MF-treated and control rats. Histopathological examination showed evident hemorrhage in the pituitary glands of some rats of groups 1-3, and in most rats of group 4. Transmission electron microscopy also revealed ultrastructural changes, but DNA ploidy analysis revealed no carcinogenicity to MF-exposed pituitary glands. Serum levels of AST, ALT, total protein, creatinine, albumin, albumin/globulin ratio and growth hormone levels did not change among the groups. The present study revealed that the action of an artificial MF on rats is not carcinogenic/or cancer-promoting, at least in the present protocol for colon carcinogenesis.
Asian Pac J Cancer Prev
PMID:Pituitary toxicity but lack of rat colon carcinogenicity of a DC-magnetic field in a medium-term bioassay. 1843 92


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