Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of p53 function and caspase 3 activity on the capacity of the antifolate, methotrexate, to promote senescence arrest and apoptotic cell death was investigated in breast tumor cells. In p53 wild-type, but caspase 3 deficient MCF-7 breast tumor cells, death of approximately 40% of the cell population was observed immediately after acute exposure to 10 microM methotrexate (the IC80 value for a 2 h drug exposure). There was no evidence of either DNA fragmentation, a sub G0 population or morphological alterations indicative of apoptosis; however, PARP cleavage was detected. Cell death was succeeded by growth arrest for at least 72 h--where arrest was characterized by expression of the senescence marker, beta-galactosidase. The response to methotrexate in MCF-7/E6 cells with attenuated p53 function was also primarily growth arrest--but lacking characteristics of senescence. In contrast, MCF-7 cells which expressed caspase 3 demonstrated a gradual and continuous loss of cell viability and unequivocal morphological evidence of apoptosis. DNA fragmentation indicative of apoptosis was also detected after exposure to methotrexate in p53 mutant MDA-MB231 breast tumor cells which also express caspase 3. Methotrexate-induced both p53 and p21waf1/cip1 in MCF-7 cells within 6 h; however, no significant DNA strand breakage was evident before 18 h, suggesting that the induction of p53 reflects a response to cellular stress other than DNA damage, such as nucleotide depletion. Overall, these studies suggest that the nature of the cellular response to methotrexate depends, in large part, on p53 and caspase function. p53 appears to be required for methotrexate-induced senescence, but not apoptosis, caspase 3 is required for DNA fragmentation and the morphological changes associated with apoptosis, while neither p53 nor caspase 3 are required for methotrexate-induced growth arrest. Furthermore, the senescence phenotype may occur in the absence of direct DNA damage.
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PMID:Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell. 1545 Sep 35

Lumbar laminectomy is one of the most common treatments for lumbar disc herniation and other lumbar disorders with serious complications, such as failed back surgery syndrome, mainly caused by epidural fibrosis (EF). The developing fibrosis causes radicular pain after the laminectomy or discectomy. Methotrexate (MTX) is a folic acid antagonist that has shown anti-proliferative effects in previous studies. The aim of our experiment is to study whether MTX has positive effects on the outcome of the laminectomy in rats. Our finding first demonstrated the beneficial effect of topical application of MTX in laminectomy models. As the results of a macroscopic scoring system, hydroxyproline content analysis, histological evaluation, the number of fibroblasts and immunohistochemistry showed that MTX suppressed the EF compared with the control group, and the inhibiting effect was in a dose-dependent manner. Furthermore, we hypothesized that the endoplasmic reticulum (ER) stress mediated the suppression effect of the EF. To verify this point of view, fibroblast cells cultured from epidural scar tissues of rats were used. CCK-8 assay, Western blot (for apoptotic genes, such as cleaved PARP) and annexin V-FITC/PI double-labelling showed that MTX could induce cell apoptosis. The expression of CHOP and GRP78 and the activation of ER stress-associated genes strongly suggested that ER stress mediated the apoptotic signalling pathway; immunohistochemistry of GRP78 and CHOP further verified this. Our findings indicate that topical application of MTX could indeed reduce EF, and the application of MTX could induce apoptosis through ER stress in rats.
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PMID:Methotrexate prevents epidural fibrosis through endoplasmic reticulum stress signalling pathway. 2801 73

Methotrexate (MTX) is a classical chemotherapeutic agent with nephrotoxicity as the most disturbing adverse effect. So far, its underlying molecular mechanisms, particularly PI3K/Akt/eNOS transduction, are inadequately explored. Several antioxidant modalities have been characterized to ameliorate MTX-induced renal injury. In this regard, Camel milk (CM) is a natural product with recognized antioxidant and anti-inflammatory features. Thus, the current study aimed to investigate the potential ameliorating effects of CM in MTX-induced kidney injury in rats. Renal tissues were studied in terms of renal injury markers, histopathology, oxidative stress, apoptosis and PI3K/Akt/eNOS signaling. CM was orally administered (10 ml kg-1) and the renal injury was induced by a single i.p. injection of MTX (20 mg kg-1). Interestingly, CM dose-dependently attenuated MTX-triggered increase of BUN and serum creatinine and renal Kim-1 expression and mitigated the renal histopathological changes. CM counteracted renal oxidative stress as manifested by lowering of lipid peroxides, restoration of NOX-1 levels and augmentation of the antioxidant defenses e.g., GSH, SOD, GPx and total antioxidant capacity. With respect to apoptosis, CM curbed the cleavage of PARP and caspase-3, downregulated p53, Bax and Cyt C proapoptotic signals and enhanced Bcl-2 and PCNA levels. In the same context, CM activated the prosurvival PI3K/Akt/eNOS pathway via enhancing PI3K p110, phospho-Akt and phospho-eNOS levels. Equally important, CM preconditioning did not interfere with MTX cytotoxicity in TK-10 or PC-3 cancer cells. Together, the current findings demonstrate, for the first time, the renoprotective effects of CM in MTX-induced kidney injury via activation of PI3K/Akt/eNOS signaling and combating oxidative stress and apoptosis.
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PMID:Camel milk attenuates methotrexate-induced kidney injury via activation of PI3K/Akt/eNOS signaling and intervention with oxidative aberrations. 2966 62

Methotrexate (MTX) is a folic acid antagonist and widely used for acute lymphoblastic leukemia (ALL) in children. MTX is associated with acute and chronic neurotoxicity during treatment, however the underlying mechanism is still poorly understood. In this study we investigate whether MTX is neurovirulent to astrocytes in the Central Nervous System (CNS) of adolescent mice. We demonstrated that MTX induced severe cytotoxicity in C6 astrocyte-like cell line and rat primary cultures of astrocytes in a dose-dependent manner. Moreover, GFAP-labeled astrocyte cells significantly decreased in the mouse spinal cord and brain. Furthermore, protein levels of PARP and pro-Caspase-3 were reduced by MTX, indicating MTX-induced apoptosis leads to the astrocytes loss. Notably, overexpression of dihydrofolate reductase (DHFR) or exogenous addition of folate markedly reversed the astrocytes toxicity induced by MTX through activating folate metabolism pathway. Taken together, our study provides evidence for neurotoxic effect of MTX-induced astrocytes apoptosis both in vitro and in vivo with disruption of folate metabolism, and additional supplement of folate may provide novel approaches for alleviating the astrocytes toxicity induced by MTX in the clinic.
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PMID:Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system. 3050 84