Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of methotrexate (MTX) on the growth and human chorionic gonadotropin (hCG) secretion of five gestational and two nongestational human choriocarcinoma cell lines was studied in vitro. A striking heterogeneity in hCG secretion was noted among the cell lines. The growth of cells which secreted large quantities of hCG, such as HCCM-5, BeWo, and IMa, was inhibited by continuous exposure to 2 X 10(-8)M MTX. In contrast, cells which secreted little hCG, such as SCH, ENAMI-1, and GCH-1, showed no response to the growth inhibitory action of 2 X 10(-8)M MTX and the 3H-thymidine uptake was not reduced by treatment with MTX at doses of up to 10(-4)M for 48 hours. The common morphologic alterations observed in the cells which responded to MTX were an increase in the number of multinucleated giant cells, the appearance of vacuoles and granules in the cytoplasm, and enlargement of the nuclei. Increased hCG secretion was observed in accordance with the appearance of such morphologically altered cells. Part of the mechanisms of resistance to MTX appeared to involve both impairment of MTX uptake by the cells and an increase in the level of intracellular dihydrofolate reductase.
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PMID:Effect of methotrexate on the growth and human chorionic gonadotropin secretion of human choriocarcinoma cell lines in vitro. 668 28

The sensitivity to methotrexate (MTX) and mechanisms of the drug resistance of seven kinds of human choriocarcinoma cell lines were studied in vitro. The results were as follows. Each cell line of HCCM-5 , BeWo, IMa, and NUC-1 secreted more than 200ng/10(6) cells/48 hours of human chorionic gonadotropin (hCG), whereas GCH-1, ENAMI-1, and SCH secreted less than 20ng/10(6) cells/48 hours. HCCM-5 cell line was the most sensitive to MTX judging from the inhibition of both 3H-thymidine uptake and cell growth in vitro. Each cell line of BeWo, IMa, and NUC-1 revealed sensitivity to 2 X 10(-8)M MTX, but such cell lines as GCH-1, ENAMI-1, and SCH showed resistance to MTX. The cell lines which revealed sensitivity to MTX incorporated more 3H-MTX and showed less intracellular dihydrofolate reductase activity than resistant cell lines.
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PMID:[MTX sensitivity and the mechanism of resistance of various choriocarcinoma cells in culture]. 668 70

Periodontal disease is a highly prevalent chronic inflammatory disease and is associated with complex microbial infection in the subgingival cavity. Recently, American Heart Association supported a century old association between periodontal disease and atherosclerotic vascular disease. We have recently shown that polybacterial periodontal infection led to aortic atherosclerosis and modulation of lipid profiles; however the underlying mechanism(s) has not been yet demonstrated. Altered nitric oxide (NO) synthesis and tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthases (NOS) has long been shown to be associated with vascular dysfunction and gastrointestinal motility disorders. We sought to examine the mechanism of periodontal infection leading to altered vascular and gastrointestinal smooth muscle relaxation, focusing on the BH4/nNOS pathways. In addition, we also have investigated how the antioxidant system (NRF2-Phase II enzyme expression) in vascular and GI specimens is altered by oral infection. Eight week old male ApoEnull mice were either sham-infected or infected orally for 16 weeks with a mixture of major periodontal bacteria Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia to induce experimental periodontitis. Serum, vascular (mesenteric), stomach, and colon specimens were collected at the end of periodontal pathogen infection. Bacterial infection induced significant (p<0.05) reductions in the levels of BH4,in ratio of BH4:BH2+B and also in nitric oxide levels compared to sham-infected controls. In addition, we identified a significant (p<0.05) reduction in eNOS dimerization, nNOS dimerization and protein expression of BH4 biosynthesis enzymes; GCH-1, DHFR and NRF2 & Phase II enzymes in infected mice versus controls in both mesenteric artery and colon tissues. However, we found no differences in nNOS/BH4 protein expression in stomach tissues of infected and sham-infected mice. This suggests that a polybacterial infection can cause significant changes in the vascular and colonic BH4/nNOS/NRF2 pathways which might lead to impaired vascular relaxation and colonic motility.
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PMID:Polybacterial Periodontal Pathogens Alter Vascular and Gut BH4/nNOS/NRF2-Phase II Enzyme Expression. 2611 Nov 53

Downregulation of CR6 interacting factor 1 (CRIF1) has been reported to induce mitochondrial dysfunction, resulting in reduced activity of endothelial nitric oxide synthase (eNOS) and NO production in endothelial cells. Tetrahydrobiopterin (BH4) is an important cofactor in regulating the balance between NO (eNOS coupling) and superoxide production (eNOS uncoupling). However, whether the decreased eNOS and NO production in CRIF1-deficient cells is associated with relative BH4 deficiency-induced eNOS uncoupling remains completely unknown. Our results showed that CRIF1 deficiency increased eNOS uncoupling and depleted levels of total biopterin and BH4 by reducing the enzymes of BH4 biosynthesis (GCH-1, PTS, SPR, and DHFR) in vivo and vitro, respectively. Supplementation of CRIF1-deficient cells with BH4 significantly increased the recovery of Akt and eNOS phosphorylation and NO synthesis. In addition, scavenging ROS with MitoTEMPO treatment replenished BH4 levels by elevating levels of GCH-1, PTS, and SPR, but with no effect on the level of DHFR. Downregulation of DHFR synthesis regulators p16 or p21 in CRIF1-deficient cells partially recovered the DHFR expression. In summary, CRIF1 deficiency inhibited BH4 biosynthesis and exacerbated eNOS uncoupling. This resulted in reduced NO production and increased oxidative stress, which contributes to endothelial dysfunction and is involved in the pathogenesis of cardiovascular diseases.
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PMID:CR6-interacting factor 1 deficiency reduces endothelial nitric oxide synthase activity by inhibiting biosynthesis of tetrahydrobiopterin. 3196 86