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)

Endothelial nitric oxide synthase (eNOS) uncoupling plays a causal role in endothelial dysfunction in many cardiovascular and metabolic diseases. Tanshinone IIA (Tan IIA), an active compound from Salvia miltiorrhiza, has been used to treat cardiovascular and metabolic diseases. However, the effects of Tan IIA on eNOS uncoupling have not been reported. We hypothesize that Tan IIA can regulate eNOS uncoupling in endothelium cells under oxidative stress. The results showed that eNOS-mediated NO generation was significantly decreased, accompanied by increased superoxide production and NOX4 expression. The ratio of eNOS dimer to monomer and NOS cofactor tetrahydrobiopterin (BH4) to 7,8-dihydrobiopterin (BH2) as well as expressions of heat-shock protein of 90kDa (HSP90), GTP cyclohydrolase-1 (GTPCH1) and dihydrofolate reductase (DHFR) were significantly decreased. Tan IIA significantly inhibited superoxide production and expression of NOX4, and increased NO generation and eNOS homodimerization, as well as expressions of HSP90, GTPCH1 and DHFR in a concentration-dependent manner. The ratio of BH4 to BH2 was also elevated by Tan IIA. In addition, Tan IIA significantly inhibited the increase in expression of PI3K in high glucose treated cells. Wortmannin, a PI3K inhibitor, significantly inhibited the high glucose induced NOX4 expression. The results demonstrated that Tan IIA restored eNOS uncoupling induced by high glucose by targeting NADPH oxidase, HSP90, GTPCH1 and DHFR, and PI3K pathway, which leads to reduced intracellular oxidative stress and increased NO generation. Tan IIA may be used as a prototype agent to restore eNOS coupling under certain cardiovascular and metabolic diseases.
 ...
PMID:Mechanism of reversal of high glucose-induced endothelial nitric oxide synthase uncoupling by tanshinone IIA in human endothelial cell line EA.hy926. 2306 42

The response of human colon cancer C85 cells to methotrexate takes the form of reversible growth arrest of the type of stress-induced senescence. In the present study it is shown that during C85 cell progression into methotrexate-induced senescence, dihydrofolate reductase, the primary intracellular target for the drug, is stabilized at the protein level and its enzymatic activity, assayed in crude cellular extracts, decreases by 2-fold. Dihydrofolate reductase inhibition results in an increase in dihydrobiopterin level and an ultimate decrease in the tetrahydrobiopterin: dihydrobiopterin ratio in senescent cells. Endothelial nitric oxide synthase expression declines. Despite concomitant upregulation of inducible nitric oxide synthase expression, no nitric oxide generation in senescent cells is detected. Progressing oxidative stress accompanies establishment of the state of senescence. DNA damage, in the form of double strand-breaks, occurs at the highest level at the senescence initiation phase and decreases as cells progress into the senescence maintenance phase.
 ...
PMID:Oxidative stress and inhibition of nitric oxide generation underlie methotrexate-induced senescence in human colon cancer cells. 2873 75