Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously clarified that sensitization with a sulfated polygalactose, carrageenan (CAR), enhances endotoxin-induced tumor necrosis factor (TNF) production and lethality in mice. The present study was performed to examine the role of nitric oxide (NO) in CAR-sensitized septic mice with two different types of NO synthase (NOS) inhibitors, a non-selective inhibitor to NOS subtypes, N omega-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor to inducible NOS, aminoguanidine. Seven or eight-week-old male ddY mice were given 5 mg of CAR intraperitoneally as a primer. Then, 5 micrograms of lipopolysaccharide (LPS) was injected into the tail vein 16 hours later the pretreatment. Marked synthesis of NO was induced in CAR-sensitized mice, as indicated by the high plasma levels of the stable endproducts, NO2-/NO3- peaking at 12 hr after the LPS challenge. The peak values at 12 hr after the LPS challenge were dependent on the dose of CAR with 1 to 5 mg, although the injection with 10 mg of CAR was adversely inhibited NO production compared with 5 mg of CAR. The LPS challenge was followed by either L-NAME (0.25, 0.5 or 1 mg) or aminoguanidine (1, 2 or 4 mg) in the septic mice sensitized with 5 mg of CAR. L-NAME reduced the plasma NO2-/NO3- level in a dose-dependent fashion, although it augmented liver injury, as measured by plasma levels of ornithine carbamyltransferase (OCT) and the LPS-induced lethality in a dose-dependent fashion. In contrast, aminoguanidine did not significantly deteriorate either liver injury or lethality in spite of the decrease of NO endproducts in a similar fashion to L-NAME. These findings suggest that the inhibition of constitutive NOS is detrimental and augments LPS-induced liver injury and subsequent lethality.
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PMID:Role of nitric oxide during carrageenan-sensitized endotoxin shock in mice. 749 Oct 89

While the L-arginine conversion assay has been utilized to measure nitric oxide synthase (NOS) activity in isolated enzyme and pure cell preparations, this method often fails to provide accurate measurements in whole tissues. Biological tissues contain variable amounts of unlabeled substrate and enzymes are present which can compete for substrate or independently form the product L-citrulline. NOS-independent conversion of radiolabeled L-arginine to L-citrulline occurs due to arginase- and ornithine transcarbamylase-mediated reactions and this limits the accuracy of this assay for measurement of NOS activity. In heart tissue, NOS-independent L-citrulline formation was observed which could not be blocked by the NOS inhibitor L-NAME but was blocked by the arginase inhibitor L-ornithine. To eliminate the effect of arginase-mediated L-citrulline formation, KCl-washed membrane particulate fractions were obtained by high-speed centrifugation. While arginase-mediated nonspecific activity was 85% concentrated in the cytosol, 93% of NOS activity was localized within the particulate fraction of the heart. The remaining arginase activity found in the crude pellet was mostly removed by a one-step KCl wash purification and when incubation periods of 8 min were utilized specific and accurate measurements of NOS activity were obtained. NOS enzymatic properties were defined for rat heart preparations with a Km of 2.9 microM for L-arginine. All NOS activity detected was calcium-dependent suggesting it originated from the constitutive endothelial isoform. Thus, NOS-independent activity can be largely eliminated from the heart tissue by assaying KCl-washed membrane particulate fractions and this enables accurate quantitation of NOS activity.
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PMID:An improved assay for measurement of nitric oxide synthase activity in biological tissues. 968 8

Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.
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PMID:Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. 3257 23