Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced nitric oxide (NO) in the brain might contribute to enhanced sympathetic drive in heart failure (HF). The aim of this study was to determine whether increased NO production induced by local overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarius (NTS) of the brain stem reduces the enhanced sympathetic drive in mice with HF. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. MI mice exhibited left ventricular dilatation and a reduced left ventricular ejection fraction. Urinary norepinephrine excretion in MI mice was greater than that in sham-operated mice, indicating that sympathetic drive was enhanced in this model. Thus this model has features that are typical of HF. Western blot analysis and immunohistochemical staining for neuronal NOS (nNOS) indicated that nNOS protein expression was significantly reduced in the brain stem of MI mice. MI mice had a significantly smaller increase in blood pressure evoked by intracisternal injection of N(G)-monomethyl-L-arginine than sham-operated mice. Adenoviral vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbeta gal) were transfected into the NTS to examine the effect of increased NO production in the NTS on the enhanced sympathetic drive in HF. After the gene transfer, urinary norepinephrine excretion was reduced in AdeNOS-transfected MI mice but not in Adbeta gal-transfected MI mice. These results indicate that nNOS expression in the brain stem, especially in the NTS, is reduced in the MI mouse model of HF, and increased NO production induced by overexpression of eNOS in the NTS attenuates the enhanced sympathetic drive in this model.
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PMID:Overexpression of eNOS in brain stem reduces enhanced sympathetic drive in mice with myocardial infarction. 1600 46

We report here the effect of aspirin on the onset of replicative senescence. Endothelial cells that were cultured until cumulative population doublings 40 showed clear signs of aging. Incubation with aspirin inhibited senescence-associated beta-galactosidase activity and increased telomerase activity. Along with the delayed onset of senescence, aspirin decreased reactive oxygen species and increased nitric oxide (NO) and cGMP levels. Furthermore, aspirin reduced the elaboration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and up-regulated the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA. These effects were specific in that other nonsteroidal anti-inflammatory drugs, such as ibuprofen or acetaminophen, did not prevent the onset of endothelial senescence. The NO synthase inhibitor l-NAME, but not its inactive d-enantiomer, led to complete inhibition of aspirin-delayed senescence. These findings demonstrate that aspirin delays the onset of endothelial senescence by preventing a decrease in NO formation/generation. This might provide a therapeutic strategy aimed at blocking aging-induced NO inhibition.
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PMID:Aspirin reduces endothelial cell senescence. 1603 99

A MerR-like regulator (NmlR -Neisseria merR-like Regulator) identified in the Neisseria gonorrhoeae genome lacks the conserved cysteines known to bind metal ions in characterized proteins of this family. Phylogenetic analysis indicates that NmlR defines a subfamily of MerR-like transcription factors with a distinctive pattern of conserved cysteines within their primary structure. NmlR regulates itself and three other genes in N. gonorrhoeae encoding a glutathione-dependent dehydrogenase (AdhC), a CPx-type ATPase (CopA) and a thioredoxin reductase (TrxB). An nmlR mutant lacked the ability to survive oxidative stress induced by diamide and cumene hydroperoxide. It also had > 50-fold lower NADH-S-nitrosoglutathione oxidoreductase activity consistent with a role for AdhC in protection against nitric oxide stress. The upstream sequences of the NmlR regulated genes contained typical MerR-like operator/promoter arrangements consisting of a dyad symmetry located between the -35 and -10 elements of the target genes. The NmlR target operator/promoters were cloned into a beta-galactosidase reporter system and promoter activity was repressed by the introduction of NmlR in trans. Promoter activity was activated by NmlR in the presence of diamide. Under metal depleted conditions NmlR did not repress P(AdhC) (or P(CopA)) promoter activity, but this was reversed in the presence of Zn(II), indicating repression was Zn(II)-dependent. Analysis of mutated promoters lacking the dyad symmetry revealed constitutive promoter activity which was independent of NmlR. Gel shift assays further confirmed that NmlR bound to the target promoters possessing the dyad symmetry. Site-directed mutagenesis of the four NmlR cysteine residues revealed that they were essential for activation of gene expression by NmlR.
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PMID:NmlR of Neisseria gonorrhoeae: a novel redox responsive transcription factor from the MerR family. 1613 33

Aerosol gene transfer of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) to rat lungs increased NOS expression and activity, and prevented hypoxic pulmonary vasoconstriction (HPV) in vivo. Hereby, we examined the effect of eNOS and iNOS aerosol gene transfer on the endothelium-dependent relaxation (EDR) and on acute HPV in isolated rat pulmonary arteries. Changes in isometric forces were recorded in organ baths for large conduit arteries (diameter 1.8+/-0.1 mm) and in a wire myograph for small resistance arteries (258+/-35 microm). Male Wistar rats were randomly aerosolized with adenovirus (Ad) encoding beta-galactosidase (control), eNOS, or iNOS. Four days later, exhaled nitric oxide was measured, NOS expression within rat lungs was evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry, vasoconstricting agonist and acetylcholine concentration response curves were generated, and the time course of HPV was recorded. Human eNOS and murine iNOS were expressed within rat lung tissue mostly in parenchyma and endothelial cells. Large arteries isolated from Ad-i, eNOS-aerosolized rats developed lower agonist-induced tension than those of control rats. The first and second contractions of the HPV were smaller in the Ad-i, eNOS-aerosolized rats. Contractions were modestly, but significantly and inversely, related to exhaled NO. Agonist- and hypoxia-induced contractions were even more reduced after eNOS aerosolization. There was no significant effect on EDR and no notable difference between small and large vessels. We conclude that adenovirus (Ad)-mediated NOS gene transfer can counteract both pharmacologically and hypoxia-induced increases in pulmonary vascular tone in isolated rat pulmonary arteries. eNOS seems as efficient as iNOS in regulating pulmonary vascular tone.
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PMID:Effect of adenovirus-mediated gene transfer of nitric oxide synthase on vascular reactivity of rat isolated pulmonary arteries. 1640 9

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and its accumulation has been associated with cardiovascular disease. We aimed to investigate the role of ADMA in endothelial cell senescence. Endothelial cells were cultured until the tenth passage. ADMA was replaced every 48 hours starting at the fourth passage. ADMA significantly accelerated senescence-associated beta-galactosidase activity. Additionally, the shortening of telomere length was significantly speeded up and telomerase activity was significantly reduced. This effect was associated with an increase of oxidative stress: both allantoin, a marker of oxygen free radical generation, and intracellular reactive oxygen species increased significantly after ADMA treatment compared with control, whereas nitric oxide synthesis decreased. Furthermore, ADMA-increased oxidative stress was accompanied by a decrease in the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA, which could be prevented by the antioxidant pyrrolidine dithiocarbamate. Exogenous ADMA also stimulated secretion of monocyte chemotactic protein-1 and interleukin-8. Co-incubation with the methyltransferase inhibitor S-adenosylhomocysteine abolished the effects of ADMA. These data suggest that ADMA accelerates senescence, probably via increased oxygen radical formation by inhibiting nitric oxide elaboration. This study provides evidence that modest changes of intracellular ADMA levels are associated with significant effects on slowing down endothelial senescence.
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PMID:Asymmetric dimethylarginine (ADMA) accelerates cell senescence. 1644 71

The discovery of tissue protective effects of erythropoietin has stimulated significant interest in erythropoietin (Epo) as a novel therapeutic approach to vascular protection. The present study was designed to determine the cerebral vascular effects of recombinant Epo in vivo. Recombinant adenoviral vectors (10(9) plaque-forming units/animal) encoding genes for human erythropoietin (AdEpo) and beta-galactosidase (AdLacZ) were injected into the cisterna magna of rabbits. After 48 h, basilar arteries were harvested for analysis of vasomotor function, Western blotting, and measurement of cGMP levels. Gene transfer of AdEpo increased the expressions of recombinant Epo and its receptor in the basilar arteries. Arteries exposed to recombinant Epo demonstrated attenuation of contractile responses to histamine (10(-9) to 10(-5) mol/l) (P < 0.05, n = 5). Endothelium-dependent relaxations to acetylcholine (10(-9) to 10(-5) mol/l) were significantly augmented (P < 0.05, n = 5), whereas endothelium-independent relaxations to a nitric oxide (NO) donor 2-(N,N-diethylamino)diazenolate-2-oxide sodium salt remained unchanged in AdEpo-transduced basilar arteries. Transduction with AdEpo increased the protein expression of endothelial NO synthase (eNOS) and phosphorylated the S1177 form of the enzyme. Basal levels of cGMP were significantly elevated in arteries transduced with AdEpo consistent with increased NO production. Our studies suggest that in cerebral circulation, Epo enhances endothelium-dependent vasodilatation mediated by NO. This effect could play an important role in the vascular protective effect of Epo.
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PMID:In vivo stimulatory effect of erythropoietin on endothelial nitric oxide synthase in cerebral arteries. 1656 20

Beta-galactosyl-pyrrolidinyl diazeniumdiolates (beta-Gal-NONOate) is a new site-specific nitric oxide (NO)-releasing compound, which releases NO once activated by beta-galactosidase. In the present experiment, we used beta-Gal-NONOate as a bactericidal reagent to investigate its effectiveness of NO releasing. Through the evaluation of intracellular NO level and the comparison of survival of E. coli transformed with lacZ gene but treated with beta-Gal-NONOate and NONOate, respectively, it's evident that beta-Gal-NONOate had a higher bactericidal activity than conventional NONOate. While either beta-Gal-NONOate- or NONOate-treated E. coli without transferred lacZ gene showed low bactericidal activity. The results revealed that beta-Gal-NONOate was a potentially efficient NO donor, which took on a novel and promising approach to deliver NO into cells.
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PMID:Delivery of nitric oxide released from beta-Gal-NONOate activation by beta-galactosidase and its activity against Escherichia coli. 1675 24

So far, nitric oxide (NO) donors have been applied to various aspects of antitumor therapy. To selectively sensitize tumor cells and avoid unwanted side effects, we recently synthesized a beta-galactosidase-activatable NO-releasing compound, beta-galactosyl-pyrrolidinyl diazeniumdiolate (beta-Gal-NONOate). In this study, we first verified its superiority over its parent diazeniumdiolate (NONOate) in terms of targeted intracellular NO-releasing and antitumor activity with 9L/LacZ cells (rat glioma cell line 9L with transformed LacZ gene) in vitro. beta-Gal-NONOate only released NO when hydrolyzed by induced beta-galactosidase in 9L/LacZ cells, which led to its more powerful cytotoxicity than that of NONOate. The results showed that beta-Gal-NONOate produced higher NO levels than NONOate in 9L/LacZ cells at equal concentration, and hence induced optimal NO levels for antitumor activity. However, in 9L cells, beta-Gal-NONOate showed less toxicity than NONOate. Therefore, it is demonstrated that beta-Gal-NONOate is a site-specific prodrug for targeting NO intracellularly as a beta-galactosidase-sensitive NO donor, and it is also expected to be a promising probe in numerous experimental settings and a potential therapeutic drug for antitumor treatment.
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PMID:A glycosylated nitric oxide donor, beta-Gal-NONOate, and its site-specific antitumor activity. 1678 37

Fluorescence imaging is the most powerful technique currently available for continuous observation of dynamic intracellular processes in living cells. However, only a very limited range of biomolecules can be visualized because of the lack of flexible design strategies for fluorescence probes. In our laboratory, it was elucidated that fluorescein which has been widely employed as a core of fluorescence probes could be understood as a directly linked electron donor/fluorophore acceptor system. Fluorescence properties of fluorescein derivatives could be easily anticipated and modulated by controlling the rate of photoinduced electron transfer (PeT) from the donor moiety to the xanthene fluorophore. Further, we found that the opposite direction of PeT from the singlet excited fluorophore to the electron acceptor moiety could be occurred. More than twenty probes for imaging of nitric oxide, beta-galactosidase, highly reactive oxygen species, zinc ion et al. have been developed according to precise and rational design strategies based on PeT mechanism.
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PMID:[Development and biological applications of various bioimaging probes]. 1701 20

Endothelium-dependent vasorelaxation of the rabbit aorta is mediated by either nitric oxide (NO) or arachidonic acid (AA) metabolites from cyclooxygenase (COX) and 15-lipoxygenase (15-LO) pathways. 15-LO-1 metabolites of AA, 11,12,15-trihydroxyeicosatrienoic acid (THETA), and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) cause concentration-dependent relaxation. We tested the hypothesis that in the 15-LO pathway of AA metabolism, 15-LO-1 is sufficient and is the rate-limiting step in inducing relaxations in rabbit aorta. Aorta and rabbit aortic endothelial cells were treated with adenoviruses containing human 15-LO-1 cDNA (Ad-15-LO-1) or beta-galactosidase (Ad-beta-Gal). Ad-15-LO-1-transduction increased the expression of a 75-kDa protein corresponding to 15-LO-1, detected by immunoblotting with an anti-human15-LO-1 antibody, and increased the production of HEETA and THETA from [(14)C]AA. Immunohistochemical studies on Ad-15-LO-1-transduced rabbit aorta showed the presence of 15-LO-1 in endothelial cells. Ad-15-LO-1-treated aortic rings showed enhanced relaxation to AA (max 31.7 +/- 3.2%) compared with Ad-beta-Gal-treated (max 12.7 +/- 3.2%) or control nontreated rings (max 13.1 +/- 1.6%) (P < 0.01). The relaxations in Ad-15-LO-1-treated aorta were blocked by the 15-LO inhibitor cinnamyl-3,4-dihydroxy-a-cyanocinnamate. Overexpression of 15-LO-1 in the rabbit aortic endothelium is sufficient to increase the production of the vasodilatory HEETA and THETA and enhance the relaxations to AA. This confirms the role of HEETA and THETA as endothelium-derived relaxing factors.
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PMID:Adenoviral expression of 15-lipoxygenase-1 in rabbit aortic endothelium: role in arachidonic acid-induced relaxation. 1704 Sep 69


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