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)

Somatostatin is found in neurons and endocrine cells in the gastrointestinal tract. The actions of somatostatin are mediated by a family of G-protein-coupled receptors that compose five subtypes (SSTR1-5), each of which is encoded by a separate gene. lacZ "knockin" mice, in which the reporter gene lacZ was engineered into the genomic locus of Sstr2 by gene targeting, were used to examine the expression pattern of Sstr2 and identify potential targets for neurally released and hormonal somatostatin in the gastrointestinal tract. In the body of the stomach, a large proportion of epithelial cells and subpopulations of myenteric neurons expressed Sstr2. Double- or triple-labeling with antisera to H(+)K(+)ATPase (to identify parietal cells) and/or histidine decarboxylase (to identify enterochromaffin-like [ECL] cells) combined with beta-galactosidase staining revealed that both parietal cells and ECL cells expressed Sstr2, and these two cell types accounted for almost all of the Sstr2-expressing epithelial cells. Somatostatin inhibits gastric acid secretion. The presence of SSTR2 on both parietal and ECL cells suggests that somatostatin acting on SSTR2 may reduce acid secretion by both acting directly on parietal cells and by reducing histamine release from ECL cells. In the small and large intestine, subpopulations of neurons in the myenteric and submucosal plexuses expressed Sstr2, and many of the Sstr2-expressing myenteric neurons also showed SSTR2(a) immunostaining. Most of Sstr2-expressing neurons in the myenteric plexus showed nitric oxide synthase (NOS) immunoreactivity. Previous studies have shown that NOS neurons are descending interneurons and anally projecting, inhibitory motor neurons. Thus, somatostatin acting at SSTR2 receptors on NOS neurons might modulate descending relaxation.
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PMID:Identification of cells expressing somatostatin receptor 2 in the gastrointestinal tract of Sstr2 knockout/lacZ knockin mice. 1244 23

We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial beta-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress-induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.
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PMID:Local expression of C-type natriuretic peptide suppresses inflammation, eliminates shear stress-induced thrombosis, and prevents neointima formation through enhanced nitric oxide production in rabbit injured carotid arteries. 1245 93

Previously, we have demonstrated that increased superoxide generation plays a role in the nitric oxide (NO)-mediated inhibition of endothelial NO synthase (NOS III) in endothelial cells (ECs). In this study we demonstrate that the source of the superoxide is likely due to both NADPH oxidase and NOS III itself. Further, this increase appears to be linked to the activation of PKC, as PMA could mimic the increase and PKC inhibition ameliorate the increase. To further investigate this phenomenon we determined the effect of overexpression of copper-zinc superoxide dismutase (CuZn-SOD) and Manganese-SOD (Mn-SOD) on the inhibitory effects of NO. Using adenoviral infection we demonstrated that SOD activity was increased and superoxide levels decreased, in both CuZn-SOD and Mn-SOD overexpressing cells compared to cells infected with an adenovirus expressing bacterial beta-galactosidase protein. However, only the CuZn-SOD overexpression reduced the NO-mediated inhibition of NOS III. In addition, the level of NO-induced peroxynitrite generation and nitrated NOS III protein were reduced only in the CuZn-SOD overexpressing cells. In conclusion, our results indicate that superoxide and peroxynitrite are involved in the inhibition of NOS III by NO, and that the scavenging of superoxide may be necessary to prevent NOS III inhibition during treatments that involve inhaled NO or NO donors.
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PMID:The overexpression of copper-zinc superoxide dismutase protects NOS III from nitric oxide-mediated inhibition. 1248 93

We examined neuroprotective effects of an adenoviral vector encoding glial cell line-derived neurotrophic factor (AxCAhGDNF) on the lesioned adult rat motoneurons in the nucleus ambiguus. After vagal nerve avulsion, AxCAhGDNF, AxCALacZ (adenovirus encoding beta-galactosidase gene) or PBS was inoculated into the jugular foramen. Four days after the avulsion and treatment with AxCALacZ, the animals expressed beta-galactosidase activity in the lesioned motoneurons in the nucleus ambiguus. The animals avulsed and inoculated with AxCAhGDNF showed immunolabeling for GDNF in the nucleus ambiguus on the treated side and expression of virus-induced human GDNF mRNA transcripts in the brainstem tissue that contained the nucleus ambiguus of the treated side. The treatment with AxCAhGDNF after avulsion prevented the loss of lesioned motoneurons in the nucleus ambiguus, ameliorated the choline acetyltransferase immunoreactivity, and also suppressed the activity of nitric oxide synthase in these neurons. These results indicate that adenovirus-mediated GDNF gene transfer may prevent the degeneration of motoneurons in humans after either vagal nerve injury or recurrent laryngeal nerve injury.
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PMID:Adenoviral GDNF gene transfer prevents motoneuron loss in the nucleus ambiguus. 1254 56

Administration of nitric oxide (NO) or NO donors to isolated carotid sinus and carotid bodies inhibits the activity of baroreceptor and chemoreceptor afferent nerves. Furthermore, NO synthase (NOS) is present in endothelial cells and in sensory nerves innervating the carotid sinus region. The major goal of this study was to determine whether overexpression of NOS in carotid sinus modulates baroreceptor activity. Rabbits were anesthetized, and adenoviral vectors (5 x 10(8) plaque-forming units) encoding genes for either beta-galactosidase (beta-Gal) or endothelial type III NOS (eNOS) were applied topically to the adventitial surface of one carotid sinus. In some experiments, the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) was applied to the carotid sinus immediately after the vector. Four to five days later, baroreceptor activity and carotid sinus diameter were measured from the vascularly isolated carotid sinus of the anesthetized rabbits. Transgene expression was confirmed by X-Gal staining of beta-Gal and measurement of NOS activity by citrulline assay. The expression was restricted to the carotid sinus adventitia. Baroreceptor activity was decreased significantly, and the pressure-activity curve was shifted to higher pressures in eNOS-transduced (n = 5) compared with beta-Gal-transduced (n = 5) carotid sinuses. The pressure corresponding to 50% of maximum activity averaged 55 +/- 6 and 76 +/- 7 mmHg in beta-Gal- and eNOS-transduced carotid sinuses, respectively (P < 0.05). Decreased baroreceptor activity was accompanied by a significant increase in carotid diameter in the eNOS-transduced carotid sinuses (n = 5). l-NAME prevented the inhibition of baroreceptor activity and the increase in carotid diameter in eNOS-transduced carotid sinuses (n = 5). We conclude that adenoviral-mediated gene transfer of eNOS to carotid sinus adventitia causes sustained, NO-dependent inhibition of baroreceptor activity and resetting of the baroreceptor function curve to higher pressures.
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PMID:Modulation of baroreceptor activity by gene transfer of nitric oxide synthase to carotid sinus adventitia. 1267 43

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization of ischemic tissue. Ex vivo expansion of EPCs might be useful for potential clinical cell therapy of myocardial ischemia. However, cultivation of primary cells leads to cellular aging (senescence), thereby severely limiting the proliferative capacity. Therefore, we investigated whether statins might be able to prevent senescence of EPCs. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased proliferation of EPCs as assessed by BrdU incorporation and colony-forming capacity. Whereas geranylgeranylpyrophosphate or farnesylpyrophosphate reduced the senescence inhibitory effect of atorvastatin, NO synthase inhibition, antioxidants, or Rho kinase inhibitors had no effect. To get further insights into the underlying downstream effects of statins, we measured telomerase activity and determined the expression of various cell cycle regulatory genes by using a microarray assay. Whereas telomerase activity did not change, atorvastatin modulated expression of cell cycle genes including upregulation of cyclins and downregulation of the cell cycle inhibitor p27Kip1. Taken together, statins inhibited senescence of EPCs independent of NO, reactive oxygen species, and Rho kinase, but dependent on geranylgeranylpyrophosphate. Atorvastatin-mediated prevention of EPC senescence appears to be mediated by the regulation of various cell cycle proteins. The inhibition of EPC senescence and induction of EPC proliferation by statins in vitro may importantly improve the functional activity of EPCs for potential cell therapy.
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PMID:HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. 1267 19

Neuropeptide Y (NPY)-expressing neurones in the arcuate nucleus densely innervate many hypothalamic nuclei. To determine the neurochemical phenotype of target neurones for NPY, we studied the immunohistochemical localization of the NPY Y1 receptor (Y1R) in discrete subpopulations of neurones in the rat hypothalamus. Among several tested populations, including hypocretin/orexin-, melanin-concentrating hormone (MCH)- and nitric oxide synthase (NOS)-positive neurones, only the latter were found to coexpress the Y1R. Numerous Y1R/NOS-positive neurones were found as a densely packaged group of cells located ventrolateral to the ventromedial nucleus, forming a band ascending towards the fornix. Lower numbers of Y1R/NOS-positive neurones were found in the perifornical area and in the peri- and paraventricular nuclei. Expression of the Y1R gene was found in the same locations in the mouse by colocalizing beta-galactosidase, a Y1R gene reporter, with NOS in a Y1R knockout mouse. To explore possible downstream targets of NO in the rat hypothalamus, the NO-regulated molecule cGMP was analysed immunohistochemically after incubation of brain slices with sodium nitroprusside, an NO donor. We observed several cGMP-positive cell bodies in the arcuate nucleus, cGMP-positive blood vessels and a cGMP-positive network of thin fibres, some of which colocalized with choline acetyltransferase.
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PMID:Neuropeptide y targets in the hypothalamus: nitric oxide synthesizing neurones express Y1 receptor. 1283 36

Biosynthesis of the tetrahydrobiopterin (BH(4)) cofactor, essential for catecholamines and serotonin production and nitric oxide synthase (NOS) activity, requires the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). Upon studying the distribution of GTPCH and PTPS with polyclonal immune sera in cross sections of rat brain, prominent nuclear staining in many neurons was observed besides strong staining in peri-ventricular structures. Furthermore, localization studies in transgenic mice expressing a Pts-LacZ gene fusion containing the N-terminal 35 amino acids of PTPS revealed beta-galactosidase in the nucleus of neurons. In contrast, PTPS-beta-galactosidase was exclusively cytoplasmic in the convoluted kidney tubules but nuclear in other parts of the nephron, indicating again that nuclear targeting may occur only in specific cell categories. Furthermore, the N terminus of PTPS acts as a domain able to target the PTPS-beta-galactosidase fusion protein to the nucleus. In transiently transfected COS-1 cells, which do not express GTPCH and PTPS endogenously, we found cytoplasmic and nuclear staining for GTPCH and PTPS. To further investigate nuclear localization of all three BH(4)-biosynthetic enzymes, we expressed Flag-fusion proteins in transiently transfected COS-1 cells and analyzed the distribution by immunolocalization and sub-cellular fractionation using anti-Flag antibodies and enzymatic assays. Whereas 5-10% of total GTPCH and PTPS and approximately 1% of total SR were present in the nucleus, only GTPCH was confirmed to be an active enzyme in nuclear fractions. The in vitro studies together with the tissue staining corroborate specific nuclear localization of BH(4)-biosynthetic proteins with yet unknown biological function.
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PMID:Nuclear localization of tetrahydrobiopterin biosynthetic enzymes. 1472 42

Neuropeptide Y (NPY) neurons abundantly innervate the hypothalamus, where NPY is involved in the regulation of a broad range of homeostatic functions. In the present work we studied NPY Y2 and Y5 receptor (R) gene expression in the mouse hypothalamus by using immunohistochemical detection of beta-galactosidase (beta-gal), a gene reporter molecule for Y2R and Y5R in Y2R-knockout (KO) and Y5R-KO mice, respectively. With this approach, cells normally expressing Y2R or Y5R are immunopositive for beta-gal. In the hypothalamus of the Y2R-KO mouse, beta-gal immunoreactivity (-ir) was found in numerous neurons of the medial preoptic nucleus as well as in the lateral anterior, periventricular, dorsomedial, tuberal, perifornical, and arcuate nuclei. Most of the dopaminergic neurons in the A13 dorsal hypothalamic group were beta-gal positive, whereas other hypothalamic dopaminergic neurons rarely displayed beta-gal-ir. In the arcuate nucleus, most of the beta-gal-positive neurons expressed NPY, but colocalizations with beta-endorphin were also found; in the tuberal and perifornical nuclei, many beta-gal-positive neurons contained nitric oxide synthase. beta-Gal-ir was also found in other forebrain regions of the Y2R-KO mouse, including the amygdala, thalamic nuclei, hippocampal CA3 area, and cortex. In the hypothalamus of the Y5R-KO mouse, beta-gal-positive neurons were found mainly in the arcuate nucleus and contained beta-endorphin. The present data show that Y2R and Y5R are expressed in distinct groups of hypothalamic neurons. High levels of Y2R expression in the preoptic nuclei suggest an involvement of Y2R in the regulation of reproductive behavior, whereas Y2R expression in the arcuate, dorsomedial, and perifornical nuclei may be relevant to feeding and body weight control. The finding that A13 dopaminergic neurons express Y2R suggests a new mechanism putatively involved in the central control of feeding, in which NPY can modulate dopamine secretion. The distribution of Y5R expression supports earlier evidence for involvement of this receptor in control of feeding and body weight via NPY's action on proopiomelanocortin-expressing neurons. J. Comp. Neurol. 470:256-265, 2004.
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PMID:Characterization of neuropeptide Y Y2 and Y5 receptor expression in the mouse hypothalamus. 1475 15

The nucleus tractus solitarius (NTS) of the brainstem is an important site for the regulation of sympathetic nerve activity. In the brain, nitric oxide (NO) has been shown to reduce blood pressure by inhibiting sympathetic nerve activity. However, most studies were performed in an acute state of anesthesia. Therefore, we developed a technique to increase the local production of NO in vivo by the transfer of endothelial NO synthase (eNOS) gene into the NTS. Adenovirus vectors encoding either the beta-galactosidase gene (Adbetagal) or the eNOS gene (AdeNOS) were infected into the NTS. In the Adbetagal-infected rats, the local expression of beta-galactosidase was confirmed by X-Gal staining, and beta-galactosidase activity was quantified using a colorimetric assay. In the AdeNOS-infected rats, the local expression of eNOS was confirmed by immunohistochemistry and Western blot analysis. Production of NO was measured by in vivo microdialysis. Blood pressure and heart rate were monitored by a radiotelemetry system in a conscious state. In the AdeNOS-infected rats, blood pressure and heart rate significantly decreased from d 5 to d 10, and then gradually recovered over time. These methods should be useful in examining the local effect on cardiovascular function of a particular substance produced by a specific gene in the brain.
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PMID:Adenovirus-mediated nitric oxide synthase gene transfer into the nucleus tractus solitarius in conscious rats. 1519 46


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