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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucokinase (GK), expressed in hepatocyte and pancreatic beta cells, has a central regulatory role in glucose metabolism. Efficient GK activity is required for normal glucose-stimulated insulin secretion, postprandial hepatic glucose uptake, and the appropriate suppression of hepatic glucose output and gluconeogenesis by elevated plasma glucose. Hepatic GK activity is subnormal in diabetes, and GK may also be decreased in the beta cells of type II diabetics. In supraphysiological concentrations, biotin promotes the transcription and translation of the GK gene in hepatocytes; this effect appears to be mediated by activation of soluble guanylate cyclase. More recent evidence indicates that biotin likewise increases GK activity in islet cells. On the other hand, high-dose biotin suppresses hepatocyte transcription of phosphoenolpyruvate carboxykinase, the rate-limiting enzyme for gluconeogenesis. Administration of high-dose biotin has improved glycemic control in several diabetic animals models, and a recent Japanese clinical study concludes that biotin (3 mg t.i.d. orally) can substantially lower fasting glucose in type II diabetics, without side-effects. The recently demonstrated utility of chromium picolinate in type II diabetes appears to reflect improved peripheral insulin sensitivity--a parameter which is unlikely to be directly influenced by biotin. Thus, the joint administration of supranutritional doses of biotin and chromium picolinate is likely to combat insulin resistance, improve beta-cell function, enhance postprandial glucose uptake by both liver and skeletal muscle, and inhibit excessive hepatic glucose production. Conceivably, this safe, convenient, nutritional regimen will constitute a definitive therapy for many type II diabetics, and may likewise be useful in the prevention and management of gestational diabetes. Biotin should also aid glycemic control in type I patients.
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PMID:High-dose biotin, an inducer of glucokinase expression, may synergize with chromium picolinate to enable a definitive nutritional therapy for type II diabetes. 1041 47

Neurohypophyseal secretion of arginine vasopressin is stimulated by decreased systemic glucose availability. Nitric oxide is produced by paraventricular and supraoptic magnocellular neurons, and is implicated in central mechanisms controlling plasma sasopressin and glucose levels. The current studies investigated the role of this neurotransmitter in glucoprivic induction of AP-1 transcriptional activity in hypothalamic vasopressinergic neurons by examining whether pharmacological manipulation of central nitric oxide/guanylate cyclase/cGMP signaling alters nuclear accumulation of Fos immunoreactivity in these cells. Adult male rats pretreated by intraventricular administration of saline exhibited extensive colabeling of vasopressinergic neurons in both brain sites for Fos following systemic injection of the glucose antimetabolite, 2-deoxy-D-glucose. Pretreatment with the nitric oxide donor. SIN1, resulted in decreased numbers of paraventricular and supraoptic Fos-positive vasopressinergic neurons during glucoprivation. In other animals. coadministration of SIN1 and the nitric-oxide sensitive guanylate cyclase inhibitor, ODQ, prior to the antimetabolite reversed these inhibitory effects of SIN1 on Fos expression by these cells. Intracerebral administration of ODQ alone did not significantly enhance expression of Fos by vasopressinergic neurons in either site. The present studies demonstrate that exogenous activation of the nitric oxide/guanylate cyclase/cGMP pathway in the brain inhibits nuclear accumulation of the AP-1 transcription factor, Fos, in vasopressinergic neurons during cellular glucopenia, and suggest that this neurotransmitter is critical for transactivational effects of glucoprivation on these neuropeptidergic neurons.
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PMID:Pharmacological manipulation of central nitric oxide/guanylate cyclase activity alters Fos expression by rat hypothalamic vasopressinergic neurons during acute glucose deprivation. 1056 36

1. Intracellular calcium concentration ([Ca2+]i) was measured in mouse whole islets of Langerhans using the calcium-sensitive fluorescent dye Indo-1. 2. Application of physiological concentrations of 17beta-oestradiol in the presence of a stimulatory glucose concentration (8 mM) potentiated the [Ca2+]i signal in 83 % of islets tested. Potentiation was manifested as either an increase in the frequency or duration of [Ca2+]i oscillations. 3. The effects caused by 17beta-oestradiol were mimicked by the cyclic nucleotide analogues 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP). 4. Direct measurements of both cyclic nucleotides demonstrated that nanomolar concentrations of 17beta-oestradiol in the presence of 8 mM glucose increased cGMP levels, yet cAMP levels were unchanged. The increment in cGMP was similar to that induced by 11 mM glucose. 5. Patch-clamp recording in intact cells showed that 8-Br-cGMP reproduced the inhibitory action of 17beta-oestradiol on ATP-sensitive K+ (KATP) channel activity. This was not a membrane-bound effect since it could not be observed in excised patches. 6. The action of 17beta-oestradiol on KATP channel activity was not modified by the specific inhibitor of soluble guanylate cyclase (sGC) LY 83583. This result indicates a likely involvement of a membrane guanylate cyclase (mGC). 7. The rapid decrease in KATP channel activity elicited by 17beta-oestradiol was greatly reduced using Rp-8-pCPT-cGMPS, a specific blocker of cGMP-dependent protein kinase (PKG). Conversely, Rp-cAMPS, which inhibits cAMP-dependent protein kinase (PKA), had little effect. 8. The results presented here indicate that rapid, non-genomic effects of 17beta-oestradiol after interaction with its binding site at the plasma membrane of pancreatic beta-cells is a cGMP-dependent phosphorylation process.
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PMID:Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are mediated by a cGMP-dependent protein kinase. 1058 11

A major transduction pathway for nitric oxide (NO) is stimulation of soluble guanylyl cyclase and the generation of cyclic GMP (cGMP). In the central nervous system, the NO-cGMP pathway has previously been associated primarily with synapses, particularly glutamatergic synapses. We report here that NO caused a large increase in the levels of cGMP in a central white matter tract devoid of synapses, namely in the rat isolated optic nerve. Cyclic GMP immunohistochemistry indicated that this response was confined to the axons. Accordingly, nerves previously subjected to 1 h of oxygen/glucose deprivation, which leads to irreversible axonal damage, displayed an 80% reduction in their subsequent capacity to generate cGMP in response to NO and a corresponding reduction in the numbers of cGMP-immunostained axons. Protection of the axon cGMP response against this insult was achieved by omission of Ca2 + or Na + from the incubation medium, and by the pharmacological agents tetrodotoxin, lamotrigine, BW619C89 and BW1003C87, all of which protect axonal structure from oxygen/glucose deprivation-induced damage. The results suggest that the NO-cGMP pathway has a hitherto unsuspected function in the optic nerve. Additionally, the expression of NO-stimulated guanylyl cyclase in optic nerve axons provides a simple, sensitive and specific marker of their functional integrity that is likely to be valuable in investigating the mechanisms responsible for axon degeneration in ischaemia and other conditions.
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PMID:Nitric oxide stimulates cGMP formation in rat optic nerve axons, providing a specific marker of axon viability. 1059 63

Acceleration of the polyol pathway under hyperglycemia is among the mechanisms implicated in the pathogenesis of diabetic complications. Although aldose reductase (AR), the rate-limiting enzyme in this pathway, is a target for pharmacological intervention of diabetic complications, the clinical efficacy of AR inhibitors has not been consistently proved. Because nitric oxide (NO) plays important roles in vascular hemodynamics and inflammatory responses that are affected under diabetic conditions, the interaction of NO with AR was investigated with rat aortic smooth muscle cells. Spontaneous NO donors, S-nitroso-N-acetylpenicillamine (SNAP) and 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamin e, elicited a dose-dependent increase in AR mRNA to a maximum of 7-fold in 12 h. The activity of AR was elevated after 10 h of SNAP treatment. These effects of NO donors were suppressed by the addition of 2-(trimethylammoniophenyl)-4,4,5, 5-tetramethylimidazoline-1-oxy 3-oxide, a scavenger of NO. Induction of AR mRNA by SNAP was completely abolished by actinomycin D or cycloheximide, but unaffected by guanylate cyclase inhibitors or genistein, a tyrosine kinase inhibitor. Pretreatment of the cells with N-acetyl-L-cysteine significantly suppressed the SNAP-induced up-regulation of AR mRNA. Under normal glucose conditions, inclusion of the AR inhibitor ponalrestat augmented the cytotoxic effect of SNAP on the cells. The level of AR mRNA also was elevated in a murine macrophage cell line RAW 264.7 stimulated with lipopolysaccharide and interferon-gamma. Inhibition of NO synthesis completely abolished the increase in AR mRNA in the stimulated cells. The up-regulation of AR by NO in the vascular lesions may modulate NO-induced cell death and the ensuing vascular remodeling during inflammatory responses.
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PMID:Nitric oxide up-regulates aldose reductase expression in rat vascular smooth muscle cells: a potential role for aldose reductase in vascular remodeling. 1072 16

We previously reported that sympathetic nerve-induced vasoconstriction in the intestine resulted in shear stress induced release of nitric oxide (NO) that led to presynaptic inhibition of transmitter release. In contrast, studies in the liver suggested a postsynaptic inhibition of vascular responses, thus leading to the hypothesis tested here that maintained catecholamine release in the liver would result in maintained metabolic catecholamine action in the face of inhibition of vascular responses. In rats, norepinephrine (NE) induced elevations in arterial glucose content were inhibited by NO synthase antagonism (N(omega)-nitro-L-arginine methyl ester (L-NAME), 10 mg/kg, intraportal) but potentiated by NO donor administration (3-morpholinosydnonimine (SIN-1), 0.2 mg/kg, intraportal). The potentiated effect of SIN-1 was abolished by indomethacin (7.5 mg/kg, intraportal). To confirm the hepatic site of metabolic effect, cats were used so that blood flow and hepatic glucose balance could be determined. SIN-1 potentiated NE-induced glucose output from the liver from 5.0 +/- 0.4 to 7.2 +/- 0.6 mg x min(-1) x kg(-1). The potentiation was blocked by methylene blue, a guanylate cyclase inhibitor. Contrary to the glucose response, L-NAME potentiated but SIN-1 attenuated NE-induced portal vasoconstriction. Thus NO is shown to produce differential modulation of vascular and metabolic effects of NE. Vasoconstriction of the hepatic vasculature is inhibited by NO, whereas the glycogenolytic response to NE is potentiated, responses that are probably mediated by prostaglandin.
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PMID:Nitric oxide inhibits norepinephrine-induced hepatic vascular responses but potentiates hepatic glucose output. 1074 58

Nitric oxide is an important bioactive signaling molecule that mediates a variety of normal physiological functions which, if altered, could contribute to the genesis of many pathological conditions, including diabetes. In the present study we have shown the involvement of NO in nickel-induced hyperglycemia in male albino rats. Administration of nickel chloride (25 to 100 micromol/kg; ip) to overnight-fasted rats resulted in significant dose and time-dependent increase in plasma glucose, attaining maximum level at 1 h posttreatment and thereafter decreasing to normal levels by 4 h. The involvement of NO in nickel-induced hyperglycemia was evident by the observation that pretreatment of rats with NG-monomethyl-l-arginine (10 to 50 micromol/kg; ip), an inhibitor of nitric oxide synthase (NOS), significantly attenuated the nickel-mediated increase in the plasma glucose levels in a dose-dependent fashion. The activity of Ca(2+)-dependent NOS (constitutive form, c-NOS) was found to be significantly elevated in adrenals (5.5-fold) and brain (1.4-fold) at 1 and 2 h posttreatment, attaining normal levels by 4 h. In contrast, the activity of c-NOS in pancreas was significantly decreased (2.8-fold) with a concomitant increase (11.6-fold) in inducible NOS (i-NOS) at the same time interval. As observed by immunoblot analysis, a significant increase in i-NOS protein expression in the pancreas was observed at 1 and 2 h posttreatment. This was associated with a significant elevation in cGMP levels in adrenals, brain, and pancreas, possibly via the stimulation of cytosolic guanylate cyclase. This elevation in cGMP was abolished by low concentration of hemoglobin. These effects were associated with the accumulation of nickel in the target tissues. Taken together, our data suggest that nickel causes a significant increase in the levels of (i) cGMP and c-NOS in adrenals and brain and (ii) i-NOS in pancreas. These events may be responsible for modulating the release of insulin from pancreas finally leading to hyperglycemic condition in rats.
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PMID:Involvement of nitric oxide in nickel-induced hyperglycemia in rats. 1083 93

Glucose transport in skeletal muscle is stimulated by two distinct stimuli, insulin and exercise. The mechanism by which exercise stimulates glucose transport is not known, although it is distinct from the insulin-mediated pathway. Recently, it has been shown that AMP-activated protein kinase (AMPK) is activated by exercise in skeletal muscle, whereas pharmacological activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) leads to increased glucose transport. It has been postulated, therefore, that AMPK may be the link between exercise and glucose transport. To address this, we have examined the signaling pathway involved in the stimulation of glucose uptake after activation of AMPK. Here we show that activation of AMPK by AICAR in rat muscle and mouse H-2Kb muscle cells activates glucose transport approximately twofold. AMPK in H-2Kb cells is also activated by hyperosmotic stress and the mitochondrial uncoupling agent, dinitrophenol, both of which lead to increased glucose transport. In contrast, insulin, which activates glucose transport two- to-threefold in both rat muscle and H-2Kb cells, has no effect on AMPK activity. A previous study has shown that AMPK phosphorylates and activates endothelial nitric oxide synthase (NOS). We show here that NOS activity in H-2Kb cells is activated after stimulation of AMPK by AICAR. Treatment of H-2Kb cells or rat muscle with NOS inhibitors completely blocks the increase in glucose transport after activation of AMPK. In addition, an inhibitor of guanylate cyclase also blocks activation of glucose transport by AICAR in H-2Kb cells. These results indicate that activation of AMPK in muscle cells stimulates glucose transport by activation of NOS coupled to downstream signaling components, including cyclic GMP.
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PMID:Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. 1111 97

We investigated, by a combined in vivo and in vitro approach, the temporal changes of islet nitric oxide synthase (NOS)-derived nitric oxide (NO) and heme oxygenase (HO)-derived carbon monoxide (CO) production in relation to insulin and glucagon secretion during acute endotoxemia induced by lipopolysaccharide (LPS) in mice. Basal plasma glucagon, islet cAMP and cGMP content after in vitro incubation, the insulin response to glucose in vivo and in vitro, and the insulin and glucagon responses to the adenylate cyclase activator forskolin were greatly increased after LPS. Immunoblots demonstrated expression of inducible NOS (iNOS), inducible HO (HO-1), and an increased expression of constitutive HO (HO-2) in islet tissue. Immunocytochemistry revealed a marked expression of iNOS in many beta-cells, but only in single alpha-cells after LPS. Moreover, biochemical analysis showed a time dependent and markedly increased production of NO and CO in these islets. Addition of a NOS inhibitor to such islets evoked a marked potentiation of glucose-stimulated insulin release. Finally, after incubation in vitro, a marked suppression of NO production by both exogenous CO and glucagon was observed in control islets. This effect occurred independently of a concomitant inhibition of guanylyl cyclase. We suggest that the impairing effect of increased production of islet NO on insulin secretion during acute endotoxemia is antagonized by increased activities of the islet cAMP and HO-CO systems, constituting important compensatory mechanisms against the noxious and diabetogenic actions of NO in endocrine pancreas.
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PMID:Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia. 1128 38

The myxomycete Physarum polycephalum expresses a calcium-independent nitric oxide (NO) synthase (NOS) resembling the inducible NOS isoenzyme in mammals. We have now cloned and sequenced this, the first nonanimal NOS to be identified, showing that it shares < 39% amino acid identity with known NOSs but contains conserved binding motifs for all NOS cofactors. It lacks the sequence insert responsible for calcium dependence in the calcium-dependent NOS isoenzymes. NOS expression was strongly up-regulated in Physarum macroplasmodia during the 5-day starvation period needed to induce sporulation competence. Induction of both NOS and sporulation competence were inhibited by glucose, a growth signal and known repressor of sporulation, and by L-N6-(1-iminoethyl)-lysine (NIL), an inhibitor of inducible NOS. Sporulation, which is triggered after the starvation period by light exposure, was also prevented by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of NO-sensitive guanylate cyclase. In addition, also expression of lig1, a sporulation-specific gene, was strongly attenuated by NIL or ODQ. 8-Bromo-cGMP, added 2 h before the light exposure, restored the capacity of NIL-treated macroplasmodia to express lig1 and to sporulate. This indicates that the second messenger used for NO signaling in sporulation of Physarum is cGMP and links this signaling pathway to expression of lig1.
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PMID:Nitric oxide synthase is induced in sporulation of Physarum polycephalum. 1135 72


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