Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor kappa B (NFkappaB), commonly a proinflammatory transcription factor, is responsible for increasing transcription of the endothelial cell nitric oxide synthase (eNOS) in response to laminar shear stress. Nitric oxide (NO) production can be stimulated by shear, and NO is known to inhibit NFkappaB activation. We hypothesized that this inhibitory action of NO on NFkappaB activation serves as a negative feedback to inhibit NFkappaB activity and eNOS transcription. Exposure of bovine aortic endothelial cells to laminar shear stimulated steady state eNOS mRNA expression and eNOS promoter activity as measured using an eNOS promoter/CAT construct. These effects of shear were enhanced by the NOS inhibitor l-NAME and decreased by the NO-donor DPTA-NO by 30-50%. The NFkappaB inhibitor panepoxydone prevented the increase in eNOS mRNA caused by shear confirming a role of NFkappaB in this response. Shear stress stimulated a transient (30 min) nuclear translocation of the NFkappaB subunit p50. Treatment with l-NAME increased binding of the NFkappaB subunit p50 to consensus oligonucleotide-coated microtiter plates, while having only minimal effect on binding of p65, strongly suggesting that nitric oxide mainly inhibits p50 activation. Using the biotin switch method, we found that shear stress stimulates p50 nitrosylation and this was prevented by l-NAME. Moreover, transfection of endothelial cells with a vector encoding the C62S p50, a variant with a point mutation of the nitrosylation site C62, markedly increased nuclear translocation of p50 and doubled eNOS mRNA expression under shear stress compared to that observed in cells transfected with wild-type p50. We conclude that this interaction between shear, NFkappaB activation, NO production and NFkappaB inhibition represents a classical negative feedback loop, which prevents sustained activation of NFkappaB. In the absence of NO, shear stimulation of NFkappaB and eNOS transcription are enhanced. Our findings emphasize the critical role of NO in modulation of the endothelial cell inflammatory state. Several common diseases, including hypercholesteremia, hypertension and diabetes, are associated with eNOS dysfunction. Under these conditions, decreased NO availability may result in sustained activation of NFkappaB in response to shear and unrestrained endothelial inflammation.
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PMID:A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. 1609 68

Arginine, a semi-essential amino acid, plays a major nutritional and metabolic role. In particular, arginine is the precursor of nitric oxide which is involved in the endothelial function. Several factors, such as hypercholesterolemia, diabetes, ageing and hypertension are established risk factors for atherosclerosis, in particular by decreasing the availability of nitric oxide. Thus, endothelial nitric oxide synthase has a pivotal role against atherosclerosis. A suitable amount of cofactor and a sufficient intake of arginine have been shown to modulate nitric oxide-induced vasodilatation: despite the fact that the intracellular concentration of arginine is well above the Km of endothelial nitric oxide synthase, an arginine supplemented-diet is effective in increasing the production of nitric oxide. Several mechanisms have been proposed to explain this "arginine paradox": co-localization of the arginine transporter with endothelial nitric oxide synthase, intracellular arginine regeneration from citrulline, balance between endothelial arginase and nitric oxide synthase. Statins which are HMG-CoA reductase inhibitors inhibit the synthesis of mevalonate, and thus that of cholesterol. In addition, statins increase the stabilization of endothelial nitric oxide synthase mRNA. The co-operation between cholesterol synthesis and the upregulation of caveolin-1 on the one hand, and the activation of endothelial nitric oxide synthase on the other hand, is very tight. A depletion of cholesterol in the caveolae induces a decrease in caveolin-1 at the cell surface allowing NOS activation. Thus statins improve nitric oxide production and vasodilatation. In a recent work in the hypercholesterolemic Watanabe rabbit, we have demonstrated that the combination of arginine with a statin, namely atorvastatin, significantly hinders the spreading of atherosclerotic plaques as compared with monotherapies. Such association of a nutriment and a drug open a new area of therapeutic strategy.
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PMID:[Arginine and statins: relationship between the nitric oxide pathway and the atherosclerosis development]. 1623 Feb 78

A high dose of tumor necrosis factor (TNF)-alpha induces endothelial dysfunction and enhances apoptosis in vitro. The present study was conducted to examine whether incubating human umbilical vein endothelial cells (HUVECs) with serum from Type 2 diabetic patients complicated with retinopathy and/or microalbuminemia demonstrate endothelial dysfunction. Serum levels of TNF-alpha and vascular endothelial growth factor (VEGF) were elevated in diabetic patients. Plasma levels of TNF-alpha, two soluble TNF-alpha receptors (sTNFR), and VEGF were assessed in diabetic patients (CD, n=21) complicated with retinopathy and/or nephropathy, uncomplicated diabetic patients (UD, n=18), and in healthy normal participants (NS, n=16). In HUVECs incubated with patient's serum, endothelial constitutive nitric oxide synthase (eNOS) protein expressions were measured by Western blot analysis. Apoptosis in HUVECs was determined by optical microscopy, DNA fragmentation, and CPP32-like protease activity. Serum TNF-alpha, sTNFR-I, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, in CD were significantly higher than in UD or NS. While, serum sTNFR-I and VEGF levels were significantly increased in the both diabetic patients, compared with those of NS, no difference was observed in the serum TNF-alpha, sTNFR-II, and ADMA levels between UD and NS. eNOS down-regulation and apoptosis were seen in HUVECs incubated with serum from CD for 24 h, but those observations were completely counteracted in the incubation by the addition of the antihuman TNF-alpha antibody. These results imply that eNOS down-regulation in CD is associated with high serum TNF-alpha levels despite of high serum of VEGF levels. Therefore, endothelial dysfunction in diabetic patients complicated with microangiopathy may, in part, be attributed to high serum TNF-alpha levels.
J Diabetes Complications
PMID:High serum TNF-alpha level in Type 2 diabetic patients with microangiopathy is associated with eNOS down-regulation and apoptosis in endothelial cells. 1626 Mar 52

The relationship between diabetes mellitus Type 1 and nitric oxide (NO) synthesis was studied in multiple low-dose streptozotocin (STZ)-treated rats and diabetic children. The aim of our experimental work was to test the effect of hyperglycemic state on the level of urinary stable NO end products and on the expression of inducible nitric oxide synthase (NOS II) in white blood cells (WBC). It was also studied whether the measurements of these parameters were suitable to predict the presence of early diabetes before its onset. The occurrence of insulitis in streptozotocin-treated rats could not be clearly demonstrated. Urinary nitrite plus nitrate level significantly increased both in diabetic rats and in children compared to controls. However, the increase of the activity and the expression of inducible NOS II were only observed in rat white blood cells and this effect was prevented by insulin treatment. In human samples, less than 25% of children showed elevated NOS II expression in white blood cells without any correlation to the level of urinary NO end products and glycated hemoglobin in blood. Correlation was found only between the activity and expression of NOS II in white blood cells of patients whose white blood cells were positive for the presence of NOS II. Measurement of urinary nitrite plus nitrate content as well as the determination of NOS II expression of white blood cells in an early phase of diabetes are not suitable predictors in humans probably due to the basic differences in the mechanism of streptozotocin-induced rat and spontaneous human Type 1 diabetes.
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PMID:Differences in the nitric oxide metabolism in streptozotocin-treated rats and children suffering from Type 1 diabetes. 1628 28

The study has been designed to investigate the effect of Bis-(maltolato) oxovanadium (BMOV), an inhibitor of protein tyrosin phosphatase (PTPase), in diabetes mellitus and hyperhomocysteinemia induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >140 mg dl(-1)) and hyperhomocysteinemia (serum homocysteine>10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard drug to improve vascular endothelial dysfunction. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. BMOV or atorvastatin markedly improved acetylcholine induced endothelium dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of BMOV has been prevented by l-NAME (25 mg kg(-1), i.p.), an inhibitor of NOS or by glibenclamide (5 mg kg(-1), i.p.), a blocker of ATP sensitive K(+) channels. Therefore, it may be concluded that BMOV induced inhibition of PTPase may activate eNOS due to opening of ATP sensitive K(+) channels and consequently reduce oxidative stress to improve vascular endothelial dysfunction.
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PMID:Inhibition of protein tyrosin phosphatase improves vascular endothelial dysfunction. 1644 49

On the rat portal vein isolated strips the essential reduction of contractive response, increase of stiffness of vascular smooth muscles at their stretching and increase of oxygen value of smooth muscles' work are revealed in conditions of experimental diabetes mellitus. The possible mechanism of such infringements is chronic hyperglycemia, which results in development of oxidative stress and reduction of NO synthesis by constitutive NOS. Indeed, the significant decrease of activity of constitutive NO-synthase and increase of the oxidative stress markers contents are shown at experimental diabetes mellitus. The similar infringements are marked at in vitro model of hyperglycemia, blockade of NO-synthase and in conditions of oxidative stress. Additional confirmation of a role of NO synthesis blockade and oxidative stress in development of such infringements at diabetes is fact that application of antioxidant melatonin and L-arginine, a precursor of NO to diabetic animals results in partial restoration of contractive reactions, reduction of stiffness and oxygen value of smooth muscles' work.
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PMID:[Mechanisms of contractile reaction changes and efficiency of oxygen utilization by portal vein smooth muscles in experimental diabetes mellitus]. 1655 93

Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH(i)) associated with elevated NADPH+H(+) (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6-129S4-Nos1(tm1Plh)/J. To explore how nNOS inhibits TDP, we compared pH(i) and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wild-type mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pH(i) than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.
Diabetes 2006 Apr
PMID:Mechanisms of time-dependent potentiation of insulin release: involvement of nitric oxide synthase. 1656 25

Diabetes mellitus compromises nitric oxide (NO)-mediated endothelium-dependent relaxation of blood vessels, which has been linked to the excessive generation of reactive oxygen species. There are also deleterious effect on nitrergic innervation, contributing to autonomic neuropathy symptoms such as impotence and gastroporesis. Poly(ADP-ribose) polymerase (PARP) is a nuclear protein stimulated by DNA damage, caused, for example, by oxidative stress. Activation has been linked to impaired endothelial nitric oxide synthase (eNOS)-mediated vasodilation in experimental diabetes. There is no information on the potential role of PARP in nitrergic nerve dysfunction, therefore, the aim was to examine the effects of PARP inhibition, using 3-aminobenzamide (3-AB) on neurally mediated gastric fundus relaxation in streptozotocin-induced diabetic rats. Eight weeks of diabetes caused a 42.5% deficit in maximum relaxation of in vitro gastric fundus strips to electrical stimulation of the non-adrenergic non-cholinergic innervation. This was largely prevented or corrected (4 weeks of treatment following 4 weeks of untreated diabetes) by 3-AB. Diabetes also markedly attenuated the maintenance of relaxation responses to prolonged stimulation, and this was partially corrected by 3-AB treatment. Experiments in the presence of the NOS inhibitor, N(G)-nitro-L-arginine, and/or blockade of the co-transmitter, vasoactive intestinal polypeptide, by alpha-chymotrypsin, showed that the beneficial effects of 3-AB were primarily due to improved nitrergic neurotransmission. Thus, PARP plays an important role in defective nitrergic neurotransmission in experimental diabetes, which may have therapeutic implications for treatment of aspects of diabetic autonomic neuropathy.
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PMID:Effects of poly(ADP-ribose) polymerase inhibition on dysfunction of non-adrenergic non-cholinergic neurotransmission in gastric fundus in diabetic rats. 1664 48

Vascular tone is regulated through the actions of locally produced agents. Among the vasoconstrictors, the most potent agent is endothelin (ET), which exerts its vasoconstrictor actions principally through ET type A (ET(A)) receptors. Of the vasodilators, nitric oxide (NO) seems to be the most important contributor to the acute regulation of vascular tone. Vasculopathy is an important feature of diabetes mellitus (DM). Endogenous ET-mediated vasoconstrictor tone is augmented in diabetic states, and conflicting results persist concerning the NO system in diabetes. The present study investigated the expressions of inducible NO synthases (iNOS) and endothelial NOS (eNOS) in the heart of diabetic animals and the effects of a selective ET(A) receptor antagonist on these alterations. Type I diabetes was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control (Con) rats received only citrate buffer. After 1 week, the streptozotocin-administered rats were randomly divided into two groups: the selective ET(A) receptor antagonist-administered group (DM+TA-0201, 1 mg/kg/day, by osmotic minipump for 2 weeks) and the DM+vehicle group (comprising the diabetic rats that received saline). The random blood glucose level was 405 +/- 103 mg/dl in DM animals, and this level was unchanged by ET antagonism. Body weight was more greatly decreased in DM rats than in Con rats, but the left ventricle to body weight ratio was increased in the DM group and was unaffected by ET antagonism. Protein expressions of eNOS and iNOS were assessed in the left ventricular tissues. eNOS expression was significantly increased in DM heart and was greatly inhibited by the treatment with ET antagonist. The expression of iNOS was also increased in early DM heart but was reversed by the ET antagonist. Thus, endothelin antagonism might be beneficial for DM heart by reversing the upregulated eNOS and iNOS expressions.
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PMID:Effects of a selective endothelin a receptor antagonist on the expressions of iNOS and eNOS in the heart of early streptozotocin-induced diabetic rats. 1674 Oct 25

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.
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PMID:Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. 1684 11


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