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)

Rhizoma polygoni cuspidate, used as a traditional Chinese herb, offered the therapeutic potential for cardiovascular diseases. Resveratrol, extracted from root of the rhizoma polygoni cuspidate has sparked increasing interest in therapeutic application. Resveratrol was shown to exert a variety of pharmacological effects including cardioprotective and cancer chemopreventive properties. However, its mechanisms of the action are not completely understood. The aim of this study was to investigate the molecular mechanism of resveratrol on preventing cardiac fibroblasts from proliferative and hypertrophic response induced by angiotensin II. Cell proliferation and cytotoxicity were detected by methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assay, respectively. Hypertrophic response of cardiac fibroblasts was measured by mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Resveratrol (25, 50, 75, and 100 microM) inhibited cardiac fibroblasts proliferation in a dose- and time-dependent manner compared with angiotensin II group (P<0.01), and the inhibitory effects were blocked by pretreatment with N(G)-nitro-l-arginine methyl ester (L-NAME) and 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ). Resveratrol increased nitric oxide (NO) and nitric oxide synthase (NOS) levels in culture medium, increased intracellular cyclic GMP (cGMP) level in cardiac fibroblasts, and decreased ANP and BNP levels in culture medium. The mRNA expression of ANP and BNP was suppressed by resveratrol. These results suggested that resveratrol inhibited cardiac fibroblasts proliferation induced by angiotensin II, and the inhibitory effect might be associated with the activation of NO-cGMP signaling pathway.
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PMID:Resveratrol inhibits proliferation of cultured rat cardiac fibroblasts: correlated with NO-cGMP signaling pathway. 1749 37

1. The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect against heart injury after ischaemia-reperfusion and to determine the possible mechanism involved. 2. Hearts isolated from male Sprague-Dawley rats were perfused on a Langendorff apparatus and subjected to 30 min global ischaemia, followed by 120 min reperfusion. Infarct size and the level of lactate dehydrogenase (LDH) in the coronary effluent were determined. In mitochondria from isolated perfused hearts, Ca(2+)-induced swelling was observed. In isolated ventricular myocytes, depolarization of the mitochondrial membrane was determined by tetramethyl-rhodamine ethyl ester (TMRE) fluorescence. Furthermore, levels of phosphorylated endothelial nitric oxide synthase (eNOS) protein were measured by western blot. 3. Pretreatment with HSYA for 5 min before ischaemia reduced infarct size and the release of LDH. Administration of 20 micromol/L atractyloside, an opener of the mitochondrial permeability transition pore, and 10 micromol/L N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, attenuated the protective effects of HSYA. In mitochondria isolated from hearts pretreated with 0.1 mmol/L HSYA for 5 min, a significant inhibition of Ca(2+)-induced swelling was observed and this inhibition was attenuated by l-NAME. In isolated ventricular myocytes, pretreatment with HSYA prevented ischaemia-induced cell death and depolarization of the mitochondrial membrane, whereas atractyloside or l-NAME attenuated the effects of HSYA. Levels of phosphorylated eNOS protein were significantly enhanced in the HSYA-treated group. 4. The findings of the present study indicate that HSYA protects the myocardium against ischaemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. The effect of HSYA on mitochondrial permeability transition pore opening may be mediated through enhanced nitric oxide production by eNOS activation.
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PMID:Evidence that hydroxysafflor yellow A protects the heart against ischaemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. 1794 91

The present study was conducted to examine the role of nitric oxide (NO), mitochondrial ATP-sensitive K(+) channels (mito K(+)(ATP) channels) and reactive oxygen species (ROS) and their interdependence in brief femoral artery ischaemia-induced myocardial preconditioning. To assess myocardial injury, myocardial infarction was induced by occlusion followed by reperfusion of the left anterior descending (LAD) coronary artery in anaesthetized rats and was assessed by triphenyl tetrazolium chloride (TTC) staining. Left ventricular function was assessed by left ventricular end-diastolic pressure (LVEDP) and the maximal rate of rise of left ventricular pressure [LV(dP/dt)(max)]. Serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were determined by colorimetric kits. Remote preconditioning (RPC) was induced by 15 min occlusion of femoral arteries followed by 10 min of reperfusion just before LAD coronary artery occlusion. Brief femoral artery ischaemia led to a 61% reduction in myocardial infarct size, 57% reduction in elevated serum LDH and 72% reduction in elevated CK-MB activities, and a significant improvement in LVEDP and LV(dP/dt)(max) compared with control animals. Pretreatment with 5-hydroxydecanoate (5-HD) or l-NAME or N-acetylcystein (NAC) blocked this protective effect of femoral artery ischaemia. Moreover, infusion of l-arginine or diazoxide before coronary artery occlusion markedly reduced the myocardial infarction and improved the left ventricular function. This effect of l-arginine was found to be abolished by the blockade of mito K(+)(ATP) channels with 5-HD and, similarly, the effect of diazoxide was blocked in the presence of a ROS scavenger, NAC. The results suggest that brief femoral artery ischaemia-induced RPC is mediated by a combination of increased NO synthesis, opening of mito K(+)(ATP) channels and increased ROS production. Moreover, it appears that NO is working upstream and acts via activation of mito K(+)(ATP) channels, which subsequently increases the production of ROS.
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PMID:Brief femoral artery ischaemia provides protection against myocardial ischaemia-reperfusion injury in rats: the possible mechanisms. 1835 57

The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-(3-NP) induced late preconditioning in rat heart. For this purpose 20-30 min before 3-NP (20 mg/kg, i.p.) injection, the rats were treated intraperitoneally with 5-hydroxydecanoate (40 mg/kg, 5-HD, mitochondrial K(ATP)-channel blocker), L-NAME (100 mg/kg, NOS inhibitor), N-2-mercaptopropionylglycine (100 mg/kg, MPG, free radical scavenger), or superoxide dismutase+catalase (10000+10000 IU/kg, SOD+CAT). Control rats received saline only without 3-NP pretreatment. After two days, hearts were isolated and perfused at a constant pressure in a Langendorff apparatus. 15-min global ischemia followed by 30-min reperfusion was applied to all hearts. Pretreatment of 3-NP significantly reduced infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) levels, and incidence of ventricular tachycardia (VT) compared with the control group receiving saline only. 5-HD, L-NAME, MPG, or SOD+CAT treatment statistically reversed 3-NP-induced reduction in infarct size. Although CK-MB, LDH levels, and incidence of VT were also reduced by L-NAME, MPG, or SOD+CAT treatment, only 5-HD significantly inhibited beneficial effects of 3-NP on all of the parameters above. These results showed that mito-K(ATP) channels play a pivotal role in late preconditioning effect of 3-NP in the isolated rat heart. However, other mediators such as reactive oxygen species and NO may be, at least in part, involved in mechanisms of this effect.
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PMID:The mechanism of the late preconditioning effect of 3-nitropropionic acid. 1895 15

There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD(+) synthesis at very low concentrations (<50 nM) in both neurons and astrocytes, but is cytotoxic at sub-physiological concentrations (>150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD(+) depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO(*))-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.
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PMID:Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. 1952 1

The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36)amide were blocked by exendin(9-39) yet preserved in Glp1r(-/-) cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36)amide vs. the GLP-1R agonist exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor.
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PMID:Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. 2017 66

Experimentally, oxygen glucose deprivation (OGD) has been widely used to mimic the environmental conditions present during cerebral ischemia-reperfusion (IR) injury. OGD is known to increase permeability across cultured cerebral endothelial cells, which models the effect of IR on permeability across the blood-brain barrier (BBB); however, studies have yet to be performed in a human model. The effect of neutrophils on the increase in BBB permeability associated with IR injury has yet to be modeled in vitro. To address these questions, the human brain endothelial cell line hCMEC/D3 was exposed to OGD with reoxygenation, and permeability was measured for a range of OGD exposure times (1-24h). One hour of exposure to OGD induced a reversible increase in permeability, unassociated with cytotoxicity (assessed from lactate dehydrogenase release). However, 12-24h OGD exposures induced sustained increases in permeability associated with cytotoxicity. The 1h permeability increase was inhibited with the nitric oxide synthase inhibitors l-NAME (10(-)(7)mol/l) and 1400W (10(-)(7)mol/l). Neutrophils (5x10(6)/ml) blocked the permeability increase associated with 1h OGD, whether applied during or after OGD exposure. Permeability remained low if neutrophils were activated with leukotriene (Lt)B(4) (10(-)(7)mol/l) or exposed to a transendothelial gradient of LtB(4), while neutrophil activation with phorbyl myristate acetate (4x10(-)(8)mol/l) induced a small increase. Neutrophils had no effect on the permeability increase induced by 12h OGD exposure. This study finds that OGD induces reversible increases in permeability linked to nitric oxide synthesis in a human culture model of the BBB and shows that neutrophils mitigate permeability increases in this context.
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PMID:Neutrophils block permeability increases induced by oxygen glucose deprivation in a culture model of the human blood-brain barrier. 2034 25

Although the cardioprotective role of carbon monoxide (CO) has been studied against myocardial ischemia-reperfusion (I/R) injury, the role of coronary endothelium and underlying mechanism in carbon monoxide-induced cardioprotection is not well understood in isolated heart. The present study was designed to determine the role of coronary endothelium in CORM-2-mediated cardioprotection during I/R injury in isolated rat heart. Preconditioning with 30microM/l and 50microM/l of CORM-2 for 10min markedly reduced lactate dehydrogenase (LDH) and creatinin kinase (CK) levels in coronary effluent after global ischemia. There was also a significant improvement in coronary flow rate, heart rate, cardiodynamic parameters and marked attenuation in infarct size. However, protective effect was abolished when hearts were pretreated with 100microM CORM-2. We observed that pretreatment with L-NAME (100microM/l), a nitric oxide synthase (NOS) inhibitor did not affect protection by CORM-2 (50microM/l). On the other hand pretreatment with Triton X-100 (0.05% for 20s) to denude endothelium before CORM-2 treatment followed by I/R injury showed similar cardioprotection. Moreover, pretreatment with K(ATP) channel inhibitor, glibenclamide almost completely reversed the cardioprotective effect of CORM-2 in endothelium-denuded hearts. These results indicate that cardioprotection by CORM-2 is highly concentration-dependent, independent of coronary endothelium and cardioprotective effect might be attributed to the activation of K(ATP) channel present on vascular smooth muscle cell (VSMC).
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PMID:Cardioprotective effect with carbon monoxide releasing molecule-2 (CORM-2) in isolated perfused rat heart: Role of coronary endothelium and underlying mechanism. 2039 2

In the present study, we investigated whether cellular damage, as demonstrated by lactate dehydrogenase (LDH) release in the human fallopian tube (FT) infected by Neisseria gonorrhoeae (Ngo), correlated with high levels of nitric oxide synthase (NOS) mRNA and enzyme activity. Infection with Ngo induced a significant increase (~35-fold) in mRNA transcripts of the inducible isoform of NOS. Paradoxically, a reduction in NOS enzyme activity was observed in infected cultures, suggesting that gonococcal infection possibly influences translation of iNOS mRNA to the enzyme. In addition, treatment with the NOS inhibitor TRIM did not prevent gonococcal-induced cellular damage. In contrast, the addition of the inhibitor L-NAME induced a 40% reduction in LDH release, which correlated with a ~50% reduction in gonococcal numbers. Moreover, treatment of normal FT explants with an exogenous NO donor, SNAP, did not induce significant cellular damage. Taken together, our data suggest that NO does not contribute to cellular damage during infection of the human FT with Neisseria gonorrhoeae.
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PMID:Nitric oxide is not involved in Neisseria gonorrhoeae-induced cellular damage of human Fallopian tubes in vitro. 2115 31

Cerebrovascular disease studies have shown similarity between humans and spontaneously hypertensive rats stroke-prone rats in the development of spontaneous stroke and transitory ischemic attacks (TIA). In addition, nitric oxide (NO) suppression by L-arginine methyl ester (L-NAME) can precipitate several vascular diseases including TIA and strokes. On the other hand, alpha-tocopherol (AT) has been associated with beneficial effects on vascular disorders. Four groups were tested to evaluate AT effects on NO inhibition: AT, control (C), AT + L-NAME, and L-NAME. During 4 weeks, all groups had their physiologic parameters evaluated and were submitted to neurological tests. After the sacrifice of the animals, total L-lactate dehydrogenase, fibrinogen levels, and platelet counts were measured. Our results demonstrated improvement in memory function and sensory-motor function of the rats treated with AT. The AT treatment also demonstrated a significant difference on the injury identifier, fibrinogen levels, and platelet count between the treated groups and the L-NAME group. In conclusion, AT reversed damaging L-NAME neurological effects and could be considered as a possible protective agent in neurological diseases.
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PMID:Alpha-tocopherol protects against memory impairment caused by L-NAME and modulates the injury marker and blood coagulant parameters. 2179 69


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