Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined if myocardial depression at the acute phase of diabetes (3 weeks after injection of streptozotocin, 60 mg/kg i.v.) is due to activation of inducible nitric oxide synthase and production of peroxynitrite, and if treatment with N-acetylcysteine (1.2 g/day/kg for 3 weeks, antioxidant) improves cardiac function. Four groups of rats were used: control, N-acetylcysteine-treated control, diabetic and N-acetylcysteine-treated diabetic. Pentobarbital-anaesthetized diabetic rats, relative to the controls, had reduced left ventricular contractility to dobutamine (1-57 microg/min/kg). The diabetic rats also had increased myocardial levels of thiobarbituric acid reactive substances, immunostaining of inducible nitric oxide synthase and nitrotyrosine, and similar baseline 15-F2t-isoprostane. N-acetylcysteine did not affect responses in the control rats; but increased cardiac contractility to dobutamine, reduced myocardial immunostaining of inducible nitric oxide synthase and nitrotyrosine and level of 15-F2t-isoprostane, and increased cardiac contractility to dobutamine in the diabetic rats. Antioxidant supplementation in diabetes reduces oxidative stress and improves cardiac function.
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PMID:The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes. 1611 76

Recently we reported that Toll-like receptor 4 (TLR4)-positive immune cells of unknown identity were responsible for the LPS-induced depression of cardiac myocyte shortening. The aim of this study is to identify the TLR4-positive cell type that is responsible for the LPS-induced cardiac dysfunction. Neither neutrophil depletion alone nor mast cell deficiency had any impact on the impairment of myocyte shortening during LPS treatment. In contrast, LPS-treated, macrophage-deficient mice demonstrated a partial reduction in shortening compared with saline-treated, macrophage-deficient mice. Because the removal of macrophages could only partially restore myocyte shortening, we also investigated the effects of removing both neutrophils and macrophages on myocyte shortening. Interestingly, endotoxemic, neutrophil-depleted, and macrophage-deficient mice had completely restored myocyte shortening. Because both macrophages and neutrophils can produce nitric oxide (NO) and TNF-alpha, we examined LPS-treated inducible NO synthase knockout (iNOSKO) mice and TNF receptor (TNFR)-deficient mice. Eliminating both TNFR1 and TNFR2 was required to restore myocyte shortening during LPS treatment, whereas iNOS deficiency had no effect. These data suggest that macrophages and to a lesser degree neutrophils cause cardiac impairment, presumably via TNF-alpha.
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PMID:Cellular and molecular mechanisms underlying LPS-associated myocyte impairment. 1617 57

Burkholderia pseudomallei, the causative agent of melioidosis, is a facultative intracellular gram-negative bacterium that is able to survive and multiply in macrophages. Previously, we reported that B. pseudomallei was able to escape macrophage killing by interfering with the expression of inducible nitric oxide synthase (iNOS). In the present study, we extended this finding and demonstrated that B. pseudomallei was able to activate the expression of suppressor of cytokine signaling 3 (SOCS3) and cytokine-inducible Src homology 2-containing protein (CIS) but not SOCS1 in a mouse macrophage cell line (RAW 264.7). The expression of SOCS3 and CIS in B. pseudomallei-infected macrophages directly correlated with a decreased gamma interferon (IFN-gamma) signaling response, as indicated by a reduction in Y701-STAT-1 phosphorylation (pY701-STAT-1). Moreover, a reduction in the expression of IFN-gamma-induced proteins, such as interferon regulatory factor 1 (IRF-1), was observed in B. pseudomallei-infected macrophages that were treated with IFN-gamma. Since pY701-STAT-1 and IRF-1 are essential transcription factors for regulating iNOS expression, the failure to activate these factors could also result in depression of iNOS expression and a loss of macrophage killing capacity. Taken together, the data indicate that the activation of SOCS3 and CIS expression in B. pseudomallei-infected macrophages interfered with IFN-gamma signaling, thus allowing the bacteria to escape killing by these phagocytic cells.
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PMID:Burkholderia pseudomallei-induced expression of suppressor of cytokine signaling 3 and cytokine-inducible src homology 2-containing protein in mouse macrophages: a possible mechanism for suppression of the response to gamma interferon stimulation. 1623 31

Nitric oxide (NO) and prostaglandins (PG) play important roles in delayed mechanisms of brain injury. While NO disrupts oxidative metabolism, prostaglandins are responsible for free radical attack in reperfusion interval. Relatively little is known about neuroprotection exerted at this level in perinatal models. The aim of this study was to investigate the effect of indomethacin and aminoguanidine on endogenous inducible nitric oxide synthase (iNOS) biosynthesis and neuroprotection in the newborn rats with hypoxic ischemic cerebral injury.Seven-day old rat pups with model of hypoxic-ischemic cerebral injury were randomly divided into four study groups. Group C (n=18; served as a control) pups were given physiologic saline (SF). Group I (n=18) pups were treated with indomethacin at a dose of 0,2 mg/kg per 12 h. Group A (n=20) pups were treated with aminoguanidine at a dose of 300 mg/kg per 8 h. Administration of drugs and SF were begun half an hour after hypoxic-ischemic insult in these groups. Group I+A (n=18) pups were treated with indomethacin at a single dose of 0.2 mg/kg 1 h before hypoxia-ischemia followed by aminoguanidine as in group A. Drugs and SF were administered for three consecutive days. On the tenth day, rat pups were decapitated and coronal sections at the level of dorsal hippocampal region of brains were evaluated. In the histopathologic examination; the mean infarcted area in group I+A was significantly lower than the control group (P<0.05). Although there was no statistically significant difference between treatment groups in terms of iNOS expression, the risk of iNOS expression was 7 times less for group I (CI: 1.6-30.8, P=0.01), 19.8 times less for group A (CI: 3.8-104, P=0.001) and 12.3 times less for group I+A (CI: 2.5-59, P=0.002) compared to group C. In conclusion, only indomethacin administration before hypoxic ischemia and followed by aminoguanidine was more effective to reduce infarct area, but we did not find any difference between treatment groups and control group for iNOS expression. So we suggest that this neuroprotection may not be related to depression of iNOS expression.
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PMID:Neuroprotective effects of indomethacin and aminoguanidine in the newborn rats with hypoxic-ischemic cerebral injury. 1625 41

The S100B is a Ca2+ binding proteins of EF-hand type and is produced primarily by astrocytes in the central nervous system. This protein has been implicated in the Ca2+-dependent regulation of a variety of intracellular functions such as protein phosphorylation, enzyme activities, cell proliferation and differentiation, dynamics of cytoskeleton constituents, structural organization of membranes, intracellular Ca2+ homeostasis, inflammation, and protection from oxidative cell damage. Recent studies suggest that released S100B exerts paracrine and autocrine effects on neurons and glia. On the other hand, elevations of S100B levels in blood or cerebrospinal fluid have been observed in patients with Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, depression, cerebral stroke and traumatic brain injury, and the levels have reached micromol/L-order at focal regions. It has been documented that the excessive S100B promotes the expression of inducible nitric oxide synthase or pro-inflammatory cytokines and exhibits detrimental effects on neurons. On studies using some animal models of the cerebral stroke or Alzheimer's disease, it is suggested that the excessive S100B produced by activated astrocytes precedes neurodegenerations. Authors discussed the relationship between neurological disorders and the S100B.
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PMID:[S100B: astrocyte specific protein]. 1663 91

Previous studies have indicated that cardiovascular abnormalities such as depressed blood pressure and heart rate occur in streptozotocin (STZ) diabetic rats. Chronic diabetes, which is associated with increased expression of inducible nitric oxide synthase (iNOS) and oxidative stress, may produce peroxynitrite/nitrotyrosine and cause nitrosative stress. We hypothesized that nitrosative stress causes cardiovascular depression in STZ diabetic rats and therefore can be corrected by reducing its formation. Control and STZ diabetic rats were treated orally for 9 weeks with N-acetylcysteine (NAC), an antioxidant and inhibitor of iNOS. At termination, the mean arterial blood pressure (MABP) and heart rate (HR) were measured in conscious rats. Nitrotyrosine and endothelial nitric oxide synthase (eNOS) and iNOS expression were assessed in the heart and mesenteric arteries by immunohistochemistry and Western blot experiments. Untreated diabetic rats showed depressed MABP and HR that was prevented by treatment with NAC. In untreated diabetic rats, levels of 15-F(2t)-isoprostane, an indicator of lipid peroxidation increased, whereas plasma nitric oxide and antioxidant concentrations decreased. Furthermore, decreased eNOS and increased iNOS expression were associated with elevated nitrosative stress in blood vessel and heart tissue of untreated diabetic rats. N-acetylcysteine treatment of diabetic rats not only restored the antioxidant capacity but also reduced the expression of iNOS and nitrotyrosine and normalized the expression of eNOS to that of control rats in heart and superior mesenteric arteries. The results suggest that nitrosative stress depress MABP and HR following diabetes. Further studies are required to elucidate the mechanisms involved in nitrosative stress mediated depression of blood pressure and heart rate.
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PMID:N-acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats. 1668 64

Nitric oxide has both an inhibitory and excitatory role in the regulation of pre-ganglionic sympathetic neurons, involving the iNOS and nNOS systems respectively. The aim of the present study was to examine cardiovascular autonomic activity in iNOS knockout mice using spectral analysis of heart rate variability (HRV), and to determine the role of iNOS in altered HRV in endotoxaemia. Electrocardiograms were recorded in anaesthetised mice, and the R-R intervals digitized for spectral analysis of HRV and cardiac rhythm regularity using sample entropy analysis. The basal heart rate was higher in iNOS knockout mice compared with controls (465+/-8 vs 415+/-13 beat/min P<0.05), with a significant increase in the low frequency power of HRV spectra in iNOS knockout mice compared with controls (49.4+/-4.3 vs 33.8+/-5.6 normalized units, P<0.05), consistent with increased cardiac sympathetic activity. Endotoxaemia is known to decrease HRV, but the role of iNOS is unknown. LPS (20 mg/kg i.p) increased basal heart rate in both wild type and iNOS knockout mice, but caused a depression of HRV and sample entropy in both groups. Studies in isolated beating atria showed that the changes of HRV under basal or post-LPS conditions disappeared in vitro, suggesting that the autonomic system is responsible for altered HRV. We conclude that disruption of iNOS gene leads to an increase in the low frequency power of HRV consistent with increased cardiac sympathetic activity. These data also demonstrate that LPS-induced decrease of HRV is independent of iNOS.
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PMID:Heart rate dynamics in iNOS knockout mice. 1679 Feb 51

There were strong evidences that NO has capital importance in the progressive vasodilatation that associates to the varied circulatory shock forms. The decreased systemic vascular resistance observed in irreversible hemorrhagic (hypovolemic) and septic shock may be due to the excess production of nitric oxide. Other forms of shock associated to anaphylaxis (anaphylactic shock, SIRS) and ischemia reperfusion injury (cardiogenic shock, organ transplants), may involve nitric oxide overproduction. In these situations, the nitric oxide-induced loss of vascular sensitivity to catecholamines and myocardial depression contributes to lethal hypotension. As NO vasodilatation is cyclic GMP-mediated, there were two therapeutical options: a) The unspecific NO synthesis inhibition by L-arginine analogs, iNOS-specific inhibition by corticoids and/or aminoguanidine and; b) Guanylyl cyclase inhibition by MB. As the NO synthesis inhibition is associated to tissue necrosis and adverse hemodynamic effects and its clinical use was associated with high mortality, the second option using MB is safer and more rational. The elaboration of this text was motivated to suggest the guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutical target.
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PMID:The guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutical target. 1701 95

The severe impairment of the microcirculation plays a substantial role in the pathogenesis of severe sepsis and septic shock, and leads to multiple organ failure and death. Therapeutic strategies to resuscitate the microcirculatory blood flow and to improve the functional capillar density are therefore essential to surmount the microcirculatory pathology and to avoid tissue hypoxia. Based on reasonable scientific evidence, early fluid resuscitation directed by defined haemodynamic and metabolic goals (EGDT) as well as the application of activated protein C (rhAPC) according to the guidelines could be recommended. Dobutamine is the first choice to improve cardiac output and to overcome myocardial depression in septic shock whereas phosphodiesterase-III-inhibitors and levosimendane are still experimental options. Furthermore selective inhibitors of iNOS, nitroglycerol, as well as vasopressin have to be investigated relating to their specific effects on the microcirculation and their influence on survival in seevere sepsis and septic shock.
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PMID:[Therapeutic options to improve the microcirculation in sepsis and septic shock]. 1727 78

We evaluated the contribution of superoxide anion (O2*-) generated by NADPH oxidase or mitochondria in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for arterial pressure maintenance are located, on cardiovascular depression induced by inducible nitric oxide synthase-derived NO after Escherichia coli lipopolysaccharide (LPS) treatment. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of LPS bilaterally into the RVLM induced progressive hypotension, bradycardia, and reduction in sympathetic vasomotor outflow over our 240-min observation period. This was accompanied by an increase in O2*- production (60-240 min) in the RVLM, alongside phosphorylation of p47(phox) or p67(phox), upregulation of gp91(phox) or p47(phox) protein, and increase in Rac-1 or NADPH oxidase activity (60-120 min), and a depression of mitochondrial respiratory enzyme activity (120-240 min). Whereas inhibition of NADPH oxidase or knockdown of the gp91(phox) or p47(phox) gene blunted the early phase (60-150 min), coenzyme Q10 or mitochondrial K(ATP) channel inhibitor antagonized the delayed phase (120-240 min) of LPS-induced increase in O2*- production in RVLM and cardiovascular depression. We conclude that, whereas NADPH oxidase-derived O2*- in RVLM participates predominantly in the early phase, O2*- generated by depression in mitochondrial respiratory enzyme activity or opening of mitoK(ATP) channels mediates the delayed phase of LPS-induced cardiovascular depression.
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PMID:NADPH oxidase- and mitochondrion-derived superoxide at rostral ventrolateral medulla in endotoxin-induced cardiovascular depression. 1744 8


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