UMLS:C0020538 - FACTA Search

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Few admissions to the ICU present a greater clinical challenge than the patient with acute liver failure (ALF), the syndrome of abrupt loss of liver function in a previously unaffected individual. Although advances in the intensive care management of patients with ALF have improved survival, the prognosis of ALF remains poor, with a 33% mortality rate and a 25% liver transplant rate in the United States. ALF adversely affects nearly every organ system, with most deaths occurring from sepsis and subsequent multiorgan system failure, and cerebral edema, resulting in intracranial hypertension (ICH) and brainstem herniation. Unfortunately, the optimal management of ALF remains poorly defined, and practices are often based on local experience and case reports rather than on randomized, controlled clinical trials. The paramount question in any patient presenting with ALF remains defining an etiology, since specific antidotes can save lives and spare the liver. This article will consider recent advances in the assignment of an etiology, the administration of etiology-specific treatment to abate the liver injury, and the management of complications (eg, infection, cerebral edema, and the bleeding diathesis) in patients with ALF. New data on the administration of N-acetylcysteine to patients with non-acetaminophen ALF, the treatment of ICH, and assessment of the need for liver transplantation will also be presented.
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PMID:Critical management decisions in patients with acute liver failure. 1898 87

Preeclampsia (PE) is a multisystem disorder that remains a major cause of maternal and foetal morbidity and death. To date, no treatment has been found that prevents the development of the disease. Endothelial dysfunction is considered to underlie its clinical manifestations, such as maternal hypertension, proteinuria and edema; and oxidative stress has been increasingly postulated as a major contributor to endothelial dysfunction in PE. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of PE in women at high increased risk of the disease. Therefore, the present study was primary designed to assess the potential benefit of antioxidant supplementation on markers of placental oxidative stress in an in vitro model of PE, since we previously found that endothelin-1 (ET-1) is able to trigger the placental secretion of stress molecules. In this regard, we evaluated the effects of vitamin C, vitamin E and N-acetylcysteine (NAC), alone or in combination, in placental villi culture after exposure to ET-1. The effect of antioxidant nutrients on trophoblast cells proliferation and vitality was also evaluated. The results obtained suggest that in a pathophysiological condition, such as PE, the deleterious effect of reactive oxygen species may be counteract by an antioxidant therapy, and there is the need to investigate the optimum dosing and timing of antioxidants administration, since an inappropriate antioxidant treatment in pregnant women may have deleterious consequences, reducing placental cells proliferation until to cell death.
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PMID:Effects of vitamin E and C on placental oxidative stress: an in vitro evidence for the potential therapeutic or prophylactic treatment of preeclampsia. 1899 35

Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature.
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PMID:Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats. 1901 70

The aim of the study is to investigate the possible mechanism of oxidative stress in the high free fatty acids (FFAs)-induced hypertension. Male Sprague-Dawley rat models were established and classified into three groups, namely the control group (NC group), the FFA group, and the N-acetylcysteine (NAC) group. Blood pressure (BP) was recorded. An organ chamber experiment was performed to determine endothelium-dependent/-independent vasodilation (EDV/EIV). Reactive oxygen species (ROS), nitrotyrosine, reduced glutathione hormone (GSH) and NO(2)(-)/NO(3)(-) levels were measured in plasma. Endothelial nitric oxide synthase (eNOS) mRNA expression in endothelial cells was evaluated by real-time PCR. The following results were observed: (1) In the FFA group, BP increased after 4 h infusion of Intralipid+heparin. In the NAC group, systolic and diastolic BP remained the same. (2) In the FFA group, the aortic rings tended to show impaired EDV in response to acetylcholine (ACh). There was no difference of EDV response in the NAC and NC groups. (3) In the FFA group, NO(2)(-)/NO(3)(-) levels were significantly reduced, and eNOS mRNA expression and activity were significantly decreased compared with the NC group. NAC administration increased eNOS mRNA expression and activity. (4) ROS and nitrotyrosine concentrations in the FFA group were higher than in the NC group, and GSH concentrations in the FFA group were lower than in the NC group. Elevated FFAs can induce elevated BP, potentially through FFA-induced impairment of EDV resulting from decreased eNOS mRNA expression and activity. Oxidative stress may also play an important role in potential mechanisms of this high FFA-induced elevated BP.
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PMID:Role of oxidative stress in elevated blood pressure induced by high free fatty acids. 1926 75

The design, synthesis and properties of a new derivatizing reagent, 1,3,5,7-tetramethyl-8-phenyl-(4-iodoacetamido)difluoroboradiaza-s-indacene (TMPAB-I), for thiol groups are presented. Using the derivatization of TMPAB-I with thiols, a new high-performance liquid chromatographic method for measuring low-molecular-weight thiol-containing compounds, including coenzyme A (CoA), glutathione, N-acetylcysteine, cysteine, homocysteine (HCys) and 6-mercaptopurine has been developed. The reaction of TMPAB-I with thiols is specific, fast and stable for both TMPAB-I and the derivatives. A baseline separation of all the six derivatives is achieved by isocratic elution on reversed-phase column within 20 min with detection wavelengths of 500 and 510 nm for the excitation and emission, respectively, and the limits of detection (signal-to-noise ratio=3) are from 1.8 fmol (CoA) to 14.0 fmol (HCys), respectively, per 20 microL injection. The utility of the proposed method has been validated by measuring thiol-containing compounds in human plasma samples from healthy persons and patients with hypertension, with recoveries of 94.2-106.8%.
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PMID:Simultaneous analysis of plasma thiols by high-performance liquid chromatography with fluorescence detection using a new probe, 1,3,5,7-tetramethyl-8-phenyl-(4-iodoacetamido)difluoroboradiaza-s-indacene. 1928 84

Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.
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PMID:Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action. 1936 Mar 15

Increased arterial pressure, angiotensin II, and cytokines each result in feedback inhibition of renin gene expression. Because angiotensin II and cytokines can stimulate reactive oxygen species production, we tested the hypothesis that oxidative stress may be a mediator of this inhibition. Treatment of renin-expressing As4.1 cells with the potent cytokine tumor necrosis factor-alpha caused an increase in the steady-state levels of cellular reactive oxygen species, which was reversed by the antioxidant N-acetylcysteine. Exogenous H(2)O(2) caused a dose- and time-dependent decrease in the level of endogenous renin mRNA and decreased the transcriptional activity of a 4.1-kb renin promoter fused to luciferase, which was maximal when the renin enhancer was present. The effect of H(2)O(2) appeared to be specific to renin, because there was no change in the expression of beta-actin or cyclophilin mRNA or transcriptional activity of the SV40 promoter. The tumor necrosis factor-alpha-induced decrease in renin mRNA was partially reversed by either N-acetylcysteine or panepoxydone, a nuclear factor kappaB (NFkappaB) inhibitor. Interestingly, H(2)O(2) did not induce NFkappaB in As4.1 cells, and panepoxydone had no effect on the downregulation of renin mRNA by H(2)O(2). The transcriptional activity of a cAMP response element-luciferase construct was decreased by both tumor necrosis factor-alpha and H(2)O(2). These data suggest that cellular reactive oxygen species can negatively regulate renin gene expression via an NFkappaB-independent mechanism involving the renin enhancer and inhibiting cAMP response element-mediated transcription. Our data further suggest that tumor necrosis factor-alpha decreases renin expression through both NFkappaB-dependent and NFkappaB-independent mechanisms, the latter involving the production of reactive oxygen species.
Hypertension 2009 Jun
PMID:Regulation of renin gene expression by oxidative stress. 1943 77

Diets containing 8% salt or 4% fructose (FR) cause insulin resistance and increase tissue methylglyoxal and advanced glycation end products (AGEs), platelet cytosolic-free calcium, and systolic blood pressure (SBP) in rats. In WKY rats, we have shown that moderately high salt, 4% NaCl (MHS) alone in diet does not cause hypertension, and when given along with 4% FR it does not have an additive effect. N-acetylcysteine (NAC) or L-arginine (ARG), treatment alone does not prevent hypertension in this model. The objectives of this study were to investigate the effect of NAC plus ARG in diet on SBP, platelet cytosolic-free calcium in a MHS + FR model, and to measure the plasma levels of methylglyoxal and the AGE, methylglyoxal-derived hydroimidazolone (MGH). At 7 weeks of age, WKY rats were divided into three groups: control group was given regular rat chow (0.7% NaCl) and water; MHS + FR group, diet containing 4% NaCl and 4% FR in drinking water; and MHS + FR + NAC + ARG group, MHS diet supplemented with 1.5% N-acetylcysteine (NAC) and 1.5% L-arginine (ARG), and 4% FR in drinking water, and followed for 6 weeks. NAC + ARG prevented the increase in platelet cytosolic-free calcium and SBP in MHS + FR treated rats. There was no difference in mean values of plasma methylglyoxal and MGH among the groups. In conclusion, NAC + ARG treatment is effective in preventing hypertension in a moderately high salt + FR-induced animal model. Plasma methylglyoxal and MGH may not represent tissue modification or, alternatively, other tissue AGEs, derived from methylglyoxal or other aldehydes, may be involved in hypertension in this model.
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PMID:Fructose and moderately high dietary salt-induced hypertension: prevention by a combination of N-acetylcysteine and L-arginine. 1980 32

Acute respiratory distress syndrome (ARDS) is the most devastating form of acute lung injury (ALI) or pulmonary edema (PE). We presented the experimental studies and clinical investigations of two serious forms of ALI. Drastic and severe PE could be induced by intracranial hypertension or cerebral compression (CC). The CC-induced PE was attributed to overactivation of the medullary sympathetic mechanism. Sympathetic vasoconstriction of the systemic and pulmonary resistance and capacitance vessels caused shift of blood volume from the splanchnic vascular beds to the lung. The hemodynamic changes led to systemic and pulmonary hypertension. Consequently, left ventricular failure as evidenced by dramatic decline in aortic flow with a slow decrease in pulmonary flow resulted in pressure and volume loading in the pulmonary circulation. These changes finally produced severe alveolar flooding and sudden death. Vasodilators such as sodium nitroprusside or nitroglycerin were capable of reducing the CC-induced pulmonary pathology and hemodynamic alterations. Fat embolism syndrome (FES) is a serious clinical problem in patients suffering from long bone fractures. ARDS may develop and cause mortality. Our laboratory reported a total of 14 subjects associated with FES and died of ARDS. We also developed a simple technique to produce FES. Corn oil was mixed with distilled water to form fatty micelles. Intravenous administration of or introduction of fatty micelles in anesthetized rats or isolated perfused lungs caused severe alveolar damage. Our clinical observation and animal experimentation revealed that infusion of fatty acids caused physical phase, resulting in microvascular obstruction accompanied by pulmonary hypertension and increased capillary permeability. Thereafter, the lipases in the lung hydrolyzed the neutral fat and released free fatty acids and biochemical mediators which were toxic to the lung. Our data have suggested that nitric oxide (NO), inducible NO synthase (iNOS), phospholipase A2, free radical and inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta and interleukin-6) are involved in the biochemical phase of FES with ARDS. The alveolar macrophages are the major source of iNOS. Later study also found that neutrophil elastase and myeloperoxidase were elevated following fat embolism. N-acetylcysteine (an antioxidant), and NOS inhibitors such as Nomega nitro-L-arginine methyl ester (L-NAME), S-methylisothiourea (SMT) or L-N6 (1-iminoethyl)-lysine (L-Nil) were able to abrogate the FES or the fat embolism-induced changes.
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PMID:From neurogenic pulmonary edema to fat embolism syndrome: a brief review of experimental and clinical investigations of acute lung injury and acute respiratory distress syndrome. 2035 24

In vascular smooth muscle cells, Axl is a key receptor tyrosine kinase, because it is upregulated in injury, increases migration and neointima formation, and is activated by reactive oxygen species. Reaction of glutathione with cysteine residues (termed "glutathiolation") is an important posttranslational redox modification that may alter protein activity and protein-protein interactions. To investigate the mechanisms by which reactive oxygen species increase Axl-dependent vascular smooth muscle cell function we assayed for glutathiolated proteins that associated with Axl in a redox-dependent manner. We identified glutathiolated nonmuscle myosin heavy chain (MHC)-IIB as a novel Axl interacting protein. This interaction was specific in that other myosins did not interact with Axl. The endogenous ligand for Axl, Gas6, increased production of reactive oxygen species in vascular smooth muscle cells and also increased the association of Axl with MHC-IIB. Antioxidants ebselen and N-acetylcysteine decreased the association of Axl with MHC-IIB in response to both Gas6 and reactive oxygen species. Blocking the Axl-MHC-IIB interaction with the specific myosin II inhibitor blebbistatin decreased phosphorylation of Axl and activation of extracellular signal-regulated kinase 1/2 and Akt. Association of MHC-IIB with Axl was increased in balloon-injured rat carotid vessels. Finally, expression of MHC-IIB was upregulated in the neointima of the carotid artery after balloon injury similar to upregulation of Axl protein expression, as shown in our previous studies. These results demonstrate a novel interaction between Axl and MHC-IIB in response to reactive oxygen species. This interaction provides a direct link between Axl and molecular motors crucial for directed cell migration, which may mediate increased migration in vascular dysfunction.
Hypertension 2010 Jul
PMID:Gas6-Axl pathway: the role of redox-dependent association of Axl with nonmuscle myosin IIB. 2047 36

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