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  1. N-Acetylcysteine Reverses Cocaine Induced Metaplasticity

    PubMed Central

    Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M. Foster; Gass, Justin T.; Lavin, Antonieta; Kalivas, Peter W

    2009-01-01

    Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry critical for regulating motivated behavior. RWe found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentation (LTP) and depression (LTD) in the nucleus accumbens core subregion following stimulation of prefrontal cortex. N-acetylcysteine treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). N-acetylcysteine treatment restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Cocaine self-administration induces metaplasticity that inhibits the further induction of synaptic plasticity, and this impairment can be reversed by N-acetylcysteine, a drug that also prevents relapse. PMID:19136971

  2. The metabolism of N-acetylcysteine by human endothelial cells.

    PubMed

    Cotgreave, I; Moldéus, P; Schuppe, I

    1991-06-21

    When human umbilical endothelial cells were depleted of their glutathione by incubation in a sulfur amino acid-free medium, subsequent incubation of the cells with this deficient medium supplemented with N-acetylcysteine resulted in a dose-dependent stimulation of the synthesis of cellular glutathione. Similarly, the inclusion of N-acetylcysteine in the medium during the period of depletion of glutathione caused a dose-dependent retardation of the depletion kinetics. In contrast, the incubation of control cells in normal medium supplemented with N-acetylcysteine did not increase cellular glutathione levels above controls. These observations indicate the presence of an N-deacetylase in/on the cells with specificity for N-acetylcysteine. Due to the large surface area of the endothelium in the vasculature it seems likely that endothelial cell N-deacetylation plays a role in the metabolic disposition of N-acetylcysteine, particularly when administered intravenously. N-Acetylcysteine is, however, a relatively poor precursor to glutathione biosynthesis in comparison to cystine. Thus, any cytoprotective, antioxidant effect exerted by N-acetylcysteine on the human endothelium is likely to be due to direct scavenging of reactive intermediates rather than by stimulated glutathione synthesis in the endothelial cells themselves.

  3. Status epilepticus following intravenous N-acetylcysteine therapy.

    PubMed

    Hershkovitz, E; Shorer, Z; Levitas, A; Tal, A

    1996-11-01

    A previously healthy 2 1/2-year-old girl developed status epilepticus followed by cortical blindness during intravenous N-acetylcysteine therapy for paracetamol ingestion. The child's vision was almost completely recovered during the 18 months follow-up period. We assume that the cortical blindness was a postictal sequela after prolonged seizure episode, most probably due to respiratory depression induced by N-acetylcysteine.

  4. Trichotillomania: a good response to treatment with N-acetylcysteine.

    PubMed

    Barroso, Livia Ariane Lopes; Sternberg, Flavia; Souza, Maria Natalia Inacio de Fraia E; Nunes, Gisele Jacobino de Barros

    2017-01-01

    Trichotillomania is considered a behavioral disorder and is characterized by the recurring habit of pulling one's hair, resulting in secondary alopecia. It affects 1% of the adult population, and 2 to 4.4% of psychiatric patients meet the diagnostic criteria. It can occur at any age and is more prevalent in adolescents and females. Its occurrence in childhood is not uncommon and tends to have a more favorable clinical course. The scalp, eyebrows and eyelashes are the most commonly affected sites. Glutamate modulating agents, such as N-acetylcysteine, have been shown to be a promising treatment. N-acetylcysteine acts by reducing oxidative stress and normalizing glutaminergic transmission. In this paper, we report a case of trichotillomania with an excellent response to N-acetylcysteine.

  5. Acquired 5-oxoproline acidemia successfully treated with N-acetylcysteine.

    PubMed

    Hundemer, Gregory L; Fenves, Andrew Z

    2017-04-01

    Acquired 5-oxoprolinemia is increasingly recognized as a cause of anion gap metabolic acidosis. It predominantly occurs in chronically ill, malnourished women with impaired renal function and chronic acetaminophen ingestion. Depletion of glutathione and cysteine stores leads to elevated 5-oxoproline levels. N-acetylcysteine, given its effect in repleting glutathione and cysteine stores, has been proposed as a potential treatment for 5-oxoprolinemia, though reports of its successful use are lacking. We present a case of 5-oxoproline metabolic acidosis that persisted despite discontinuation of acetaminophen. However, the acidosis rapidly resolved with N-acetylcysteine administration.

  6. Protective effects of N-acetylcysteine on experimentally undescended testis.

    PubMed

    Uyeturk, Ugur; Cetinkaya, Ayhan; Ozyalvacli, Gulzade; Tekce, Buket Kin; Ozyalvacli, Mehmet Emin; Kemahli, Eray; Gucuk, Adnan

    2014-04-01

    We evaluated the efficacy of N-acetylcysteine for testicular damage induced by undescended testes in rats. Flutamide was injected in the abdomen of pregnant rats daily from days 14 to 20 of gestation. Male offspring with cryptorchidism were randomly divided into 2 groups. Healthy male rats without undescended testes comprised the control group (group 1). Group 2 (undescended testes without N-acetylcysteine) received no treatment. Group 3 (undescended testes plus N-acetylcysteine) received intraperitoneal N-acetylcysteine daily. At 70 days after experiment initiation the testes were removed for histopathological and biochemical analysis. Mean malonyl dialdehyde values were lowest in group 1 and highest in group 2. In group 3 malonyl dialdehyde levels were significantly lower than in group 2 (p <0.001). Conversely, mean glutathione peroxidase was highest in group 1 and lowest in group 2. Glutathione peroxidase levels in group 3 were significantly higher than in group 2 (p <0.001). Histopathological differences between groups 1 and 3 in the modified Johnsen score were not significant (p = 0.041). However, the differences between these groups and group 2 were significant (p <0.001). The median apoptotic cell count did not differ between groups 1 and 3 but it was significantly higher in group 2 than in the other groups (p = 0.03 and <0.001, respectively). N-acetylcysteine may alleviate undescended testis induced damage to testes through its antioxidant effects. The underlying mechanism of these effects merits further investigation. Long-term studies are also needed as well as comparative animal and human studies. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  7. N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct.

    PubMed

    Mlejnek, Petr; Dolezel, Petr

    2014-09-05

    Geldanamycin (GDN) is a benzoquinone ansamycin antibiotic with anti-proliferative activity on tumor cells. GDN cytotoxicity has been attributed to the disruption of heat shock protein 90 (Hsp90) binding and stabilizing client proteins, and by the induction of oxidative stress with concomitant glutathione (GSH) depletion. The later mechanism of cytotoxicity can be abrogated by N-acetylcysteine (NAC). It was suggested that NAC prevents GDN cytotoxicity mainly by the restoring of glutathione (GSH) level (Clark et al., 2009). Here we argue that NAC does not protect cells from the GDN cytotoxicity by restoring the level of GSH. A detailed LC/MS/MS analysis of cell extracts indicated formation of GDN adducts with GSH. The amount of the GDN-GSH adduct is proportional to the GDN concentration and increases with incubation time. While nanomolar and low micromolar GDN concentrations induce cell death without an apparent GSH decrease, only much higher micromolar GDN concentrations cause a significant GSH decrease. Therefore, only high micromolar GDN concentrations can cause cell death which might be related to GSH depletion. Addition of NAC leads to the formation of adducts with GDN which diminish formation of GDN adducts with GSH. NAC also forms stable adducts with GDN extracellularly. Although NAC induces an increase in the GSH pool, this effect is not crucial for abrogation of GDN cytotoxicity. Indeed, the presence of NAC in the growth medium causes a rapid conversion of GDN into the GDN-NAC adduct, which is the real cause of the abrogated GDN cytotoxicity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Sun, Tong; Liu, Jing; Zhao, De Wei

    2016-01-01

    Abstract There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis. Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1. Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to −0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02–0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: −0.13–0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: −0.06–0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19–106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3–5.12; P = 0.28) between the N-acetylcysteine group and the control group. N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes

  9. Recommendations for the paracetamol treatment nomogram and side effects of N-acetylcysteine.

    PubMed

    Koppen, A; van Riel, A; de Vries, I; Meulenbelt, J

    2014-06-01

    Treatment of paracetamol intoxication consists of administration of N-acetylcysteine, preferably shortly after paracetamol ingestion. In most countries, the decision to treat patients with N-acetylcysteine depends on the paracetamol plasma concentration. In the literature, different arguments are given regarding when to treat paracetamol overdose. Some authors do not recommend treatment with N-acetylcysteine at low paracetamol plasma concentrations since unnecessary adverse effects may be induced. But no treatment with N-acetylcysteine at higher paracetamol plasma concentrations may lead to unnecessary severe morbidity and mortality. In this review, we provide an overview on the severity and prevalence of adverse side effects after N-acetylcysteine administration and the consequences these side effects may have for the treatment of paracetamol intoxication. The final conclusion is to continue using the guidelines of the Dutch National Poisons Information Centre for N-acetylcysteine administration in paracetamol intoxication.

  10. Effects of N-Acetylcysteine on Thresholds and Otoacoustic Emissions Following Noise Exposure

    DTIC Science & Technology

    2004-12-01

    EFFECTS OF N- ACETYLCYSTEINE ON THRESHOLDS AND OTOACOUSTIC EMISSIONS FOLLOWING NOISE EXPOSURE Barbara Acker-Mills, Ph.D*., CPT Martin Robinette...wearing ear plugs, muffs, etc.. The current study evaluated the effectiveness of one antioxidant, N- acetylcysteine (NAC), on temporary cochlear changes...4. TITLE AND SUBTITLE Effects Of N- Acetylcysteine On Thresholds And Otoacoustic Emissions Following Noise Exposure 5a. CONTRACT NUMBER 5b

  11. N-acetylcysteine improves coronary and peripheral vascular function.

    PubMed

    Andrews, N P; Prasad, A; Quyyumi, A A

    2001-01-01

    We investigated whether N-acetylcysteine (NAC), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion. Coronary atherosclerosis is associated with endothelial dysfunction and reduced NO activity. In 16 patients undergoing cardiac catheterization, seven with and nine without atherosclerosis, we assessed endothelium-dependent vasodilation with acetylcholine (ACH) and endothelium-independent vasodilation with nitroglycerin (NTG) and sodium nitroprusside (SNP) before and after intracoronary NAC. In 14 patients femoral vascular responses to ACH, NTG and SNP were measured before and after NAC. Intraarterial NAC did not change resting coronary or peripheral vascular tone. N-acetylcysteine potentiated ACH-mediated coronary vasodilation; coronary blood flow was 36 +/- 11% higher (p < 0.02), and epicardial diameter changed from -1.2 +/- 2% constriction to 4.7 +/- 2% dilation after NAC (p = 0.03). Acetylcholine-mediated femoral vasodilation was similarly potentiated by NAC (p = 0.001). Augmentation of the ACH response was similar in patients with or without atherosclerosis. N-acetylcysteine did not affect NTG-mediated vasodilation in either the femoral or coronary circulations and did not alter SNP responses in the femoral circulation. In contrast, coronary vasodilation with SNP was significantly greater after NAC (p < 0.05). Thiol supplementation with NAC improves human coronary and peripheral endothelium-dependent vasodilation. Nitroglycerin responses are not enhanced, but SNP-mediated responses are potentiated only in the coronary circulation. These NO-enhancing effects of thiols reflect the importance of the redox state in the control of vascular function and may be of therapeutic benefit in treating acute and chronic manifestations of atherosclerosis.

  12. N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice.

    PubMed

    Bowers, M S; Jackson, A; Maldoon, P P; Damaj, M I

    2016-03-01

    N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured 18-24 h after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.)-precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine was found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.

  13. N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice

    PubMed Central

    Bowers, M.S.; Jackson, A.; Maldoon, P.P.; Damaj, M. I.

    2016-01-01

    Rationale N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. Objectives The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. Methods N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia were measured 18 - 24 hrs after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: Mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.) precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. Results Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine were found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. Conclusions These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence. PMID:26676982

  14. N-Acetylcysteine Use in Non-Acetaminophen-Induced Acute Liver Failure.

    PubMed

    McPheeters, Chelsey M; VanArsdale, Vanessa M; Weant, Kyle A

    2016-01-01

    This article will review the available evidence related to the management of non-acetaminophen induced acute liver failure with N-acetylcysteine. Randomized controlled trials and a meta-analysis were included in this review. The efficacy of N-acetylcysteine in the treatment of acute liver failure from causes other than acetaminophen toxicity was evaluated. The efficacy of N-acetylcysteine in non-acetaminophen-induced acute liver failure is limited to specific patient populations. Patients classified as Coma Grade I or II are more likely to benefit from the use of this agent. The use of N-acetylcysteine is associated with improved transplant-free survival, not overall survival, in adults. N-Acetylcysteine does not improve the overall survival of patients with non-acetaminophen-induced acute liver failure but may be beneficial in those patients with Coma Grades I-II. Liver transplantation remains the only definitive therapy in advanced disease.

  15. N-acetylcysteine inhibits muscle fatigue in humans.

    PubMed Central

    Reid, M B; Stokić, D S; Koch, S M; Khawli, F A; Leis, A A

    1994-01-01

    N-acetylcysteine (NAC) is a nonspecific antioxidant that selectively inhibits acute fatigue of rodent skeletal muscle stimulated at low (but not high) tetanic frequencies and that decreases contractile function of unfatigued muscle in a dose-dependent manner. The present experiments test the hypothesis that NAC pretreatment can inhibit acute muscular fatigue in humans. Healthy volunteers were studied on two occasions each. Subjects were pretreated with NAC 150 mg/kg or 5% dextrose in water by intravenous infusion. The subject then sat in a chair with surface electrodes positioned over the motor point of tibialis anterior, an ankle dorsiflexor of mixed-fiber composition. The muscle was stimulated to contract electrically (40-55 mA, 0.2-ms pulses) and force production was measured. Function of the unfatigued muscle was assessed by measuring the forces produced during maximal voluntary contractions (MVC) of ankle dorsiflexor muscle groups and during electrical stimulation of tibialis anterior at 1, 10, 20, 40, 80, and 120 Hz (protocol 1). Fatigue was produced using repetitive tetanic stimulations at 10 Hz (protocol 1) or 40 Hz (protocol 2); intermittent stimulations subsequently were used to monitor recovery from fatigue. The contralateral leg then was studied using the same protocol. Pretreatment with NAC did not alter the function of unfatigued muscle; MVC performance and the force-frequency relationship of tibialis anterior were unchanged. During fatiguing contractions stimulated at 10 Hz, NAC increased force output by approximately 15% (P < 0.0001), an effect that was evident after 3 min of repetitive contraction (P < 0.0125) and persisted throughout the 30-min protocol. NAC had no effect on fatigue induced using 40 Hz stimuli or on recovery from fatigue. N-acetylcysteine pretreatment can improve performance of human limb muscle during fatiguing exercise, suggesting that oxidative stress plays a causal role in the fatigue process and identifying antioxidant

  16. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents

    PubMed Central

    Gray, Kevin M.; Carpenter, Matthew J.; Baker, Nathaniel L.; DeSantis, Stacia M.; Kryway, Elisabeth; Hartwell, Karen J.; McRae-Clark, Aimee L.; Brady, Kathleen T.

    2012-01-01

    Objective Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine, via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy targeting substance dependence. We sought to investigate N-acetylcysteine as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have limited efficacy. Method In this 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (age 15-21, N = 116) received N-acetylcysteine (1200 mg) or placebo twice daily, each added to a contingency management intervention and brief (≤10 minute) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid tests during treatment among participants receiving N-acetylcysteine versus placebo, via intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. Results N-acetylcysteine was well tolerated with minimal adverse events. N-acetylcysteine participants had more than twice the odds, compared to placebo participants, of submitting negative urine cannabinoid tests during treatment (odds ratio = 2.4, [95% CI: 1.1-5.2], p = 0.029). Exploratory secondary abstinence outcomes numerically favored N-acetylcysteine, but were not statistically significant. Conclusions This is the first randomized trial of pharmacotherapy for cannabis dependence in any age group yielding a positive primary cessation outcome via intent-to-treat analysis. Findings support N-acetylcysteine as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents. Further research is needed to replicate these findings and explore the efficacy of N-acetylcysteine across a variety of treatment contexts and outcomes. Trial Registration clinicaltrials.gov identifier: NCT 01005810 PMID:22706327

  17. Ulcers caused by bullous morphea: successful therapy with N-acetylcysteine and topical wound care.

    PubMed

    Rosato, E; Veneziano, M L; Di Mario, A; Molinaro, I; Pisarri, S; Salsano, F

    2013-01-01

    Bullous morphea is an uncommon form of localized scleroderma. The pathogenesis is unknown and treatment of coexistent ulcers is difficult. The pathogenesis of bullae formation in morphea is multifactorial, but reactive oxygen species production appears to play a key role. We report a patient with bullous morphea with long-standing ulcers whom we successfully treated with N-acetylcysteine and topical wound care. N-acetylcysteine, an antioxidant sulfhydryl substance, promotes the healing of ulcers in patients with bullous morphea.

  18. The effect of N-acetylcysteine on mechanical fatigue resistance of antibiotic-loaded bone cement.

    PubMed

    Sukur, Erhan; Akar, Abdulhalim; Topcu, Huseyin Nevzat; Cicekli, Ozgur; Kochai, Alauddin; Turker, Mehmet

    2018-05-31

    This biomechanical study evaluates the effect of N-acetylcysteine alone and in combination with the most commonly used antibiotic-loaded bone cement mixtures. We mixed eight bone cement mixture groups including combinations of N-acetylcysteine, gentamicin, teicoplanin, and vancomycin and applied a four-point bending test individually to each sample on days 1 and 15 using an MTS Acumen test device. The result was less than 50 MPa-the limit declared by the ISO (International Standards Organization)-in only the "gentamicin + bone cement + N-acetylcysteine" group. Mechanical fatigue resistance of the bone cement decreased significantly with the addition of N-acetylcysteine both on day 1 and day 15 (p <  0.001). With the addition of N-acetylcysteine into the "gentamicin + bone cement" and "vancomycin + bone cement" mixtures, a significant decrease in mechanical fatigue resistance was observed both on day 1 and day 15 (p <  0.001). In contrast, with the addition of N-acetylcysteine into the "teicoplanin + bone cement" mixture, no significant difference in mechanical fatigue resistance was observed on days 1 and 15 (p = 0.093, p = 0.356). Preliminary results indicate that adding N-acetylcysteine to teicoplanin-loaded bone cement does not significantly affect the cement's mechanical resistance, potentially leading to a new avenue for preventing and treating peri-prosthetic joint infection. N-acetylcysteine may, therefore, be considered as an alternative agent to be added to antibiotic-loaded bone cement mixtures used in the prevention of peri-prosthetic joint infection.

  19. Minocycline and N-acetylcysteine: A Synergistic Drug Combination to Treat Traumatic Brain Injury

    DTIC Science & Technology

    2012-10-01

    W81XWH-10-2-0171 TITLE: Minocycline and N-acetylcysteine: a synergistic drug combination to treat traumatic brain injury PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Minocycline and N-acetylcysteine: a synergistic drug combination to treat traumatic brain injury 5a. CONTRACT NUMBER 5b...The grantee previously found screened that the combination of minocycline (MINO) and N-acetyl cysteine (NAC) synergistically improved brain function

  20. Minocycline and N-acetylcysteine: A Synergistic Drug Combination to Treat Traumatic Brain Injury

    DTIC Science & Technology

    2011-10-01

    AD_________________ Award Number: W81XWH-10-2-0171 TITLE: Minocycline and N-acetylcysteine: A... Minocycline and N-acetylcysteine: A Synergistic Drug Combination to Treat Traumatic Brain Injury 5b. GRANT NUMBER W81XWH-10-2-0171 5c. PROGRAM...combination of minocycline (MINO) and N-acetyl cysteine (NAC) synergistically improved brain function when dosed one hour following closed cortical

  1. N-acetylcysteine inhibits endothelial cell invasion and angiogenesis.

    PubMed

    Cai, T; Fassina, G; Morini, M; Aluigi, M G; Masiello, L; Fontanini, G; D'Agostini, F; De Flora, S; Noonan, D M; Albini, A

    1999-09-01

    The thiol N-acetylcysteine (NAC) is a chemopreventive agent that acts through a variety of mechanisms and can prevent in vivo carcinogenesis. We have previously shown that NAC inhibits invasion and metastasis of malignant cells as well as tumor take. Neovascularization is critical for tumor mass expansion and metastasis formation. We investigated whether a target of the anti-cancer activity of NAC could be the inhibition of the tumor angiogenesis-associated phenotype in vitro and in vivo using the potent angiogenic mixture of Kaposi's sarcoma cell products as a stimulus. Two endothelial (EAhy926 and human umbilical vein endothelial [HUVE]) cell lines were utilized in a panel of assays to test NAC ability in inhibiting chemotaxis, invasion, and gelatinolytic activity in vitro. NAC treatment of EAhy926 and HUVE cells in vitro dose-dependently reduced their ability to invade a reconstituted basement membrane, an indicator of endothelial cell activation. Invasion of HUVE cells was inhibited with an ID50 of 0.24 mM NAC, whereas inhibition of chemotaxis required a 10 fold higher doses, indicating that invasion is a preferential target. NAC inhibited the enzymatic activity and conversion to active forms of the gelatinase produced by endothelial cells. The matrigel in vivo assay was used for the evaluation of angiogenesis; NAC strongly inhibited neovascularization of the matrigel sponges in response to Kaposi's sarcoma cell products. NAC prevented angiogenesis while preserving endothelial cells, implying that it could be safely used as an anti-angiogenic treatment.

  2. Beneficial effects of n-acetylcysteine on ischaemic brain injury

    PubMed Central

    Cuzzocrea, Salvatore; Mazzon, Emanuela; Costantino, Giuseppina; Serraino, Ivana; Dugo, Laura; Calabrò, Giusy; Cucinotta, Giovanni; De Sarro, Angela; Caputi, A P

    2000-01-01

    Nitric oxide (NO), peroxynitrite, formed from NO and superoxide anion, poly (ADP-ribole) synthetase have been implicated as mediators of neuronal damage following focal ischaemia. Here we have investigated the effects of n-acetylcysteine (NAC) treatment in Mongolian gerbils subjected to cerebral ischaemia.Treatment of gerbils with NAC (20 mg kg−1 30 min before reperfusion and 1, 2 and 6 h after reperfusion) reduced the formation of post-ischaemic brain oedema, evaluated by water content.NAC also attenuated the increase in the brain levels of malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischaemia.Positive staining for nitrotyrosine was found in the hippocampus in Mongolian gerbils subjected to cerebral ischaemia. Hippocampus tissue sections from Mongolian gerbils subjected to cerebral ischaemia also showed positive staining for poly (ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received NAC.NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischaemia and reperfusion.Histological observations of the pyramidal layer of CA1 showed a reduction of neuronal loss in animals that received NAC.These results show that NAC improves brain injury induced by transient cerebral ischaemia. PMID:10903958

  3. [Effectiveness of N-acetylcysteine in the treatment of schizophrenia].

    PubMed

    Miyake, Nobumi; Miyamoto, Seiya

    2016-04-01

    Oxidative stress and neuroinflammation have recently been focused on the pathological hypotheses of schizophrenia. N-acetylcysteine (NAC) is a precursor of endogenous antioxidant glutathione and has antioxidant, anti-inflammatory, and neuroprotective properties. NAC is widely available as an over-the-counter nutritional supplement. Increasing lines of evidence suggest that NAC is effective for various mental disorders. In randomized controlled trials, treatment with NAC as an add-on to antipsychotics showed beneficial effects and safety profiles in patients with chronic schizophrenia. The results of a recent preclinical study using a neurodevelopmental model of schizophrenia suggest that NAC may have promising effects in an early stage of schizophrenia and an at-risk mental state. However, there is little clinical evidence for the efficacy and safety of NAC at these stages of schizophrenia. In this review, we summarize the evidence regarding the effectiveness of NAC for the treatment of schizophrenia and its prodromal stage. We also introduce the preliminary results of our research on NAC.

  4. The promise of N-acetylcysteine in neuropsychiatry.

    PubMed

    Berk, Michael; Malhi, Gin S; Gray, Laura J; Dean, Olivia M

    2013-03-01

    N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. N-acetylcysteine for major depressive episodes in bipolar disorder.

    PubMed

    Magalhães, Pedro V; Dean, Olívia M; Bush, Ashley I; Copolov, David L; Malhi, Gin S; Kohlmann, Kristy; Jeavons, Susan; Schapkaitz, Ian; Anderson-Hunt, Murray; Berk, Michael

    2011-12-01

    In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo. These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.

  6. Interactive effects of N-acetylcysteine and antidepressants.

    PubMed

    Costa-Campos, Luciane; Herrmann, Ana P; Pilz, Luísa K; Michels, Marcus; Noetzold, Guilherme; Elisabetsky, Elaine

    2013-07-01

    N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. N-Acetylcysteine reverses cocaine-induced metaplasticity.

    PubMed

    Moussawi, Khaled; Pacchioni, Alejandra; Moran, Megan; Olive, M Foster; Gass, Justin T; Lavin, Antonieta; Kalivas, Peter W

    2009-02-01

    Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

  8. S-phenyl-N-acetylcysteine in urine of rats and workers after exposure to benzene

    SciTech Connect

    Jongeneelen, F.J.; Dirven, H.A.; Leijdekkers, C.M.

    1987-05-01

    An HPLC method for the determination of S-phenyl-N-acetylcysteine in urine is described. The sensitivity is 6 mumol/L (CV = 9%) urine. Exposure of rats to six different concentrations of benzene, ranging from 0-30 ppm, was highly associated with urinary excretion of S-phenyl-N-acetylcysteine (r = 0.86) and with total phenol (r = 0.81). A background level of phenol was found in urine of both non-exposed rats and of non-exposed referents. However, no background excretion of S-phenyl-N-acetylcysteine was found, either in rats or in humans. In urine of exposed rats, the level of S-phenyl-N-acetylcysteine was approximately five times lower than the phenolmore » level. Workers occupationally exposed to benzene, showing high levels of urinary phenol, revealed low concentrations of urinary S-phenyl-N-acetylcysteine. The biological monitoring of industrial exposure to benzene by determination of S-phenyl-N-acetylcysteine in urine is not better than the determination of phenol in urine.« less

  9. Topical N-acetylcysteine improves wound healing comparable to dexpanthenol: an experimental study.

    PubMed

    Oguz, Abdullah; Uslukaya, Omer; Alabalık, Ulas; Turkoglu, Ahmet; Kapan, Murat; Bozdag, Zubeyir

    2015-04-01

    In this study, we aimed to compare the effects of dexpanthenol and N-acetylcysteine on wound healing. The wound healing process is a multifaceted sequence of activities associated with tissue restoration process. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. A total of 30 rats were divided into 3 equal groups. A linear 2-cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 3% N-acetylcysteine cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21st day, all wounds were excised and histologically evaluated. The epithelialization and granulation rates between the groups were revealed to be similar in microscopic evaluations. Although the fibrosis was remarkable in the control group as compared with the other groups, it was similar in N-acetylcysteine and dexpanthenol groups. Angiogenesis rate was remarkable in the N-acetylcysteine group compared with the others. In multiple-comparison analysis, Dexpanthenol and N-acetylcysteine groups had similar results in terms of wound healing rates (P < 0.05), which were both higher than in the control group (P > 0.05). The efficacy of N-acetylcysteine in wound healing is comparable to dexpanthenol, and both substances can be used to improve wound healing.

  10. Topical N-Acetylcysteine Improves Wound Healing Comparable to Dexpanthenol: An Experimental Study

    PubMed Central

    Oguz, Abdullah; Uslukaya, Omer; Alabalık, Ulas; Turkoglu, Ahmet; Kapan, Murat; Bozdag, Zubeyir

    2015-01-01

    In this study, we aimed to compare the effects of dexpanthenol and N-acetylcysteine on wound healing. The wound healing process is a multifaceted sequence of activities associated with tissue restoration process. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. A total of 30 rats were divided into 3 equal groups. A linear 2-cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 3% N-acetylcysteine cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21st day, all wounds were excised and histologically evaluated. The epithelialization and granulation rates between the groups were revealed to be similar in microscopic evaluations. Although the fibrosis was remarkable in the control group as compared with the other groups, it was similar in N-acetylcysteine and dexpanthenol groups. Angiogenesis rate was remarkable in the N-acetylcysteine group compared with the others. In multiple-comparison analysis, Dexpanthenol and N-acetylcysteine groups had similar results in terms of wound healing rates (P < 0.05), which were both higher than in the control group (P > 0.05). The efficacy of N-acetylcysteine in wound healing is comparable to dexpanthenol, and both substances can be used to improve wound healing. PMID:25583306

  11. Systemic inflammation and oxidative stress post-lung resection: Effect of pretreatment with N-acetylcysteine.

    PubMed

    Bastin, Anthony J; Davies, Nathan; Lim, Eric; Quinlan, Greg J; Griffiths, Mark J

    2016-01-01

    N-acetylcysteine has been used to treat a variety of lung diseases, where is it thought to have an antioxidant effect. In a randomized placebo-controlled double-blind study, the effect of N-acetylcysteine on systemic inflammation and oxidative damage was examined in patients undergoing lung resection, a human model of acute lung injury. Eligible adults were randomized to receive preoperative infusion of N-acetylcysteine (240 mg/kg over 12 h) or placebo. Plasma thiols, interleukin-6, 8-isoprostane, ischaemia-modified albumin, red blood cell glutathione and exhaled breath condensate pH were measured pre- and post-operatively as markers of local and systemic inflammation and oxidative stress. Patients undergoing lung resection and one-lung ventilation exhibited significant postoperative inflammation and oxidative damage. Postoperative plasma thiol concentration was significantly higher in the N-acetylcysteine-treated group. However, there was no significant difference in any of the measured biomarkers of inflammation or oxidative damage, or in clinical outcomes, between N-acetylcysteine and placebo groups. Preoperative administration of N-acetylcysteine did not attenuate postoperative systemic or pulmonary inflammation or oxidative damage after lung resection. NCT00655928 at ClinicalTrials.gov. © 2015 Asian Pacific Society of Respirology.

  12. Prevention of gentamicin ototoxicity with N-acetylcysteine and vitamin A.

    PubMed

    Aladag, I; Guven, M; Songu, M

    2016-05-01

    To investigate the use of systemic N-acetylcysteine and vitamin A in the prevention of gentamicin ototoxicity in rats. Forty-two Wistar rats were divided into four groups according to treatment: intratympanic saline, intratympanic gentamicin, intraperitoneal vitamin A after intratympanic gentamicin, and intraperitoneal N-acetylcysteine after intratympanic gentamicin. Signal-to-noise ratio and distortion product otoacoustic emissions were evaluated in all groups. N-acetylcysteine had a significant protective effect at 1.5, 2, 3, 4, 6 and 8 kHz, whilst vitamin A had a significant protective effect at 2, 3, 4 and 6 kHz, as determined by the distortion product otoacoustic emission measurements. According to the signal-to-noise measurements, N-acetylcysteine had a significant protective effect at 1.5, 2, 3, 4, 6 and 8 kHz, whilst vitamin A had a significant protective effect at 3, 6 and 8 kHz. Gentamicin-induced hearing loss in rats may be prevented by the concomitant use of vitamin A and N-acetylcysteine. Specifically, N-acetylcysteine appeared to have a more protective effect than vitamin A for a greater range of noise frequencies.

  13. N-Acetylcysteine Restores Sevoflurane Postconditioning Cardioprotection against Myocardial Ischemia-Reperfusion Injury in Diabetic Rats.

    PubMed

    Lin, Jiefu; Wang, Tingting; Li, Yalan; Wang, Mengxia; Li, Haobo; Irwin, Michael G; Xia, Zhengyuan

    2016-01-01

    The effect of sevoflurane postconditioning (sevo-postC) cardioprotection is compromised in diabetes which is associated with increased oxidative stress. We hypothesized that antioxidant N-Acetylcysteine may enhance or restore sevo-postC cardioprotection in diabetes. Control or streptozotocin-induced Type 1 diabetic rats were either untreated or treated with N-Acetylcysteine for four weeks starting at five weeks after streptozotocin injection and were subjected to myocardial ischemia-reperfusion injury (IRI), in the absence or presence of sevo-postC. Diabetes showed reduction of cardiac STAT3 activation (p-STAT3) and adiponectin with concomitantly increase of FoxO1 and CD36, which associated with reduced sevo-postC cardioprotection. N-Acetylcysteine and sevo-postC synergistically reduced the infarct size in diabetic groups. N-Acetylcysteine remarkably increased cardiac p-STAT3 which was further enhanced by sevo-postC. N-Acetylcysteine but not sevo-postC decreased myocardial FoxO1 while sevo-postC but not N-Acetylcysteine significantly increased myocardiac adiponectin in diabetic rats. It is concluded that late stage diabetic rats displayed reduction of cardiac p-STAT3, adiponectin deficiency, and increase of FoxO1 and CD36 expression, which may be responsible for the loss of myocardial responsiveness to sevo-postC cardioprotection. N-Acetylcysteine restored Sevo-postC cardioprotection in diabetes possibly through enhancing cardiac p-STAT3 and adiponectin and reducing Fox1 and CD36.

  14. Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

    PubMed Central

    Madayag, Aric; Lobner, Doug; Kau, Kristen S.; Mantsch, John R.; Abdulhameed, Omer; Hearing, Matthew; Grier, Mark D.; Baker, David A.

    2010-01-01

    Cocaine produces a persistent reduction in cystine-glutamate exchange via system xc- in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc- influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc- activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered prior to daily cocaine to determine the impact of increased cystine-glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered prior to cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered prior to daily cocaine also prevented the persistent reduction in system xc- activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in 35S cystine transport via system xc-, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least three weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc- activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking. PMID:18094234

  15. N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish.

    PubMed

    Robinson, Bonnie; Dumas, Melanie; Gu, Qiang; Kanungo, Jyotshna

    2018-06-08

    N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine's adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine's adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism. Published by Elsevier B.V.

  16. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis.

    PubMed

    Fernandes, Brisa S; Dean, Olivia M; Dodd, Seetal; Malhi, Gin S; Berk, Michael

    2016-04-01

    To assess the utility of N-acetylcysteine administration for depressive symptoms in subjects with psychiatric conditions using a systematic review and meta-analysis. A computerized literature search was conducted in MEDLINE, Embase, the Cochrane Library, SciELO, PsycINFO, Scopus, and Web of Knowledge. No year or country restrictions were used. The Boolean terms used for the electronic database search were (NAC OR N-acetylcysteine OR acetylcysteine) AND (depression OR depressive OR depressed) AND (trial). The last search was performed in November 2014. The literature was searched for double-blind, randomized, placebo-controlled trials using N-acetylcysteine for depressive symptoms regardless of the main psychiatric condition. Using keywords and cross-referenced bibliographies, 38 studies were identified and examined in depth. Of those, 33 articles were rejected because inclusion criteria were not met. Finally, 5 studies were included. Data were extracted independently by 2 investigators. The primary outcome measure was change in depressive symptoms. Functionality, quality of life, and manic and anxiety symptoms were also examined. A full review and meta-analysis were performed. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% CIs were calculated. Five studies fulfilled our inclusion criteria for the meta-analysis, providing data on 574 participants, of whom 291 were randomized to receive N-acetylcysteine and 283 to placebo. The follow-up varied from 12 to 24 weeks. Two studies included subjects with bipolar disorder and current depressive symptoms, 1 included subjects with MDD in a current depressive episode, and 2 included subjects with depressive symptoms in the context of other psychiatric conditions (1 trichotillomania and 1 heavy smoking). Treatment with N-acetylcysteine improved depressive symptoms as assessed by Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale when compared to placebo (SMD = 0.37; 95% CI = 0

  17. A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine.

    PubMed

    Zell-Kanter, Michele; Coleman, Patrick; Whiteley, Patrick M; Leikin, Jerrold B

    2013-01-01

    The objective of this report is to describe an acidemic patient with one of the largest recorded acetaminophen ingestions in a patient with acidemia who was treated with supportive care and intravenous (IV) N-acetylcysteine. A 59-year-old female with a history of depression was found comatose. In the Emergency Department, she was obtunded with agonal respirations and immediately intubated. Activated charcoal was given through a nasogastric tube. An initial acetaminophen serum level was 1141 mg/L. The patient was started on IV N-acetylcysteine. The acetaminophen level peaked 2 hours later at 1193 mg/L. She was continued on the IV N-acetylcysteine protocol. The next day her aspartate aminotransferase was 3150 U/L, alanine aminotransferase was 2780 U/L, and creatinine phosphokinase was 16,197 U/L. There was no elevation in bilirubin or international normalized ratio (INR). Transaminase levels decreased on day 3 and normalized by day 4 when she was transferred to a psychiatric unit. Few cases have been reported of strikingly elevated acetaminophen levels in poisoned patients who did not receive hemodialysis. These patients did have increased lactate levels, and some had normal liver function tests. All of these patients received N-acetylcysteine and survived the poisoning without sequelae. This patient in this report was unique in that she had the highest reported serum acetaminophen level with acidosis and was treated successfully with only IV N-acetylcysteine and supportive care.

  18. A potential role for N-acetylcysteine in the management of methamphetamine dependence.

    PubMed

    McKetin, Rebecca; Dean, Olivia M; Baker, Amanda L; Carter, Greg; Turner, Alyna; Kelly, Peter J; Berk, Michael

    2017-03-01

    Methamphetamine dependence is a growing problem in Australia and globally. Currently, there are no approved pharmacotherapy options for the management of methamphetamine dependence. N-acetylcysteine is one potential pharmacotherapy option. It has received growing attention as a therapy for managing addictions because of its capacity to restore homeostasis to brain glutamate systems disrupted in addiction and thereby reduce craving and the risk of relapse. N-acetylcysteine also has antioxidant properties that protect against methamphetamine-induced toxicity and it may therefore assist in the management of the neuropsychiatric and neurocognitive effects of methamphetamine. This commentary overviews the actions of N-acetylcysteine and evidence for its efficacy in treating addiction with a particular focus on its potential utility for methamphetamine dependence. We conclude that the preliminary evidence indicates a need for full-scale trials to definitively establish whether N-acetylcysteine has a therapeutic benefit and the nature of this benefit, for managing methamphetamine dependence. [McKetin R, Dean O, Baker A. L, Carter G, Turner A, Kelly P. J, Berk M. A potential role for N-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev 2017;36:153-159]. © 2016 Australasian Professional Society on Alcohol and other Drugs.

  19. N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.

    PubMed

    Catapano, Joseph; Zhang, Jennifer; Scholl, David; Chiang, Cameron; Gordon, Tessa; Borschel, Gregory H

    2017-05-01

    Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.

  20. N-acetylcysteine for sepsis and systemic inflammatory response in adults.

    PubMed

    Szakmany, Tamas; Hauser, Balázs; Radermacher, Peter

    2012-09-12

    Death is common in systemic inflammatory response syndrome (SIRS) or sepsis-induced multisystem organ failure and it has been thought that antioxidants such as N-acetylcysteine could be beneficial. We assessed the clinical effectiveness of intravenous N-acetylcysteine for the treatment of patients with SIRS or sepsis. We searched the following databases: Cochrane Central Register of Clinical Trials (CENTRAL) (The Cochrane Library 2011, Issue 12); MEDLINE (January 1950 to January 2012); EMBASE (January 1980 to January 2012); CINAHL (1982 to January 2012); the NHS Trusts Clinical Trials Register and Current Controlled Trials (www.controlled-trials.com); LILACS; KoreaMED; MEDCARIB; INDMED; PANTELEIMON; Ingenta; ISI Web of Knowledge and the National Trials Register to identify all relevant randomized controlled trials available for review. We included only randomized controlled trials (RCTs) in the meta-analysis. We independently performed study selection, quality assessment and data extraction. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We included 41 fully published studies (2768 patients). Mortality was similar in the N-acetylcysteine group and the placebo group (RR 1.06, 95% CI 0.79 to 1.42; I(2) = 0%). Neither did N-acetylcysteine show any significant effect on length of stay, duration of mechanical ventilation or incidence of new organ failure. Early application of N-acetylcysteine to prevent the development of an oxidato-inflammatory response did not affect the outcome, nor did late application that is after 24 hours of developing symptoms. Late application was associated with cardiovascular instability. Overall, this meta-analysis puts doubt on the safety and utility of intravenous N-acetylcysteine as an adjuvant therapy in SIRS and sepsis. At best, N-acetylcysteine is ineffective in reducing mortality and complications in this patient population. At worst, it can be harmful

  1. Effect of N-Acetylcysteine on Adipose-Derived Stem Cell and Autologous Fat Graft Survival in a Mouse Model.

    PubMed

    Gillis, Joshua; Gebremeskel, Simon; Phipps, Kyle D; MacNeil, Lori A; Sinal, Christopher J; Johnston, Brent; Hong, Paul; Bezuhly, Michael

    2015-08-01

    Autologous fat grafting is a popular reconstructive technique, but is limited by inconsistent graft retention. The authors examined whether a widely available, clinically safe antioxidant, N-acetylcysteine, could improve adipose-derived stem cell survival and graft take when added to tumescent solution during fat harvest. Inguinal fat pads were harvested from C57BL/6 mice using tumescent solution with or without N-acetylcysteine. Flow cytometric, proliferation, and differentiation assays were performed on isolated primary adipose-derived stem cells and 3T3-L1 preadipocytes treated with or without hydrogen peroxide and/or N-acetylcysteine. N-Acetylcysteine-treated or control grafts were injected under recipient mouse scalps and assessed by serial micro-computed tomographic volumetric analysis. Explanted grafts underwent immunohistochemical analysis. In culture, N-acetylcysteine protected adipose-derived stem cells from oxidative stress and improved cell survival following hydrogen peroxide treatment. Combined exposure to both N-acetylcysteine and hydrogen peroxide led to a 200-fold increase in adipose-derived stem cell proliferation, significantly higher than with either agent alone. N-Acetylcysteine decreased differentiation of adipose-derived stem cells into mature adipocytes, as evidenced by decreased transcription of adipocyte differentiation markers and reduced Oil Red-O staining. In vivo, N-acetylcysteine treatment resulted in improved graft retention at 3 months compared with control (46 versus 17 percent; p = 0.027). N-Acetylcysteine-treated grafts demonstrated less fibrosis and inflammation, and a 33 percent increase in adipocyte density compared with controls (p < 0.001) that was not associated with increased vascularity. These findings provide proof of principle for the addition of N-acetylcysteine to tumescent harvest solution in the clinical setting to optimize fat graft yields.

  2. A Biomedical Application of Activated Carbon Adsorption: An Experiment Using Acetaminophen and N-Acetylcysteine.

    ERIC Educational Resources Information Center

    Rybolt, Thomas R.; And Others

    1988-01-01

    Illustrates an interesting biomedical application of adsorption from solution and demonstrates some of the factors that influence the in vivo adsorption of drug molecules onto activated charcoal. Uses acetaminophen and N-acetylcysteine for the determination. Suggests several related experiments. (MVL)

  3. Similarities between N-acetylcysteine and Glutathione in Binding to Lead(II) Ions

    PubMed Central

    Sisombath, Natalie S.; Jalilehvand, Farideh

    2015-01-01

    N -acetylcysteine is a natural thiol-containing antioxidant, a precursor for cysteine and glutathione, and a potential detoxifying agent for heavy metal ions. However, previous accounts of the efficiency of N-acetylcysteine (H2NAC) in excretion of lead are few and contradicting. Here we report results on the nature of lead(II) complexes formed with N-acetylcysteine in aqueous solution, which were obtained by combining information from several spectroscopic methods, including 207Pb, 13C and 1H NMR, Pb LIII-edge X-ray absorption, Ultraviolet-visible (UV-vis.) spectroscopy and electro-spray ionization mass spectrometry (ESI-MS). Two series of solutions were used containing CPb(II) = 10 and 100 mM, respectively, varying the H2NAC / Pb(II) mole ratios from 2.1 to 10.0 at pH = 9.1 – 9.4. The coordination environments obtained resemble those previously found for the Pb(II) glutathione system: at a ligand-to-lead mole ratio of 2.1 dimeric or oligomeric Pb(II) N-acetylcysteine complexes are formed, while a tri-thiolate [Pb(NAC)3]4− complex dominates in solutions with H2NAC/Pb(II) mole ratios > 3.0. PMID:26624959

  4. Minocycline and N-acetylcysteine: A Synergistic Drug Combination to Treat Traumatic Brain Injury

    DTIC Science & Technology

    2013-10-01

    Contract Number: W81XWH-10-2-0171 TITLE: Minocycline and...30September2012-29September2013 4. TITLE AND SUBTITLE Minocycline and N-acetylcysteine: a synergistic drug combination to treat...grantee previously found screened that the combination of minocycline (MINO) and N-acetyl cysteine (NAC) synergistically improved brain function when

  5. The Role of N-Acetylcysteine in the Prevention of Contrast-Induced Nephrotoxicity

    SciTech Connect

    Sandhu, Caron; Belli, Anna-Maria; Oliveira, David B.

    2006-06-15

    Purpose. To determine the role of prophylactic N-acetylcysteine in the prevention of contrast-induced nephrotoxicity. Methods. One hundred and sixteen patients undergoing noncoronary angiography, with or without pre-existing renal impairment, were randomly assigned to receive prophylactic oral N-acetylcysteine or no treatment. Serum creatinine (sCr) was measured prior to angiography and 48 hr after the procedure. Urine samples were collected before and after the examination for measurement of malondialdehyde (MDA) concentration. Contrast-induced nephrotoxicity (CIN) was defined as a rise in serum creatinine of 0.5 mg/dl (44 mmol/l) at 48 hr. Results. Complete data were available on 106 patients, 53 of whom hadmore » received N-acetylcysteine. There were no significant differences between the two groups in baseline characteristics, type of angiogram, or volume and concentration of contrast used. Three patients (2.8%), all of whom had received N-acetylcysteine, developed CIN. In the N-acetylcysteine group, the mean serum creatinine in patients with renal impairment was 151.0 {+-} 44.2 {mu}mol/l prior to the procedure and 155.6 {+-} 48.6 {mu}mol/l (p = 0.49) after the procedure. Respective values for those without renal impairment were 79.6 {+-} 15.1 {mu}mol/l and 81.2 {+-} 20.0 {mu}mol/l (p = 0.65). In the group that had not received N-acetylcysteine, the mean serum creatinine levels before and after the procedure were 150.0 {+-} 58.1 and 141.4 {+-} 48.0 {mu}mol/l (p = 0.17) in patients with renal impairment and 79.7 {+-} 14.2 and 81.4 {+-} 15.4 {mu}mol/l (p = 0.34) in those without renal impairment. In both groups, no significant change in urinary MDA concentration was observed. Conclusion. There is no benefit to the prophylactic administration of N-acetylcysteine in patients undergoing peripheral angiography using current contrast media.« less

  6. N-acetylcysteine in Acute Organophosphorus Pesticide Poisoning: A Randomized, Clinical Trial.

    PubMed

    El-Ebiary, Ahmad A; Elsharkawy, Rasha E; Soliman, Nema A; Soliman, Mohammed A; Hashem, Ahmed A

    2016-08-01

    Organophosphorus poisoning is a major global health problem with hundreds of thousands of deaths each year. Research interest in N-acetylcysteine has grown among increasing evidence of the role of oxidative stress in organophosphorus poisoning. We aimed to assess the safety and efficacy of N-acetylcysteine as an adjuvant treatment in patients with acute organophosphorus poisoning. This was a randomized, controlled, parallel-group trial on 30 patients suffering from acute organophosphorus poisoning, who were admitted to the Poison Control Center of Tanta University Emergency Hospital, Tanta, Egypt, between April and September 2014. Interventions included oral N-acetylcysteine (600 mg three times daily for 3 days) as an added treatment to the conventional measures versus only the conventional treatment. Outcome measures included mortality, total dose of atropine administered, duration of hospitalization and the need for ICU admission and/or mechanical ventilation. A total of 46 patients were screened and 30 were randomized. No significant difference was found between both groups regarding demographic characteristics and the nature or severity of baseline clinical manifestations. No major adverse effects to N-acetylcysteine therapy were reported. Malondialdehyde significantly decreased and reduced glutathione significantly increased only in the NAC-treated patients. The patients on NAC therapy required less atropine doses than those who received only the conventional treatment; however, the length of hospital stay showed no significant difference between both groups. The study concluded that the use of N-acetylcysteine as an added treatment was apparently safe, and it reduced atropine requirements in patients with acute organophosphorus pesticide poisoning. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  7. Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication.

    PubMed

    Paridaens, Annelies; Raevens, Sarah; Colle, Isabelle; Bogaerts, Eliene; Vandewynckel, Yves-Paul; Verhelst, Xavier; Hoorens, Anne; van Grunsven, Leo A; Van Vlierberghe, Hans; Geerts, Anja; Devisscher, Lindsey

    2017-05-01

    Acetaminophen overdose in mice is characterized by hepatocyte endoplasmic reticulum stress, which activates the unfolded protein response, and centrilobular hepatocyte death. We aimed at investigating the therapeutic potential of tauroursodeoxycholic acid, a hydrophilic bile acid known to have anti-apoptotic and endoplasmic reticulum stress-reducing capacities, in experimental acute liver injury induced by acetaminophen overdose. Mice were injected with 300 mg/kg acetaminophen, 2 hours prior to receiving tauroursodeoxycholic acid, N-acetylcysteine or a combination therapy, and were euthanized 24 hours later. Liver damage was assessed by serum transaminases, liver histology, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, expression profiling of inflammatory, oxidative stress, unfolded protein response, apoptotic and pyroptotic markers. Acetaminophen overdose resulted in a significant increase in serum transaminases, hepatocyte cell death, unfolded protein response activation, oxidative stress, NLRP3 inflammasome activation, caspase 1 and pro-inflammatory cytokine expressions. Standard of care, N-acetylcysteine and, to a lesser extent, tauroursodeoxycholic treatment were associated with significantly lower transaminase levels, hepatocyte death, unfolded protein response activation, oxidative stress markers, caspase 1 expression and NLRP3 levels. Importantly, the combination of N-acetylcysteine and tauroursodeoxycholic acid improved serum transaminase levels, reduced histopathological liver damage, UPR-activated CHOP, oxidative stress, caspase 1 expression, NLRP3 levels, IL-1β levels and the expression of pro-inflammatory cytokines and this to a greater extend than N-acetylcysteine alone. These findings indicate that a combination strategy of N-acetylcysteine and tauroursodeoxycholic acid surpasses the standard of care in acetaminophen-induced liver injury in mice and might represent an attractive therapeutic opportunity for acetaminophen

  8. Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

    PubMed

    Sun, Tong; Liu, Jing; Zhao, De Wei

    2016-05-01

    There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis.Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1.Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to -0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02-0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: -0.13-0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: -0.06-0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19-106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3-5.12; P = 0.28) between the N-acetylcysteine group and the control group.N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity

  9. [Decreasing reperfusion damage with N-acetylcysteine in experimental pancreas transplantion].

    PubMed

    Mayer, H; Thies, J; Schmidt, J; Gebhard, M M; Herfarth, C; Klar, E

    1998-01-01

    In this study we investigated the effect of donor and recipient conditioning with N-acetylcysteine on the ischemia/reperfusion injury after experimental pancreas-transplantation. We performed standardized pancreaticoduodenal transplantation in male lewis rats. The pancreas was perfused with UW-solution, harvested and conserved at 4 degrees C. Cold ischemia time was 1.5 hours and 16 hours respectively. The microcirculation in the transplanted organ was quantified by means of intravital microscopy 1.5 hours after implantation and reperfusion in the recipient. After 16 hours of cold ischemia we found a significant reduction in capillary erythrocyte velocity and a significantly enhanced leucocyte/endothelium interaction. The treatment with N-acetylcysteine resulted in a significant improvement of these microcirculatory disorders after prolonged cold ischemia.

  10. N-acetylcysteine in Cleistanthus collinus Poisoning: A Report of Two Cases in Children.

    PubMed

    Sharma, Shreya; Rameshkumar, Ramachandran; Mahadevan, Subramanian

    2016-12-01

    Cleistanthus collinus, also known as Oduvanthalai in Tamil, is the most commonly encountered plant poison in southern India. The leaves are used for poisoning humans (suicide or homicide) and animals (cattle and fish) and as an abortifacient, especially in rural south India. Although this poisoning is commonly reported in adults, data regarding the use of N-acetylcysteine in pediatric poisoning is lacking. We report two previously healthy male siblings of pediatric age group who ingested the liquid extracted from crushed leaves of this plant given to them by their mother as a means of deliberate harm. Both patients developed distal renal tubular acidosis, with hypokalemia. The younger sibling also developed myocardial toxicity. Other significant findings noted include hypocalcemia, hypomagnesemia and elevated liver enzymes. Both patients received supportive care along with N-acetylcysteine infusion, and showed complete recovery within 10 days. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

    PubMed Central

    Dean, Olivia; Giorlando, Frank; Berk, Michael

    2011-01-01

    There is an expanding field of research investigating the benefits of alternatives to current pharmacological therapies in psychiatry. N-acetylcysteine (NAC) is emerging as a useful agent in the treatment of psychiatric disorders. Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. This review outlines the current literature regarding the use of NAC in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder. N-acetylcysteine has shown promising results in populations with these disorders, including those in whom treatment efficacy has previously been limited. The therapeutic potential of this acetylated amino acid is beginning to emerge in the field of psychiatric research. PMID:21118657

  12. Biological Activities and Potential Oral Applications of N-Acetylcysteine: Progress and Prospects

    PubMed Central

    Pei, Yanping; Liu, Huan; Yang, Yi; Yang, Yanwei

    2018-01-01

    N-Acetylcysteine (NAC), a cysteine prodrug and glutathione (GSH) precursor, has been used for several decades in clinical therapeutic practices as a mucolytic agent and for the treatment of disorders associated with GSH deficiency. Other therapeutic activities of NAC include inhibition of inflammation/NF-κB signaling and expression of proinflammatory cytokines. N-Acetylcysteine is also a nonantibiotic compound possessing antimicrobial property and exerts anticarcinogenic and antimutagenic effects against certain types of cancer. Recently, studies describing potentially important biological and pharmacological activities of NAC have stimulated interests in using NAC-based therapeutics for oral health care. The present review focused on the biological activities of NAC and its potential oral applications. The potential side effects of NAC and formulations for drug delivery were also discussed, with the intent of advancing NAC-associated treatment modalities in oral medicine. PMID:29849877

  13. N-acetylcysteine does not prevent post-endoscopic retrograde cholangiopancreatography hyperamylasemia and acute pancreatitis

    PubMed Central

    Milewski, Janusz; Rydzewska, Grazyna; Degowska, Malgorzata; Kierzkiewicz, Maciej; Rydzewski, Andrzej

    2006-01-01

    AIM: Acute pancreatitis (AP) is the most common and often severe complication of endoscopic retrograde cholangiopancreatography (ERCP). The early step in the pathogenesis of acute pancreatitis is probably the capillary endothelial injury mediated by oxygen-derived free radicals. N-acetylcysteine - a free radical scavenger may be potentially effective in preventing post-ERCP acute pancreatitis and it is also known that N-acetylcysteine (ACC) can reduce the severity of disease in experimental model of AP. METHODS: One hundred and six patients were randomly allocated to two groups. Fifty-five patients were given N-acetylcysteine (two 600 mg doses orally 24 and 12 h before ERCP and 600 mg was given iv, twice a day for two days after the ERCP). The control group consisted of 51 patients who were given iv. isotonic saline twice a day for two days after the ERCP. Serum and urine amylase activities were measured before ERCP and 8 and 24 h after the procedure. The primary outcome parameter was post-ERCP acute pancreatitis and the secondary outcome parameters were differences between groups in serum and urine amylase activity. RESULTS: There were no significant differences in the rate of post-ERCP pancreatitis between two groups (10 patients overall, 4 in the ACC group and 6 in the control group). There were also no significant differences in baseline and post-ERCP serum and urine amylase activity between ACC group and control group. CONCLUSION: N-acetylcysteine fails to demonstrate any significant preventive effect on post-ERCP pancreatitis, as well as on serum and urine amylase activity. PMID:16773694

  14. N-acetylcysteine does not prevent post-endoscopic retrograde cholangiopancreatography hyperamylasemia and acute pancreatitis.

    PubMed

    Milewski, Janusz; Rydzewska, Grazyna; Degowska, Malgorzata; Kierzkiewicz, Maciej; Rydzewski, Andrzej

    2006-06-21

    Acute pancreatitis (AP) is the most common and often severe complication of endoscopic retrograde cholangiopancreatography (ERCP). The early step in the pathogenesis of acute pancreatitis is probably the capillary endothelial injury mediated by oxygen-derived free radicals. N-acetylcysteine - a free radical scavenger may be potentially effective in preventing post-ERCP acute pancreatitis and it is also known that N-acetylcysteine (ACC) can reduce the severity of disease in experimental model of AP. One hundred and six patients were randomly allocated to two groups. Fifty-five patients were given N-acetylcysteine (two 600 mg doses orally 24 and 12 h before ERCP and 600 mg was given iv, twice a day for two days after the ERCP). The control group consisted of 51 patients who were given iv. isotonic saline twice a day for two days after the ERCP. Serum and urine amylase activities were measured before ERCP and 8 and 24 h after the procedure. The primary outcome parameter was post-ERCP acute pancreatitis and the secondary outcome parameters were differences between groups in serum and urine amylase activity. There were no significant differences in the rate of post-ERCP pancreatitis between two groups (10 patients overall, 4 in the ACC group and 6 in the control group). There were also no significant differences in baseline and post-ERCP serum and urine amylase activity between ACC group and control group. N-acetylcysteine fails to demonstrate any significant preventive effect on post-ERCP pancreatitis, as well as on serum and urine amylase activity.

  15. A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery

    PubMed Central

    Bagger-Sjöbäck, Dan; Strömbäck, Karin; Hakizimana, Pierre; Plue, Jan; Larsson, Christina; Hultcrantz, Malou; Papatziamos, Georgios; Smeds, Henrik; Danckwardt-Lillieström, Niklas; Hellström, Sten; Johansson, Ann; Tideholm, Bo; Fridberger, Anders

    2015-01-01

    Background Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. Methods We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. Findings One year after surgery, high-frequency hearing had improved 2.7 ± 3.8 dB in the placebo group (67 patients analysed) and 2.4 ± 3.7 dB in the treated group (72 patients; means ± 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. Conclusions N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy. Trial Registration ClinicalTrials.gov NCT00525551 PMID:25763866

  16. N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

    PubMed

    Levi Bolin, B; Alcorn, Joseph L; Lile, Joshua A; Rush, Craig R; Rayapati, Abner O; Hays, Lon R; Stoops, William W

    2017-09-01

    Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study.

    PubMed

    Okuda, Ryo; Matsushima, Hidekazu; Oba, Tomohiro; Kawabe, Rie; Matsubayashi, Minako; Amano, Masako; Nishizawa, Tomotaka; Honda, Koujiro

    2016-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. The efficacy of N-acetylcysteine in patients with IPF remains controversial. The aim of this research was to investigate the efficacy of inhaled N-acetylcysteine. This study was designed as a single-center, single-arm, prospective clinical trial. Each patient who had IPF received 352.4mg of inhaled N-acetylcysteine twice daily. In total, 28 patients were enrolled. The mean values of the respiratory function parameters at the initiation of therapy were as follows: forced vital capacity (FVC), 2.27L and %FVC, 76.2%. The mean change in FVC during 26 weeks prior to the inhaled N-acetylcysteine therapy was -170mL, a significant decrease (p=0.019). The mean change in FVC during 26 weeks after the initiation of inhaled N-acetylcysteine therapy was -70mL (p=0.06). When the patients were classified into two groups according to the degree of decline in FVC (≥100mL vs. <100mL) during the 26-week period prior to the initiation of therapy, inhaled N-acetylcysteine showed a greater efficacy in attenuating FVC decline in the ≥100-mL group than in the <100-mL group. Inhaled N-acetylcysteine therapy was effective in patients with mild-to-moderate IPF and was more beneficial in patients who had greater declines in FVC before the initiation of therapy. (UMIN title: Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis, UMIN000016706, 2015/03/04.). Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  18. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study.

    PubMed

    Grant, Jon E; Odlaug, Brian L; Kim, Suck Won

    2009-07-01

    Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior. To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania. Twelve-week, double-blind, placebo-controlled trial. Ambulatory care center. Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years). N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks. Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population. Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P < .001) and the Psychiatric Institute Trichotillomania Scale (P = .001). Fifty-six percent of patients "much or very much improved" with N-acetylcysteine use compared with 16% taking placebo (P = .003). Significant improvement was initially noted after 9 weeks of treatment. This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated. Pharmacologic modulation of the glutamate system may prove to be useful in

  19. Effect of N-acetylcysteine on vascular endothelium function in aorta from oophorectomized rats.

    PubMed

    Delgado, J L; Landeras, J; Carbonell, L F; Parilla, J J; Abad, L; Quesada, T; Fiol, G; Hernández, I

    1999-01-01

    1. Experiments were performed to examine and to compare vascular endothelial function in aortic rings from oophorectomized and from ovary-intact rats and to test the effect of thiol compound as N-acetylcysteine on endothelial function. 2. In precontracted aortic rings from oophorectomized and intact rats, vascular endothelial function was evaluated by measuring changes in isometric force in response to cumulative doses of superoxide dismutase, acetylcholine and sodium nitroprusside. 3. In studies designed to assess the tone-related release of nitric oxide from aortic rings moderately precontracted with phenylephrine, superoxide dismutase produced a lower concentration-related relaxant response in aortic rings from oophorectomized rats than from ovary intact rats. 4. Acetylcholine caused a concentration- and endothelium-dependent relaxation of less magnitude in aortic rings from oophorectomized animals compared with those from ovary-intact rats. Addition of N-omega-nitro-L-arginine methyl ester eliminated the relaxation induced by both superoxide dismutase and acetylcholine. 5. No differences between groups were noticed in the concentration-relaxation curve induced by sodium nitroprusside. 6. Preincubation with N-acetylcysteine normalized the depressed vasorelaxant response to acetylcholine in the aortic rings from oophorectomized rats, whereas the concentration-response curve for acetylcholine in aortic rings from ovary-intact rats did not alter. 7. These results suggest that the absence of ovary estrogens is associated with a vascular endothelium dysfunction that can be reverted by addition of N-acetylcysteine, a thiol-containing compound with a free radical scavenger effect.

  20. N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

    PubMed

    Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

    1989-09-01

    Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

  1. SPICE/K2 Synthetic Marijuana-Induced Toxic Hepatitis Treated with N-Acetylcysteine

    PubMed Central

    Sheikh, Israr A.; Lukšič, Miha; Ferstenberg, Richard; Culpepper-Morgan, Joan A.

    2014-01-01

    Patient: Male, 45 Final Diagnosis: Spice/K2 induced liver injury Symptoms: Lethargy • somnolence • fatigue Medication: N-acetylcysteine Clinical Procedure: — Specialty: Gastroenterology Objective: Rare disease Background: Spice/K2 is one of several street names for synthetic marijuana. These hallucinogens are increasingly sold over the internet and in “head” shops. They are usually household herbs that are sprayed with chemicals that become centrally active compounds when burned together and inhaled by smoking. Case Report: We present a case of a 45-year-old male substance abuser who was admitted with evidence of hepatocellular necrosis and worsening liver failure. Tests for acetaminophen were negative, as were tests for alcohol. The patient was empirically treated with N-acetylcysteine. Hepatocellular damage was abated and the patient made a full recovery. Upon regaining consciousness, the patient admitted to smoking Spice/K2. Other toxicities have been reported with synthetic marijuana use, but not liver toxicity. Conclusions: Physicians need to have a high index of suspicion for unknown hepatotoxins in substance abusers. N-acetylcysteine can be given if there is no contraindication. PMID:25548903

  2. Oral administration of the antioxidant, N-acetylcysteine, abrogates diabetes-induced endothelial dysfunction.

    PubMed

    Pieper, G M; Siebeneich, W

    1998-07-01

    Oxidative stress is believed to play an important role in the development of vascular complications associated with diabetes mellitus. In this study, we examined the efficacy of long-term treatment with the antioxidant, N-acetylcysteine, in preventing the development of defective endothelium-dependent relaxation in streptozotocin-induced, Sprague-Dawley diabetic rats. At 48 h after injection of streptozotocin, a portion of diabetic rats received 250 mg/L N-acetylcysteine in drinking water for a total duration of 8 weeks. Oral administration did not alter the increase in blood glucose or the reduction in serum insulin but did modestly reduce total glycosylated hemoglobin. In precontracted thoracic aortic rings suspended in isolated tissue baths, endothelium-dependent relaxation to acetylcholine was impaired in diabetic rings compared with control rings. Endothelium-independent relaxation to nitroglycerin was unaltered. Long-term oral administration of N-acetylcysteine did not alter responses to nitroglycerin but completely prevented the defective relaxation to acetylcholine. These studies indicate a dissociation between glycemic control and correction of endothelial dysfunction and suggest that long-term exposure to reactive oxygen subsequent to diabetes rather than hyperglycemia per se is responsible for the development of endothelial dysfunction in diabetes mellitus.

  3. Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats.

    PubMed

    Pereira-Filho, Gustavo; Ferreira, Clarissa; Schwengber, Alex; Marroni, Cláudio; Zettler, Cláudio; Marroni, Norma

    2008-01-01

    Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. The animals were randomly in three experimental groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.

  4. N-Acetylcysteine's Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements.

    PubMed

    Chertoff, Jason

    2018-02-01

    To review the data surrounding the utility of N-acetylcysteine (NAC) in sepsis and identify areas needed for additional research. A review of articles describing the mechanisms of action and clinical use of NAC in sepsis. Despite many advances in critical care medicine, still as many as 50% of patients with septic shock die. Treatments thus far have focused on resuscitation and restoration of macrocirculatory targets in the early phases of sepsis, with less focus on microcirculatory dysfunction. N-acetylcysteine, due to its anti-inflammatory and antioxidative properties, has been readily investigated in sepsis and has yielded largely incongruous and disappointing results. In addition to its known anti-inflammatory and antioxidative roles, one underappreciated property of NAC is its ability to vasodilate the microcirculation and improve locoregional blood flow. Some investigators have sought to capitalize on this mechanism with promising results, as evidenced by microcirculatory vasodilation, improvements in regional blood flow and oxygen delivery, and reductions in lactic acidosis, organ failure, and mortality. In addition to its antioxidant and anti-inflammatory properties, N-acetylcysteine possesses vasodilatory properties that could benefit the microcirculation in sepsis. It is imperative that we investigate these properties to uncover NAC's full potential for benefit in sepsis.

  5. N-Acetylcysteine supplementation reduces oxidative stress and DNA damage in children with β-thalassemia.

    PubMed

    Ozdemir, Zeynep Canan; Koc, Ahmet; Aycicek, Ali; Kocyigit, Abdurrahim

    2014-01-01

    There are several reports that increased oxidative stress and DNA damage were found in β-thalassemia major (β-TM) patients. In this study, we aimed to evaluate the effects of N-acetylcysteine (NAC) and vitamin E on total oxidative stress and DNA damage in children with β-TM. Seventy-five children with transfusion-dependent β-thalassemia (β-thal) were randomly chosen to receive 10 mg/kg/day of NAC or 10 IU/kg/day of vitamin E or no supplementation; 28 healthy controls were also included in the study. Serum total oxidant status (TOS) and total antioxidant capacity (TAC) were measured, oxidative stress index (OSI) was calculated, and mononuclear DNA damage was assessed by alkaline comet assay; they were determined before treatment and after 3 months of treatment. Total oxydent status, OSI, and DNA damage levels were significantly higher and TAC levels were significantly lower in the thalassemic children than in the healthy controls (p < 0.001). In both supplemented groups, mean TOS and OSI levels were decreased; TAC and pre transfusion hemoglobin (Hb) levels were significantly increased after 3 months (p ≤ 0.002). In the NAC group, DNA damage score decreased (p = 0.001). N-Acetylcysteine and vitamin E may be effective in reducing serum oxidative stress and increase pre transfusion Hb levels in children with β-thal. N-Acetylcysteine also can reduce DNA damage.

  6. Precise determination of N-acetylcysteine in pharmaceuticals by microchip electrophoresis.

    PubMed

    Rudašová, Marína; Masár, Marián

    2016-01-01

    A novel microchip electrophoresis method for the rapid and high-precision determination of N-acetylcysteine, a pharmaceutically active ingredient, in mucolytics has been developed. Isotachophoresis separations were carried out at pH 6.0 on a microchip with conductivity detection. The methods of external calibration and internal standard were used to evaluate the results. The internal standard method effectively eliminated variations in various working parameters, mainly run-to-run fluctuations of an injected volume. The repeatability and accuracy of N-acetylcysteine determination in all mucolytic preparations tested (Solmucol 90 and 200, and ACC Long 600) were more than satisfactory with the relative standard deviation and relative error values <0.7 and <1.9%, respectively. A recovery range of 99-101% of N-acetylcysteine in the analyzed pharmaceuticals predetermines the proposed method for accurate analysis as well. This work, in general, indicates analytical possibilities of microchip isotachophoresis for the quantitative analysis of simplified samples such as pharmaceuticals that contain the analyte(s) at relatively high concentrations. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. External anal sphincter fatigue is not improved by N-acetylcysteine in an animal model.

    PubMed

    Healy, C F; McMorrow, C; O'Herlihy, C; O'Connell, P R; Jones, J F X

    2008-06-01

    Oxidative stress is associated with skeletal muscle fatigue. This study tests the hypotheses that N-acetylcysteine (NAC) reduces fatigue and accelerates recovery of the rat external anal sphincter (EAS). Fifteen female Wistar rats were killed humanely. The EAS was mounted as a ring preparation and electrically stimulated with 50 Hz trains of 200 ms in duration every 4 s for three and a half minutes. Three groups were analysed: a control group (n = 5), a group pretreated with NAC (10(-4) mol L(-1); n = 5) and a group pretreated with NAC (10(-3) mol L(-1); n = 5). A novel fatigue index was formulated and was compared to a conventional method of expressing fatigue. There was no significant difference at concentrations of NAC (10(-4) mol L(-1); P > 0.05). At high concentrations of NAC (10(-3) mol L(-1)) there was a significant depression in peak twitch amplitude before fatigue (P = 0.04). N-acetylcysteine in both concentrations used, did not alter fatigue or recovery of the rat EAS. There was a significant positive correlation between the two methods of expressing fatigue but the conventional method produced a higher fatigue index (22.4% on average). N-acetylcysteine does not ameliorate fatigue or accelerate recovery of the EAS and may not be a useful medical therapy for faecal incontinence.

  8. Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats.

    PubMed

    Farshid, Amir Abbas; Tamaddonfard, Esmaeal; Najafi, Sima

    2015-10-01

    In this study, the effect of separate and combined intraperitoneal (i.p.) injections of histidine and n-acetylcysteine were investigated on experimental damage induced by doxorubicin (DOX) in sciatic nerve of rats. DOX was i.p. injected at a dose of 4 mg/kg once weekly for four weeks. Histidine and n-acetylcysteine were i.p. injected at a same dose of 20 mg/kg. Cold and mechanical allodynia were recorded using acetone spray and von Frey filaments tests, respectively. The sciatic nerve damage was evaluated by light microscopy. Plasma levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Histidine and especially n-acetylcysteine at a same dose of 20 mg/kg suppressed cold and mechanical allodynia, improved sciatic nerve lesions and reversed MDA and TAC levels in DOX-treated groups. Combination treatment with histidine and n-acetylcysteine showed better responses when compared with them used alone. The results of the present study showed peripheral neuroprotective effects for histidine and n-acetylcysteine. Reduction of free radical-induced toxic effects may have a role in neuroprotective properties of histidine and n-acetylcysteine.

  9. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects.

    PubMed

    Al-Samhari, Marwa M; Al-Rasheed, Nouf M; Al-Rejaie, Salim; Al-Rasheed, Nawal M; Hasan, Iman H; Mahmoud, Ayman M; Dzimiri, Nduna

    2016-03-01

    Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P < 0.05), serum corticosterone (P < 0.001), and hydrogen peroxide (P < 0.001), while restored glutathione concentration. Treatment of the rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant-like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy. © 2015 by the Society for Experimental Biology and Medicine.

  10. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects

    PubMed Central

    Al-Samhari, Marwa M; Al-Rasheed, Nouf M; Al-Rejaie, Salim; Al-Rasheed, Nawal M; Hasan, Iman H; Dzimiri, Nduna

    2015-01-01

    Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P < 0.05), serum corticosterone (P < 0.001), and hydrogen peroxide (P < 0.001), while restored glutathione concentration. Treatment of the rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant-like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy. PMID:26643864

  11. N-Acetylcysteine in the Treatment of Excoriation Disorder: A Randomized Clinical Trial.

    PubMed

    Grant, Jon E; Chamberlain, Samuel R; Redden, Sarah A; Leppink, Eric W; Odlaug, Brian L; Kim, Suck Won

    2016-05-01

    Excoriation (skin-picking) disorder (SPD) is a disabling, underrecognized condition in which individuals repeatedly pick at their skin, leading to noticeable tissue damage. To date, there has been no clearly effective pharmacologic or psychological treatment for SPD. To determine whether N-acetylcysteine, an amino acid that appears to restore extracellular glutamate concentration in the nucleus accumbens, will be more effective than placebo in reducing compulsive picking behavior. A randomized, double-blind trial was conducted at ambulatory care centers at the University of Minnesota (September 12, 2011, to June 15, 2012) and the University of Chicago (December 17, 2012, to June 26, 2015) and included 66 adults with SPD. Data analysis was performed from July 16 to September 9, 2015. N-acetylcysteine (dosing range, 1200-3000 mg/d) or placebo was administered for 12 weeks. Participants were assessed using measures of skin-picking severity, including the modified Yale-Brown Obsessive Compulsive Scale (NE-YBOCS); total scores range from 0 to 40, with higher scores reflective of greater symptom severity. Another measure of skin-picking severity was the Clinical Global Impression-Severity Scale; total scores range from 1 (normal) to 7 (among the most extremely ill patients), and improvement ratings range from 7 (very much worse) to 1 (very much improved). Selected cognitive tasks included the Intra-dimensional/Extra-dimensional Shift Task to examine cognitive flexibility, with the key outcome measures being the number of errors, and Stop-Signal Reaction Time task, which evaluates motor inhibition. Outcomes were examined using a linear mixed-effects model. Of the 66 participants (31 randomized to placebo and 35 to N-acetylcysteine) included in the analysis, 59 (89%) were women; mean (SD) age was 34.8 (11.0) years. Compared with placebo, N-acetylcysteine treatment was associated with significant improvements in the NE-YBOCS. At baseline, NE-YBOCS scores were 18.9 and 17

  12. Efficacy of simethicone and N-acetylcysteine as premedication in improving visibility during upper endoscopy.

    PubMed

    Chang, Wei-Kuo; Yeh, Ming-Kung; Hsu, Hsuang-Chun; Chen, Hsuan-Wei; Hu, Ming-Kuan

    2014-04-01

    Simethicone and N-acetylcysteine have been widely used in improving endoscopic visibility. However, the optimal dose, volume, and dosing time for the premedication regimen are still unclear. Our aim was to assess the efficacy of premedication in improving endoscopic visibility and determine the contributions of dose, volume, and premedication time. A total of 1849 patients were prospectively treated in three groups: group A: 100-mg simethicone suspension in 5 mL water; group B: 100-mg simethicone suspension in 100 mL water; and group C: 100-mg simethicone suspension in 100 mL water containing 200 mg N-acetylcysteine. Mucosa visibility was assessed at seven sites of upper gastrointestinal tract. The sum of scores was considered as total mucosal visibility score (TMVS). The upper body of stomach had the worst visibility score for all groups. TMVS of groups B and C were significantly lower than those of group A. Group C had a significantly fewer patients requiring endoscopic flushing than groups A and B. The TMVS for groups B and C were significantly lower than for group A within 30 min of beginning premedication. Beyond 30 min of premedication, there was no significant difference in the TMVS among groups. Premedication using 100 mg simethicone in 100 mL of water improves endoscopic visibility. Addition of N-acetylcysteine to simethicone in 100 mL of water reduces the need for endoscopic flushing. For patients unable to tolerate a large fluid volume, a 5-mL simethicone suspension administered more than 30 min prior to upper endoscopy is suggested. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  13. Prevention and reversal of selenite-induced cataracts by N-acetylcysteine amide in Wistar rats.

    PubMed

    Maddirala, Yasaswi; Tobwala, Shakila; Karacal, Humeyra; Ercal, Nuran

    2017-04-26

    The present study sought to evaluate the efficacy of N-acetylcysteine amide (NACA) eye drops in reversing the cataract formation induced by sodium selenite in male Wistar rat pups. Forty male Wistar rat pups were randomly divided into a control group, an N-acetylcysteine amide-only group, a sodium selenite-induced cataract group, and a NACA-treated sodium selenite-induced cataract group. Sodium selenite was injected intraperitoneally on postpartum day 10, whereas N-acetylcysteine amide was injected intraperitoneally on postpartum days 9, 11, and 13 in the respective groups. Cataracts were evaluated at the end of week 2 (postpartum day 14) when the rat pups opened their eyes. N-acetylcysteine amide eye drops were administered beginning on week 3 until the end of week 4 (postpartum days 15 to 30), and the rats were sacrificed at the end of week 4. Lenses were isolated and examined for oxidative stress parameters such as glutathione, lipid peroxidation, and calcium levels along with the glutathione reductase and thioltransferase enzyme activities. Casein zymography and Western blot of m-calpain were performed using the water soluble fraction of lens proteins. Morphological examination of the lenses in the NACA-treated group indicated that NACA was able to reverse the cataract grade. In addition, glutathione level, thioltransferase activity, m-calpain activity, and m-calpain level (as assessed by Western blot) were all significantly higher in the NACA-treated group than in the sodium selenite-induced cataract group. Furthermore, sodium selenite- injected rat pups had significantly higher levels of malondialdehyde, glutathione reductase enzyme activity, and calcium levels, which were reduced to control levels upon treatment with NACA. The data suggest that NACA has the potential to significantly improve vision and decrease the burden of cataract-related loss of function. Prevention and reversal of cataract formation could have a global impact. Development of

  14. Effects of N-acetylcysteine and L-arginine in the antioxidant system of C2C12 cells.

    PubMed

    Da Silva, E P; Lambertucci, R H

    2015-06-01

    The aim of this study was to evaluate the effects of N-acetylcysteine or L-arginine in the antioxidant system of skeletal muscle cells in culture. We used C2C12 cells which were supplemented or not with N-acetylcysteine or L-arginine at different time points. Antioxidant enzymes' activities and protein expression were evaluated. Additionally, superoxide production by cytochrome c reduction method was carried out. It was observed that the supplementation with either N-acetylcysteine or L-arginine was capable to acutely reduce superoxide production (after 30 and 60 minutes). Surprisingly, N-acetylcysteine supplementation also induced an increased production of superoxide during the period of 24 hours. Moreover, both supplements were capable to improve the activity and protein expression of some antioxidants enzymes. In conclusion, we have found new evidences showing that N-acetylcysteine or L-arginine supplementation can provide some benefits to the antioxidant system of skeletal muscle cells in culture. Further studies have to be carried out to evaluate if such benefits could also occur in an in vivo model, with possible benefits for athletes' health and performance.

  15. Prebiotic formation of 'energy-rich' thioesters from glyceraldehyde and N-acetylcysteine

    NASA Technical Reports Server (NTRS)

    Weber, A. L.

    1984-01-01

    The 'energy-rich' thioester, N-acetyl-S-lactoylcysteine, is formed from low concentrations of glyceraldehyde and N-acetylcysteine under anaerobic conditions at ambient temperature in aqueous solutions of sodium phosphate (pH 7.0). Reactions with 2mM glyceraldehyde, 2mM N-acetylcysteine, and 500 mM sodium phosphate (pH 7.0) convert about 0.3 percent/day of the glyceraldehyde to lactoyl thioester. The formation of lactoyl thioester in similar reactions with 500 mM imidazole hydrochloride (pH 7.0) is supported by the thiol-dependence of lactate formation, which is 3-fold greater in the presence of thiol (0.11 percent/day) than in the absence of thiol (0.04 percent/day). The formation of lactoly thioester is thought to proceed by the phosphate (or imidazole)-catalyzed dehydration of glyceraldehyde, which adds to the thiol to form a hemithioacetal that rearranges to the thioester. A limited amount of a second thioester, N-acetyl-S-glyceroyl-cysteine, is also formed at the beginning of these reactions. The significance of these reactions to the origin of life is discussed.

  16. N-acetylcysteine administration does not improve patient outcome after liver resection

    PubMed Central

    Robinson, Stuart M; Saif, Rehan; Sen, Gourab; French, Jeremy J; Jaques, Bryon C; Charnley, Richard M; Manas, Derek M; White, Steven A

    2013-01-01

    Background Post-operative hepatic dysfunction is a major cause of concern when undertaking a liver resection. The generation of reactive oxygen species (ROS) as a result of hepatic ischaemia/reperfusion (I/R) injury can result in hepatocellular injury. Experimental evidence suggests that N-acetylcysteine may ameliorate ROS-mediated liver injury. Methods A cohort of 44 patients who had undergone a liver resection and receiving peri-operative N-acetylcysteine (NAC) were compared with a further cohort of 44 patients who did not. Liver function tests were compared on post-operative days 1, 3 and 5. Peri-operative outcome data were retrieved from a prospectively maintained database within our unit. ResultsAdministration of NAC was associated with a prolonged prothrombin time on the third post-operative day (18.4 versus 16.4 s; P = 0.002). The incidence of grades B and C liver failure was lower in the NAC group although this difference did not reach statistical significance (6.9% versus 14%; P = 0.287). The overall complication rate was similar between groups (32% versus 25%; P = ns). There were two peri-operative deaths in the NAC group and one in the control group (P = NS). ConclusionIn spite of promising experimental evidence, this study was not able to demonstrate any advantage in the routine administration of peri-operative NAC in patients undergoing a liver resection. PMID:23458723

  17. N-acetylcysteine restores nitric oxide-mediated effects in the fetoplacental circulation of preeclamptic patients.

    PubMed

    Bisseling, Tanya M; Maria Roes, Eva; Raijmakers, Maarten T M; Steegers, Eric A P; Peters, Wilbert H M; Smits, Paul

    2004-07-01

    Preeclampsia is associated with an imbalance between oxidants and antioxidants, resulting in reduced effects of the endothelium-derived, relaxing-factor nitric oxide (NO). Antioxidants, like N-acetylcysteine (NAC), remove reactive oxygen species, resulting in an improvement of endothelial function. We aimed to investigate the effect of NAC on the NO-pathway in the human fetoplacental circulation in preeclampsia and control pregnancies. The NO-pathway was investigated by use of the NO-synthase inhibitor L-NAME in an ex vivo cotyledon perfusion model. At baseline, fetoplacental arterial pressure was comparable in preeclamptic pregnancies (n=8) and control pregnancies (n=8), and increased dose-dependently after L-NAME. The maximal L-NAME-induced rise in fetoplacental arterial pressure was attenuated in preeclamptic versus control pregnancies (20.8 +/- 2.0 mm Hg vs 36.7 +/- 3.5 mm Hg, P<.05). Addition of NAC increased the L-NAME-induced rise in fetoplacental arterial pressure to 36.4 +/- 3.4 mm Hg in preeclampsia pregnancies (P<.05) and to 49.2 +/- 2.6 mm Hg in control pregnancies (P<.05). Preeclampsia is associated with a dysfunction of the NO-pathway. N-acetylcysteine increases NO-mediated effects in the fetoplacental circulation in preeclamptic placentas as well as in healthy control placentas.

  18. Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine

    PubMed Central

    Venugopal, Divya; Zahid, Muhammad; Mailander, Paula C; Meza, Jane L.; Rogan, Eleanor G.; Cavalieri, Ercole L.; Chakravarti, Dhrubajyoti

    2009-01-01

    A growing number of studies indicate that breast cancer initiation is related to abnormal estrogen oxidation to form an excess of estrogen-3,4-quinones, which react with DNA to form depurinating adducts and induce mutations. This mechanism is often called estrogen genotoxicity. 4-catechol estrogens, precursors of the estrogen-3,4-quinones, were previously shown to account for most of the transforming and tumorigenic activity. We examined whether estrogen-induced transformation can be reduced by inhibiting the oxidation of a 4-catechol estrogen to its quinone. We demonstrate that E6 cells (a normal mouse epithelial cell line) can be transformed by a single treatment with a catechol estrogen or its quinone. The transforming activities of 4-hydroxyestradiol and estradiol-3,4-quinone were comparable. N-acetylcysteine, a common antioxidant, inhibited the oxidation of 4-hydroxyestradiol to the quinone and consequent formation of DNA adducts. It also drastically reduced estrogen-induced transformation of E6 cells. These results strongly implicate estrogen genotoxicity in mammary cell transformation. Since N-acetylcysteine is well-tolerated in clinical studies, it may be a promising candidate for breast cancer prevention. PMID:18226522

  19. Prebiotic formation of `energy-rich' thioesters from glyceraldehyde and N-acetylcysteine

    NASA Astrophysics Data System (ADS)

    Weber, Arthur L.

    1984-03-01

    The ‘energy-rich’ thioester, N-acetyl-S-lactoylcysteine, is formed from low concentrations of glyceraldehyde and N-acetylcysteine under anaerobic conditions at ambient temperature in aqueous solutions of sodium phosphate (pH 7.0). Reactions with 2 mM glyceraldehyde, 2 mM N-acetylcysteine, and 500 mM sodium phosphate (pH 7.0) convert about 0.3%/day of the glyceraldehyde to lactoyl thioester. The formation of lactoyl thioester in similar reactions with 500 mM imidazole hydrochloride (pH 7.0) is supported by the thiol-dependence of lactate formation, which is 3-fold greater in the presence of thiol (0.11%/day) than in the absence of thiol (0.04%/day). The formation of lactoyl thioester is thought to proceed by the phosphate (or imidazole)-catalyzed dehydration of glyceraldehyde to give pyruvaldehyde, which adds to the thiol to form a hemithioacetal that rearranges to the thioester. A limited amount of a second thioester, N-acetyl-S-glyceroyl-cysteine, is also formed at the beginning of these reactions. The significance of these reactions to the origin of life is discussed.

  20. Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression

    PubMed Central

    Mitsopoulos, Panagiotis; Suntres, Zacharias E.

    2011-01-01

    Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N-acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity. PMID:21584258

  1. Computerized N-acetylcysteine physician order entry by template protocol for acetaminophen toxicity.

    PubMed

    Thompson, Trevonne M; Lu, Jenny J; Blackwood, Louisa; Leikin, Jerrold B

    2011-01-01

    Some medication dosing protocols are logistically complex for traditional physician ordering. The use of computerized physician order entry (CPOE) with templates, or order sets, may be useful to reduce medication administration errors. This study evaluated the rate of medication administration errors using CPOE order sets for N-acetylcysteine (NAC) use in treating acetaminophen poisoning. An 18-month retrospective review of computerized inpatient pharmacy records for NAC use was performed. All patients who received NAC for the treatment of acetaminophen poisoning were included. Each record was analyzed to determine the form of NAC given and whether an administration error occurred. In the 82 cases of acetaminophen poisoning in which NAC was given, no medication administration errors were identified. Oral NAC was given in 31 (38%) cases; intravenous NAC was given in 51 (62%) cases. In this retrospective analysis of N-acetylcysteine administration using computerized physician order entry and order sets, no medication administration errors occurred. CPOE is an effective tool in safely executing complicated protocols in an inpatient setting.

  2. N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.

    PubMed

    Giam, Beverly; Chu, Po-Yin; Kuruppu, Sanjaya; Smith, A Ian; Horlock, Duncan; Kiriazis, Helen; Du, Xiao-Jun; Kaye, David M; Rajapakse, Niwanthi W

    2016-04-01

    Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidantN-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice (n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 (MST-1;n = 18) to administerN-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks. At the end of this period, cardiac remodeling and function was assessed via echocardiography. Fibrosis, oxidative stress, and expression of collagen types I andIIIwere quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, inMST-1 compared to wild type (P ≤ 0.001). InMST-1 mice administeredN-acetylcysteine, perivascular and interstitial fibrosis were 40% and 57% less, respectively, compared to those treated with saline (P ≤ 0. 03). Cardiac oxidative stress was 119% greater inMST-1 than in wild type (P < 0.001) andN-acetylcysteine attenuated oxidative stress inMST-1 by 42% (P = 0.005). These data indicate thatN-acetylcysteine can blunt cardiac fibrosis and related remodeling in the setting of heart failure potentially by reducing oxidative stress. This study provides the basis to investigate the role ofN-acetylcysteine in chronic heart failure. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  3. N-acetylcysteine does not influence the activity of endothelium-derived relaxing factor in vivo.

    PubMed

    Creager, M A; Roddy, M A; Boles, K; Stamler, J S

    1997-02-01

    Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol

  4. Effect of N-acetylcysteine on microcirculation of mucosa in rat ileum in a model of intestinal inflammation.

    PubMed

    Ruh, Joachim; Schmidt, Eduard; Vogel, Frank

    2003-05-01

    Oxygen radicals are formed by the endothelium and blood cells and have specific functions in various organs systems. On the level of the microcirculation, oxygen radicals take part in the regulation of the leukocyte-endothelial interaction. The involvement of oxygen radicals has previously been found in conditions such as sepsis, ischemia-reperfusion, and inflammation. Indomethacin is a clinically applied nonsteroidal antiphlogistic, and in previous studies in the rat, it has been found to induce an inflammatory reaction in the small intestine characterized by edema and reddening of the intestinal epithelium, ulceration, and dysregulation in the intestinal-epithelial barrier function. In the present study, we investigated the effect of N-acetylcysteine on erythrocyte velocity and the arteriolar diameter of the main arteriole in single villi, thus providing insight in the perfusion of the mucosa in indomethacin-induced intestinal inflammation. N-Acetylcysteine is known to inactivate superoxide and its precursors. Therefore, we used N-acetylcysteine to investigate whether superoxide and its precursors participate in the regulation of blood supply to single villi in this animal model. We found that indomethacin induced an increase in villous perfusion that was significantly reduced by N-acetylcysteine, indicating that superoxide and its precursors may participate in the regulation of blood supply to the mucosa in this animal model of intestinal inflammation.

  5. N-acetylcysteine supplementation decreases osteoclast differentiation and increases bone mass in mice fed a high-fat diet

    USDA-ARS?s Scientific Manuscript database

    Studies have demonstrated that obesity induced by high-fat diets increases bone resorption, decreases trabecular bone mass, and reduces bone strength in various animal models. This study investigated whether N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, alters glutathione statu...

  6. The effect of N-acetylcysteine on cardiac contractility to dobutamine in rats with streptozotocin-induced diabetes.

    PubMed

    Cheng, Xing; Xia, Zhengyuan; Leo, Joyce M; Pang, Catherine C Y

    2005-09-05

    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.

  7. Limited theraputic effect of n-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis

    USDA-ARS?s Scientific Manuscript database

    Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. Hypothesis: Since inflammation and oxidative stress can promote insulin resistance, effective treatment with anti-oxidants, e.g. N-acetylcysteine (NAC), may rest...

  8. N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death

    PubMed Central

    Zheng, Jie; Lou, Jessica R.; Zhang, Xiao-Xi; Benbrook, Doris M.; Hanigan, Marie H.; Lind, Stuart E.; Ding, Wei-Qun

    2013-01-01

    A variety of metal-binding compounds have been found to exert anti-cancer activity. We postulated that N-acetylcysteine (NAC), which is a membrane-permeable metal-binding compound, might have anti-cancer activity in the presence of metals. We found that NAC/Cu(II) significantly alters growth and induces apoptosis in human cancer lines, yet NAC/Zn(II) and NAC/Fe(III) do not. We further confirmed that this cytotoxicity of NAC/Cu(II) is attributed to reactive oxygen species (ROS). These findings indicate that the combination of Cu(II) and thiols generates cytotoxic ROS that induce apoptosis in cancer cells. They also indicate a fourth class of anti-neoplastic metal-binding compounds, the “ROS generator”. PMID:20667650

  9. N-acetylcysteine for neuropsychiatric symptoms in a woman with Williams syndrome.

    PubMed

    Pineiro, Mildred Lopez; Roberts, Antoinette M; Waxler, Jessica L; Mullett, Jennifer E; Pober, Barbara R; McDougle, Christopher J

    2014-11-01

    Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described. © The Author(s) 2014.

  10. Use of N-Acetylcysteine in Psychiatric Conditions among Children and Adolescents: A Scoping Review.

    PubMed

    Naveed, Sadiq; Amray, Afshan; Waqas, Ahmed; Chaudhary, Amna M; Azeem, Muhammad W

    2017-11-29

    N-acetylcysteine (NAC) is a well-known antidote for acetaminophen toxicity and is easily available over the counter. It has antioxidant and anti-inflammatory properties and an established tolerance and safety profile. Owing to its neuroprotective effects, its clinical use has recently expanded to include the treatment of different psychiatric and non-psychiatric disorders. Although a number of randomized controlled trials have documented the clinical evidence for NAC, there are no reviews that summarize the evidence. The present scoping review summarizes the study designs, the patient characteristics, the evidence and the limitations in randomized controlled trials designed to explore the efficacy of NAC for psychiatric conditions in the pediatric population.

  11. Effects of N-acetylcysteine on noise-induced temporary threshold shift and temporary emission shift

    NASA Astrophysics Data System (ADS)

    Robinette, Martin

    2004-05-01

    Animal research has shown that antioxidants can provide significant protection to the cochlea from traumatic noise exposure with some benefit when given after the exposure. Similar results in humans would have a significant impact on both prevention and treatment of noise-induced hearing loss. The current study evaluates the effectiveness of N-acetylcysteine (NAC) on temporary threshold shift (TTS) by using both behavioral and physiological measures. Sixteen healthy, normal-hearing subjects were given NAC or a placebo prior to exposure to a 10-min, 102-dB narrow-band noise, centered at 2 kHz. This exposure was designed to induce a 10-15-dB TTS. Following the noise exposure, pure-tone thresholds (Bekesy) and transient-evoked otoacoustic emissions (TEOAE) were measured for 60 min to monitor the effects of NAC on TTS recovery. Postexposure measures were compared to baseline data. [Work supported by American BioHealth Group.

  12. Spectroscopic study of N-acetylcysteine and N-acetylcystine/hydrogen peroxide complexation

    NASA Astrophysics Data System (ADS)

    Picquart, Michel; Abedinzadeh, Zohreh; Grajcar, Lydie; Baron, Marie Héléne

    1998-03-01

    A spectroscopic study of N-acetylcysteine (RSH) and N-acetylcystine (RSSR) has been performed using infrared absorption and Raman scattering in order to pinpoint the sites of complexation of these two species with H 2O 2. Molecules of RSH and RSSR were studied in KBr pellets, and in aqueous solutions of H 2O, D 2O and H 2O with H 2O 2 (1 mol l -1) to characterize the specific influence of the solvent molecules. A time-resolved Raman study was performed for RSH-H 2O 2 in aqueous solution at 1:1 molar ratio in order to observe the formation of RSSR and to discuss the mechanism of this redox reaction.

  13. [A girl with self-harm treated with N-acetylcysteine (NAC)].

    PubMed

    Rus, C P

    Deliberate and recurrent self-harm could be regarded as addictive behaviour that can be treated with medication. In addiction, the dopaminergic mesolimbic reward system is activated. Pain caused by cutting stimulates the reward system through the opioid system. Glutamatergic neurotransmission follows the same pathway and plays a role in addiction as well. In this case-study a 17-year-old girl was successfully treated with N-acetylcysteine (nac) in order to reduce the frequency of self-cutting. In addition, in this case nac reduced the symptoms of attention deficit/hyperactivity disorder and depression. nac modulates the glutamatergic neurotransmission. This article provides possible explanations for the effect of nac in this case.

  14. Bioaccumulation and toxicodynamics of cadmium to freshwater planarian and the protective effect of N-acetylcysteine.

    PubMed

    Wu, Jui-Pin; Chen, Hon-Cheng; Li, Mei-Hui

    2012-08-01

    Although toxic responses of freshwater planarians after exposure to environmental toxicants can be observed through external toxicological end points, physiological responses inside the bodies of treated planarians have rarely been investigated. The present study was designed, using cadmium (Cd) as a reference toxicant, to determine its bioaccumulation and toxicodynamics in the freshwater planarian, Dugesia japonica, after acute toxicity was obtained. Accumulated Cd concentrations, metallothionein levels, and the oxidative status in planarians were determined after exposure to Cd. Furthermore, we hypothesized that the acute death of Cd-treated planarians was associated with increased oxidative stress. After Cd-treated planarians were coexposed to antioxidant, N-acetylcysteine (NAC), we found that NAC protected planarians from Cd lethality by maintaining the oxidative status and decreasing the bioaccumulation of Cd. The results of the present study support planarians being used as a practical model for toxicological studies of environmental contaminants in the future.

  15. Antiatherogenic effects of S-nitroso-N-acetylcysteine in hypercholesterolemic LDL receptor knockout mice.

    PubMed

    Krieger, M H; Santos, K F R; Shishido, S M; Wanschel, A C B A; Estrela, H F G; Santos, L; De Oliveira, M G; Franchini, K G; Spadari-Bratfisch, R C; Laurindo, F R M

    2006-02-01

    The pathophysiology of the NO/NO synthase system and dysfunctional changes in the endothelium in the early phases of the atherogenic process are incompletely understood. In this study, we investigated the effects of the nitrosothiol NO donor S-nitroso-N-acetylcysteine (SNAC) in the early prevention of plaque development in the hypercholesterolemic LDLr-/- mice as well as the changes in endothelium-dependent relaxation and NO synthase expression. LDLr-/- mice were fed a 1.25% cholesterol-enriched diet for 15 days. Plasma cholesterol/triglyceride levels increased and this increase was accompanied by the development of aortic root lesions. Aortic vasorelaxation to acetylcholine was increased, although endothelium-independent relaxation in response to sodium nitroprusside did not change, which suggest stimulated NO release enhanced. This dysfunction was associated with enhanced aortic superoxide production and with increased levels of constitutive NOS isoform expression, particularly neuronal NOS. SNAC (S-nitroso-N-acetylcysteine) administration (0.51 micromol/kg/day i.p. for 15 days) decreased the extent of the plaque by 55% in hypercholesterolemic mice, but had no effects on vasomotor changes. It did, however, lead to a decrease in constitutive NOS expression. The SNAC induced only minor changes in plasma lipid profile. The present study has shown that, in early stages of plaque development in LDLr-/- mice, specific changes in NO/NO synthase system develop, that are characterized by increased endothelium-dependent vasorelaxation and increased constitutive NOS expression. Since the development of plaque and the indicator of endothelial cell dysfunction were prevented by SNAC, such treatment may constitute a novel strategy for the halting of progression of early plaque.

  16. Oral N-acetylcysteine and exercise tolerance in mild chronic obstructive pulmonary disease.

    PubMed

    Hirai, Daniel M; Jones, Joshua H; Zelt, Joel T; da Silva, Marianne L; Bentley, Robert F; Edgett, Brittany A; Gurd, Brendon J; Tschakovsky, Michael E; O'Donnell, Denis E; Neder, J Alberto

    2017-05-01

    Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with N -acetylcysteine (NAC) on respiratory, cardiovascular, and locomotor muscle function and exercise tolerance in patients with mild COPD. Thirteen patients [forced expiratory volume in 1 s (FEV 1 )-to-forced vital capacity ratio < lower limit of normal (LLN) and FEV 1 ≥ LLN) were enrolled in a double-blind, randomized crossover study to receive NAC (1,800 mg/day) or placebo for 4 days. Severe-intensity constant-load exercise tests were performed with noninvasive measurements of central hemodynamics (stroke volume, heart rate, and cardiac output via impedance cardiography), arterial blood pressure, pulmonary ventilation and gas exchange, quadriceps muscle oxygenation (near-infrared spectroscopy), and estimated capillary blood flow. Nine patients completed the study with no major adverse clinical effects. Although NAC elevated plasma glutathione by ~27% compared with placebo ( P < 0.05), there were no differences in exercise tolerance (placebo: 325 ± 47 s, NAC: 336 ± 51 s), central hemodynamics, arterial blood pressure, pulmonary ventilation or gas exchange, locomotor muscle oxygenation, or capillary blood flow from rest to exercise between conditions ( P > 0.05 for all). In conclusion, modulation of plasma redox status with oral NAC treatment was not translated into beneficial effects on central or peripheral components of the oxygen transport pathway, thereby failing to improve exercise tolerance in nonhypoxemic patients with mild COPD. NEW & NOTEWORTHY Acute antioxidant treatment with N -acetylcysteine (NAC) elevated plasma glutathione but did not modulate central or

  17. N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes

    PubMed Central

    2014-01-01

    Background Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes. Methods Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed. Results Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment. Conclusions Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes. PMID:24533448

  18. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections.

    PubMed

    Blasi, Francesco; Page, Clive; Rossolini, Gian Maria; Pallecchi, Lucia; Matera, Maria Gabriella; Rogliani, Paola; Cazzola, Mario

    2016-08-01

    In airway infections, biofilm formation has been demonstrated to be responsible for both acute and chronic events, and constitutes a genuine challenge in clinical practice. Difficulty in eradicating biofilms with systemic antibiotics has led clinicians to consider the possible role of non-antibiotic therapy. The aim of this review is to examine current evidence for the use of N-acetylcysteine (NAC) in the treatment of biofilm-related respiratory infections. Electronic searches of PUBMED up to September 2015 were conducted, searching for 'biofilm', 'respiratory tract infection', 'N-acetylcysteine', 'cystic fibrosis', 'COPD', 'bronchiectasis', 'otitis', and 'bronchitis' in titles and abstracts. Studies included for review were primarily in English, but a few in Italian were also selected. Biofilm formation may be involved in many infections, including ventilator-associated pneumonia, cystic fibrosis, bronchiectasis, bronchitis, and upper respiratory airway infections. Many in vitro studies have demonstrated that NAC is effective in inhibiting biofilm formation, disrupting preformed biofilms (both initial and mature), and reducing bacterial viability in biofilms. There are fewer clinical studies on the use of NAC in disruption of biofilm formation, although there is some evidence that NAC alone or in combination with antibiotics can decrease the risk of exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, and rhinosinusitis. However, the usefulness of NAC in the treatment of cystic fibrosis and bronchiectasis is still matter of debate. Most of the studies published to date have used oral or intramuscular NAC formulations. Evidence from in vitro studies indicates that NAC has good antibacterial properties and the ability to interfere with biofilm formation and disrupt biofilms. Results from clinical studies have provided some encouraging findings that need to be confirmed and expanded using other routes of administration of NAC such as

  19. [The application of N-acetylcysteine in optimization of specific pharmacological therapies].

    PubMed

    Hołyńska-Iwan, Iga; Wróblewski, Marcin; Olszewska-Słonina, Dorota; Tyrakowski, Tomasz

    2017-09-29

    Based on the analysis of data from clinical trials it could be postulated that N-acetylcysteine has a positive impact on the treatment of various diseases. However, less is known about specific molecular and physiological mechanisms underlying the reported therapeutic effects. N-acetylcysteine (NAC, N-acetyl-L-cysteine) is an amino acid derivative containing a thiol group. It is a precursor of L-cysteine and glutathione. NAC is well absorbed and safe for the body at doses up to 300 mg per kg of body weight. Side effects are relatively rare. NAC is used as an mucolytic agent in adjunctive therapy of respiratory diseases causing the retention of secretions, as well as an antidote in the treatment of paracetamol poisoning. Moreover, NAC protects against the toxic effects of reactive oxygen species and their active metabolites. NAC is involved in free radical scavenging processes via several independent mechanisms, including a direct reduction of free radicals, providing substrates for oxidation-reduction reactions and activation of antioxidant enzymes. In the blood, NAC decreases the level of low density lipoprotein peroxidation. In various tissues, NAC may increase the levels of glutathione and cysteine and stimulate the superoxide dismutase action. NAC is used as a supplement in the treatment of various diseases associated with impaired exterior and intracellular oxidative balance. NAC increases the concentrations of amino acids and their derivatives, including cysteine, cystine, and glutathione. It also stabilizes the antioxidant status of the cells and the intercellular spaces. NAC changes the levels of transcription factors, modifying the transcription of selected genes and acting on the protein translation. It works on the activation of several enzymes in the cells and outside the cells. Based on the analysis of data from clinical trials it can be concluded, that an administration of NAC may be beneficial for these groups of patients, in whom the reversible

  20. Antiinflammatory Effect of N-Acetylcysteine Combined with Exogenous Surfactant in Meconium-Induced Lung Injury.

    PubMed

    Mikolka, P; Kopincova, J; Mikusiakova, L Tomcikova; Kosutova, P; Calkovska, A; Mokra, D

    2016-01-01

    Neonatal meconium aspiration syndrome (MAS) can be treated by exogenous surfactant (S). However, aspirated meconium initiates local inflammation and oxidation which may inactivate surfactant and reduce its action. This experimental study estimated whether combined use of surfactant and the antioxidant N-acetylcysteine (NAC) can enhance effectiveness of therapy. Meconium-instilled rabbits were non-treated (M), treated with monotherapies (M + S, M + NAC), combined therapy (M + S + NAC), or received saline instead of meconium (controls, C). Surfactant therapy consisted of two lung lavages (BAL) with diluted Curosurf (5 mg phospholipids/ml, 10 ml/kg) followed by undiluted Curosurf (100 mg phospholipids/kg). N-acetylcysteine (Acc Injekt, 10 mg/kg) was given intravenously in M + S + NAC group 10 min after surfactant therapy. Animals were oxygen-ventilated for additional 5 h. Then, differential white cell count in the blood (WBC) was determined. Left lung was saline-lavaged and differential cell count in BAL was determined. In right lung tissue, wet/dry weight ratio, oxidation markers (TBARS, 3NT) and interleukines (IL-2, IL-6, IL-13, and TNFα) using ELISA and RT-PCR were estimated. Combined S + NAC therapy significantly decreased W/D ratio, TBARS, 3NT, and IL, whereas the effect of monotherapies (either S or NAC) was less obvious. In conclusion, addition of NAC to surfactant treatment may enhance the therapeutic outcome in MAS.

  1. The effects of sildenafil and n-acetylcysteine on ischemia and reperfusion injury in gastrocnemius muscle and femoral artery endothelium.

    PubMed

    Aksu, Volkan; Yüksel, Volkan; Chousein, Serchat; Taştekin, Ebru; İşcan, Şahin; Sağiroğlu, Gönül; Canbaz, Suat; Sunar, Hasan

    2015-02-01

    We aimed to examine the effects of sildenafil and n-acetylcystein on ischemia/reperfusion injury in femoral artery endothelium and gastrocnemius muscle. 32 rats of Sprague-Dawley breed were randomly divided into four groups (n=8). Median laparotomy was performed, then a 120-minute ischemia was created by microvascular clamping of infrarenal aorta, followed by the release of clamping. In sildenafil group, 1 mg/kg of sildenafil infusion and in the n-acetylcystein group, 100 mg/kg of n-acetylcystein infusion was administered after release of clamps. Blood samples and tissue samples of femoral artery and gastrocnemius muscle were extracted for a histopathological evaluation. Serum levels of malondialdehyde in ischemia/reperfusion group (6.16±0.79) were higher compared to the control group (4.69±0.33), whereas a significant decrease was detected in sildenafil (5.17±0.50) and n-acetylcystein (4.96±0.49) groups. Femoral artery tissue sections of the control group, mean tumor necrosis factor alpha and hypoxy-induced factor-1 alpha immunoreactivity were found to be negative. In the ischemia/reperfusion group, mean tumor necrosis factor α immunoreactivity was intense and mean hypoxy-induced factor-1 alpha immunoreactivity was 51-75%. In the ischemia/reperfusion+Sildenafil and ischemia/reperfusion+NAS groups, mean tumor necrosis factor α immunoreactivity was slight and mean hypoxy-induced factor-1 alpha immunoreactivity was 26-50%. In conclusion, sildenafil and n-acetylcystein may reduce femoral artery endothelium and gastrocnemius muscle injury following lower extremity ischemia/reperfusion. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  2. N-acetylcysteine treatment blocks the development of ethanol-induced behavioural sensitization and related ΔFosB alterations.

    PubMed

    Morais-Silva, Gessynger; Alves, Gabrielle Cunha; Marin, Marcelo T

    2016-11-01

    Ethanol addiction is a serious public health problem that still needs more effective pharmacological treatment. A key factor in the development and maintenance of this disease is the advent of neuroadaptations in the mesocorticolimbic brain pathway upon chronic ethanol abuse. In general, these neuroadaptations are maladaptive and affect numerous neurotransmitter systems and intracellular molecules. One of these molecules is ΔFosB, a transcription factor that is altered after chronic drug use. Behavioural sensitization is a useful model for the study of the neuroadaptations related to addiction. Recent works have shown a role for the imbalance of glutamatergic neurotransmission in the symptoms found in addicted people. In this sense, the treatment with N-acetylcysteine, a l-cysteine prodrug that acts by restoring extrasynaptic concentrations of glutamate through the activation of cystine-glutamate antiporter, has shown promising results in the treatment of addiction. Thus, an animal model of behavioural sensitization was used to evaluate the effects of N-acetylcysteine treatment in the behavioural and molecular alterations induced by chronic ethanol administration. Swiss mice were subject to 13 days of daily ethanol administration to induce behavioural sensitization. Two hours before each ethanol administration and locomotor activity evaluation, the animals received intraperitoneally N-acetylcysteine injections. Immediately after the last test session, their brains were removed for ΔFosB and cystine-glutamate antiporter quantification. It was found that N-acetylcysteine treatment blocked ethanol-induced behavioural sensitization, the increase of ΔFosB content in the prefrontal cortex, and its reduction in the nucleus accumbens. The results suggest a possible use of N-acetylcysteine in ethanol-related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders.

    PubMed

    Back, Sudie E; McCauley, Jenna L; Korte, Kristina J; Gros, Daniel F; Leavitt, Virginia; Gray, Kevin M; Hamner, Mark B; DeSantis, Stacia M; Malcolm, Robert; Brady, Kathleen T; Kalivas, Peter W

    2016-11-01

    The antioxidant N-acetylcysteine is being increasingly investigated as a therapeutic agent in the treatment of substance use disorders (SUDs). This study explored the efficacy of N-acetylcysteine in the treatment of posttraumatic stress disorder (PTSD), which frequently co-occurs with SUD and shares impaired prefrontal cortex regulation of basal ganglia circuitry, in particular at glutamate synapses in the nucleus accumbens. Veterans with PTSD and SUD per DSM-IV criteria (N = 35) were randomly assigned to receive a double-blind, 8-week course of N-acetylcysteine (2,400 mg/d) or placebo plus cognitive-behavioral therapy for SUD (between March 2013 and April 2014). Primary outcome measures included PTSD symptoms (Clinician-Administered PTSD Scale, PTSD Checklist-Military) and craving (Visual Analog Scale). Substance use and depression were also assessed. Participants treated with N-acetylcysteine compared to placebo evidenced significant improvements in PTSD symptoms, craving, and depression (β values < -0.33; P values < .05). Substance use was low for both groups, and no significant between-group differences were observed. N-acetylcysteine was well tolerated, and retention was high. This is the first randomized controlled trial to investigate N-acetylcysteine as a pharmacologic treatment for PTSD and SUD. Although preliminary, the findings provide initial support for the use of N-acetylcysteine in combination with psychotherapy among individuals with co-occurring PTSD and SUD. ClinicalTrials.gov identifier: NCT02499029. © Copyright 2016 Physicians Postgraduate Press, Inc.

  4. The protective effect of N-acetylcysteine on oxidative stress in the brain caused by the long-term intake of aspartame by rats.

    PubMed

    Finamor, Isabela A; Ourique, Giovana M; Pês, Tanise S; Saccol, Etiane M H; Bressan, Caroline A; Scheid, Taína; Baldisserotto, Bernardo; Llesuy, Susana F; Partata, Wânia A; Pavanato, Maria A

    2014-09-01

    Long-term intake of aspartame at the acceptable daily dose causes oxidative stress in rodent brain mainly due to the dysregulation of glutathione (GSH) homeostasis. N-Acetylcysteine provides the cysteine that is required for the production of GSH, being effective in treating disorders associated with oxidative stress. We investigated the effects of N-acetylcysteine treatment (150 mg kg(-1), i.p.) on oxidative stress biomarkers in rat brain after chronic aspartame administration by gavage (40 mg kg(-1)). N-Acetylcysteine led to a reduction in the thiobarbituric acid reactive substances, lipid hydroperoxides, and carbonyl protein levels, which were increased due to aspartame administration. N-Acetylcysteine also resulted in an elevation of superoxide dismutase, glutathione peroxidase, glutathione reductase activities, as well as non-protein thiols, and total reactive antioxidant potential levels, which were decreased after aspartame exposure. However, N-acetylcysteine was unable to reduce serum glucose levels, which were increased as a result of aspartame administration. Furthermore, catalase and glutathione S-transferase, whose activities were reduced due to aspartame treatment, remained decreased even after N-acetylcysteine exposure. In conclusion, N-acetylcysteine treatment may exert a protective effect against the oxidative damage in the brain, which was caused by the long-term consumption of the acceptable daily dose of aspartame by rats.

  5. Rebamipide increases the amount of mucin-like substances on the conjunctiva and cornea in the N-acetylcysteine-treated in vivo model.

    PubMed

    Urashima, Hiroki; Okamoto, Takashi; Takeji, Yasuhiro; Shinohara, Hisashi; Fujisawa, Shigeki

    2004-08-01

    Rebamipide increases the amount of mucin-like substances in the stomach. We aimed to determine the effects of rebamipide on the amount of mucin-like substances in the conjunctiva and cornea of N-acetylcysteine-treated eyes. Furthermore, we attempted to evaluate the effects of rebamipide on the wound healing of N-acetylcysteine-treated eyes. The model was created by instilling 10% N-acetylcysteine solutions into rabbit eyes. Rebamipide was then applied on the day following the completion of N-acetylcysteine treatment. The amount of mucin-like substances on the conjunctiva and cornea was measured using the Alcian-blue binding method. The degree of damage was evaluated using scores based on the areas and densities of the cornea and conjunctival after staining using a rose Bengal solution under blind conditions. Rebamipide increased the level of mucin-like substances on the conjunctiva of N-acetylcysteine-treated eyes when instilled at concentrations of 0.3% or higher, and 1% rebamipide increased the amount of mucin-like substances covering the cornea. Moreover, 1% rebamipide improved the rose Bengal scores of the cornea and conjunctiva in N-acetylcysteine-treated eyes. Rebamipide increased mucin-like substances on the cornea and conjunctiva of N-acetylcysteine-treated eyes. In accordance with the mucin-increasing effects, rebamipide improved the rose Bengal scores for the cornea and conjunctiva of N-acetylcysteine-treated eyes. However, the relevance of these findings to dry eyes is unclear because it is not known whether the change in mucus expression in the N-acetylcysteine model is similar to what occurs in aqueous tear deficiency. Consequently, it may be worth trying on an animal model of keratoconjunctivitis sicca.

  6. Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats.

    PubMed

    Günther, Mattias; Davidsson, Johan; Plantman, Stefan; Norgren, Svante; Mathiesen, Tiit; Risling, Mårten

    2015-09-01

    We examined the effects of N-acetylcysteine amide (NACA) in the secondary inflammatory response following a novel method of focal penetrating traumatic brain injury (TBI) in rats. N-acetylcysteine (NAC) has limited but well-documented neuroprotective effects after experimental central nervous system ischemia and TBI, but its bioavailability is very low. We tested NACA, a modified form of NAC with higher membrane and blood-brain barrier permeability. Focal penetrating TBI was produced in male Sprague-Dawley rats randomly selected for NACA treatment (n=5) and no treatment (n=5). In addition, four animals were submitted to sham surgery. After 2 hours or 24 hours the brains were removed, fresh frozen, cut in 14 μm coronal sections and subjected to immunohistochemistry, immunofluorescence, Fluoro-Jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. All treated animals were given 300 mg/kg NACA intraperitoneally (IP) 2 minutes post trauma. The 24 hour survival group was given an additional bolus of 300 mg/kg IP after 4 hours. NACA treatment decreased neuronal degeneration by Fluoro-Jade at 24 hours with a mean change of 35.0% (p<0.05) and decreased TUNEL staining indicative of apoptosis at 2 hours with a mean change of 38.7% (p<0.05). Manganese superoxide dismutase (MnSOD) increased in the NACA treatment group at 24 hours with a mean change of 35.9% (p<0.05). Levels of migrating macrophages and activated microglia (Ox-42/CD11b), nitric oxide-producing inflammatory enzyme iNOS, peroxynitrite marker 3-nitrotyrosine, NFκB translocated to the nuclei, cytochrome C and Bcl-2 were not affected. NACA treatment decreased neuronal degeneration and apoptosis and increased levels of antioxidative enzyme MnSOD. The antiapoptotic effect was likely regulated by pathways other than cytochrome C. Therefore, NACA prevents brain tissue damage after focal penetrating TBI, warranting further studies towards a clinical application. Copyright © 2015

  7. Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: results from a prospective, randomized, double-blind study.

    PubMed

    Spies, C D; Reinhart, K; Witt, I; Meier-Hellmann, A; Hannemann, L; Bredle, D L; Schaffartzik, W

    1994-11-01

    Deactivation of endothelium-derived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an impairment in microcirculatory blood flow. We investigated whether treatment with the sulfhydryl donor and oxygen radical scavenger, N-acetylcysteine, would improve whole-body oxygen consumption (VO2), gastric intramucosal pH, and veno-arterial CO2 gradient (veno-arterial PCO2) during septic shock. Prospective, randomized, double-blind study conducted over 2 yrs. Septic shock patients admitted to the intensive care unit. Fifty-eight patients requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to septic shock, were included in this study. All patients were examined within 72 hrs after the onset of sepsis. They were optimally resuscitated by conventional means with volume and inotropic agents, and exhibited stable clinical conditions (hemodynamic values, body temperature, hemoglobin, FIO2). A gastric tonometer was inserted to measure the gastric intramucosal pH. Subjects randomly received either 150 mg/kg of intravenous N-acetylcysteine or placebo over a 15-min period, then a continuous infusion of 12.5 mg/hr of N-acetylcysteine or placebo over approximately 90 mins. Infusion measurements were begun 60 mins after the beginning of infusion and lasted approximately 30 mins. The infusion was then discontinued and 2 hrs later the final measurements were taken. Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II scores, Multiple Organ Failure scores) did not differ significantly, nor did pre- and 2-hr postinfusion measurements differ between any of the groups. Thirteen (45%) patients responded (i.e., showed an increase in VO2 > 10%, reaching a mean of 19%) to the N-acetylcysteine infusion. The N-acetylcysteine responders also showed an increase in gastric intramucosal pH, a decrease in veno-arterial PCO2, an increase in oxygen delivery, cardiac index, stroke index, and left

  8. N-acetylcysteine neither lowers plasma homocysteine concentrations nor improves brachial artery endothelial function in cardiac transplant recipients.

    PubMed

    Miner, S E S; Cole, D E C; Evrovski, J; Forrest, Q; Hutchison, S J; Holmes, K; Ross, H J

    2002-05-01

    N-acetylcysteine is a novel antioxidant that has been reported to reduce plasma homocysteine concentrations and improve endothelial function. Cardiac transplant recipients have a high incidence of coronary endothelial dysfunction and hyperhomocysteinemia, both of which may lead to the development of transplantation coronary artery disease. It was hypothesized that N-acetylcysteine would reduce plasma homocysteine concentrations and improve brachial endothelial function in cardiac transplant recipients. A cohort of stable cardiac transplant recipients was recruited from the outpatient clinic at the Toronto General Hospital, Toronto, Ontario. Brachial artery endothelial functions were studied according to standard techniques to determine flow-mediated dilation of the brachial artery. Plasma homocysteine concentrations were assayed using high performance liquid chromatography with electrochemical detection and pulsed integrated amperometry. After baseline testing, patients were treated in an unblinded fashion with N-acetylcysteine 500 mg/day. After 10 weeks of therapy, patients returned for follow-up endothelial function and homocysteine testing. Thirty-one patients were initially enrolled. Two patients withdrew due to excessive gastrointestinal upset. Two patients did not return for follow-up testing. The remaining 27 patients tolerated the treatment well. At baseline, 85% of the patients had hyperhomocysteinemia (greater than 15 mol/L) with a mean plasma concentration of 18.6 4.7 mol/L. No changes in homocysteine concentrations were seen at follow-up. At baseline, the average flow-mediated dilation was only 4.7 6.3%. No changes were seen at follow-up. Hyperhomocysteinemia and brachial endothelial dysfunction are common in stable cardiac transplant recipients and are unaffected by supplementation with N-acetylcysteine.

  9. N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression.

    PubMed

    Xia, Zhengyuan; Liu, Min; Wu, Yong; Sharma, Vijay; Luo, Tao; Ouyang, Jingping; McNeill, John H

    2006-11-21

    The circulatory inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is increased in pathological conditions, such as diabetes, which initiate or exacerbate vascular endothelial injury. Both nitric oxide (NO) and reactive oxygen species may play a dual role (i.e., inhibiting or promoting) in TNF-alpha-induced endothelial cell apoptosis. We investigated the effects of the antioxidant N-acetylcysteine on TNF-alpha-induced apoptosis in human vascular endothelial cell (cell line ECV304) apoptosis, NO production and lipid peroxidation. Cultured vascular endothelial cell (ECV304) were either not treated (control), or treated with TNF-alpha (40 ng/ml) alone or TNF-alpha in the presence of N-acetylcysteine at 30 mmol/l or 1 mmol/l, respectively, for 24 h. Cell viability was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was assessed by flow cytometry. TNF-alpha-induced endothelial cell apoptosis was associated with increased inducible NO synthase but reduced endothelial NO synthase (eNOS) protein expression. NO production and the levels of the lipid peroxidation product malondialdehyde were concomitantly increased. Treatment with NAC at 30 mmol/l restored eNOS expression and further increased NO production as compared to TNF-alpha alone, resulting in improved cell viability and reduced apoptosis. This was accompanied by increased superoxide dismutase activity, increased glutathione peroxidase production and reduced malondialdehyde levels. N-acetylcysteine at 1 mmol/l, however, did not have significant effects on TNF-alpha-induced endothelial cell apoptosis and cell viability despite it slightly enhanced glutathione peroxidase production. N-acetylcysteine attenuation of TNF-alpha-induced human vascular endothelial cell apoptosis is associated with the restoration of eNOS expression.

  10. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy.

    PubMed

    Riga, Maria G; Chelis, Leonidas; Kakolyris, Stylianos; Papadopoulos, Stergios; Stathakidou, Sofia; Chamalidou, Eleni; Xenidis, Nikolaos; Amarantidis, Kyriakos; Dimopoulos, Prokopios; Danielides, Vasilios

    2013-02-01

    Ototoxicity is a common and irreversible adverse effect of cisplatin treatment with great impact on the patients' quality of life. N-acetylcysteine is a low-molecular-weight agent which has shown substantial otoprotective activity. The role of transtympanic infusions of N-acetylcysteine was examined in a cohort of patients treated with cisplatin-based regimens. Twenty cisplatin-treated patients were subjected, under local anesthesia, to transtympanic N-acetylcysteine (10%) infusions in 1 ear, during the hydration procedure preceding intravenous effusion of cisplatin. The contralateral ear was used as control. The number of transtympanic infusions was respective to the number of administered cycles. Hearing acuity was evaluated before each cycle with pure tone audiometry by an audiologist blinded to the treated ear. A total of 84 transtympanic infusions were performed. In treated ears, no significant changes in auditory thresholds were recorded. In the control ears cisplatin induced a significant decrease of auditory thresholds at the 8000 Hz frequency band (P=0.008). At the same frequency (8000 Hz), the changes in auditory thresholds were significantly larger for the control ears than the treated ones (P=0.005). An acute pain starting shortly after the injection and lasting for a few minutes seemed to be the only significant adverse effect. Transtympanic injections of N-acetylcysteine seem to be a feasible and effective otoprotective strategy for the prevention of cisplatin-induced ototoxicity. Additional studies are required to further clarify the efficiency of this treatment and determine the optimal dosage and protocol.

  11. N-Acetylcysteine as adjunctive treatment in severe malaria: A randomized double blinded placebo controlled clinical trial

    PubMed Central

    Charunwatthana, Prakaykaew; Faiz, M. Abul; Ruangveerayut, Ronnatrai; Maude, Richard; Rahman, M. Ridwanur; Roberts, L. Jackson; Moore, Kevin; Yunus, Emran Bin; Hoque, M. Gofranul; Hasan, Mahatab Uddin; Lee, Sue J.; Pukrittayakamee, Sasithon; Newton, Paul N.; White, Nicholas J.; Day, Nicholas P.J.; Dondorp, Arjen M.

    2009-01-01

    Objective Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral N-acetylcysteine as an adjunct to artesunate treatment of severe falciparum malaria. Design A randomized double-blind placebo controlled trial on the use of high dose intravenous NAC as adjunctive treatment to artesunate. Setting A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh. Patients One hundred and eight adult patients with severe falciparum malaria. Interventions Patients were randomized to receive N-acetylcysteine or placebo as adjunctive treatment to intravenous artesunate. Measurements and main results A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p=0.74) or coma recovery times (p=0.46). Parasite clearance time was increased from 30h (range 6h to 144h) to 36h (range 6h to 120h) (p=0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared to patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC. Conclusion Systemic oxidative stress is increased in severe malaria. Treatment with N-acetylcysteine had no effect on outcome in patients with severe falciparum malaria in this setting. PMID:19114891

  12. N-acetylcysteine reduces the renal oxidative stress and apoptosis induced by hemorrhagic shock.

    PubMed

    Moreira, Miriam Aparecida; Irigoyen, Maria Claudia; Saad, Karen Ruggeri; Saad, Paulo Fernandes; Koike, Marcia Kiyomi; Montero, Edna Frasson de Souza; Martins, José Luiz

    2016-06-01

    Renal ischemia/reperfusion injury induced by hemorrhagic shock (HS) and subsequent fluid resuscitation is a common cause of acute renal failure. The objective of this study was to evaluate the effect of combining N-acetylcysteine (NAC) with fluid resuscitation on renal injury in rats that underwent HS. Two groups of male Wistar rats were induced to controlled HS at 35 mm Hg mean arterial pressure for 60 min. After this period, the HS and fluid resuscitation (HS/R) group was resuscitated with lactate containing 50% of the blood that was withdrawn. The HS/R + NAC group was resuscitated with Ringer's lactate combined with 150 mg/kg of NAC and blood. The sham group animals were catheterized but were not subjected to shock. All animals were kept under anesthesia and euthanized after 120 min of fluid resuscitation or observation. Animals treated with NAC presented attenuation of histologic lesions, reduced oxidative stress, and apoptosis markers when compared with animals from the HS/R group. The serum creatinine was similar in all the groups. NAC is a promising drug for combining with fluid resuscitation to attenuate the kidney injury associated with HS. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Antimicrobial activity of alexidine alone and associated with N-acetylcysteine against Enterococcus faecalis biofilm

    PubMed Central

    Silveira, Luiz Fernando Machado; Baca, Pilar; Arias-Moliz, María Teresa; Rodríguez-Archilla, Alberto; Ferrer-Luque, Carmen María

    2013-01-01

    The purpose of this study was to assess the efficacy of alexidine (ALX), alone and combined with N-acetylcysteine (NAC), in eradicating two Enterococcus faecalis strain biofilms. The biofilms of E. faecalis ATCC 29212 and the clinical isolate E. faecalis D1 were grown in the MBEC-high-throughput device for 24 h and were exposed to five twofold dilutions of ALX (2%–0.007 8%) alone and combined with 100 mg⋅mL−1 NAC, for 1 and 5 min. Eradication was defined as 100% kill of biofilm bacteria. The Student's t-test was used to compare the efficacy of the associations of the two irrigants. After 1-min contact time, ALX eradicated the biofilms at all concentrations except for 0.007 8% and 0.015 6%–0.007 8% with E. faecalis ATCC 29212 and E. faecalis D1, respectively. Similar results for eradication and concentration were obtained when it was combined with 100 mg⋅mL−1 NAC. After 5 min of contact time, ALX alone and combined with NAC eradicated all enterococci biofilms. ALX showed antimicrobial properties against the two E. faecalis strain biofilms tested at very low concentrations, and its combined use with NAC was not seen to enhance its activity. PMID:23970139

  14. Effects of oral N-acetylcysteine on fatigue, critical power, and W' in exercising humans.

    PubMed

    Corn, Sarah D; Barstow, Thomas J

    2011-09-15

    The accumulation of reactive oxygen species (ROS) is associated with muscular fatigue. The antioxidant N-acetylcysteine (NAC) can extend time to fatigue (TTF), but the effect appears to be exercise intensity dependent. The purpose of this study was to determine the effects of an acute oral dose of NAC on time to fatigue (TTF), critical power (CP), W' (curvature constant), V(O2) kinetics and muscle EMG during cycling exercise. Male (n=7) subjects performed four tests at power outputs corresponding to 80, 90, 100, and 110% of the peak power output achieved during the incremental test (Pmax) under NAC and placebo (PLA) conditions. TTF was increased only in the 80% Pmax trial (p=0.033). CP was higher with NAC (NAC: 232±28 W versus PLA: 226±31 W; p=0.032), but W' tended to decrease (NAC: 15.5±3.8 kJ versus W': 16.4±4.5 kJ; p=0.10). The change in W' was negatively related to the change in CP (r = -0.96). MdPF and RMS of EMG tended to change less with NAC. There were no significant differences in V(O2) kinetics. These results demonstrate that oral NAC was successful in extending time to fatigue at 80% Pmax but not at higher work rates. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Thiol redox transitions in cell signaling: a lesson from N-acetylcysteine.

    PubMed

    Parasassi, Tiziana; Brunelli, Roberto; Costa, Graziella; De Spirito, Marco; Krasnowska, Ewa; Lundeberg, Thomas; Pittaluga, Eugenia; Ursini, Fulvio

    2010-06-29

    The functional status of cells is under the control of external stimuli affecting the function of critical proteins and eventually gene expression. Signal sensing and transduction by messengers to specific effectors operate by post-translational modification of proteins, among which thiol redox switches play a fundamental role that is just beginning to be understood. The maintenance of the redox status is, indeed, crucial for cellular homeostasis and its dysregulation towards a more oxidized intracellular environment is associated with aberrant proliferation, ultimately related to diseases such as cancer, cardiovascular disease, and diabetes. Redox transitions occur in sensitive cysteine residues of regulatory proteins relevant to signaling, their evolution to metastable disulfides accounting for the functional redox switch. N-acetylcysteine (NAC) is a thiol-containing compound that is able to interfere with redox transitions of thiols and, thus, in principle, able to modulate redox signaling. We here review the redox chemistry of NAC, then screen possible mechanisms to explain the effects observed in NAC-treated normal and cancer cells; such effects involve a modification of global gene expression, thus of functions and morphology, with a leitmotif of a switch from proliferation to terminal differentiation. The regulation of thiol redox transitions in cell signaling is, therefore, proposed as a new tool, holding promise not only for a deeper explanation of mechanisms, but indeed for innovative pharmacological interventions.

  16. Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin.

    PubMed

    Aluigi, M G; De Flora, S; D'Agostini, F; Albini, A; Fassina, G

    2000-01-01

    N-Acetylcysteine (NAC) is a drug bearing multiple preventive properties that can inhibit genotoxicity and carcinogenicity. NAC also inhibits invasion and metastasis of malignant cells, as well as tumor take. We recently demonstrated the effects of NAC on Kaposi's sarcoma cells supernatant-induced invasion in vitro and angiogenesis in vivo. Many anticancer agents act through cytotoxicity of rapidly proliferating cells and several antineoplastic drugs induce apoptosis of cancer cells. Since endothelial cells are the target for the inhibition of angiogenesis, we wanted to verify that NAC, while inhibiting tumor vascularization and endothelial cell invasion would not induce endothelial cell apoptosis. We tested the ability of NAC to modulate apoptosis and cytogenetic damage in vitro and to promote differentiation on a reconstituted basement membrane (matrigel) in two endothelial cell lines (EAhy926 and HUVE). Treatment with NAC protected endothelial cells from TGF-beta-induced apoptosis and paraquat-induced cytogenetic damage. Therefore, NAC acts as an antiangiogenic agent and, at the same time, appears to prevent apoptosis and oxygen-related genotoxicity in endothelial cells.

  17. Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells.

    PubMed

    Tsai, J C; Jain, M; Hsieh, C M; Lee, W S; Yoshizumi, M; Patterson, C; Perrella, M A; Cooke, C; Wang, H; Haber, E; Schlegel, R; Lee, M E

    1996-02-16

    Pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) have been used as antioxidants to prevent apoptosis in lymphocytes, neurons, and vascular endothelial cells. We report here that PDTC and NAC induce apoptosis in rat and human smooth muscle cells. In rat aortic smooth muscle cells, PDTC induced cell shrinkage, chromatin condensation, and DNA strand breaks consistent with apoptosis. In addition, overexpression of Bcl-2 suppressed vascular smooth muscle cell death caused by PDTC and NAC. The viability of rat aortic smooth muscle cells decreased within 3 h of treatment with PDTC and was reduced to 30% at 12 h. The effect of PDTC and NAC on smooth muscle cells was not species specific because PDTC and NAC both caused dose-dependent reductions in viability in rat and human aortic smooth muscle cells. In contrast, neither PDTC nor NAC reduced viability in human aortic endothelial cells. The use of antioxidants to induce apoptosis in vascular smooth muscle cells may help prevent their proliferation in arteriosclerotic lesions.

  18. N-acetylcysteine – passe-partout or much ado about nothing?

    PubMed Central

    Aitio, Mirja-Liisa

    2006-01-01

    In experimental studies, the old mucolytic agent N-acetylcysteine (NAC) has had beneficial effects in disorders supposedly linked to oxidative stress. Numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases. NAC added to the conventional therapy of human immunodeficiency virus infection might be of benefit; in respect of chronic obstructive pulmonary disease, systematic reviews and meta-analyses suggested that prolonged treatment with NAC is efficacious, but a recent multicentre study has questioned this. In a large intervention trial on cancer recurrence, NAC was ineffective. NAC infusions have been widely used in acute hepatic failure but convincing evidence of its benefits is lacking. A preliminary study reported that NAC is effective in preventing radiocontrast-induced nephropathy but thereafter highly mixed results have been published, and even meta-analyses disagree on its efficacy. In intensive care NAC has mostly been a disappointment but recently it has ‘given promises’ in surgery with cardiopulmonary bypass. NAC therapy is routine only in paracetamol intoxication. PMID:16390346

  19. Improvement of hepatic microhemodynamics by N-acetylcysteine after warm ischemia.

    PubMed

    Koeppel, T A; Thies, J C; Lehmann, T; Gebhard, M M; Herfarth, C; Otto, G; Post, S

    1996-01-01

    In this study we investigated the influence of N-acetylcysteine (NAC) on the hepatic microcirculation after warm ischemia by intravital fluorescence microscopy. Clamping of the left liver lobe was performed in 20 male Wistar rats for 70 min. The treatment group (n = 10) received 400 mg NAC/kg body weight 20 min prior to clamping. After reperfusion, acinar and sinusoidal perfusions were observed as well as the leukocyte-endothelium interaction. Phagocytic activity was assessed after application of latex beads. NAC reduced the number of nonperfused sinusoids in all acinar zones. A reduction in zone 1 (portal) was achieved from 15.5 to 7.1% (p < 0.0001), in zone 2 (midzonal) from 14.6 to 6.1% (p < 0.0001) and in zone 3 (central) from 11.9 to 2.9% (p < 0.0001). There were no significant differences in leukocyte adherence as well as in phagocytic activity detectable. We conclude that NAC improves hepatic microcirculation after warm ischemia by increasing sinusoidal blood flow.

  20. N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

    PubMed Central

    Taut, F J H; Schmidt, H; Zapletal, C M; Thies, J C; Grube, C; Motsch, J; Klar, E; Martin, E

    2001-01-01

    In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P ≤ 0·02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment. PMID:11422213

  1. The role of the thiol N-acetylcysteine in the prevention of tumor invasion and angiogenesis.

    PubMed

    Morini, M; Cai, T; Aluigi, M G; Noonan, D M; Masiello, L; De Flora, S; D'Agostini, F; Albini, A; Fassina, G

    1999-01-01

    We have extensively studied the effects of N-acetylcysteine (NAC), a cytoprotective drug that can prevent in vivo carcinogenesis. Here we review our findings NAC completely inhibits gelatinolytic activity of metalloproteases and chemotactic and invasive activities of tumor cells. In addition, NAC reduces the number of lung metastases when malignant murine melanoma cells are injected into nude mice. NAC treatment decreases the weight of primary tumors and produces a dose-related increase in tumor latency. Moreover, oral administration of NAC reduces the formation of spontaneous metastases. In experimental metastasis assays, we have found a synergistic reduction in the number of lung metastases after treatment with doxorubicin (DOX) and NAC in nude mice. In tumorigenicity and spontaneous metastasis assays, the combined administration of DOX and oral NAC again has shown synergistic effects on the frequency and weight of primary tumors and local recurrences and completely prevented the formation of lung metastases. The addition of NAC to endothelial cells strongly reduces their invasive activity in response to angiogenic stimuli. NAC inhibited the degradation and release of radiolabeled type IV collagen by activated endothelial cells, indicating that NAC blocks gelatinase activity. Oral administration of NAC reduces the angiogenic response induced by KS tumor cell products, confirming the ability of NAC to inhibit the invasive activity of endothelial cells in vivo and thereby blocking angiogenesis.

  2. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities

    PubMed Central

    Bavarsad Shahripour, Reza; Harrigan, Mark R; Alexandrov, Andrei V

    2014-01-01

    Background There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways. Aim and discussion Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Conclusion Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage. PMID:24683506

  3. [The role of N-acetylcysteine against the injury of pulmonary artery induced by LPS].

    PubMed

    Huang, Xin-li; Ling, Yi-ling; Zhu, Tie-nian

    2002-11-01

    To investigate the alleviating effect of N-acetylcysteine (NAC) on lung injury induced by lipopolysaccharides (LPS) and its mechanism. The effects of NAC on changes of the pulmonary arterial reactivity and the ultrastructure of pulmonary arterial endothelium induced by LPS were observed with the isolated artery ring technique and scanning electron microscope (SEM). Malondialdehyde (MDA), nitric oxide (NO) contents and superoxide dismutase (SOD) activity of pulmonary artery tissues were detected. The exposure of pulmonary artery to LPS (4 microg/ml, 7 h) led to reduction of endothelium-dependent relaxation response to acetylcholine (ACh), which was reversed by the concomitant exposure to NAC (0.5 mmol/L, 7 h), whereas NAC itself had no effect on the response. Significant structural injury were observed under SEM in LPS group and alleviated the changes in LPS + NAC group. The MDA, NO contents increased but SOD activity decreased in LPS group, which were reversed by the concomitant exposure to NAC. NAC protects pulmonary artery endothelium and enhances endothelium-dependent relaxation response of pulmonary artery by antioxidation effect, which may be one of the mechanisms of its reversing pulmonary artery hypertension and following lung injury induced by LPS.

  4. N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein

    PubMed Central

    Cui, Yuqi; Narasimhulu, Chandrakala A.; Liu, Lingjuan; Zhang, Qingbin; Liu, Patrick Z.; Li, Xin; Xiao, Yuan; Zhang, Jia; Hao, Hong; Xie, Xiaoyun; He, Guanglong; Cui, Lianqun; Parthasarathy, Sampath; Liu, Zhenguo

    2015-01-01

    Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox-LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR−/−) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR−/− mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia. PMID:26536834

  5. L-N-Acetylcysteine protects against radiation-induced apoptosis in a cochlear cell line.

    PubMed

    Low, Wong-Kein; Sun, Li; Tan, Michelle G K; Chua, Alvin W C; Wang, De-Yun

    2008-04-01

    L-N-Acetylcysteine (L-NAC) significantly reduced reactive oxygen species (ROS) generation and cochlear cell apoptosis after irradiation. The safe and effective use of L-NAC in reducing radiation-induced sensorineural hearing loss (SNHL) should be verified by further in vivo studies. Radiation-induced SNHL is a common complication after radiotherapy of head and neck tumours. There is growing evidence to suggest that ROS play an important role in apoptotic cochlear cell death from ototoxicity, resulting in SNHL. The aim of this study was to evaluate the effectiveness of L-NAC, an antioxidant, on radiation-induced apoptosis in cochlear cells. The OC-k3 cochlear cell line was studied after 0 and 20 Gy of gamma-irradiation. Cell viability assay was performed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Flow cytometry and TUNEL assay were done with and without the addition of 10 mmol/L of L-NAC. Intracellular generation of ROS was detected by 2',7'-dichlorofluorescein diacetate, with comparisons made using fluorescence intensity. L-NAC increased the viability of cells after irradiation. Generation of ROS was demonstrated at 1 h post-irradiation and was significantly reduced by L-NAC (p<0.0001). Flow cytometry and TUNEL assay showed cell apoptosis at 72 h post-irradiation, which was diminished by the addition of L-NAC.

  6. Evaluation of in vitro storage characteristics of cold stored platelet concentrates with N acetylcysteine (NAC).

    PubMed

    Handigund, Mallikarjun; Bae, Tae Won; Lee, Jaehyeon; Cho, Yong Gon

    2016-02-01

    Platelets play a vital role in hemostasis and thrombosis, and their demand and usage has multiplied many folds over the years. However, due to the short life span and storage constraints on platelets, it is allowed to store them for up to 7 days at room temperature (RT); thus, there is a need for an alternative storage strategy for extension of shelf life. Current investigation involves the addition of 50 mM N acetylcysteine (NAC) in refrigerated concentrates. Investigation results revealed that addition of NAC to refrigerated concentrates prevented platelet activation and reduced the sialidase activity upon rewarming as well as on prolonged storage. Refrigerated concentrates with 50 mM NAC expressed a 23.91 ± 6.23% of CD62P (P-Selectin) and 22.33 ± 3.42% of phosphotidylserine (PS), whereas RT-stored platelets showed a 46.87 ± 5.23% of CD62P and 25.9 ± 6.48% of phosphotidylserine (PS) after 5 days of storage. Further, key metabolic parameters such as glucose and lactate accumulation indicated reduced metabolic activity. Taken together, investigation and observations indicate that addition of NAC potentially protects refrigerated concentrates by preventing platelet activation, stabilizing sialidase activity, and further reducing the metabolic activity. Hence, we believe that NAC can be a good candidate for an additive solution to retain platelet characteristics during cold storage and may pave the way for extension of storage shelf life. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why.

    PubMed

    Aldini, Giancarlo; Altomare, Alessandra; Baron, Giovanna; Vistoli, Giulio; Carini, Marina; Borsani, Luisa; Sergio, Francesco

    2018-05-09

    The main molecular mechanisms explaining the well-established antioxidant and reducing activity of N-acetylcysteine (NAC), the N-acetyl derivative of the natural amino acid l-cysteine, are summarised and critically reviewed. The antioxidant effect is due to the ability of NAC to act as a reduced glutathione (GSH) precursor; GSH is a well-known direct antioxidant and a substrate of several antioxidant enzymes. Moreover, in some conditions where a significant depletion of endogenous Cys and GSH occurs, NAC can act as a direct antioxidant for some oxidant species such as NO 2 and HOX. The antioxidant activity of NAC could also be due to its effect in breaking thiolated proteins, thus releasing free thiols as well as reduced proteins, which in some cases, such as for mercaptoalbumin, have important direct antioxidant activity. As well as being involved in the antioxidant mechanism, the disulphide breaking activity of NAC also explains its mucolytic activity which is due to its effect in reducing heavily cross-linked mucus glycoproteins. Chemical features explaining the efficient disulphide breaking activity of NAC are also explained.

  8. Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn.

    PubMed

    Csontos, C; Rezman, B; Foldi, V; Bogar, L; Drenkovics, L; Röth, E; Weber, G; Lantos, J

    2012-05-01

    Oxidative stress and inflammation generate edema in burns. The aim of our study was to assess effect of N-acetylcysteine (NAC) on oxidative stress, inflammation, fluid requirement, multiple organ dysfunction (MOD) score and vasoactive drug requirement. In this study 15 patients were on standard therapy, whereas for other 15 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Levels of malondialdehyde, protein sulfhydril (PSH) groups, reduced gluthation (GSH), activity of myeloperoxidase, catalase and superoxide dismutase enzymes and induced free radical generating capacity were measured as well as concentrations of TNF-α, IL-6, IL-8, and IL-10. MOD score, use of vasopressor agents and fluid utilisation were recorded daily. NAC treatment increased GSH level on days 4-5 (p<0.05) and PSH level on days 2-6 (p<0.05) compared to controls. Plasma IL-6 was lower on days 4-5 (p<0.05), IL-8 on days 4-6 (p<0.05) and IL-10 on days 4-6 (p<0.05) in NAC group. NAC group received less catecholamines than controls (p<0.01) from day 4 without significant differences in MOD score. NAC treatment is associated with a diminished oxidative stress reflected in preserved antioxidant levels, lower inflammation mirrored in lower interleukin levels and less vasopressor requirement. Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

  9. N-Acetylcysteine Reverses Anxiety and Oxidative Damage Induced by Unpredictable Chronic Stress in Zebrafish.

    PubMed

    Mocelin, Ricieri; Marcon, Matheus; D'ambros, Simone; Mattos, Juliane; Sachett, Adrieli; Siebel, Anna M; Herrmann, Ana P; Piato, Angelo

    2018-06-06

    There is accumulating evidence on the use of N-acetylcysteine (NAC) in the treatment of patients with neuropsychiatric disorders. As a multi-target drug and a glutathione precursor, NAC is a promising molecule in the management of stress-related disorders, for which there is an expanding field of research investigating novel therapies targeting oxidative pathways. The deleterious effects of chronic stress in the central nervous system are a result of glutamatergic hyperactivation, glutathione (GSH) depletion, oxidative stress, and increased inflammatory response, among others. The aim of this study was to investigate the effects of NAC in zebrafish submitted to unpredictable chronic stress (UCS). Animals were initially stressed or not for 7 days, followed by treatment with NAC (1 mg/L, 10 min) or vehicle for 7 days. UCS decreased the number of entries and time spent in the top area in the novel tank test, which indicate increased anxiety levels. It also increased reactive oxygen species (ROS) levels and lipid peroxidation (TBARS) while decreased non-protein thiols (NPSH) and superoxide dismutase (SOD) activity. NAC reversed the anxiety-like behavior and oxidative damage observed in stressed animals. Additional studies are needed to investigate the effects of this agent on glutamatergic modulation and inflammatory markers related to stress. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in mood disorders, anxiety, post-traumatic stress disorder, and other conditions associated with stress.

  10. Isolation of tissue layers in hermatypic corals by N-acetylcysteine: morphological and proteomic examinations

    NASA Astrophysics Data System (ADS)

    Peng, S.-E.; Luo, Y.-J.; Huang, H.-J.; Lee, I.-T.; Hou, L.-S.; Chen, W.-N. U.; Fang, L.-S.; Chen, C.-S.

    2008-03-01

    Corals are diploblastic in body pattern and include two tissue layers, the epidermis and gastrodermis, interconnected by an acellular matrix mesoglea. During development, cells in these tissue layers differentiate morphologically and functionally. In most hermatypic corals, the gastrodermis further develops an ability to associate with microalgae dinoflagellates. This endosymbiosis occurs inside specific host gastrodermal cells, and its mechanism still remains unclear notwithstanding decades of research. The delay in progress is partly due to the difficulty in separating the gastrodermis and its symbionts from the epidermis for detailed cellular and biochemical investigations. The present study reports a simple method to separate these two tissue layers in hermatypic corals using the reducing agent, N-acetylcysteine (NAC). Efficient tissue and proteomic isolations are demonstrated by microscopy and two-dimensional SDS polyacrylamide gel electrophoresis (2D SDS-PAGE). The NAC treatment was able to separate tissue layers without inducing protein degradation. Furthermore, the sensitivity of protein detection greatly increases in the isolated tissue layers. The application of the present technique provides future research on endosymbiosis and coral development with a tool for higher accuracy and sensitivity.

  11. Synergistic protective effect of N-acetylcysteine and taurine against cisplatin-induced nephrotoxicity in rats.

    PubMed

    Abdel-Wahab, Wessam M; Moussa, Farouzia I; Saad, Najwa A

    2017-01-01

    Cisplatin (cis-diaminedichloroplatinum II; CDDP) is an effective anticancer drug, but it has limitations because of its nephrotoxicity. This study investigates the protective effect of N -acetylcysteine (NAC) and taurine (TAU), both individually and in combination, against CDDP nephrotoxicity in rats. For this purpose, 48 male rats were assigned into eight groups (n=6) as follows: 1) control group, 2) NAC group, 3) TAU group, 4) NAC-TAU group, 5) CDDP group, 6) CDDP-NAC group, 7) CDDP-TAU group, and 8) CDDP-NAC-TAU group. Cisplatin was administered as a single intraperitoneal injection at a concentration of 6 mg/kg. Three days after CDDP administration, NAC (50 mg/kg) and/or TAU (50 mg/kg) were administered three times weekly for four consecutive weeks. Kidney function markers in serum, urinary glucose and protein, as well as oxidant and antioxidant parameters in renal tissue were assessed. Administration of CDDP significantly elevated urinary glucose and protein, as well as serum creatinine, urea, and uric acid. Moreover, CDDP enhanced lipid peroxidation and suppressed the major enzymatic antioxidants in the kidney tissue. Treatment with NAC or TAU protected against the alterations in the serum, urine, and renal tissue when used individually along with CDDP. Furthermore, a combined therapy of both was more effective in ameliorating CDDP-induced nephrotoxicity, which points out to their synergistic effect.

  12. N-acetylcysteine and acute retinal laser lesions in the colubrid snake eye

    NASA Astrophysics Data System (ADS)

    Elliott, William R., III; Rentmeister-Bryant, Heike K.; Barsalou, Norman; Beer, Jeremy; Zwick, Harry

    2004-07-01

    This study examined the role of oxidative stress and the effect of a single dose treatment with N-Acetylcysteine (NAC) on the temporal development of acute laser-induced retinal injury. We used the snake eye/Scanning Laser Ophthalmoscope (SLO) model, an in vivo, non-invasive ocular imaging technique, which has the ability to image cellular retinal detail and allows for studying morphological changes of retinal injury over time. For this study 12 corn-snakes (Elaphe g. guttata) received 5 laser exposures per eye, followed by either a single dose of the antioxidant NAC (150mg/kg, IP in sterile saline) or placebo. Laser exposures were made with a Nd: VO4 DPSS, 532nm laser, coaxially aligned to the SLO. Shuttered pulses were 20msec x 50 mW; 1mJ each. Retinal images were taken using a Rodenstock cSLO and were digitally recorded at 1, 6, 24-hrs, and at 3-wks post-exposure. Lesions were assessed by two raters blind to the conditions of the study yielding measures of damaged area and counts of missing or damaged photoreceptors. Treated eyes showed a significant beneficial effect overall, and these results suggest that oxidative stress plays a role in laser-induced retinal injury. The use of NAC or a similar antioxidant shows promise as a therapeutic tool.

  13. Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.

    PubMed

    Rendell, Rachel; Fairhall, Sarah; Graham, Stuart; Rutter, Steve; Auton, Philippa; Smith, Adam; Perrott, Rosi; Jugg, Bronwen

    2018-06-15

    The toxic industrial chemical (TIC 1 ) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

  14. Ozone-induced impairment of mucociliary transport and its prevention with N-acetylcysteine

    SciTech Connect

    Allegra, L.; Moavero, N.E.; Rampoldi, C.

    1991-09-30

    The effects of an oxidizing gaseous pollutant on tracheal mucous velocity have been studied in conscious sheep. Acute (2 hours) exposure to 1.0 ppm of ozone showed an effect on tracheal mucous velocity that resulted in a significant decrease 40 minutes and 2 hours after exposure (35% and 40% of the baseline, respectively). Repeated exposure for longer periods (4 days, 5 hours/day) to 1.0 ppm of ozone also significantly decreased tracheal mucous velocity during the first and the second day (-47% and -70% of the baseline, respectively), but during the following days of exposure adaptation took place (tracheal mucous velocitymore » ranging from -42% to -55% of baseline). The tracheal mucous velocity still significantly decreased 5 days after the last exposure. N-Acetylcysteine, known both for its mucolytic and antioxidizing properties, has been demonstrated to prevent significantly all of the immediate effects of either short-term or long-term ozone exposures on mucociliary functions.« less

  15. Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders

    PubMed Central

    Gipson, Cassandra D.; Malcolm, Robert J.; Kalivas, Peter W.; Gray, Kevin M.

    2014-01-01

    There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs. PMID:24442756

  16. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.

    PubMed

    Deepmala; Slattery, John; Kumar, Nihit; Delhey, Leanna; Berk, Michael; Dean, Olivia; Spielholz, Charles; Frye, Richard

    2015-08-01

    N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Compatibility and osmolality of inhaled N-acetylcysteine nebulizing solution with fenoterol and ipratropium.

    PubMed

    Lee, Tzung-Yi; Chen, Chi-Ming; Lee, Chun-Nin; Chiang, Yi-Chun; Chen, Hsiang-Yin

    2005-04-15

    The compatibility, pH, and osmolality of N-acetylcysteine (NAC) nebulizing solution in the presence of ipratropium bromide or fenoterol hydrobromide were studied. Portions (400 microL) of each mixture were sampled immediately upon mixing and one, two, three, four, five, six, and seven hours after mixing and assayed by high-performance liquid chromatography. Osmolality was measured by sampling 100 microL from the filling cup at a five-minute interval during nebulization and by the freezing-point-depression method. Adding NAC solution to fenoterol solution raised the pH from 3.20 to 7.90 and the osmolality to a mean +/- S.D. of 1400.67 +/- 4.51 mOsm/kg. Fenoterol concentrations decreased to 93.71% and NAC concentrations to 92.54% of initial concentrations after seven hours. Mixing ipratropium with NAC solution raised the pH from 3.74 to 7.95 and the osmolality to a mean +/- S.D. of 1413 +/- 11.79 mOsm/kg. The initial ipratropium concentration declined 7.39% and 10.91% one and two hours after mixing with NAC solution, respectively. NAC and ipratropium were stable in nebulizing solution within one hour of mixing. NAC and fenoterol were compatible for at least seven hours.

  18. N-acetylcysteine prevents stress-induced anxiety behavior in zebrafish.

    PubMed

    Mocelin, Ricieri; Herrmann, Ana P; Marcon, Matheus; Rambo, Cassiano L; Rohden, Aline; Bevilaqua, Fernanda; de Abreu, Murilo Sander; Zanatta, Leila; Elisabetsky, Elaine; Barcellos, Leonardo J G; Lara, Diogo R; Piato, Angelo L

    2015-12-01

    Despite the recent advances in understanding the pathophysiology of anxiety disorders, the pharmacological treatments currently available are limited in efficacy and induce serious side effects. A possible strategy to achieve clinical benefits is drug repurposing, i.e., discovery of novel applications for old drugs, bringing new treatment options to the market and to the patients who need them. N-acetylcysteine (NAC), a commonly used mucolytic and paracetamol antidote, has emerged as a promising molecule for the treatment of several neuropsychiatric disorders. The mechanism of action of this drug is complex, and involves modulation of antioxidant, inflammatory, neurotrophic and glutamate pathways. Here we evaluated the effects of NAC on behavioral parameters relevant to anxiety in zebrafish. NAC did not alter behavioral parameters in the novel tank test, prevented the anxiety-like behaviors induced by an acute stressor (net chasing), and increased the time zebrafish spent in the lit side in the light/dark test. These data may indicate that NAC presents an anti-stress effect, with the potential to prevent stress-induced psychiatric disorders such as anxiety and depression. The considerable homology between mammalian and zebrafish genomes invests the current data with translational validity for the further clinical trials needed to substantiate the use of NAC in anxiety disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects.

    PubMed

    Minarini, Alessandro; Ferrari, Silvia; Galletti, Martina; Giambalvo, Nina; Perrone, Daniela; Rioli, Giulia; Galeazzi, Gian Maria

    2017-03-01

    N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways. Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder. Despite initial optimism, recent findings regarding NAC efficacy in autism have been disappointing. Expert opinion: These preliminary positive results require further confirmation in larger samples and with longer follow-ups. Given its high tolerability and wide availability, NAC represents an important target to investigate in the field of new adjunctive treatments for psychiatric conditions.

  20. N-acetylcysteine prevents the development of gastritis induced by Helicobacter pylori infection.

    PubMed

    Jang, Sungil; Bak, Eun-Jung; Cha, Jeong-Heon

    2017-05-01

    Helicobacter pylori (H. pylori) is a human gastric pathogen, causing various gastric diseases ranging from gastritis to gastric adenocarcinoma. It has been reported that combining N-acetylcysteine (NAC) with conventional antibiotic therapy increases the success rate of H. pylori eradication. We evaluated the effect of NAC itself on the growth and colonization of H. pylori, and development of gastritis, using in vitro liquid culture system and in vivo animal models. H. pylori growth was evaluated in broth culture containing NAC. The H. pylori load and histopathological scores of stomachs were measured in Mongolian gerbils infected with H. pylori strain 7.13, and fed with NAC-containing diet. In liquid culture, NAC inhibited H. pylori growth in a concentration-dependent manner. In the animal model, 3-day administration of NAC after 1 week from infection reduced the H. pylori load; 6-week administration of NAC after 1 week from infection prevented the development of gastritis and reduced H. pylori colonization. However, no reduction in the bacterial load or degree of gastritis was observed with a 6-week administration of NAC following 6-week infection period. Our results indicate that NAC may exert a beneficial effect on reduction of bacterial colonization, and prevents the development of severe inflammation, in people with initial asymptomatic or mild H. pylori infection.

  1. Protective effects of N-acetylcysteine against monosodium glutamate-induced astrocytic cell death.

    PubMed

    Park, Euteum; Yu, Kyoung Hwan; Kim, Do Kyung; Kim, Seung; Sapkota, Kumar; Kim, Sung-Jun; Kim, Chun Sung; Chun, Hong Sung

    2014-05-01

    Monosodium glutamate (MSG) is a flavor enhancer, largely used in the food industry and it was reported to have excitotoxic effects. Higher amounts of MSG consumption have been related with increased risk of many diseases, including Chinese restaurant syndrome and metabolic syndromes in human. This study investigated the protective effects of N-acetylcysteine (NAC) on MSG-induced cytotoxicity in C6 astrocytic cells. MSG (20 mM)-induced reactive oxygen species (ROS) generation and apoptotic cell death were significantly attenuated by NAC (500 μM) pretreatment. NAC effectively inhibited the MSG-induced mitochondrial membrane potential (MMP) loss and intracellular reduced glutathione (GSH) depletion. In addition, NAC significantly attenuated MSG-induced endoplasmic reticulum (ER) stress markers, such as XBP1 splicing and CHOP, PERK, and GRP78 up-regulation. Furthermore, NAC prevented the changes of MSG-induced Bcl-2 expression level. These results suggest that NAC can protect C6 astrocytic cells against MSG-induced oxidative stress, mitochondrial dysfunction, and ER stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Current evidence for the use of N-acetylcysteine following liver resection.

    PubMed

    Kemp, Richard; Mole, Jonathan; Gomez, Dhanny

    2018-06-01

    N-acetylcysteine (NAC) has many uses in medicine; notable in the management of paracetamol toxicity, acute liver failure and liver surgery. The aim of this review was to critically appraise the published literature for the routine use of NAC in liver resection surgery. An electronic search was performed of EBSCOhost (Medline and CINAHL database), PubMed and the Cochrane Library for the period 1990-2016. MeSH headings: 'acetyl-cysteine', 'liver resection' and 'hepatectomy' were used to identify all relevant articles published in English. Following the search criteria used, three articles were included. Two of these studies were randomized controlled trials. All the studies collated data on morbidity and mortality. All three studies did not show a significant difference in overall complications rates in patients that underwent hepatic resection that had NAC infusion compared with patients that did not. In one study, NAC administration was associated with a higher frequency of grade A post-hepatectomy liver failure. In another study, a significantly higher incidence of delirium was observed in the NAC group, which led to the trial to be terminated early. The current published data do not support the routine use of NAC following liver resection. © 2017 Royal Australasian College of Surgeons.

  3. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status.

    PubMed

    Ciftci, Halil; Verit, Ayhan; Savas, Murat; Yeni, Ercan; Erel, Ozcan

    2009-07-01

    To examine whether a beneficial effect of N-acetylcysteine (NAC) on semen parameters and oxidative/antioxidant status in idiopathic male infertility exists. The production of reactive oxygen species is a normal physiologic event in various organs. However, overproduction of reactive oxygen species can be detrimental to sperm and has been associated with male infertility. Our study included 120 patients who had attended our clinic and were diagnosed with idiopathic infertility according to medical history and physical and seminal examination findings, as initial evaluations. The patients were divided randomly into 2 groups. Those in the study group (60 men) were given NAC (600 mg/d orally) for 3 months; the control group (60 men) received a placebo. The oxidative status was determined by measuring the total antioxidant capacity, total peroxide and oxidative stress index in plasma samples. The sperm parameters were evaluated after NAC treatment and were compared with those in the control group. NAC had significant improving effects on the volume, motility, and viscosity of semen. After NAC treatment, the serum total antioxidant capacity was greater and the total peroxide and oxidative stress index were lower in the NAC-treated group compared with the control group. These beneficial effects resulted from reduced reactive oxygen species in the serum and reduced viscosity of the semen. No significant differences were found in the number or morphology of the sperm between the 2 groups. We believe that NAC could improve some semen parameters and the oxidative/antioxidant status in patients with male infertility.

  4. N-acetylcysteine negatively regulates Notch3 and its malignant signaling

    PubMed Central

    Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

    2016-01-01

    Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors. PMID:27102435

  5. N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

    PubMed

    Zhang, Xiong; Wang, Ya-Nan; Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

    2016-05-24

    Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

  6. Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine.

    PubMed

    Sagara, M; Satoh, J; Wada, R; Yagihashi, S; Takahashi, K; Fukuzawa, M; Muto, G; Muto, Y; Toyota, T

    1996-03-01

    N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats.

  7. N-acetylcysteine supplementation reduces oxidative stress for cytosine arabinoside in rat model.

    PubMed

    Balci, Yasemin Isik; Acer, Semra; Yagci, Ramazan; Kucukatay, Vural; Sarbay, Hakan; Bozkurt, Kerem; Polat, Aziz

    2017-02-01

    Cytosine arabinoside (ARA-C) is a pyrimidine analog that may cause keratoconjunctivitis when used in high doses. The underlying mechanism may be the increased amounts of reactive oxygen radicals that may damage the DNA synthesis of corneal and conjunctival epithelial cells. Topical corticosteroids are one of the prophylactic treatments for keratoconjunctivitis induced by ARA-C. Forty Wistar-type albino rats were included in this study the rats were divided into four groups. The first group (Group 1) received only ARA-C, the second group (Group 2) received ARA-C and N-acetylcysteine (NAC), the third group (Group 3) received only NAC and the fourth group (Group 4) was the control group. The total oxidant status (TOS), the total antioxidant capacity and the oxidative stress index (OSI) measurements of the cornea and the conjunctiva were evaluated in these four groups. The mean TOS and OSI value was the highest in Group 1 and the lowest in Group 3. The differences in TOS and OSI values were statistically significant between Group 1 and Group 2. There are decreases in TOS and OSI values in rats which received ARA-C with NAC administration. NAC may have a protective effect on ARA-C-induced keratoconjunctivitis.

  8. Oxidative transformation of tunichromes - Model studies with 1,2-dehydro-N-acetyldopamine and N-acetylcysteine.

    PubMed

    Kuang, Qun F; Abebe, Adal; Evans, Jason; Sugumaran, Manickam

    2017-08-01

    Tunichromes are 1,2-dehydrodopa containing bioactive peptidyl derivatives found in blood cells of several tunicates. They have been implicated in metal sequestering, tunic formation, wound healing and defense reaction. Earlier studies conducted on these compounds indicate their extreme liability, high reactivity and easy oxidative polymerization. Their reactions are also complicated by the presence of multiple dehydrodopyl units. Since they have been invoked in crosslinking and covalent binding, to understand the reactivities of these novel compounds, we have taken a simple model compound that possess the tunichrome reactive group viz., 1,2-dehydro-N-acetyldopamine (Dehydro NADA) and examined its reaction with N-acetylcysteine in presence of oxygen under both enzymatic and nonenzymatic conditions. Ultraviolet and visible spectral studies of reaction mixtures containing dehydro NADA and N-acetylcysteine in different molar ratios indicated the production of side chain and ring adducts of N-acetylcysteine to dehydro NADA. Liquid chromatography and mass spectral studies supported this contention and confirmed the production of several different products. Mass spectral analysis of these products show the potentials of dehydro NADA to form side chain adducts that can lead to polymeric products. This is the first report demonstrating the ability of dehydro dopyl units to form adducts and crosslinks with amino acid side chains. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Therapeutic effect of budesonide/formoterol, montelukast and N-acetylcysteine for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

    PubMed

    Kim, Sei Won; Rhee, Chin Kook; Kim, Yoo Jin; Lee, Seok; Kim, Hee Je; Lee, Jong Wook

    2016-05-26

    Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is currently treated with systemic corticosteroids despite poor efficacy and side effects. This study investigated the therapeutic effect of budesonide/formoterol, montelukast and n-acetylcysteine, which are suggested as treatment options for BOS after HSCT. After diagnosis of BOS, 61 patients were treated with budesonide/formoterol, montelukast and n-acetylcysteine for 3 months. Pulmonary function test and COPD assessment test (CAT) were performed before and after the combination therapy. Therapeutic response was evaluated by changes in forced expiratory volume in 1 s (FEV1) or CAT score. After 3 months of combination treatment, mean FEV1 increased by 220 mL (p < 0.001) and residual volume decreased by 200 mL (p =0 .005). Median CAT score also significantly decreased from 15.5 to 11.0 (p = 0.001). The overall response rate to combination therapy was 82 %. Comparing the no-response group and the response group, the forced vital capacity (% predicted) decline between pre-HSCT and BOS diagnosis was significantly greater in the response group (p = 0.036). Combination treatment with budesonide/formoterol, montelukast and n-acetylcysteine significantly improved lung function and respiratory symptoms in patients with BOS after allogeneic HSCT without serious side effects.

  10. Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment

    PubMed Central

    Pósfai, B; Cserép, C; Hegedüs, P; Szabadits, E; Otte, D M; Zimmer, A; Watanabe, M; Freund, T F; Nyiri, G

    2016-01-01

    Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment. PMID:27163208

  11. Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: significance of combination therapy.

    PubMed

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Morris, David Lawson

    2014-11-12

    Bromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years. As such, the potential values of these agents in cancer therapy have been variably reported in the literature. In the present study, the efficacy of bromelain and N-acetylcysteine in single agent and combination treatment of human gastrointestinal carcinoma cells was evaluated in vitro and the underlying mechanisms of effect were explored. The growth-inhibitory effects of bromelain and N-acetylcysteine, on their own and in combination, on a panel of human gastrointestinal carcinoma cell lines, including MKN45, KATO-III, HT29-5F12, HT29-5M21 and LS174T, were assessed by sulforhodamine B assay. Moreover, the influence of the treatment on the expression of a range of proteins involved in the regulation of cell cycle and survival was investigated by Western blot. The presence of apoptosis was also examined by TUNEL assay. Bromelain and N-acetylcysteine significantly inhibited cell proliferation, more potently in combination therapy. Drug-drug interaction in combination therapy was found to be predominantly synergistic or additive. Mechanistically, apoptotic bodies were detected in treated cells by TUNEL assay. Furthermore, Western blot analysis revealed diminution of cyclins A, B and D, the emergence of immunoreactive subunits of caspase-3, caspase-7, caspase-8 and cleaved PARP, withering or cleavage of procaspase-9, overexpression of cytochrome c, reduced expression of anti-apoptotic Bcl-2 and pro-survival phospho-Akt, the emergence of the autophagosomal marker LC3-II and deregulation of other autophagy-related proteins, including Atg3, Atg5, Atg7, Atg12 and Beclin 1. These results were more prominent in combination therapy. We report for the first time to our knowledge the growth-inhibitory and cytotoxic effects of bromelain and N-acetylcysteine, in

  12. N-acetylcysteine attenuates endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo.

    PubMed

    Schmidt, H; Schmidt, W; Müller, T; Böhrer, H; Gebhard, M M; Martin, E

    1997-05-01

    To determine the influence of N-acetylcysteine on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics. Randomized, blinded, controlled trial. Experimental laboratory. Thirty male Wistar rats. After pretreatment with N-acetylcysteine (150 mg/kg; n = 40; group A) or 0.9% saline solution (n = 10; group B) animals were given an intravenous infusion of endotoxin (Escherichia coli lipopolysaccharide 026:B6; 2 mg/kg/hr) over 120 mins. Animals in the control group (n = 10; group C) received a volume-equivalent infusion of 0.9% saline solution. Leukocyte adherence, red cell velocity (VRBC), vessel diameters, venular wall shear rate, and macromolecular leakage were determined in mesenteric postcapillary venules using in vivo videomicroscopy at baseline and at 30, 50, 90, and 120 mins after the start of the endotoxin challenge. Endotoxin exposure induced a marked increase in adherent leukocytes (group B: baseline, 391 +/- 24 cells/mm2; 120 mins, 1268 +/- 131 cells/mm2; p < .01). N-acetylcysteine pretreatment attenuated the adherence of leukocytes during endotoxemia (baseline, 366 +/- 28 cells/mm2; 120 mins, 636 +/- 49 cells/mm2; p < .01 vs. baseline; p < .01 vs. group B). Leukocyte adherence in control animals (group C) did not increase significantly. Administration of N-acetylcysteine did not influence the decrease in VRBC observed during endotoxemia. In group B1 VRBC decreased during the infusion of endotoxin from 2.0 +/- 0.2 mm/sec at baseline to 1.1 +/- 0.2 mm/ sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C), and in group A from 2.2 +/- 0.2 mm/sec to 1.1 +/- 0.1 mm/sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C). In group C, VRBC remained unchanged (baseline, 1.7 +/- 0.2 mm/sec; at 120 mins, 1.5 +/- 0.2 mm/sec). The venular diameters remained unchanged in all groups during the entire study period. After 120 mins, the venular wall shear rate decreased from 502 +/- 62 secs-1 at baseline to 272

  13. A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

    PubMed Central

    Hardan, Antonio Y.; Fung, Lawrence K.; Libove, Robin A.; Obukhanych, Tetyana V.; Nair, Surekha; Herzenberg, Leonore A.; Frazier, Thomas W.; Tirouvanziam, Rabindra

    2016-01-01

    Background An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant in the treatment of behavioral disturbance in children with autism. Methods This is a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice-daily for 4 weeks and 900 mg three-times-daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist – Irritability subscale) and safety measures were performed at baseline, 4, 8, and 12 weeks. Secondary measures included the ABC-Stereotypy subscale, Repetitive Behavior Scale – Revised (RBS-R), and Social Responsiveness Scale (SRS). Results Thirty-three subjects (31 males, 2 females; aged 3.2–10.7 years) were randomized in the study. Follow-up data was available on fourteen subjects in the NAC group and fifteen in the placebo group. Oral NAC was well-tolerated with limited side effects. Compared to placebo, NAC resulted in significant improvements on ABC-Irritability subscale (F=6.80; p<.001; d=.96). Conclusions Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted. ClinicalTrials.gov Identifier NCT00627705 PMID:22342106

  14. N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery.

    PubMed

    Lopez, B L; Snyder, J W; Birenbaum, D S; Ma, X I

    1998-10-01

    Previous studies have suggested that N-acetylcysteine (NAC) may confer additional protection in acetaminophen (APAP) overdose by improving hepatic microcirculation. We hypothesize that NAC enhances release of nitric oxide (NO) from the vasculature. Sprague-Dawley rat superior mesenteric artery rings were suspended in oxygenated Krebs-Henseleit tissue baths and contracted with U-46619 (a thromboxane A2-mimetic). In part 1, the effect of NAC on endothelial cell (EC) release of NO was assessed by measurement of vasorelaxation induced by acetylcholine (ACh, an EC-dependent vasorelaxor) in the presence and absence of NAC. In part 2, the effect of glutathione (a major component of NAC hepatoprotection) was examined by measuring ACh-induced vasorelaxation in rings from rats treated with L-buthionine sulfoxamine (BSO, a glutathione synthesis inhibitor). Data were analyzed by repeated-measures ANOVA. Addition of 15 to 30 mmol/L NAC after ring contraction had no direct vasodilatory effect. By contrast, pretreatment of rings with NAC (15 mmol/L) enhanced vasorelaxation induced by ACh (95.0% +/- 7.9% versus 62.3% +/- 7.6% for control; ACh dose, 1 mumol/L; P < .001) or by A23187, a receptor-independent, NO-mediated vasodilator (91.6% +/- 9.6% versus 68.3% +/- 12.1% for control; A23187 dose, 1 mumol/L; P < .001). In rings from BSO-treated rats, NAC also enhanced vasorelaxation (76.5% +/- 7.1%; P < .001 versus control), but to a lesser degree than in nontreated rats. NAC enhances endothelium-dependent vasodilation in an isolated rat mesenteric artery ring preparation. In addition to its antioxidant effects, NAC may decrease APAP hepatotoxicity by stimulating NO production and improving microvascular circulation.

  15. Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation.

    PubMed

    Koeppel, T A; Lehmann, T G; Thies, J C; Gehrcke, R; Gebhard, M M; Herfarth, C; Otto, G; Post, S

    1996-05-15

    Recent observations showed an improvement of hepatic macro- and microhemodynamics as well as survival rates after warm ischemia of the liver following treatment with N-acetylcysteine (NAC). In this study we assessed the influence of NAC on the hepatic microcirculation after orthotopic liver transplantation (OLT) using intravital fluorescence microscopy. OLT with simultaneous arterialization was performed in 16 male Lewis rats following cold storage in University of Wisconsin solution for 24 hr. Within the experimental group (n = 8) donors received NAC (400 mg/kg) 25 min before hepatectomy. In addition, high-dose treatment of recipients with NAC (400 mg/kg) was started with reperfusion. Control animals (n = 8) received an equivalent amount of Ringer's solution. Intravital fluorescence microscopy was performed 30-90 min after reperfusion assessing acinar and sinusoidal perfusion, leukocyte-endothelium interaction, and phagocytic activity. Treatment with NAC reduced the number of nonperfused sinusoid from 52.4 +/- 0.8% to 15.7 +/- 0.5% (p = 0.0001) (mean +/- SEM). Furthermore, we achieved a significant reduction of leukocytes adhering to sinusoidal endothelium (per mm2 liver surface) from 351.9 +/- 13.0 in controls to 83.6 +/- 4.2 in the experimental group (P = 0.0001). In postsinusoidal venules, treatment with NAC decreased the number of sticking leukocytes (per mm2 endothelium) from 1098.5 +/- 59.6 to 425.9 +/- 37.7 (P = 0.0001). Moreover, bile flow was significantly increased after therapy with NAC (4.3 +/- 1.2 vs. 2.2 +/- 0.7 ml/90 min x 100g liver) (P < 0.05). Phagocytic activity was not influenced by application of NAC. We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.

  16. Antihypertensive mechanisms of chronic captopril or N-acetylcysteine treatment in L-NAME hypertensive rats.

    PubMed

    Zicha, Josef; Dobesová, Zdenka; Kunes, Jaroslav

    2006-12-01

    Hypertension due to chronic inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME-treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 microg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME-treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.

  17. N-acetylcysteine-induced vasodilation involves voltage-gated potassium channels in rat aorta.

    PubMed

    Han, Wei-Qing; Zhu, Ding-Liang; Wu, Ling-Yun; Chen, Qi-Zhi; Guo, Shu-Jie; Gao, Ping-Jin

    2009-05-22

    N-acetylcysteine (NAC) has a protective effect against vascular dysfunction by decreasing the level of reactive oxygen species (ROS) in experimental and human hypertension. This study was designed to examine whether NAC would relax vascular rings in vitro via nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, extracellular Ca2+ and/or K+ channels. Rat aortic arteries were mounted in an organ bath, contracted with 0.1, 0.5 or 1 micromol/L phenylephrine to plateau, and the vasodilatory effect of NAC was examined in the absence or presence of ROS scavengers, inhibitors of NO-cGMP pathway or K+ channels. Vascular smooth muscle cells (VSMCs) were loaded with a calcium sensitive fluorescent dye fluo-3 AM, and [Ca2+](i) was determined with laser-scanning confocal microscopy. NAC (0.1-4 mmol/L) dose-dependently relaxed rat aorta pre-contracted with phenylephrine. Endothelium removal, endothelial nitric oxide synthase inhibitor N(omega)-Nitro-l-arginine (L-NNA) (100 micromol/L) or soluble guanylyl cyclase (sGC) inhibitor (ODQ) (10 micromol/L) did not affect NAC-induced vasodilation. In contrast, NAC-induced vasodilation was blunted after extracellular calcium was removed and calcium imaging showed that 4 mmol/L NAC quickly decreased [Ca2+](i) in fluo-3 AM loaded VSMCs. NAC-induced vasodilation was significantly reduced in the presence of voltage-gated K+ channels (Kv) inhibitor 4-aminopyridine (4-AP). The vasodilatory effect of NAC may be explained at least partly by activation of voltage-gated K+ channels.

  18. Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.

    PubMed

    Schneider, Markus P; Delles, Christian; Schmidt, Bernhard M W; Oehmer, Sebastian; Schwarz, Thomas K; Schmieder, Roland E; John, Stefan

    2005-08-01

    It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension. In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively. Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05). We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.

  19. Effect of N-acetylcysteine on endothelial dysfunction in dialysis patients.

    PubMed

    Sahin, Garip; Yalcin, Ahmet Ugur; Akcar, Nevbahar

    2007-01-01

    Patients with K/DOQI stage 5 chronic kidney disease (CKD) have higher incidence of cardiovascular events due to the oxidative stress and endothelial dysfunction (ED). The aim of this study is to evaluate the effects of N-acetylcysteine (NAC), which might prevent cardiovascular events by improving oxidative stress on endothelial cells in patients with CKD. Thirty uremic patients (age 40 +/- 12 years, 6 males) on hemodialysis (HD) were evaluated for ED by using high-resolution Doppler ultrasound of brachial artery before and after 6 weeks of oral NAC (2 x 600 mg) medication. Also, 13 healthy controls (35 +/- 9 years, 5 males) were included in the study. Reactive hyperemia following 5 min forearm ischemia was accepted as endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and compared to endothelium-independent vasodilatation in response to sublingual glyceril trinitrate (GTN). Patients on HD had lower DeltaFMD (0.28 +/- 0.17 vs. 0.41 +/- 0.11, p < 0.05) and FMD% (7.5 +/- 5.05 vs. 11.33 +/- 2.95, p < 0.05) than the controls. Baseline DeltaGTN and GTN% were similar in two groups. NAC treatment significantly increased the DeltaFMD (0.41 +/- 0.11, p < 0.001 vs. baseline) and FMD% (10.59 +/- 3.22, p < 0.01 vs. baseline) of patients on HD, while it had no effect on DeltaGTN and GTN%. These results suggest that NAC treatment could improve the ED by preventing the reduction of FMD in patients on HD. Copyright 2007 S. Karger AG, Basel.

  20. Blood cardioplegia with N-acetylcysteine may reduce coronary endothelial activation and myocardial oxidative stress.

    PubMed

    Rodrigues, Alfredo J; Evora, Paulo R B; Bassetto, Solange; Alves, Lafaiete; Scorzoni Filho, Adilson; Origuela, Eliana A; Vicente, Walter V A

    2009-01-01

    The aim of this prospective study was to compare the efficacy of intermittent antegrade blood cardioplegia with or without n-acetylcysteine (NAC) in reducing myocardial oxidative stress and coronary endothelial activation. Twenty patients undergoing elective isolated coronary artery bypass graft surgery were randomly assigned to receive intermittent antegrade blood cardioplegia (32 degrees C-34 degrees C) with (NAC group) or without (control group) 300 mg of NAC. For these 2 groups we compared clinical outcome, hemodynamic evolution, systemic plasmatic levels of troponin I, and plasma concentrations of malondialdehyde (MDA) and soluble vascular adhesion molecule 1 (sVCAM-1) from coronary sinus blood samples. Patient demographic characteristics and operative and postoperative data findings in both groups were similar. There was no hospital mortality. Comparing the plasma levels of MDA 10 min after the aortic cross-clamping and of sVCAM-1 30 min after the aortic cross-clamping period with the levels obtained before the aortic clamping period, we observed increases of both markers, but the increase was significant only in the control group (P= .039 and P= .064 for MDA; P= .004 and P= .064 for sVCAM-1). In both groups there was a significant increase of the systemic serum levels of troponin I compared with the levels observed before cardiopulmonary bypass (P< .001), but the differences between the groups were not significant (P= .570). Our investigation showed that NAC as an additive to blood cardioplegia in patients undergoing on-pump coronary artery bypass graft surgery may reduce oxidative stress and the resultant coronary endothelial activation.

  1. N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

    PubMed

    Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

    2017-01-01

    Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure

  2. N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress

    PubMed Central

    Wang, Gangduo; Wang, Jianling; Ma, Huaxian; Ansari, G.A.S.; Khan, M. Firoze

    2017-01-01

    Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL+/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL+/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day through drinking water). TCE exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies. PMID:23993974

  3. Nebulized heparin and N-acetylcysteine for smoke inhalational injury: A case report.

    PubMed

    Ashraf, Umair; Bajantri, Bharat; Roa-Gomez, Gabriella; Venkatram, Sindhaghatta; Cantin, Amanda; Diaz-Fuentes, Gilda

    2018-05-01

    Every year, ∼40,000 people suffer burn-related injuries in the United States. Despite recent advances, the odds of dying from exposure to fire, flames, or smoke are one in ∼1500. Smoke inhalation causes injury to the airways via a complex physiological process, and the treatment is mainly supportive. Many recent interventions aim to decrease the formation of fibrin casts, the main cause of airway damage in these patients. Among these, treatment with a combination of nebulized heparin and N-acetylcysteine (NAC) has shown benefit. We describe the case of a 58-year-old man who presented after smoke inhalation during a fire. Soot was found in the nostrils when he was admitted to our hospital, and after he began coughing up carbonaceous material, he was electively intubated and placed on volume assist control ventilation. Bronchoscopy on the first day of intensive care confirmed the injury from smoke inhalation and revealed mucosal edema and soot involving the tracheobronchial tree. Inhaled unfractionated heparin of 10,000 IU in 3 mL of 0.9% normal saline alternating every 2 hours with 3 mL of 20% NAC was started 48 hours after admission and continued for 7 days. Bronchoscopy on the fifth day of intensive care showed significant improvement in airway edema and a resolution of soot. On the basis of our experience with this case and limited literature, we posit that nebulized heparin and NAC may be of benefit in patients with inhalational smoke-induced lung injury and mild-to-severe lung injury scores.

  4. l-N-acetylcysteine protects outer hair cells against TNFα initiated ototoxicity in vitro.

    PubMed

    Tillinger, Joshua A; Gupta, Chhavi; Ila, Kadri; Ahmed, Jamal; Mittal, Jeenu; Van De Water, Thomas R; Eshraghi, Adrien A

    2018-08-01

    The present study is aimed at determining the efficacy and exploring the mechanisms by which l-N-acetylcysteine (l-NAC) provides protection against tumor necrosis factor-alpha (TNFα)-induced oxidative stress damage and hair cell loss in 3-day-old rat organ of Corti (OC) explants. Previous work has demonstrated a high level of oxidative stress in TNFα-challenged OC explants. TNFα can potentially play a significant role in hair cell loss following an insult to the inner ear. l-NAC has shown to provide effective protection against noise-induced hearing loss in laboratory animals but mechanisms of this otoprotective effect are not well-defined. Rat OC explants were exposed to either: (1) saline control (N = 12); (2) TNFα (2 μg/ml, N = 12); (3) TNFα+l-NAC (5 mM, N = 12); (4) TNFα+l-NAC (10 mM, N = 12); or (5) l-NAC (10 mM, N = 12). Outer hair cell (OHC) density, levels of reactive oxygen species (ROS), lipid peroxidation of cell membranes, gluthathione activity, and mitochondrial viability were assayed. l-NAC (5 and 10 mM) provided protection for OHCs from ototoxic level of TNFα in OC explants. Groups treated with TNFα+l-NAC (5 mM) showed a highly significant reduction of both ROS (p < 0.01) and 4-hydroxy-2-nonenal immunostaining (p < 0.001) compared to TNFα-challenged explants. Total glutathione levels were low in TNFα-challenged explants compared to control and TNFα+l-NAC (5 mM) treated explants (p < 0.001). l-NAC is a promising treatment for protecting auditory HCs from TNFα-induced oxidative stress and subsequent loss via programmed cell death.

  5. Effects of dexpanthenol and N-acetylcysteine pretreatment in rats before renal ischemia/reperfusion injury.

    PubMed

    Sen, Huseyin; Deniz, Suleyman; Yedekci, A Erturk; Inangil, Gokhan; Muftuoglu, Tuba; Haholu, Aptullah; Ozkan, Sezai

    2014-11-01

    We investigated the anti-inflammatory and protective effects of concomitant use of dexpanthenol (DXP) and N-acetylcysteine (NAC) induced ischemia/reperfusion (I/R) injury of kidney. Forty rats were randomly divided into 5 groups. In all groups except for Group 1(Sham), renal arteries bilaterally occluded with vascular clamp for IR injury. Group 1(Sham), received a single dose of 10 mL/kg isotonic saline daily by intraperitoneal (IP) injection for three days. Group 2(IR), received a single dose of 10 mL/kg isotonic saline daily by IP injection for three days. Group 3(IR + NAC), received 300 mg/kg NAC daily by IP injection for three days. Group 4(IR + DXP), received 500 mg/kg DXP daily by IP injection for three days. Group 5(IR + NAC + DXP), received 500 mg/kg DXP and 300 mg/kg NAC daily by IP injection for three days. Serum urea (BUN), creatinine (Cr) and neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2, siderocalin) levels were measured as kidney function tests. TNF-α levels were measured as inflammatory marker. Tissue sections were evaluated histopathologically under light microscopy. IR + NAC + DXP group received both NAC and DXP before induction of renal I/R and as the biochemical and histopathological data revealed the results of the IR + NAC + DXP group and sham group were similar. Biochemically and histopathologically, combined use of NAC and DXP has better results when each of them used alone. We concluded that concomitant use of DXP and NAC plays a major role against I/R injury and may be useful in acute treatment of I/R induced renal failure.

  6. N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress

    PubMed Central

    Chen, Fangping; Hadfield, Jessalyn M.; Berzingi, Chalak; Hollander, John M.; Miller, Diane B.; Nichols, Cody E.

    2013-01-01

    Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77–82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca2+ concentration responses to extracellular Ca2+ (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10−3 M) normalized calcium handling in response to ISO and extracellular Ca2+ concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca2+ (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy. PMID:23722706

  7. Dual behavior of N-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains.

    PubMed

    Bauer, Alison K; Fitzgerald, Mary; Ladzinski, Adam T; Lenhart Sherman, Sydney; Maddock, Benjamin H; Norr, Zoe M; Miller, Robert R

    2017-10-01

    Ethanol (EtOH) causes oxidative stress in embryos. Because N-acetylcysteine (NAC) failures and successes in ameliorating EtOH-induced oxidative stress have been reported, the objective was to determine if exogenous NAC ameliorated EtOH-induced oxidative stress within embryonic chick brains. Control eggs were injected with approximately 25 µl of water on day 0, 1, and 2 of development (E 0-2 ). Experimental eggs were injected with dosages of either 3.0 mmol EtOH/kg egg; 747 µmol NAC/kg egg; 3.0 mmol EtOH and 747 µmol NAC/kg egg; 1000 µmol NAC/kg egg; or 3.0 mmol EtOH and 1000 µmol NAC/kg during the first 3 days of development (E 0-2 ). At 11 days of development (E 11 ; late embryogenesis), brains were harvested and subsequently assayed for oxidative stress markers including the loss of long-chain membrane polyunsaturated fatty acids (PUFAs); the accumulation of lipid hydroperoxides (LPO); decreased glutathione (GSH) and glutathione/glutathione disulfide (GSSG) levels; and decreased glutathione peroxidase (GPx) activities. EtOH (3 mmol/kg egg), medium NAC (747 µmol/kg egg), and EtOH and medium NAC promoted oxidative stress. These treatments caused decreased brain membrane long-chain PUFAs; increased LPO levels; decreased GSH levels and GSH/GSSG levels; and decreased Se-dependent GPx activities. High NAC dosages (1000 µmol/kg egg) attenuated EtOH-induced oxidative stress within EtOH and high NAC-treated chick brains. Exogenous EtOH and/or medium NAC propagated oxidative stress. Meanwhile, high NAC ameliorated EtOH-induced oxidative stress.

  8. N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy

    PubMed Central

    Wilder, Tanganyika; Ryba, David M.; Wieczorek, David F.; Wolska, Beata M.

    2015-01-01

    S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca2+ sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca2+ ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca2+ sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM. PMID:26432840

  9. N-acetylcysteine protects against star fruit-induced acute kidney injury.

    PubMed

    Shimizu, Maria Heloisa Massola; Gois, Pedro Henrique França; Volpini, Rildo Aparecido; Canale, Daniele; Luchi, Weverton Machado; Froeder, Leila; Heilberg, Ita Pfeferman; Seguro, Antonio Carlos

    2017-11-01

    Star fruit (SF) is a popular fruit, commonly cultivated in many tropical countries, that contains large amount of oxalate. Acute oxalate nephropathy and direct renal tubular damage through release of free radicals are the main mechanisms involved in SF-induced acute kidney injury (AKI). The aim of this study was to evaluate the protective effect of N-acetylcysteine (NAC) on SF-induced nephrotoxicity due to its potent antioxidant effect. Male Wistar rats received SF juice (4 mL/100 g body weight) by gavage after a 12 h fasting and water deprivation. Fasting and water deprivation continued for 6 h thereafter to warrant juice absorption. Thereafter, animals were allocated to three experimental groups: SF (n = 6): received tap water; SF + NAC (n = 6): received NAC (4.8 g/L) in drinking water for 48 h after gavage; and Sham (n = 6): no interventions. After 48 h, inulin clearance studies were performed to determine glomerular filtration rate. In a second series of experiment, rats were housed in metabolic cages for additional assessments. SF rats showed markedly reduced inulin clearance associated with hyperoxaluria, renal tubular damage, increased oxidative stress and inflammation. NAC treatment ameliorated all these alterations. Under polarized light microscopy, SF rats exhibited intense calcium oxalate birefringence crystals deposition, dilation of renal tubules and tubular epithelial degeneration, which were attenuate by NAC therapy. Our data show that therapeutic NAC attenuates renal dysfunction in a model of acute oxalate nephropathy following SF ingestion by reducing oxidative stress, oxaluria, and inflammation. This might represent a novel indication of NAC for the treatment of SF-induced AKI.

  10. Oxidative Stress and Respiratory System: Pharmacological and Clinical Reappraisal of N-Acetylcysteine

    PubMed Central

    Santus, Pierachille; Corsico, Angelo; Solidoro, Paolo; Braido, Fulvio; Di Marco, Fabiano

    2014-01-01

    The large surface area for gas exchange makes the respiratory system particularly susceptible to oxidative stress-mediated injury. Both endogenous and exogenous pro-oxidants (e.g. cigarette smoke) trigger activation of leukocytes and host defenses. These mechanisms interact in a “multilevel cycle” responsible for the control of the oxidant/antioxidant homeostasis. Several studies have demonstrated the presence of increased oxidative stress and decreased antioxidants (e.g. reduced glutathione [GSH]) in subjects with chronic obstructive pulmonary disease (COPD), but the contribution of oxidative stress to the pathophysiology of COPD is generally only minimally discussed. The aim of this review was to provide a comprehensive overview of the role of oxidative stress in the pathogenesis of respiratory diseases, particularly COPD, and to examine the available clinical and experimental evidence on the use of the antioxidant N-acetylcysteine (NAC), a precursor of GSH, as an adjunct to standard therapy for the treatment of COPD. The proposed concept of “multilevel cycle” helps understand the relationship between respiratory diseases and oxidative stress, thus clarifying the rationale for using NAC in COPD. Until recently, antioxidant drugs such as NAC have been regarded only as mucolytic agents. Nevertheless, several clinical trials indicate that NAC may reduce the rate of COPD exacerbations and improve small airways function. The most plausible explanation for the beneficial effects observed in patients with COPD treated with NAC lies in the mucolytic and antioxidant effects of this drug. Modulation of bronchial inflammation by NAC may further account for these favorable clinical results. PMID:24787454

  11. N-acetylcysteine reverses immunotoxic effects of methyl mercury and augments murine lymphocyte proliferation in vitro

    SciTech Connect

    Omara, F.; Fournier, M.; Bernier, J.

    1995-12-31

    N-Acetylcysteine (NAC) is a thiol antioxidant used clinically to treat chronic inflammatory lung disorders and acetaminophen poisoning in humans. The authors evaluated in vitro the effect of NAC on mitogen-induced blastogenesis in C57BI/6 mouse splenocytes by {sup 3}H-thymidine uptake, and its ability to protect against the immunotoxic effects of methyl mercury on lymphocyte proliferation. Lymphocyte proliferation stimulated by optimal and suboptimal concentrations of concanavalin A (Con A), lipopolysaccharide (LPS), or a combination of calcium ionophore A23187 and phorbol-12-myristate-13-acetate (PMA) were markedly enhanced by NAC. NAC itself was a weak mitogen. The kinetics of the NAC effect on splenocyte proliferation weremore » mitogen dependent. NAC enhanced Con A-induced splenocyte proliferation in a dose-dependent and linear manner but enhanced the LPS-induced response at 50--400 {micro}g/ml of NAC followed by a decline in response to control value at higher concentrations. In splenocytes stimulated with PMA plus A23187, NAC increased proliferation at 50--200 pg/ml followed by a constant response at 200--1,000 {micro}g/ml NAC. When splenocytes were stimulated with higher concentrations of Con A (10 {micro}g/ml) or LPS (150 {micro}g/ml) which markedly suppress splenocyte proliferation, NAC significantly enhanced the Con A-induced response and reversed the inhibitory effect of high concentrations of LPS. NAC also protected lymphocytes against mitogen activation-induced cell death. Methyl mercury at 5 {times} 10{sup {minus}7}--1 {times} 10{sup {minus}6} suppressed Con A- and LPS-induced splenocyte proliferation by over 80%. However, NAC completely reversed the immunotoxic effects of methyl mercury on the mitogen-induced splenocyte proliferation even when the cells were pre-incubated with methyl mercury for 6 or 24 hr before stimulation with the mitogens.« less

  12. N-acetylcysteine Protects Mice from High Fat Diet-induced Metabolic Disorders.

    PubMed

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-08-01

    To study the effects of N-acetylcysteine (NAC, C5H9NO3S) on diet-induced obesity and obesity-related metabolic disorders. Six-week-old male C57BL/6 mice fed a chow or high-fat diet (HFD) were treated with NAC (2 g/L) in drinking water for 11 weeks. Its influences on body weight and food intake were manually measured, and influence on body composition were analyzed by magnetic residence imaging. Glucose meter and ELISA were used to determine serum glucose and insulin levels, as well as lipid content in the liver. The effects of NAC treatment on mRNA levels of genes involved in inflammation, thermogenesis, and lipid metabolism in various tissues were determined by real time PCR. NAC supplementation inhibited the increase of fat mass and the development of obesity when mice were fed an HFD. NAC treatment significantly lowered HFD-induced macrophage infiltration, and enhanced adiponectin gene expression, resulting in reduced hyperglycemia and hyperinsulinemia, and improvement of insulin resistance. NAC oral administration suppressed hepatic lipid accumulation, as evidenced by lower levels of triglyceride and cholesterol in the liver. The beneficial effects are associated with a decrease of hepatic Pparγ and its target gene expression, and an increase in the expression of genes responsible for lipid oxidation and activation of farnesoid X receptor. Furthermore, NAC treatment also stimulates expression of thermogenic genes. These results provide direct proof of the protective potential of NAC against HFD-induced obesity and obesity-associated metabolic disorders.

  13. N-acetylcysteine with apocynin prevents hyperoxaluria-induced mitochondrial protein perturbations in nephrolithiasis.

    PubMed

    Sharma, Minu; Sud, Amit; Kaur, Tanzeer; Tandon, Chanderdeep; Singla, S K

    2016-09-01

    Diminished mitochondrial activities were deemed to play an imperative role in surged oxidative damage perceived in hyperoxaluric renal tissue. Proteomics is particularly valuable to delineate the damaging effects of oxidative stress on mitochondrial proteins. The present study was designed to apply large-scale proteomics to describe systematically how mitochondrial proteins/pathways govern the renal damage and calcium oxalate crystal adhesion in hyperoxaluria. Furthermore, the potential beneficial effects of combinatorial therapy with N-acetylcysteine (NAC) and apocynin were studied to establish its credibility in the modulation of hyperoxaluria-induced alterations in mitochondrial proteins. In an experimental setup with male Wistar rats, five groups were designed for 9 d. At the end of the experiment, 24-h urine was collected and rats were euthanized. Urinary samples were analyzed for kidney injury marker and creatinine clearance. Transmission electron microscopy revealed distorted renal mitochondria in hyperoxaluria but combinatorial therapy restored the normal mitochondrial architecture. Mitochondria were isolated from renal tissue of experimental rats, and mitochondrial membrane potential was analyzed. The two-dimensional electrophoresis (2-DE) based comparative proteomic analysis was performed on proteins isolated from renal mitochondria. The results revealed eight differentially expressed mitochondrial proteins in hyperoxaluric rats, which were identified by Matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) analysis. Identified proteins including those involved in important mitochondrial processes, e.g. antioxidant defense, energy metabolism, and electron transport chain. Therapeutic administration of NAC with apocynin significantly expunged hyperoxaluria-induced discrepancy in the renal mitochondrial proteins, bringing them closer to the controls. The results provide insights to further understand the underlying

  14. N-acetylcysteine ameliorates liver injury in a rat model of intestinal ischemia reperfusion.

    PubMed

    Kalimeris, Konstantinos; Briassoulis, Panagiotis; Ntzouvani, Agathi; Nomikos, Tzortzis; Papaparaskeva, Kleio; Politi, Aikaterini; Batistaki, Chrysanthi; Kostopanagiotou, Georgia

    2016-12-01

    N-acetylcysteine (NAC) is an antioxidant with direct and indirect antioxidant actions used in the clinical setting. Oxidative stress is known to play a pivotal role in the intestinal ischemia reperfusion (IIR). Therefore, we studied the effect of different pretreatment regimens with NAC on the IIR injury in rats. Thirty-five male Wistar rats were randomly assigned to five groups. In group sham, only laparotomy was performed. Group control underwent IIR without NAC. In the other groups, NAC was administered intraperitoneally with different regimens: 150 mg/kg before ischemia (NAC 150), 300 mg/kg before ischemia (NAC 300), and 150 mg/kg before ischemia plus 150 mg/kg 5 min before reperfusion (NAC 150 + 150). Measurements in tissues and blood were conducted at 4 h of reperfusion following exsanguination. Histological score of the liver was significantly improved in NAC 300 compared with control (1.7 ± 0.5 versus 2.9 ± 1.1, respectively, P = 0.05). In addition, NAC treatment significantly reduced liver transaminases in all groups of treatment, mostly in group NAC 300. Plasma malondialdehyde levels were lower with NAC treatment, although not statistically significant. Lung glutathione peroxidase was significantly increased in group NAC 300 (P = 0.04), while the other oxidation biomarkers showed no significant differences. NAC exerts a significant protective role in liver injury following IIR, which seems to be independent of an intestinal protective effect. Additional administration of NAC before reperfusion was of no further benefit. The most effective regimen among the compared regimens was that of 300 mg/kg before ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.

    PubMed

    Wright, Dean J; Gray, Laura J; Finkelstein, David I; Crouch, Peter J; Pow, David; Pang, Terence Y; Li, Shanshan; Smith, Zoe M; Francis, Paul S; Renoir, Thibault; Hannan, Anthony J

    2016-07-15

    Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system x c - In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system x c - and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system x c - and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study.

    PubMed

    Prado, Eduardo; Maes, Michael; Piccoli, Luiz Gustavo; Baracat, Marcela; Barbosa, Décio Sabattini; Franco, Olavo; Dodd, Seetal; Berk, Michael; Vargas Nunes, Sandra Odebrecht

    2015-09-01

    N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (CO(EXH)) (secondary outcome), and quit rates as defined by CO(EXH) < 6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. NAC treatment significantly reduced the daily number of cigarettes used (Δ mean ± SD = -10.9 ± 7.9 in the NAC-treated versus -3.2 ± 6.1 in the placebo group) and CO(EXH) (Δ mean ± SD = -10.4 ± 8.6 ppm in the NAC-treated versus -1.5 ± 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by CO(EXH) < 6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.

  17. N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement.

    PubMed

    Jastrzębska, Joanna; Frankowska, Malgorzata; Filip, Malgorzata; Atlas, Daphne

    2016-09-01

    Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts. In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10-daily extinction training sessions to examine subsequent cocaine seeking. AD4 (25-75 mg kg(-1)) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25-50 mg kg(-1), AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25 mg kg(-1)) or NAC (100 mg kg(-1)) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior. Our results demonstrate that AD4 is effective at blocking cocaine-seeking behavior, highlighting its potential clinical use toward cocaine use disorder.

  18. The role of depressive symptoms in treatment of adolescent cannabis use disorder with N-Acetylcysteine.

    PubMed

    Tomko, Rachel L; Gilmore, Amanda K; Gray, Kevin M

    2018-05-21

    Relative to adults, adolescents are at greater risk of developing a cannabis use disorder (CUD) and risk may be exacerbated by co-occurring depressive symptoms. N-Acetylcysteine (NAC), an over-the-counter antioxidant, is thought to normalize glutamate transmission. Oxidative stress and glutamate transmission are disrupted in both depression and CUD. Thus, NAC may be particularly effective at promoting cannabis abstinence among adolescents with elevated depressive symptoms. Secondary analyses were conducted using a sub-sample of adolescents with CUD (N = 74) who participated in an 8-week randomized placebo-controlled clinical trial examining the efficacy of NAC for cannabis cessation. It was hypothesized that NAC would reduce severity of depressive symptoms, and that decreases depressive symptom severity would mediate decreases in positive weekly urine cannabinoid tests (11-nor-9-carboxy-Δ9-tetrahydrocannabinol). Additionally, it was expected that adolescents with greater severity of baseline depressive symptoms would be more likely to become abstinent when assigned NAC relative to placebo. Results from linear mixed models and generalized estimating equations did not suggest that NAC reduced severity of depressive symptoms, and the hypothesis that NAC's effect on cannabis cessation would be mediated by reduced depressive symptoms was not supported. However, an interaction between treatment condition and baseline severity of depressive symptoms as a predictor of weekly urine cannabinoid tests was significant, suggesting that NAC was more effective at promoting abstinence among adolescents with heightened baseline depressive symptoms. These secondary findings, though preliminary, suggest a need for further examination of the role of depressive symptoms in treatment of adolescent CUD with NAC. Copyright © 2018. Published by Elsevier Ltd.

  19. Acute chloroform ingestion successfully treated with intravenously administered N-acetylcysteine.

    PubMed

    Dell'Aglio, Damon M; Sutter, Mark E; Schwartz, Michael D; Koch, David D; Algren, D A; Morgan, Brent W

    2010-06-01

    Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases.

  20. N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes.

    PubMed

    Araki, Shunsuke; Dobashi, Kazushige; Kubo, Kazuyasu; Kawagoe, Rinko; Yamamoto, Yukiyo; Shirahata, Akira

    2007-12-01

    The present study was designed to determine whether N-acetylcysteine (NAC), a potent antioxidant, modulates nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) in adipocytes. Stimulation by the combination of 5 microg/ml of LPS and 100 ng/ml of TNF-alpha (LT) significantly enhanced NO production in 3T3-L1 adipocytes. Preincubation of the cells with NAC (5-20 mM) for 24 h suppressed the increased NO production in a dose-dependent manner. The production of NO was decreased by 49% at the concentration of 20 mM of NAC. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) protein, detected by immunoblot analysis, and iNOS mRNA, determined by real-time reverse-transcriptase coupled polymerase chain reaction analysis. Nuclear factor-kappa B (NF-kappa B) was significantly activated by LT-treatment, while the pretreatment with 20 mM of NAC prevented the activity by 42%. Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, also inhibited the LT-mediated NO production dose-dependently. One hundred microM of PDTC inhibited the NO production by 46%. We also investigated the effect of NAC and PDTC on the production of interleukein-6 (IL-6), which is regulated transcriptionally by NF-kappa B in 3T3-L1 adipocytes. IL-6 production was markedly increased by LT stimulus, and the enhanced secretion of IL-6 was suppressed in a dose-dependent manner by pretreatment with NAC or PDTC. These results suggest that NAC regulates iNOS expression and NO production in adipocytes through the modulating activation of NF-kappa B.

  1. N-acetylcysteine Ameliorates Prostatitis via miR-141 Regulating Keap1/Nrf2 Signaling.

    PubMed

    Wang, Liang-Liang; Huang, Yu-Hua; Yan, Chun-Yin; Wei, Xue-Dong; Hou, Jian-Quan; Pu, Jin-Xian; Lv, Jin-Xing

    2016-04-01

    Chronic prostatitis was the most common type of prostatitis and oxidative stress was reported to be highly elevated in prostatitis patients. In this study, we determined the effect of N-acetylcysteine (NAC) on prostatitis and the molecular mechanism involved in it. Male Sprague-Dawley rats were divided into three groups: control group (group A, n = 20), carrageenan-induced chronic nonbacterial prostatitis (CNP) model group (group B, n = 20), and carrageenan-induced CNP model group with NAC injection (group C, n = 20). Eye score, locomotion score, inflammatory cell count, cyclooxygenase 2 (COX2) expression, and Evans blue were compared in these three groups. The expression of miR-141 was determined by quantitative real-time PCR (qRT-PCR). Moreover, protein expressions of Kelch-like ECH-associated protein-1 (Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) and its target genes were examined by Western blot. Luciferase reporter assay was performed in RWPE-1 cells transfected miR-141 mimic or inhibitor and the plasmid carrying 3'-UTR of Keap1. The value of eye score, locomotion score, inflammatory cell count, and Evans blue were significantly decreased in group C, as well as the expression of COX2, when comparing to that of group B. These results indicated that NAC relieved the carrageenan-induced CNP. Further, we found that NAC increased the expression of miR-141 and activated the Keap1/Nrf2 signaling. Luciferase reporter assay revealed that miR-141 mimic could suppress the activity of Keap1 and stimulate the downstream target genes of Nrf2. In addition, miR-141 inhibitor could reduce the effect of NAC on prostatitis. NAC ameliorates the carrageenan-induced prostatitis and prostate inflammation pain through miR-141 regulating Keap1/Nrf2 signaling.

  2. N-Acetylcysteine (NAC)-Induced Hyponatremia Caused by an Electronic Medical Record (EMR) Order Error.

    PubMed

    Furmaga, Jakub; Wax, Paul; Kleinschmidt, Kurt

    2015-09-01

    Intravenous N-acetylcysteine (NAC) causes few adverse drug events, with mild anaphylactoid reactions being the most common. Hyponatremia as a complication of hypoosmolar NAC solution has been reported. We describe how a locally constructed electronic medical record (EMR) order set for IV NAC resulted in a seizure from hyponatremia due to excess free water administration. A 13-month-old female with no past medical history presented to a hospital after ingesting an unknown number of acetaminophen 500 mg tablets. The 4-h acetaminophen concentration was 343 mcg/mL, and she was started on IV NAC. 8.2 h into her 21-h IV NAC protocol, she developed a tonic-clonic seizure. Repeat serum sodium was 124 mEq/L, a decrease from 142 mEq/L at the time of admission. She was treated with hypertonic saline, lorazepam, and levetiracetam and had no further seizures. A brain MRI and EEG were both normal. After the seizure was stabilized, the providers noticed that the patient had receive a total of 900 mL of D5W (112.5 mL/kg) in the first 9 h of hospitalization. This was caused by a poorly constructed, restrictive, EMR order set that did not allow customization of the IV NAC preparation. Because the 21-h IV NAC administration involves preparation of 3 different doses infused over 3 different time intervals, an order set was developed to reduce ordering errors. However, error in its construction caused the pharmacist to prepare a solution containing too much free water, decreasing patient's intravascular sodium and resulting in a seizure. The purposes of our case report were to highlight the dangers of overreliance on EMR order sets and to recognize hyponatremic seizures as an adverse reaction of an inappropriately prepared IV NAC.

  3. Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.

    PubMed

    Yolland, Caitlin O B; Phillipou, Andrea; Castle, David J; Neill, Erica; Hughes, Matthew E; Galletly, Cherrie; Smith, Zoe M; Francis, Paul S; Dean, Olivia M; Sarris, Jerome; Siskind, Dan; Harris, Anthony W F; Rossell, Susan L

    2018-05-30

    Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted

  4. N-acetylcysteine-induced headache in hospitalized patients with acute acetaminophen overdose.

    PubMed

    Zyoud, Sa'ed H; Awang, Rahmat; Sulaiman, Syed Azhar Syed; Al-Jabi, Samah W

    2011-06-01

    Intravenous N-acetylcysteine (IV-NAC) is usually regarded as a safe antidote to acetaminophen overdose. However, during infusion of the loading dose, adverse drug reactions such as a headache may occur. The objectives of this study were to investigate the prevalence of headache in patients presenting to hospital after acetaminophen overdose and to determine which clinical findings are most predictive of headache among these patients. This is a retrospective cohort study of hospital admissions for acute acetaminophen overdose that was conducted over a period of 4 years from January 1, 2005 to December 31, 2008. Demographic data, clinical characteristics, and predictors of headache were analyzed. spss 15 was used for data analysis. Two-hundred and fifty-five patients were studied; their mean age was 23.1 ± 1.6; 83.9% of them were women and 14.9% had a headache during hospitalization. Headache among patients was significantly associated with IV-NAC administration (P = 0.001), intentional ingestion of drug (P = 0.04), acetaminophen concentration above 'possible toxicity' treatment line (P = 0.04), a high acetaminophen concentration (P = 0.04), and a long hospital stay (P = 0.03). Multiple logistic regression showed a significant risk factor for headache in patients administered IV-NAC (P = 0.04). We recorded a high frequency of headache in patients with acute acetaminophen overdose in our geographical area. This study suggests that among those patients, the use of IV-NAC is associated with an increased risk of headache. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

  5. Normobaric Hyperoxia Extends Neuro- and Vaso-Protection of N-Acetylcysteine in Transient Focal Ischemia.

    PubMed

    Liu, Yushan; Liu, Wen-Cao; Sun, Yanyun; Shen, Xianzhi; Wang, Xiaona; Shu, Hui; Pan, Rong; Liu, Chun-Feng; Liu, Wenlan; Liu, Ke Jian; Jin, Xinchun

    2017-07-01

    N-acetylcysteine (NAC), a precursor of glutathione that reduces reperfusion-induced injury, has been shown protection when it was administered pre-ischemia. However, less is known about the effect when it was given post-ischemia and there is no positive result associated with anti-oxidant in clinical trials. This study investigated the neuro- and vaso-protection of post-ischemia NAC administration as well as combining NAC with normobaric hyperoxia (NBO). Male Sprague-Dawley rats were exposed to NBO or normoxia during 2-h occlusion of the middle cerebral artery, followed by 48-h reperfusion. NAC or vehicle was intraperitoneally administered to rats immediately before reperfusion onset. NAC and NBO treatments produced 1.2 and 30 % reduction of infarction volume, respectively, and combination treatment showed greater reduction (59.8 %) as well as more decrease of hemispheric swelling volume. Of note, combination therapy showed improved neurological assessment and motor function which were sustained for 7 days after reperfusion. We also determined that the combination therapy showed greater inhibitory effects on tight junction protein degradation accompanied by Evan's blue extravasation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) induction, and poly ADP-ribose polymerase (PARP)-1 activation in ischemic brain tissue. Our results showed that although post-ischemia NAC administration had limited protection, combination treatment of NAC plus NBO effectively prevented blood-brain barrier (BBB) damage and significantly improved the outcome of brain injury, providing new evidence to support the concept that "cocktail" treatment targeting different stages provides better neuro- and vaso-protection than current individual treatment that has all failed in their clinical trials.

  6. Effects of Zinc and N-Acetylcysteine in Damage Caused by Lead Exposure in Young Rats.

    PubMed

    Pedroso, Taíse F; Oliveira, Cláudia S; Fonseca, Mariana M; Oliveira, Vitor A; Pereira, Maria Ester

    2017-12-01

    This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8-12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl 2 ) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl 2 (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl 2 plus NAC for 5 days (3rd-7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th-12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl 2 pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl 2 , NAC, and ZnCl 2 plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl 2 and NAC prevented the alterations induced by AcPb.

  7. N-acetylcysteine stimulates protein synthesis in enterocytes independently of glutathione synthesis.

    PubMed

    Yi, Dan; Hou, Yongqing; Wang, Lei; Long, Minhui; Hu, Shengdi; Mei, Huimin; Yan, Liqiong; Hu, Chien-An Andy; Wu, Guoyao

    2016-02-01

    Dietary supplementation with N-acetylcysteine (NAC) has been reported to improve intestinal health and treat gastrointestinal diseases. However, the underlying mechanisms are not fully understood. According to previous reports, NAC was thought to exert its effect through glutathione synthesis. This study tested the hypothesis that NAC enhances enterocyte growth and protein synthesis independently of cellular glutathione synthesis. Intestinal porcine epithelial cells were cultured for 3 days in Dulbecco's modified Eagle medium containing 0 or 100 μM NAC. To determine a possible role for GSH (the reduced form of glutathione) in mediating the effect of NAC on cell growth and protein synthesis, additional experiments were conducted using culture medium containing 100 μM GSH, 100 μM GSH ethyl ester (GSHee), diethylmaleate (a GSH-depletion agent; 10 μM), or a GSH-synthesis inhibitor (buthionine sulfoximine, BSO; 20 μM). NAC increased cell proliferation, GSH concentration, and protein synthesis, while inhibiting proteolysis. GSHee enhanced cell proliferation and GSH concentration without affecting protein synthesis but inhibited proteolysis. Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein degradation. At the signaling level, NAC augmented the protein abundance of total mTOR, phosphorylated mTOR, and phosphorylated 70S6 kinase as well as mRNA levels for mTOR and p70S6 kinase in IPEC-1 cells. Collectively, these results indicate that NAC upregulates expression of mTOR signaling proteins to stimulate protein synthesis in enterocytes independently of GSH generation. Our findings provide a hitherto unrecognized biochemical mechanism for beneficial effects of NAC in intestinal cells.

  8. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults.

    PubMed

    Gray, Kevin M; Sonne, Susan C; McClure, Erin A; Ghitza, Udi E; Matthews, Abigail G; McRae-Clark, Aimee L; Carroll, Kathleen M; Potter, Jennifer S; Wiest, Katharina; Mooney, Larissa J; Hasson, Albert; Walsh, Sharon L; Lofwall, Michelle R; Babalonis, Shanna; Lindblad, Robert W; Sparenborg, Steven; Wahle, Aimee; King, Jacqueline S; Baker, Nathaniel L; Tomko, Rachel L; Haynes, Louise F; Vandrey, Ryan G; Levin, Frances R

    2017-08-01

    Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Do Montelukast Sodium and N-Acetylcysteine Have a Nephroprotective Effect on Unilateral Ureteral Obstruction? A Placebo Controlled Trial in a Rat Model.

    PubMed

    Sunay, Melih; Karakan, Tolga; Aydın, Arif; Koca, Gökhan; Börcek, Pınar; Öğüş, Elmas

    2015-10-01

    We assessed the nephroprotective effects of montelukast sodium and N-acetylcysteine on secondary renal damage due to unilateral ureteral obstruction in a rat model. In this study 30 Wistar albino male rats were randomized into 3 groups, including placebo, N-acetylcysteine and montelukast sodium. Three rats served as the control group. The left ureter of the rats was sutured with 4-zero polyglactin sutures. Medications were given 3 days before obstruction and continued for 15 days. Dimercaptosuccinic acid renal scintigraphy was performed before obstruction and on day 15. Rats were sacrificed on day 15 and histopathological examinations were done. We biochemically assessed oxidative stress markers (myeloperoxidase and malondialdehyde), sulfhydryl and total nitrite for lipid peroxidation, oxidative protein damage and antioxidant levels, respectively. On pathological examination inflammation and tubular epithelial damage in the N-acetylcysteine and montelukast sodium groups were less than in the placebo group (p <0.05). No difference was seen in normal kidneys. Myeloperoxidase, malondialdehyde and total nitrite levels in the N-acetylcysteine group, and myeloperoxidase and malondialdehyde levels in the montelukast sodium group were lower than in the placebo group (p <0.05). No statistical difference was seen in sulfhydryl levels (p >0.05) or among the N-acetylcysteine, montelukast sodium and placebo groups on scintigraphy (p >0.05). No pathological, chemical and scintigraphic differences were seen among the N-acetylcysteine, montelukast sodium and sham treated groups (p >0.05). N-acetylcysteine and montelukast sodium have a protective effect against obstructive damage of the kidney. However, further investigations are needed. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  10. Experimental and clinical evidence for modification of hepatic ischaemia–reperfusion injury by N-acetylcysteine during major liver surgery

    PubMed Central

    Jegatheeswaran, Santhalingam; Siriwardena, Ajith K

    2011-01-01

    Background Hepatic ischaemia–reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation. Methods A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group. Results Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival. Conclusion N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery. PMID:21241423

  11. Intravenous N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomized, Controlled Trials

    PubMed Central

    Sun, Zikai; Fu, Qiang; Cao, Longxing; Jin, Wen; Cheng, LingLing; Li, Zhiliang

    2013-01-01

    Background Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media. Study Design Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed. Results Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q = 17.42, P = 0.04; I2 = 48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics. Conclusion This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different

  12. Antimicrobial Activity of Penicillin G and N-acetylcystein on Planktonic and Sessile Cells of Streptococcus suis.

    PubMed

    Espinosa, Ivette; Báez, Michel; Lobo, Evelyn; Martínez, Siomara; Gottschalk, Marcelo

    2016-01-01

    The aim of this study was to investigate the capacity of Streptococcus suis strains to form biofilms and to evaluate the antimicrobial activity of Penicillin G and N-acetylcystein (NAC) on both S. suis sessile and planktonic forms. Only non-typeable isolates of S. suis were correlated with a greater biofilm formation capacity. The MCI of Penicillin G and NAC required for inhibiting biofilm growth were higher than the required concentration for inhibiting planktonic growth. The combinations of NAC and Penicillin G showed a strong synergistic activity that inhibited biofilm formation and disrupted the pre-formed biofilm of S. suis.

  13. Effects of n-acetylcysteine in a rat model of ischemia and reperfusion injury.

    PubMed

    Cuzzocrea, S; Mazzon, E; Costantino, G; Serraino, I; De Sarro, A; Caputi, A P

    2000-08-18

    Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of n-acetylcysteine (NAC), a free radical scavenger, in rats subjected to SAO shock. Treatment of rats with NAC (applied at 20 mg/kg, 5 min prior to reperfusion, followed by an infusion of 20 mg/kg/h) attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. NAC also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine in the plasma of the SAO-shocked rats after reperfusion. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) synthetase (PARS) revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and PARS were markedly reduced in tissue sections obtained from SAO-shocked rats which had received NAC. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localised in the vascular endothelial cells. Ileum tissue section obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. NAC treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). NAC treatment improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and significantly improved survival. Taken together, our results clearly demonstrate that NAC

  14. Protective effect of N-acetylcysteine against oxygen radical-mediated coronary artery injury.

    PubMed

    Rodrigues, A J; Evora, P R B; Schaff, H V

    2004-08-01

    The present study investigated the protective effect of N-acetylcysteine (NAC) against oxygen radical-mediated coronary artery injury. Vascular contraction and relaxation were determined in canine coronary arteries immersed in Kreb's solution (95% O2-5% CO2), incubated or not with NAC (10 mM), and exposed to free radicals (FR) generated by xanthine oxidase (100 mU/ml) plus xanthine (0.1 mM). Rings not exposed to FR or NAC were used as controls. The arteries were contracted with 2.5 microM prostaglandin F2alpha. Subsequently, concentration-response curves for acetylcholine, calcium ionophore and sodium fluoride were obtained in the presence of 20 microM indomethacin. Concentration-response curves for bradykinin, calcium ionophore, sodium nitroprusside, and pinacidil were obtained in the presence of indomethacin plus Nomega-nitro-L-arginine (0.2 mM). The oxidative stress reduced the vascular contraction of arteries not exposed to NAC (3.93 +/- 3.42 g), compared to control (8.56 +/- 3.16 g) and to NAC group (9.07 +/- 4.0 g). Additionally, in arteries not exposed to NAC the endothelium-dependent nitric oxide (NO)-dependent relaxation promoted by acetylcholine (1 nM to 10 microM) was also reduced (maximal relaxation of 52.1 +/- 43.2%), compared to control (100%) and NAC group (97.0 +/- 4.3%), as well as the NO/cyclooxygenase-independent receptor-dependent relaxation provoked by bradykinin (1 nM to 10 microM; maximal relaxation of 20.0 +/- 21.2%), compared to control (100%) and NAC group (70.8 +/- 20.0%). The endothelium-independent relaxation elicited by sodium nitroprusside (1 nM to 1 microM) and pinacidil (1 nM to 10 microM) was not affected. In conclusion, the vascular dysfunction caused by the oxidative stress, expressed as reduction of the endothelium-dependent relaxation and of the vascular smooth muscle contraction, was prevented by NAC.

  15. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2014-01-01

    Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

  16. Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status.

    PubMed

    Hildebrandt, Wulf; Sauer, Roland; Bonaterra, Gabriel; Dugi, Klaus A; Edler, Lutz; Kinscherf, Ralf

    2015-11-01

    Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy. We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers. We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL. NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% ± 3.0% (placebo: 4.1% ± 3.6%) while increasing those of cysteine by 28.1% ± 5.7% (placebo: 4.0% ± 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction. Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men

  17. N-acetylcysteine amid reduces pancreatic damage in a rat model of acute necrotizing pancreatitis.

    PubMed

    Turkyilmaz, Serdar; Usta, Arif; Cekic, Arif Burak; Alhan, Etem; Kural, Birgül Vanizor; Ercin, Cengiz

    2016-06-15

    Inflammatory explosion and oxidative stress are important mechanisms of injury in acute necrotizing pancreatitis (ANP). This study investigated the effects of N-acetylcysteine amid (NACA), a novel cell-permeant antioxidant with anti-inflammatory activity, on experimental ANP in rats. Fifty-two adult male Sprague-Dawley rats were used, and ANP was induced by cerulein. The animals were divided into four groups which were sham + saline, sham + NACA, ANP + saline, and ANP + NACA. NACA (2.2 mg/kg, i.p) was administered for 6 h, after the induction of ANP. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density, renal/hepatic functions, and changes in some enzyme markers for pancreas and lung tissues were investigated. Induction of ANP increased mortality from 0% in the sham group to 43.75% in the ANP + saline group (P < 0.05), and administration of NACA significantly reduced mortality to 12.5% (P < 0.05). Induction of ANP also caused increases in pancreatic necrosis, serum amylase, alanine aminotransferase (ALT), interleukin-6, LDH in bronchoalveolar lavage fluid, serum urea, tissue myeloperoxidase in pancreas and lung tissues and malondialdehyde. There was less pronounced increase in these parameters in NACA treated group. Compared with ANP group, ANP + NACA group had lower levels of pancreatic necrosis (0.5 ± 0.2 versus 1.45 ± 0.2, P < 0.05) and inflammation (0.6 ± 0.2 versus 1.29 ± 00.3, P < 0.05) scores. Administration of NACA significantly decreased the ANP-induced mortality and also provided significant improvements in hemodynamic changes. The obtained positive effects of NACA on the course of pancreatitis indicates its potential usefulness in the management of ANP. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. N-ACETYLCYSTEINE REDUCES DISEASE ACTIVITY BY BLOCKING MTOR IN T CELLS OF LUPUS PATIENTS

    PubMed Central

    Lai, Zhi-Wei; Hanczko, Robert; Bonilla, Eduardo; Caza, Tiffany N.; Clair, Brandon; Bartos, Adam; Miklossy, Gabriella; Jimah, John; Doherty, Edward; Tily, Hajra; Francis, Lisa; Garcia, Ricardo; Dawood, Maha; Yu, Jianghong; Ramos, Irene; Coman, Ioana; Faraone, Stephen V.; Phillips, Paul E.; Perl, Andras

    2012-01-01

    Background Systemic lupus erythematosus (SLE) patients exhibit T-cell dysfunction which can be regulated through the mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione. Therefore, the safety, tolerance, and efficacy of glutathione-precursor N-acetylcysteine (NAC) were examined in this randomized double-blind placebo-controlled study. Methods 36 SLE patients received daily placebo or 1.2 g, 2.4 g or 4.8 g of NAC. Disease activity was monthly evaluated by BILAG, SLEDAI and fatigue assessment scale (FAS) before, during, and after 3-month treatment. Δψm and mTOR were assessed by flow cytometry. 42 healthy subjects matched for patients’ age, gender, and ethnicity were studied as controls. Results NAC was tolerated by all patients up to 2.4 g/day while 33% of those receiving 4.8 g/day had reversible nausea. Placebo or 1.2 g/day NAC did not influence disease activity. Considered together, 2.4 g and 4.8 g NAC reduced: 1) SLEDAI after 1 month (p=0.0007), 2 months (p=0.0009), 3 months (p=0.0030) and 4 months (p=0.0046); 2) BILAG after 1 month (p=0.029) and 3 months (p=0.0009); and 3) FAS after 2 months (p=0.002) and 3 months (p=0.004). NAC increased Δψm (p=0.0001) in all T cells, it profoundly reduced mTOR activity (p=0.0001), enhanced apoptosis (p=0.0004) and reversed expansion of CD4−/CD8− T cells (1.35 ± 0.12-fold; p=0.008), stimulated Foxp3 expression in CD4+/CD25+ T cells (p=0.045), and reduced anti-DNA production (p=0.049). Conclusions This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes. PMID:22549432

  19. N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress

    SciTech Connect

    Wang, Gangduo; Wang, Jianling; Ma, Huaxian

    Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL +/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day through drinking water). TCEmore » exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies. - Highlights: • TCE led to increased autoantibodies, supporting its potential to induce autoimmunity. • TCE exposure led to increases in lipid perioxidation and protein carbonyls. • TCE exposure

  20. Protective Effect of N-acetylcysteine on Liver Damage During Chronic Intrauterine Hypoxia in Fetal Guinea Pig

    PubMed Central

    Hashimoto, Kazumasa; Pinkas, Gerard; Evans, LaShauna; Liu, Hongshan; Al-Hasan, Yazan

    2012-01-01

    Chronic exposure to hypoxia during pregnancy generates a stressed intrauterine environment that may lead to fetal organ damage. The objectives of the study are (1) to quantify the effect of chronic hypoxia in the generation of oxidative stress in fetal guinea pig liver and (2) to test the protective effect of antioxidant treatment in hypoxic fetal liver injury. Pregnant guinea pigs were exposed to either normoxia (NMX) or 10.5% O2 (HPX, 14 days) prior to term (65 days) and orally administered N-acetylcysteine ([NAC] 10 days). Near-term anesthetized fetuses were excised and livers examined by histology and assayed for malondialdehyde (MDA) and DNA fragmentation. Chronic HPX increased erythroid precursors, MDA (NMX vs HPX; 1.26 ± 0.07 vs 1.78 ± 0.07 nmol/mg protein; P < .001, mean ± standard error of the mean [SEM]) and DNA fragmentation levels in fetal livers (0.069 ± 0.01 vs 0.11 ± 0.005 OD/mg protein; P < .01). N-acetylcysteine inhibited erythroid aggregation and reduced (P < .05) both MDA and DNA fragmentation of fetal HPX livers. Thus, chronic intrauterine hypoxia generates cell and nuclear damage in the fetal guinea pig liver. Maternal NAC inhibited the adverse effects of fetal liver damage suggestive of oxidative stress. The suppressive effect of maternal NAC may implicate the protective role of antioxidants in the prevention of liver injury in the hypoxic fetus. PMID:22534333

  1. Potentiation of chemotherapeutics by bromelain and N-acetylcysteine: sequential and combination therapy of gastrointestinal cancer cells

    PubMed Central

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Liauw, Winston; Morris, David Lawson

    2016-01-01

    Intraperitoneal chemotherapy together with cytoreductive surgery is the standard of care for a number of peritoneal surface malignancies. However, this approach fails to maintain the complete response and disease recurs due to microscopic residual disease. Although safer than systemic chemotherapy regimens, locoregional treatment with chemotherapeutics can induce toxicity which is a major concern affecting the patient’s treatment protocol and outcome. For an enhanced treatment efficacy, efforts should be made to maximize cytotoxic effects of chemotherapeutic agents on tumor cells while minimizing their toxic effects on host cells. Bromelain and N-acetylcysteine are two natural agents with good safety profiles shown to have anti-cancer effects. However, their interaction with chemotherapeutics is unknown. In this study, we investigated if these agents have the potential to sensitize in vitro gastrointestinal cancer models to cisplatin, paclitaxel, 5-fluorouracil, and vincristine. The drug-drug interaction was also analyzed. Our findings suggest that combination of bromelain and N-acetylcysteine with chemotherapeutic agents could give rise to an improved chemotherapeutic index in therapeutic approaches to peritoneal surface malignancies of gastrointestinal origin so that maximum benefits could result from less toxic and more patient-friendly doses. This represents a potentially efficacious strategy for the enhancement of microscopic cytoreduction and is a promising area for future research. PMID:27186409

  2. Surgically Induced Necrotizing Scleritis Following Strabismus Surgery Treated Successfully with Topical N-acetylcysteine in a Child with Congenital Fibrosis of Extraocular Muscles and Varadi Papp Syndrome.

    PubMed

    Rajamani, Muralidhar; Nagasubramanian, Vidhya; Ayyavoo, Ahila; Raghupathy, Palany; Dandapani, Ramamurthy

    2017-03-01

    Surgically induced necrotizing scleritis (SINS) is a rare but serious disorder that can develop many years after strabismus surgery. It is generally treated with high-dose steroids or immunosuppression. We describe a patient with Varadi Papp syndrome and congenital fibrosis of the extraocular muscles, who developed surgically induced necrotizing scleritis a month after strabismus surgery and was successfully managed by oral vitamin C and topical N-acetylcysteine 10%. While SINS is conventionally treated with steroids/immunosuppression, a conservative approach may be tried in milder cases. The role of topical N-acetylcysteine in managing this complication needs to be explored.

  3. Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro.

    PubMed

    Gillissen, A; Jaworska, M; Orth, M; Coffiner, M; Maes, P; App, E M; Cantin, A M; Schultze-Werninghaus, G

    1997-03-01

    Nacystelyn (NAL), a recently-developed lysine salt of N-acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O2- and H2O2 in cell-free assay systems; (2) to reduce O2- and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O2-, in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l-1) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l-1), total intracellular GSH (GSH + 2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAC), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAC, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n = 10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l-1). In accordance with the results obtained from cell-free, in vitro assays, O2- released by PMN was not affected. Ambroxol (concentrations: 10

  4. Premedication with simethicone and N-acetylcysteine in improving visibility during upper endoscopy: a double-blind randomized trial.

    PubMed

    Elvas, Luís; Areia, Miguel; Brito, Daniel; Alves, Susana; Saraiva, Sandra; Cadime, Ana T

    2017-02-01

    Background and study aim  Upper endoscopy is the most common method for the diagnosis of upper gastrointestinal tract diseases. The aim of this study was to determine whether premedication with simethicone or N -acetylcysteine improves mucosal visualization during upper endoscopy. Patients and methods  This was a randomized, double-blind, placebo-controlled study of 297 patients scheduled for upper endoscopy who were premedicated 15 - 30 minutes before the procedure with: 100 mL of water (placebo, group A); water plus 100 mg simethicone (group B); water plus 100 mg simethicone plus 600 mg N -acetylcysteine (group C). The primary outcome measure was the quality of mucosal visualization (score: excellent, adequate or inadequate). Results  The addition of simethicone (group B) or simethicone plus N -acetylcysteine to the water (group C) improved the visualization scores of endoscopies compared with water alone (group A). In particular, groups B and C produced a significantly higher percentage of endoscopies with excellent visualization for the esophagus (91.1 % and 86.7 %, respectively, vs. 71.4 % in group A; P  < 0.001) and stomach (76.2 % and 74.5 % vs. 38.8 % in group A; P  < 0.001). For the duodenum, the use of simethicone also showed an increase in the endoscopies with excellent visualization compared with water alone (85.1 % vs. 73.5 %; P  = 0.042). There were no significant differences in scores between groups B and C or between gastric scores in patients with previous subtotal gastrectomy (B and C vs. A): 60.0 % and 42.1 % vs. 28.6 % ( P  = 0.14). The rate of reported lesions was higher in group B but without statistical significance. Conclusions  Premedication with simethicone resulted in better mucosal visibility. Such premedication might improve diagnostic yield, and should be considered for standard practice. Trial registered at ClinicalTrials.gov (NCT02357303). © Georg Thieme Verlag KG Stuttgart

  5. N-Acetylcysteine in the Treatment of Pediatric Trichotillomania: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial

    ERIC Educational Resources Information Center

    Bloch, Michael H.; Panza, Kaitlyn E.; Grant, Jon E.; Pittenger, Christopher; Leckman, James F.

    2013-01-01

    Objective: To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. Method: A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary…

  6. Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant.

    PubMed

    Aliakbarian, Mohsen; Nikeghbalian, Saman; Ghaffaripour, Sina; Bahreini, Amin; Shafiee, Mohammad; Rashidi, Mohammad; Rajabnejad, Yaser

    2017-08-01

    One of the main concerns in liver transplant is the prolonged ischemia time, which may lead to primary graft nonfunction or delayed function. N-acetylcysteine is known as a hepato-protective agent in different studies, which may improve human hepatocyte viability in steatotic donor livers. This study investigated whether N-acetylcysteine can decrease the rate of ischemia-reperfusion syndrome and improve short-term outcome in liver transplant recipients. This was a double-blind, randomized, control clinical trial of 115 patients. Between April 2012 and January 2013, patients with orthotopic liver transplant were randomly divided into 2 groups; in 49 cases N-acetylcysteine was added to University of Wisconsin solution as the preservative liquid (experimental group), and in 66 cases standard University of Wisconsin solution was used (control group). We compared postreperfusion hypotension, inotrope requirement before and after portal reperfusion, intermittent arterial blood gas analysis and potassium measurement, pathological review of transplanted liver, in-hospital complications, morbidity, and mortality. There was no significant difference between the groups regarding time to hepatic artery reperfusion, hospital stay, vascular complications, inotrope requirement before and after portal declamping, and blood gas analysis. Hypotension after portal reperfusion was significantly more common in experimental group compared with control group (P = .005). Retransplant and in-hospital mortality were comparable between the groups. Preservation of the liver inside Univer-sity of Wisconsin solution plus N-acetylcysteine did not change the rate of ischemia reperfusion injury and short-term outcome in liver transplant recipients.

  7. N-acetylcysteine in contrast-induced acute kidney injury: clinical use against principles of evidence-based clinical medicine!

    PubMed

    Sadat, Umar

    2014-01-01

    Contrast-induced acute kidney injury (CI-AKI) is one of the most widely discussed and debated topic in cardiovascular medicine and N-acetylcysteine (NAC) is the most widely used pharmacological agent assessed in clinical trials for offering renal protection against CI-AKI. Results of these clinical trials are though split between those that favor its use and vice versa. In this brief communication we discuss the latest research advances regarding the use of NAC against CI-AKI. Recent clinical evidence and overview of in-depth statistical analyses of relevant clinical trials and their meta-analyses do not support the use of NAC in prophylaxis against CI-AKI. Adequate hydration before and after contrast media exposure, along with avoidance of nephrotoxic drugs, remains the recommended prophylaxis against CI-AKI.

  8. Chemical Changes in Nonthermal Plasma-Treated N-Acetylcysteine (NAC) Solution and Their Contribution to Bacterial Inactivation.

    PubMed

    Ercan, Utku K; Smith, Josh; Ji, Hai-Feng; Brooks, Ari D; Joshi, Suresh G

    2016-02-02

    In continuation of our previous reports on the broad-spectrum antimicrobial activity of atmospheric non-thermal dielectric barrier discharge (DBD) plasma treated N-Acetylcysteine (NAC) solution against planktonic and biofilm forms of different multidrug resistant microorganisms, we present here the chemical changes that mediate inactivation of Escherichia coli. In this study, the mechanism and products of the chemical reactions in plasma-treated NAC solution are shown. UV-visible spectrometry, FT-IR, NMR, and colorimetric assays were utilized for chemical characterization of plasma treated NAC solution. The characterization results were correlated with the antimicrobial assays using determined chemical species in solution in order to confirm the major species that are responsible for antimicrobial inactivation. Our results have revealed that plasma treatment of NAC solution creates predominantly reactive nitrogen species versus reactive oxygen species, and the generated peroxynitrite is responsible for significant bacterial inactivation.

  9. Enhanced inhibition of bacterial biofilm formation and reduced leukocyte toxicity by chloramphenicol:β-cyclodextrin:N-acetylcysteine complex.

    PubMed

    Aiassa, Virginia; Zoppi, Ariana; Becerra, M Cecilia; Albesa, Inés; Longhi, Marcela R

    2016-11-05

    The purpose of this study was to improve the physicochemical and biological properties of chloramphenicol (CP) by multicomponent complexation with β-cyclodextrin (β-CD) and N-acetylcysteine (NAC). The present work describes the ability of solid multicomponent complex (MC) to decrease biomass and cellular activity of Staphylococcus by crystal violet and XTT assay, and leukocyte toxicity, measuring the increase of reactive oxygen species by chemiluminescence, and using 123-dihydrorhodamine. In addition, MC was prepared by the freeze-drying or physical mixture methods, and then characterized by scanning electron microscopy and powder X-ray diffraction. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the MC and its association binding constants, respectively. The results obtained allowed us to conclude that MC formation is an effective pharmaceutical strategy that can reduce CP toxicity against leukocytes, while enhancing its solubility and antibiofilm activity. Copyright © 2016. Published by Elsevier Ltd.

  10. Determination of the radioprotective effects of topical applications of MEA, WR-2721, and N-acetylcysteine on murine skin

    SciTech Connect

    Verhey, L.J.; Sedlacek, R.

    1983-01-01

    Topical applications of MEA (beta-mercaptoethylamine or cysteamine), WR-2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid), and N-acetylcysteine (NAC) were tested for their ability to protect the normal skin of the hind legs of mice against acute and late damage from single doses of /sup 137/Cs radiation. No significant protection was observed with either WR-2721 or NAC. MEA was shown to offer significant protection against acute skin damage in both buffered and unbuffered forms, but no significant protection against late contraction. The use of topical MEA on unanesthetized animals breathing carbogen (95% O2, 5% CO2) appears to give an enhanced level of radioprotection over that shownmore » for anesthetized, air-breathing animals.« less

  11. Comparative behavioral toxicity of four sulfhydryl radioprotective compounds in mice: Wr2721, cysteamine, diethyldithiocarbamate, and n-acetylcysteine

    SciTech Connect

    Landauer, M.R.; Davis, H.D.; Dominitz, J.A.

    1988-01-01

    A number of sulfhydryl compounds have been shown to protect against ionizing radiation. One of the most effective radioprotectors is S-2(3-aminopropylamino)ethylphosphorothioic acid, also known aas ethiofos, gammaphos, or WR-2721 (Davidson, 1980; Giambarresi and Jacobs, 1987). This drug is currently under clinical investigation for its potential in protecting normal tissue during radiation treatment and chemotherapy (Blumberg et al., 1982; Glover et al., 1988; Yuhas et al., 1980). B-Mercaptoethylamine (MEA, cysteamine) was for years the standard against which the effectiveness of other radioprotectors was judged, but is more toxic than WR-2721 (Giambarresi and Jacobs, 1987). Diethyldithiocarbamate (DDC) and N-acetylcysteine (NAC) are othermore » compounds shown to have radioprotective properties (Milas et al., 1988; Weiss et al., 1984). Studies in a variety of animal species have shown significant behavioral toxicity after administration of WR-2721 (Bogo et al., 1985; Bogo, 1988; Landauer et al., 1987b, 1988).« less

  12. Chemical Changes in Nonthermal Plasma-Treated N-Acetylcysteine (NAC) Solution and Their Contribution to Bacterial Inactivation

    PubMed Central

    Ercan, Utku K.; Smith, Josh; Ji, Hai-Feng; Brooks, Ari D.; Joshi, Suresh G.

    2016-01-01

    In continuation of our previous reports on the broad-spectrum antimicrobial activity of atmospheric non-thermal dielectric barrier discharge (DBD) plasma treated N-Acetylcysteine (NAC) solution against planktonic and biofilm forms of different multidrug resistant microorganisms, we present here the chemical changes that mediate inactivation of Escherichia coli. In this study, the mechanism and products of the chemical reactions in plasma-treated NAC solution are shown. UV-visible spectrometry, FT-IR, NMR, and colorimetric assays were utilized for chemical characterization of plasma treated NAC solution. The characterization results were correlated with the antimicrobial assays using determined chemical species in solution in order to confirm the major species that are responsible for antimicrobial inactivation. Our results have revealed that plasma treatment of NAC solution creates predominantly reactive nitrogen species versus reactive oxygen species, and the generated peroxynitrite is responsible for significant bacterial inactivation. PMID:26832829

  13. Assessing the effects of melatonin and N-acetylcysteine on the McFarlane flap using a rat model

    PubMed Central

    Tunç, Süphan; Kesiktas, Erol; Yilmaz, Yeliz; Açikalin, Arbil; Oran, Gökçen; Yavuz, Metin; Gencel, Eyüphan; Eser, Cengiz

    2016-01-01

    OBJECTIVE To determine the effects of N-acetylcysteine (NAC) and melatonin, alone and in combination, on McFarlane flap viability in a rat model. METHODS Forty Wistar rats were divided into four groups and received daily intraperitoneal injections for one week before surgery: control (sham [n=10]); melatonin (n=10); NAC (n=10); and NAC+melatonin (n=10). One week after surgery, the experiment was terminated and photographs were taken for topographic studies. A transillumination study was performed to observe vascularization in the flaps and biopsies were obtained for histopathological studies. RESULTS Flap viability was significantly greater in the antioxidant- (ie, NAC and melatonin) treated groups compared with the control group; however, there were no significant differences among the groups that received antioxidants. CONCLUSIONS Melatonin and NAC are important antioxidants that can be used alone or in combination to increase flap viability and prevent distal necrosis in rats. PMID:28439512

  14. N-Acetylcysteine Amide Protects Against Oxidative Stress–Induced Microparticle Release From Human Retinal Pigment Epithelial Cells

    PubMed Central

    Carver, Kyle A.; Yang, Dongli

    2016-01-01

    Purpose Oxidative stress is a major factor involved in retinal pigment epithelium (RPE) apoptosis that underlies AMD. Drusen, extracellular lipid- and protein-containing deposits, are strongly associated with the development of AMD. Cell-derived microparticles (MPs) are small membrane-bound vesicles shed from cells. The purpose of this study was to determine if oxidative stress drives MP release from RPE cells, to assess whether these MPs carry membrane complement regulatory proteins (mCRPs: CD46, CD55, and CD59), and to evaluate the effects of a thiol antioxidant on oxidative stress–induced MP release. Methods Retinal pigment epithelium cells isolated from human donor eyes were cultured and treated with hydrogen peroxide (H2O2) to induce oxidative stress. Isolated MPs were fixed for transmission electron microscopy or processed for component analysis by flow cytometry, Western blot analysis, and confocal microscopy. Results Transmission electron microscopy showed that MPs ranged in diameter from 100 to 1000 nm. H2O2 treatment led to time- and dose-dependent elevations in MPs with externalized phosphatidylserine and phosphatidylethanolamine, known markers of MPs. These increases were strongly correlated to RPE apoptosis. Oxidative stress significantly increased the release of mCRP-positive MPs, which were prevented by a thiol antioxidant, N-acetylcysteine amide (NACA). Conclusions This is the first evidence that oxidative stress induces cultured human RPE cells to release MPs that carry mCRPs on their surface. The levels of released MPs are strongly correlated with RPE apoptosis. N-acetylcysteine amide prevents oxidative stress–induced effects. Our findings indicate that oxidative stress reduces mCRPs on the RPE surface through releasing MPs. PMID:26842754

  15. Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats

    PubMed Central

    Cai, Zhaobin; Shi, Tingting; Zhuang, Rangxiao; Fang, Hongying; Jiang, Xiaojie; Shao, Yidan; Zhou, Hongping

    2018-01-01

    With the development of science and technology, and development of artery bypass, methods such as cardiopulmonary cerebral resuscitation have been practiced in recent years. Despite this, some methods fail to promote or recover the function of tissues and organs, and in some cases, may aggravate dysfunction and structural damage to tissues. The latter is typical of ischemia-reperfusion (IR) injury. Lipid peroxidation mediated by free radicals is an important process of myocardial IR injury. Myocardial IR has been demonstrated to induce the formation of large numbers of free radicals in rats, which promotes the peroxidation of lipids within unsaturated fatty acids in the myocardial cell membrane. Markers of lipid peroxidation include malondialdehyde, superoxide dismutase and lactic dehydrogenase. Recent studies have demonstrated that N-acetylcysteine (NAC) is able to dilate blood vessels, prevent oxidative damage, improve immunity, inhibit apoptosis and the inflammatory response and promote glutathione synthesis in cells. NAC also improves the systolic function of myocardial cells and cardiac function, prevents myocardial apoptosis, protects ventricular remodeling and vascular remodeling, reduces opiomelanocortin levels in the serum and increases the content of nitric oxide in the serum, thus improving vascular endothelial function. Therefore, NAC has potent pharmacological activity; however, the relatively fast metabolism of NAC, along with its large clinical dose and low bioavailability, limit its applications. The present study combined NAC with medicinal activated carbons, and prepared N-acetylcysteine activated carbon sustained-release microcapsules (ACNACs) to overcome the limitations of NAC. It was demonstrated that ACNACs exerted greater effective protective effects than NAC alone on myocardial IR injury in rats. PMID:29434769

  16. Premedication with N-acetylcysteine and simethicone improves mucosal visualization during gastroscopy: a randomized, controlled, endoscopist-blinded study.

    PubMed

    Neale, James R; James, Shirley; Callaghan, James; Patel, Praful

    2013-07-01

    Diagnostic gastroscopy provides a unique opportunity to diagnose early oesophagogastric neoplasia; however, intraluminal mucus and bile can obscure mucosal visualization. The aim of this study was to determine whether the use of a premedication solution containing the mucolytic agent N-acetylcysteine and the surfactant simethicone improves mucosal visualization within a UK diagnostic gastroscopy service. A total of 75 consecutive patients were recruited from a single (S.J.) endoscopist's diagnostic gastroscopy list. They were randomized into three treatment groups: (a) standard control=clear fluids only for 6 h, nil by mouth for 2 h; (b) water control=standard control+100 ml sterile water (given 20 min before gastroscopy); and (c) solution=standard control+100 ml investigated solution (20 min before gastroscopy). The endoscopist was blinded to patient preparation. Inadequate mucosal visualization was defined as fluid/mucus during gastroscopy that could not be suctioned and required flushing with water. The volume of flush, the site at which it was used and the total procedure times were recorded. All three groups showed no statistical difference for age, sex ratio, procedure priority or indication. The mean volume of flush required to obtain clear mucosa was significantly less in the solution group compared with the other groups. The mean overall procedure time was also less in the solution group compared with the other groups. Premedication with N-acetylcysteine and simethicone markedly improves mucosal visibility during gastroscopy. It also reduces the time taken for the procedure. This low-cost and well-tolerated intervention may improve detection of early neoplasia.

  17. Vitamin B5 and N-acetylcysteine in nonalcoholic steatohepatitis: a pre-clinical study in a dietary mouse model

    PubMed Central

    Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L.; Michelotti, Gregory Alexander; de Almeida Pereira, Thiago; Xie, Guanhua; Moylan, Cynthia A.; Diehl, Anna Mae

    2015-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free Coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. Objectives We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. Methods CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD-diet fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Results Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity, and correlated with worse liver cell apoptosis, inflammation and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. Conclusion In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH. PMID:26403427

  18. N-acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats.

    PubMed

    Nagareddy, Prabhakara Reddy; Xia, Zhengyuan; MacLeod, Kathleen M; McNeill, John H

    2006-04-01

    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.

  19. N-acetylcysteine modulates doxorubicin-induced oxidative stress and antioxidant vitamin concentrations in liver of rats.

    PubMed

    Koçkar, M Cem; Nazıroğlu, Mustafa; Celik, Omer; Tola, H Tahsin; Bayram, Dilek; Koyu, Ahmet

    2010-12-02

    Doxorubicin (DOX) is a chemotherapeutic agent, and is widely used in cancer treatment. The most common side effect of DOX was indicated on cardiovascular system by experimental studies. There are some studies suggesting oxidative stress-induced toxic changes on liver related to DOX administration. The aim of the present study was to evaluate whether antioxidant N-acetylcysteine (NAC) relieves oxidative stress in DOX- induced liver injury in rat. Twenty-four male rats were equally divided into three groups. First group was used as a control. Second group received single dose of DOX. NAC for 10 days was given to constituting the third group after giving one dose of DOX. After 10 days of the experiment, liver tissues were taken from all animals. Lipid peroxidation (LP) levels were higher in the DOX group than in control whereas LP levels were lower in the DOX+NAC group than in control. Vitamin C and vitamin E levels were lower in the DOX group than in control whereas vitamin C and vitamin E levels were higher in the DOX+NAC group than in the DOX group. Reduced glutathione levels were higher in the DOX+NAC group than in control and DOX group. Glutathione peroxidase, vitamin A and β-carotene values were not changed in the three groups by DOX and NAC administrations. In histopathological evaluation of DOX group, there were mononuclear cell infiltrations, vacuolar degeneration, hepatocytes with basophilic nucleus and sinusoidal dilatations. The findings were totally recovered by NAC administration. In conclusion, N-acetylcysteine induced modulator effects on the doxorubicin-induced hepatoxicity by inhibiting free radical production and supporting the antioxidant vitamin levels. Copyright © 2010 John Wiley & Sons, Ltd.

  20. Multidrug Resistance-Associated Protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine Sulfoximine

    PubMed Central

    Akan, Ilhan; Akan, Selma; Akca, Hakan; Savas, Burhan; Ozben, Tomris

    2005-01-01

    Background Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs. Results N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC. Conclusion Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells. PMID:16042792

  1. Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

    PubMed

    Pasupathy, Sivabaskari; Tavella, Rosanna; Grover, Suchi; Raman, Betty; Procter, Nathan E K; Du, Yang Timothy; Mahadavan, Gnanadevan; Stafford, Irene; Heresztyn, Tamila; Holmes, Andrew; Zeitz, Christopher; Arstall, Margaret; Selvanayagam, Joseph; Horowitz, John D; Beltrame, John F

    2017-09-05

    Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P =0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P <0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively ( P =0.08). High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced

  2. Oral Cysteamine bitartrate and N-acetylcysteine combination for patients with infantile neuronal ceroid lipofuscinosis:a pilot study

    PubMed Central

    Levin, Sondra W.; Baker, Eva H.; Zein, Wadih M.; Zhang, Zhongjian; Quezado, Zenaide M.N.; Miao, Ning; Gropman, Andrea; Griffin, Kurt J.; Bianconi, Simona; Chandra, Goutam; Khan, Omar I.; Caruso, Rafael C.; Liu, Aiyi; Mukherjee, Anil B.

    2014-01-01

    Summary Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1-deficiency causes lysosomal ceroid accumulation leading to INCL pathogenesis. Previously, we reported that phosphocysteamine and N-acetylcysteine mediated ceroid depletion in cultured cells from INCL patients. We conducted a pilot study to determine whether a combination of cysteamine bitartrate and N-acetylcysteine is beneficial for these patients. Methods Patients (6-month to 3-years old) with any combination of 2 of the 7 most lethal PPT1 mutations were admitted. All patients were recruited from physician referrals and the PPT1 mutations were analyzed prior to admission. Patients were evaluated by electroretinography(ERG), brain MRI and MRS, electroencephalography (EEG), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Patients received oral cysteamine bitartrate (60mg/kg/day) and N-acetylcysteine (60mg/kg/day) and were evaluated every 6 to 12 months until they showed isoelectric EEG attesting to a vegetative state or were too sick to travel. Outcomes were compared with the reported INCL natural history. In two cases, the disease progression was compared with that of a sibling who was above the age limit for inclusion into the protocol. Findings Between March, 2001, and June, 2011, we recruited 10 children with INCL but one was lost to follow-up after the first visit. Thus, a total of 9 patients (5 females and 4 males) were studied. At the first follow-up visit, peripheral leukocytes in all 9 patients showed virtually complete depletion of GRODs and 7 of 9 patients manifested less irritability and/or improved alertness based upon parental and physician observations. Evaluation by Denver scale showed acquisition of no new developmental skills and retinal function assessed by ERG progressively declined

  3. Oxidative stress in hemodialysis patients receiving intravenous iron therapy and the role of N-acetylcysteine in preventing oxidative stress.

    PubMed

    Swarnalatha, G; Ram, R; Neela, Prasad; Naidu, M U R; Dakshina Murty, K V

    2010-09-01

    To determine the contribution of injectable iron administered to hemodialysis (HD) patients in causing oxidative stress and the beneficial effect of N-acetylcysteine (NAC) in reducing it, we studied in a prospective, double blinded, randomized controlled, cross over trial 14 adult HD patients who were randomized into two groups; one group received NAC in a dose of 600 mgs twice daily for 10 days prior to intravenous iron therapy and the other group received placebo. Both the groups were subjected to intravenous iron therapy, 100 mg of iron sucrose in 100 mL of normal saline given over a period of one hour. Blood samples for the markers of oxidative stress were taken before and after iron therapy. After the allowance of a week of wash out period for the effect of N-acetylcysteine we crossed over the patients to the opposite regimen. We measured the lipid peroxidation marker, malondiaaldehyde (MDA), to evaluate the oxidative stress and total anti-oxidant capacity (TAC) for the antioxidant level in addition to the highly sensitive C-reactive protein (HsCRP). Non-invasive assessment of endothelial dysfunction was measured by digital plethysmography before and after intravenous iron therapy. There was an increase of MDA (21.97 + 3.65% vs 7.06 + 3.65%) and highly sensitive C-reactive protein (HsCRP) (11.19 + 24.63% vs 13.19 + 7.7%) after iron administration both in the placebo and the NAC groups. NAC reduced the baseline acute systemic generation of oxidative stress when compared to placebo, which was statistically significant with MDA (12.76 + 4.4% vs 9.37 + 4.40%: P = 0.032) but not with HsCRP though there was a declining trend (2.85 + 22.75 % vs 8.93 + 5.19%: P = 0.112). Pre-treatment with NAC reduced the endothelial dysfunction when compared to placebo, but it was not statistically significant, except for reflection index (RI). We conclude that in our HD patients NAC reduced the oxidative stress before and after the administration of intravenous iron therapy in

  4. A randomized controlled trial of pre-procedure simethicone and N-acetylcysteine to improve mucosal visibility during gastroscopy - NICEVIS.

    PubMed

    Basford, Peter John; Brown, James; Gadeke, Lisa; Fogg, Carole; Haysom-Newport, Ben; Ogollah, Reuben; Bhattacharyya, Rupam; Longcroft-Wheaton, Gaius; Thursby-Pelham, Fergus; Neale, James R; Bhandari, Pradeep

    2016-11-01

    Background and study aims: Mucosal views can be impaired by residual bubbles and mucus during gastroscopy. This study aimed to determine whether a pre-gastroscopy drink containing simethicone and N-acetylcysteine improves mucosal visualisation. Patients and methods: We conducted a randomized controlled trial recruiting 126 subjects undergoing routine gastroscopy. Subjects were randomized 1:1:1 to receive: A-pre-procedure drink of water, simethicone and N-acetylcysteine (NAC); B-water alone; or C-no preparation. Study endoscopists were blinded to group allocation. Digital images were taken at 4 locations (lower esophagus/upper gastric body/antrum/fundus), and rated for mucosal visibility (MV) using a 4-point scale (1 = best, 4 = worst) by 4 separate experienced endoscopists. The primary outcome measure was mean mucosal visibility score (MVS). Secondary outcome measures were procedure duration and volume of fluid flush required to achieve adequate mucosal views. Results: Mean MVS for Group A was significantly better than for Group B (1.35 vs 2.11, P  < 0.001) and Group C (1.35 vs 2.21, P  < 0.001). Mean flush volume required to achieve adequate mucosal views was significantly lower in Group A than Group B (2.0 mL vs 31.5 mL, P  = 0.001) and Group C (2.0 mL vs 39.2 mL P  < 0.001). Procedure duration did not differ significantly between any of the 3 groups. MV scores at each of the 4 locations demonstrated significantly better mucosal visibility in Group A compared to Group B and Group C ( P  < 0.0025 for all comparisons). Conclusions: A pre-procedure drink containing simethicone and NAC significantly improves mucosal visibility during gastroscopy and reduces the need for flushes during the procedure. Effectiveness in the lower esophagus demonstrates potential benefit in Barrett's oesophagus surveillance gastroscopy.

  5. N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.

    PubMed

    Herrera, Emilio A; Cifuentes-Zúñiga, Francisca; Figueroa, Esteban; Villanueva, Cristian; Hernández, Cherie; Alegría, René; Arroyo-Jousse, Viviana; Peñaloza, Estefania; Farías, Marcelo; Uauy, Ricardo; Casanello, Paola; Krause, Bernardo J

    2017-02-15

    Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs. In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance

  6. Storing red blood cells with vitamin C and N-acetylcysteine prevents oxidative stress-related lesions: a metabolomics overview

    PubMed Central

    Pallotta, Valeria; Gevi, Federica; D’Alessandro, Angelo; Zolla, Lello

    2014-01-01

    Background Recent advances in red blood cell metabolomics have paved the way for further improvements of storage solutions. Materials and methods In the present study, we exploited a validated high performance liquid chromatography-mass spectrometry analytical workflow to determine the effects of vitamin C and N-acetylcysteine supplementation (anti-oxidants) on the metabolome of erythrocytes stored in citrate-phosphate-dextrose saline-adenine-glucose-mannitol medium under blood bank conditions. Results We observed decreased energy metabolism fluxes (glycolysis and pentose phosphate pathway). A tentative explanation of this phenomenon could be related to the observed depression of the uptake of glucose, since glucose and ascorbate are known to compete for the same transporter. Anti-oxidant supplementation was effective in modulating the redox poise, through the promotion of glutathione homeostasis, which resulted in decreased haemolysis and less accumulation of malondialdehyde and oxidation by-products (including oxidized glutathione and prostaglandins). Discussion Anti-oxidants improved storage quality by coping with oxidative stress at the expense of glycolytic metabolism, although reservoirs of high energy phosphate compounds were preserved by reduced cyclic AMP-mediated release of ATP. PMID:25074788

  7. Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.

    PubMed

    Coulson, James; Thompson, John Paul

    2010-02-01

    The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro. HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA. NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol. Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.

  8. N-acetylcysteine normalizes the urea cycle and DNA repair in cells from patients with Batten disease.

    PubMed

    Kim, June-Bum; Lim, Nary; Kim, Sung-Jo; Heo, Tae-Hwe

    2012-12-01

    Batten disease is an inherited disorder characterized by early onset neurodegeneration due to the mutation of the CLN3 gene. The function of the CLN3 protein is not clear, but an association with oxidative stress has been proposed. Oxidative stress and DNA damage play critical roles in the pathogenesis of neurodegenerative diseases. Antioxidants are of interest because of their therapeutic potential for treating neurodegenerative diseases. We tested whether N-acetylcysteine (NAC), a well-known antioxidant, improves the pathology of cells from patients with Batten disease. At first, the expression levels of urea cycle components and DNA repair enzymes were compared between Batten disease cells and normal cells. We used both mRNA expression levels and Western blot analysis. We found that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. The treatment of Batten disease cells with NAC for 48 h attenuated activities of the urea cycle and of DNA repair, as indicated by the substantially decreased expression levels of carbamoyl phosphate synthetase 1, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta proteins compared with untreated Batten cells. NAC may serve in alleviating the burden of urea cycle and DNA repair processes in Batten disease cells. We propose that NAC may have beneficial effects in patients with Batten disease. Copyright © 2012 John Wiley & Sons, Ltd.

  9. N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells.

    PubMed

    Zhang, Xinsheng; Banerjee, Atrayee; Banks, William A; Ercal, Nuran

    2009-06-12

    Oxidative stress plays an important role in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Methamphetamine (METH) is an amphetamine analog that causes degeneration of the dopaminergic system in mammals and subsequent oxidative stress. In our present study, we have used immortalized human brain microvascular endothelial (HBMVEC) cells to test whether N-acetylcysteine amide (NACA), a novel antioxidant, prevents METH-induced oxidative stress in vitro. Our studies showed that NACA protects against METH-induced oxidative stress in HBMVEC cells. NACA significantly protected the integrity of our blood brain barrier (BBB) model, as shown by permeability and trans-endothelial electrical resistance (TEER) studies. NACA also significantly increased the levels of intracellular glutathione (GSH) and glutathione peroxidase (GPx). Malondialdehyde (MDA) levels increased dramatically after METH exposure, but this increase was almost completely prevented when the cells were treated with NACA. Generation of reactive oxygen species (ROS) also increased after METH exposure, but was reduced to control levels with NACA treatment, as measured by dichlorofluorescin (DCF). These results suggest that NACA protects the BBB integrity in vitro, which could prevent oxidative stress-induced damage; therefore, the effectiveness of this antioxidant should be evaluated for the treatment of neurodegenerative diseases in the future.

  10. N-Acetylcysteine and deferoxamine reduce pulmonary oxidative stress and inflammation in rats after coal dust exposure

    SciTech Connect

    Pinho, R.A.; Silveira, P.C.L.; Silva, L.A.

    2005-11-01

    Coal dust inhalation induces oxidative damage and inflammatory infiltration on lung parenchyma. Thus, the aim of this study was to determine whether N-acetylcysteine (NAC) administered alone or in combination with deferoxamine (DFX), significantly reduced the inflammatory infiltration and oxidative damage in the lungs of rats exposed to coal dust. Forty-two male Wistar rats (200-250 g) were exposed to the coal dust (3 mg/0.5 mL saline, 3 days/week, for 3 weeks) by intratracheal instillation. The animals were randomly divided into three groups: saline 0.9% (n = 8), supplemented with NAC (20 mg/kg of body weight/day, intraperitoneal injection (i.p.)) (n = 8),more » and supplemented with NAC (20 mg/kg of body weight/day, i.p.) plus DFX (20 mg/kg of body weight/week) (n = 8). Control animals received only saline solution (0.5 mL). Lactate dehydrogenase activity and total cell number were determined in the bronchoalveolar lavage fluid. We determined lipid peroxidation and oxidative protein damage parameters and catalase and superoxide dismutase activities in the lungs of animals. Intratracheal instillation of coal dust in the lungs of rats led to an inflammatory response and induced significant oxidative damage. The administration of NAC alone or in association with DFX reduced the inflammatory response and the oxidative stress parameters in rats exposed to coal dust.« less

  11. N-acetylcysteine does not improve the endothelial and smooth muscle function in the human saphenous vein.

    PubMed

    Sharif, Muhammad Anees; Bayraktutan, Ulvi; Young, Ian Stuart; Soong, Chee Voon

    2007-01-01

    Oxidative stress can lead to vein graft dysfunction in the saphenous vein. This ex vivo study is aimed to compare the effects of increasing concentrations of the antioxidant N-acetylcysteine (NAC) with heparinized saline (HS) on endothelial and smooth muscle function in the human saphenous vein. Long saphenous vein segment obtained during infrainguinal bypass surgery was divided into 7 rings; 1 immersed in HS and the remaining 6 in increasing NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, 0.03%, and 0.04%). Rings were mounted in an organ bath, and relaxant responses to acetylcholine and sodium nitroprusside were assessed through isometric tension studies. Endothelium-dependent relaxations were observed in 77 vein segments from 11 patients. No significant difference was seen in veins treated with either lower NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, and 0.03%) or HS. However, HS-treated veins showed significantly better relaxation compared to those treated with maximum (0.04%) NAC (P < .05). Endothelium-independent relaxations were observed in 91 segments from 13 patients. No difference in relaxation was observed between veins treated with HS or any of the NAC concentrations. In conclusion, lower NAC concentrations do not offer better endothelial protection than HS, whereas the highest NAC concentration has a detrimental effect on endothelium-dependent relaxation. Moreover, NAC did not show beneficial effect on direct smooth muscle relaxation.

  12. Efficacy of N-acetylcysteine, D-mannose and Morinda citrifolia to Treat Recurrent Cystitis in Breast Cancer Survivals

    PubMed Central

    MARCHIORI, DEBORA; PAOLO ZANELLO, PIER

    2017-01-01

    Background/Aim: Breast cancer survivors in adjuvant therapy, frequently experience the estrogen deficiency with genitourinary symptoms mostly represented by recurrent bacterial cystitis. The objective of the present study was to evaluate the effectiveness of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract (NDM), when associated to antibiotic therapy, in reducing the persistence of recurrent cystitis in this risk population. Patients and Methods: Sixty breast cancer survived women with recurrent cystitis were retrospectively examined. Group 1, comprised of 40 patients treated with antibiotic therapy associated with NDM lasting for six months, Group 2 comprised of 20 patients treated with antibiotics alone. Results: The use of NDM in combination with antibiotic therapy showed a significant reduction in positive urine cultures, compared to antibiotics alone. Subjects of Group 1 rather than those of Group 2, showed improvement in symptoms score of urgency, frequency, urge incontinence, recurrent cystitis, bladder and urethral pain. Conclusion: In breast cancer survived women affected by genitourinary discomfort, the combination of NDM and antibiotic therapy showed a greater efficacy in reducing urinary tract infections and urinary discomfort with respect to antibiotic use only. PMID:28882961

  13. Efficacy of N-acetylcysteine, D-mannose and Morinda citrifolia to Treat Recurrent Cystitis in Breast Cancer Survivals.

    PubMed

    Marchiori, Debora; Zanello, Pier Paolo

    2017-01-01

    Breast cancer survivors in adjuvant therapy, frequently experience the estrogen deficiency with genitourinary symptoms mostly represented by recurrent bacterial cystitis. The objective of the present study was to evaluate the effectiveness of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract (NDM), when associated to antibiotic therapy, in reducing the persistence of recurrent cystitis in this risk population. Sixty breast cancer survived women with recurrent cystitis were retrospectively examined. Group 1, comprised of 40 patients treated with antibiotic therapy associated with NDM lasting for six months, Group 2 comprised of 20 patients treated with antibiotics alone. The use of NDM in combination with antibiotic therapy showed a significant reduction in positive urine cultures, compared to antibiotics alone. Subjects of Group 1 rather than those of Group 2, showed improvement in symptoms score of urgency, frequency, urge incontinence, recurrent cystitis, bladder and urethral pain. In breast cancer survived women affected by genitourinary discomfort, the combination of NDM and antibiotic therapy showed a greater efficacy in reducing urinary tract infections and urinary discomfort with respect to antibiotic use only. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.

    PubMed

    Masha, A; Manieri, C; Dinatale, S; Bruno, G A; Ghigo, E; Martina, V

    2009-12-01

    Nitric oxide (NO) plays a wide spectrum of biological actions including a positive role in oocyte maturation and ovulation. Free radicals levels have been shown elevated in polycystic ovary syndrome (PCOS) and therefore would be responsible for quenching NO that, in turn, would play a role in determining oligo- or amenorrhea connoting PCOS. Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months. Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored. Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment (3.00, 0.18-5.83 vs 0.00, 0.00-0.83; p<0.02). Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment (2.12, 1.46-4.42 vs 3.48, 1.62-5.95; p<0.05). In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.

  15. Protective Effect of N-Acetylcysteine Amide on Blast-Induced Increase in Intracranial Pressure in Rats

    PubMed Central

    Kawoos, Usmah; McCarron, Richard M.; Chavko, Mikulas

    2017-01-01

    Blast-induced traumatic brain injury is associated with acute and possibly chronic elevation of intracranial pressure (ICP). The outcome after TBI is dependent on the progression of complex processes which are mediated by oxidative stress. So far, no effective pharmacological protection against TBI exists. In this study, rats were exposed to a single or repetitive blast overpressure (BOP) at moderate intensities of 72 or 110 kPa in a compressed air-driven shock tube. The degree and duration of the increase in ICP were proportional to the intensity and frequency of the blast exposure(s). In most cases, a single dose of antioxidant N-acetylcysteine amide (NACA) (500 mg/kg) administered intravenously 2 h after exposure to BOP significantly attenuated blast-induced increase in ICP. A single dose of NACA was not effective in improving the outcome in the group of animals that were subjected to repetitive blast exposures at 110 kPa on the same day. In this group, two treatments with NACA at 2 and 4 h post-BOP exposure resulted in significant attenuation of elevated ICP. Treatment with NACA prior to BOP exposure completely prevented the elevation of ICP. The findings indicate that oxidative stress plays an important role in blast-induced elevated ICP as treatment with NACA-ameliorated ICP increase, which is frequently related to poor functional recovery after TBI. PMID:28634463

  16. Escherichia coli cellular responses to exposure to atmospheric-pressure dielectric barrier discharge plasma-treated N-acetylcysteine solution.

    PubMed

    Ercan, U K; Sen, B; Brooks, A D; Joshi, S G

    2018-04-06

    To understand the underlying cellular mechanisms during inactivation of Escherichia coli in response to antimicrobial solution of nonthermal plasma-activated N-acetylcysteine (NAC). The recommended techniques were used to demonstrate E. coli cellular and transcriptomic changes caused associated with peroxynitrite and compared with plasma-treated NAC solution. The findings demonstrate that E. coli cells respond to plasma-treated NAC and undergo severe oxidative and nitrosative stress, and leading to stress-induced damages to different components of bacterial cells, which includes loss of membrane potential, formation of oxidized glutathione (GSSG), formation of nitrotyrosine (a known marker of nitrosative stress), DNA damage, and generated a prominent pool of peroxynitrite. Reverse-transcriptase (RT)-polymerase chain reaction analysis of reactive nitrogen species (RNS) responsive genes indicated their differential expressions. For the first time, we report that the plasma-treated NAC solution activates predominantly nitrosative stress-responsive genes in E. coli and is responsible for cell death. The reactive species generated in solutions by nonthermal plasma treatment depends on the type of solution or solvent used. The plasma-treated NAC solution rapidly inactivates E. coli, mostly involving highly RNS generated in NAC solution, and has high potential as disinfectant. © 2018 The Society for Applied Microbiology.

  17. Effects of N-acetylcysteine on isolated skeletal muscle contractile properties after an acute bout of aerobic exercise.

    PubMed

    Jannig, Paulo R; Alves, Christiano R R; Voltarelli, Vanessa A; Bozi, Luiz H M; Vieira, Janaina S; Brum, Patricia C; Bechara, Luiz R G

    2017-12-15

    The current study tested the hypotheses that 1) an acute bout of aerobic exercise impairs isolated skeletal muscle contractile properties and 2) N-acetylcysteine (a thiol antioxidant; NAC) administration can restore the impaired muscle contractility after exercise. At rest or immediately after an acute bout of aerobic exercise, extensor digitorum longus (EDL) and soleus muscles from male Wistar rats were harvested for ex vivo skeletal muscle contraction experiments. Muscles from exercised animals were incubated in Krebs Ringer's buffer in absence or presence of 20mM of NAC. Force capacity and fatigue properties were evaluated. Exercised EDL and soleus displayed lower force production across various stimulation frequencies (p<0.001), indicating that skeletal muscle force production was impaired after an acute bout of exercise. However, NAC treatment restored the loss of force production in both EDL and soleus after fatiguing exercise (p<0.05). Additionally, NAC treatment increased relative force production at different time points during a fatigue-induced protocol, suggesting that NAC treatment mitigates fatigue induced by successive contractions. NAC treatment improves force capacity and fatigue properties in ex vivo skeletal muscle from rats submitted to an acute bout of aerobic exercise. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury

    PubMed Central

    Sun, Yong; Pu, Li-Yong; Lu, Ling; Wang, Xue-Hao; Zhang, Feng; Rao, Jian-Hua

    2014-01-01

    AIM: To investigate the effects of N-acetylcysteine (NAC) on endoplasmic reticulum (ER) stress and tissue injury during liver ischemia reperfusion injury (IRI). METHODS: Mice were injected with NAC (300 mg/kg) intraperitoneally 2 h before ischemia. Real-time polymerase chain reaction and western blotting determined ER stress molecules (GRP78, ATF4 and CHOP). To analyze the role of NAC in reactive oxygen species (ROS)-mediated ER stress and apoptosis, lactate dehydrogenase (LDH) was examined in cultured hepatocytes treated by H2O2 or thapsigargin (TG). RESULTS: NAC treatment significantly reduced the level of ROS and attenuated ROS-induced liver injury after IRI, based on glutathione, malondialdehyde, serum alanine aminotransferase levels, and histopathology. ROS-mediated ER stress was significantly inhibited in NAC-treated mice. In addition, NAC treatment significantly reduced caspase-3 activity and apoptosis after reperfusion, which correlated with the protein expression of Bcl-2 and Bcl-xl. Similarly, NAC treatment significantly inhibited LDH release from hepatocytes treated by H2O2 or TG. CONCLUSION: This study provides new evidence for the protective effects of NAC treatment on hepatocytes during IRI. Through inhibition of ROS-mediated ER stress, NAC may be critical to inhibit the ER-stress-related apoptosis pathway. PMID:25386077

  19. A comparative study on radioprotective effect of N-acetylcysteine against 12C6+ ion versus X-rays

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Zhang, Hong; Zhang, Luwei

    Purpose: The aim of this study was to evaluate the different protective efficacy of N-acetylcysteine (NAC, 200 mg/kg dose) against 12C6+ ion (4 Gy) and X-rays (4 Gy) - induced damage in vivo model. Method: Kung-Ming female mice were divided into six groups, each composed of twelve animals: control group, two irradiation groups, and two NAC-treated groups, as well as NAC alone-treated group. An acute study was carried out to determine alterations in the oxidative stress (malondialdehyde level) using with colorimetric method and cell apoptosis measuring by flow cytometry as well as DNA-single strand break analyzing by comet assay at 2h after irradiation in mouse liver. Results: Compared with respective irradiation group, NAC can significantly ameliorate injury induced by two types of ionizing irradiation, which marked by the decrease of malondialdehyde level, and the reduction of apoptosis cells percentage and DNA damage. But the greater efficacy of NAC was prominently observed to inhibit the damage induced by X-rays, suggesting that NAC-mediated protective effect is more advisable to X-rays than 12C6+ ion irradiation. Moreover, NAC treatment alone did not result in any damage as compared to the control group. Conclusion: NAC may merit development as a potential radioprotective agent. Furthermore, NAC might exert its best effort to respond X rays-caused damage.

  20. A theoretical and matrix-isolation FT-IR investigation of the conformational landscape of N-acetylcysteine

    NASA Astrophysics Data System (ADS)

    Boeckx, Bram; Ramaekers, Riet; Maes, Guido

    2010-06-01

    The conformational landscape of N-acetylcysteine (NAC) has been investigated by a combined experimental matrix-isolation FT-IR and theoretical methodology. This combination is a powerful tool to study the conformational behavior of relatively small molecules. Geometry optimizations at the HF/3-21 level resulted in 438 different geometries with an energy difference smaller than 22 kJ mol -1. Among these, six conformations were detected with a relative energy difference smaller than 10 kJ mol -1 at the DFT(B3LYP)/6-31++G∗∗ level of theory. These were finally subjected to MP2/6-31++G∗∗ optimizations which resulted in five minima. The vibrational and thermodynamical properties of these conformations were calculated at both the DFT and MP2 methodologies. Experimentally NAC was isolated in an argon matrix at 16 K after being sublimated at 323 K. The most stable MP2 form appeared to be dominant in the experimental spectra but the presence of three other conformations with Δ EMP2 < 10 kJ mol -1 was also demonstrated. The experimentally observed abundance of the H-bond containing conformations appeared to be in good accordance with the predicted MP2 value.

  1. N-acetylcysteine Amide Augments the Therapeutic Effect of Neural Stem Cell-Based Antiglioma Oncolytic Virotherapy

    PubMed Central

    Kim, Chung Kwon; Ahmed, Atique U; Auffinger, Brenda; Ulasov, Ilya V; Tobias, Alex L; Moon, Kyung-Sub; Lesniak, Maciej S

    2013-01-01

    Current research has evaluated the intrinsic tumor-tropic properties of stem cell carriers for targeted anticancer therapy. Our laboratory has been extensively studying in the preclinical setting, the role of neural stem cells (NSCs) as delivery vehicles of CRAd-S-pk7, a gliomatropic oncolytic adenovirus (OV). However, the mediated toxicity of therapeutic payloads, such as oncolytic adenoviruses, toward cell carriers has significantly limited this targeted delivery approach. Following this rationale, in this study, we assessed the role of a novel antioxidant thiol, N-acetylcysteine amide (NACA), to prevent OV-mediated toxicity toward NSC carriers in an orthotropic glioma xenograft mouse model. Our results show that the combination of NACA and CRAd-S-pk7 not only increases the viability of these cell carriers by preventing reactive oxygen species (ROS)-induced apoptosis of NSCs, but also improves the production of viral progeny in HB1.F3.CD NSCs. In an intracranial xenograft mouse model, the combination treatment of NACA and NSCs loaded with CRAd-S-pk7 showed enhanced CRAd-S-pk7 production and distribution in malignant tissues, which improves the therapeutic efficacy of NSC-based targeted antiglioma oncolytic virotherapy. These data demonstrate that the combination of NACA and NSCs loaded with CRAd-S-pk7 may be a desirable strategy to improve the therapeutic efficacy of antiglioma oncolytic virotherapy. PMID:23883863

  2. Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status.

    PubMed

    Zhou, Jie; Coles, Lisa D; Kartha, Reena V; Nash, Nardina; Mishra, Usha; Lund, Troy C; Cloyd, James C

    2015-08-01

    There is an increasing interest in using N-acetylcysteine (NAC) as a treatment for neurodegenerative disorders to increase glutathione (GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg(-1) stable-labeled NAC. Plasma, red blood cells (RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH (GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline (AUCb0-280 ) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  3. Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia.

    PubMed

    Nie, Xingju; Lowe, Danielle W; Rollins, Laura Grace; Bentzley, Jessica; Fraser, Jamie L; Martin, Renee; Singh, Inderjit; Jenkins, Dorothea

    2016-07-01

    Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  4. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial.

    PubMed

    Berk, Michael; Dean, Olivia; Cotton, Sue M; Gama, Clarissa S; Kapczinski, Flavio; Fernandes, Brisa S; Kohlmann, Kristy; Jeavons, Susan; Hewitt, Karen; Allwang, Christine; Cobb, Heidi; Bush, Ashley I; Schapkaitz, Ian; Dodd, Seetal; Malhi, Gin S

    2011-12-01

    Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need. This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder. In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE=0.8). This reduction was statistically significant (p<0.001). Improvements in functioning and quality of life were similarly evident. These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. The effects of N-acetylcysteine on cocaine reward and seeking behaviors in a rat model of depression.

    PubMed

    Frankowska, Małgorzata; Jastrzębska, Joanna; Nowak, Ewa; Białko, Magdalena; Przegaliński, Edmund; Filip, Małgorzata

    2014-06-01

    Depression and substance-abuse (e.g., cocaine) disorders are common concurrent diagnoses. In the present study, we combined bilateral olfactory bulbectomy (OBX) with a variety of procedures of intravenous cocaine self-administration and extinction/reinstatement in rats. We also investigated the effects of N-acetylcysteine (NAC) on rewarding and seeking behaviors for cocaine in OBX rats and compared the drug's effects in sham-operated control animals (SHAM). The occurrence of depressive symptoms before introduction to cocaine self-administration enhanced subsequent cocaine-seeking behaviors but did not significantly influence cocaine's rewarding properties or extinction training. NAC (25-100mg/kg) given acutely or repeatedly did not alter the co-occurrence of cocaine reward and depression but effectively reduced the cocaine-seeking behavior observed in both phenotypes. Our results indicate that depression behavior is linked to more pronounced drug craving and a higher propensity to relapse in rats. We also show the lack of efficacy of repeated NAC treatment on SHAM or OBX animals in terms of cocaine self-administration, while the drug was an effective blocker of cocaine-seeking behavior in both studied phenotypes, with a more pronounced drug effect observed in OBX animals. The last finding demonstrates the potential clinical utility of NAC to reduce cocaine seeking enhanced by co-existing depression. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Adjunctive N-acetylcysteine in depression: exploration of interleukin-6, C-reactive protein and brain-derived neurotrophic factor.

    PubMed

    Hasebe, Kyoko; Gray, Laura; Bortolasci, Chiara; Panizzutti, Bruna; Mohebbi, Mohammadreza; Kidnapillai, Srisaiyini; Spolding, Briana; Walder, Ken; Berk, Michael; Malhi, Gin; Dodd, Seetal; Dean, Olivia M

    2017-12-01

    This study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression. We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment. NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment. Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.

  7. Storing red blood cells with vitamin C and N-acetylcysteine prevents oxidative stress-related lesions: a metabolomics overview.

    PubMed

    Pallotta, Valeria; Gevi, Federica; D'alessandro, Angelo; Zolla, Lello

    2014-07-01

    Recent advances in red blood cell metabolomics have paved the way for further improvements of storage solutions. In the present study, we exploited a validated high performance liquid chromatography-mass spectrometry analytical workflow to determine the effects of vitamin C and N-acetylcysteine supplementation (anti-oxidants) on the metabolome of erythrocytes stored in citrate-phosphate-dextrose saline-adenine-glucose-mannitol medium under blood bank conditions. We observed decreased energy metabolism fluxes (glycolysis and pentose phosphate pathway). A tentative explanation of this phenomenon could be related to the observed depression of the uptake of glucose, since glucose and ascorbate are known to compete for the same transporter. Anti-oxidant supplementation was effective in modulating the redox poise, through the promotion of glutathione homeostasis, which resulted in decreased haemolysis and less accumulation of malondialdehyde and oxidation by-products (including oxidized glutathione and prostaglandins). Anti-oxidants improved storage quality by coping with oxidative stress at the expense of glycolytic metabolism, although reservoirs of high energy phosphate compounds were preserved by reduced cyclic AMP-mediated release of ATP.

  8. N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials.

    PubMed

    Zheng, W; Zhang, Q-E; Cai, D-B; Yang, X-H; Qiu, Y; Ungvari, G S; Ng, C H; Berk, M; Ning, Y-P; Xiang, Y-T

    2018-05-01

    This systematic review and meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive N-acetylcysteine (NAC), an antioxidant drug, in treating major depressive disorder (MDD), bipolar disorder, and schizophrenia. The PubMed, Cochrane Library, PsycINFO, CNKI, CBM, and WanFang databases were independently searched and screened by two researchers. Standardized mean differences (SMDs), risk ratios, and their 95% confidence intervals (CIs) were computed. Six RCTs (n = 701) of NAC for schizophrenia (three RCTs, n = 307), bipolar disorder (two RCTs, n = 125), and MDD (one RCT, n = 269) were identified and analyzed as separate groups. Adjunctive NAC significantly improved total psychopathology (SMD = -0.74, 95% CI: -1.43, -0.06; I 2 = 84%, P = 0.03) in schizophrenia, but it had no significant effect on depressive and manic symptoms as assessed by the Young Mania Rating Scale in bipolar disorder and only a small effect on major depressive symptoms. Adverse drug reactions to NAC and discontinuation rates between the NAC and control groups were similar across the three disorders. Adjunctive NAC appears to be a safe treatment that has efficacy for schizophrenia, but not for bipolar disorder or MDD. Further higher quality RCTs are warranted to determine the role of adjunctive NAC in the treatment of major psychiatric disorders. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Successful use of N-acetylcysteine to treat severe hepatic injury caused by a dietary fitness supplement.

    PubMed

    El Rahi, Cynthia; Thompson-Moore, Nathaniel; Mejia, Patricia; De Hoyos, Patricio

    2015-06-01

    In the absence of adequate premarketing efficacy and safety evaluations, adverse events from over-the-counter supplements are emerging as a public health concern. Specifically, bodybuilding products are being identified as a frequent cause of drug-induced liver injury. We present a case of a 20-year-old Hispanic male who presented with acute nausea and vomiting accompanied by severe right upper quadrant abdominal pain, shivering, and shortness of breath. Laboratory data pointed to mixed cholestatic and hepatocellular damage, and after exclusion of known alternate etiologies, the patient was diagnosed with acute drug-induced liver injury secondary to the use of "Friction," a bodybuilding supplement. Treatment with N-acetylcysteine (NAC) 20% oral solution was initiated empirically at a dose of 4000 mg [DOSAGE ERROR CORRECTED] (70 mg/kg) every 4 hours and was continued once the diagnosis was made. Within 48 hours of admission to our hospital, the patient began to show clinical resolution of right abdominal pain and tolerance to oral diet associated with a significant decline toward normal in his liver function tests and coagulopathy. The WHO-UMC causality assessment system suggested a "certain causality" between exposure to the supplement and the acute liver injury. In the event of suspected drug-induced liver injury, treatment with NAC should be considered given its favorable risk-benefit profile. © 2015 Pharmacotherapy Publications, Inc.

  10. High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON Study.

    PubMed

    Zheng, Jin-Ping; Wen, Fu-Qiang; Bai, Chun-Xue; Wan, Huan-Ying; Kang, Jian; Chen, Ping; Yao, Wan-Zhen; Ma, Li-Jun; Xia, Qi-Kui; Gao, Yi; Zhong, Nan-Shan

    2013-04-01

    Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation; from a pathophysiological point of view it involves many components, including mucus hypersecretion, oxidative stress and inflammation. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. Long-term efficacy of NAC 600mg/d in COPD is controversial; a dose-effect relationship has been demonstrated, but at present it is not known whether a higher dose provides clinical benefits. The PANTHEON Study is a prospective, ICS stratified, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial designed to assess the efficacy and safety of high-dose (1200 mg/daily) NAC treatment for one year in moderate-to-severe COPD patients. The primary endpoint is the annual exacerbation rate. Secondary endpoints include recurrent exacerbations hazard ratio, time to first exacerbation, as well as quality of life and pulmonary function. The hypothesis, design and methodology are described and baseline characteristics of recruited patients are presented. 1006 COPD patients (444 treated with maintenance ICS, 562 ICS naive, aged 66.27±8.76 yrs, average post-bronchodilator FEV1 48.95±11.80 of predicted) have been randomized at 34 hospitals in China. Final results of this study will provide objective data on the effects of high-dose (1200 mg/daily) long-term NAC treatment in the prevention of COPD exacerbations and other outcome variables.

  11. N-Acetylcysteine treatment of dystrophic mdx mice results in protein thiol modifications and inhibition of exercise induced myofibre necrosis.

    PubMed

    Terrill, Jessica R; Radley-Crabb, Hannah G; Grounds, Miranda D; Arthur, Peter G

    2012-05-01

    Oxidative stress is implicated as a factor that increases necrosis of skeletal muscles in Duchenne Muscular Dystrophy (DMD) and the dystrophic mdx mouse. Consequently, drugs that minimize oxidative stress are potential treatments for muscular dystrophy. This study examined the in vivo benefits to mdx mice of an antioxidant treatment with the cysteine precursor N-acetylcysteine (NAC), administered in drinking water. NAC was completely effective in preventing treadmill exercise-induced myofibre necrosis (assessed histologically) and the increased blood creatine kinase levels (a measure of sarcolemma leakiness) following exercise were significantly lower in the NAC treated mice. While NAC had no effect on malondialdehyde level or protein carbonylation (two indicators of irreversible oxidative damage), treatment with NAC for one week significantly decreased the oxidation of glutathione and protein thiols, and enhanced muscle protein thiol content. These data provide in vivo evidence for protective benefits of NAC treatment on dystropathology, potentially via protein thiol modifications. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Effect of chitosan-N-acetylcysteine conjugate in a mouse model of botulinum toxin B-induced dry eye.

    PubMed

    Hongyok, Teeravee; Chae, Jemin J; Shin, Young Joo; Na, Daero; Li, Li; Chuck, Roy S

    2009-04-01

    To evaluate the effect of a thiolated polymer lubricant, chitosan-N-acetylcysteine conjugate (C-NAC), in a mouse model of dry eye. Eye drops containing 0.5% C-NAC, 0.3% C-NAC, a vehicle (control group), artificial tears, or fluorometholone were applied in a masked fashion in a mouse model of induced dry eye from 3 days to 4 weeks after botulinum toxin B injection. Corneal fluorescein staining was periodically recorded. Real-time reverse transcriptase-polymerase chain reaction and immunofluorescence staining were performed at the end of the study to evaluate inflammatory cytokine expressions. Mice treated with C-NAC, 0.5%, and fluorometholone showed a downward trend that was not statistically significant in corneal staining compared with the other groups. Chitosan-NAC formulations, fluorometholone, and artificial tears significantly decreased IL-1beta (interleukin 1beta), IL-10, IL-12alpha, and tumor necrosis factor alpha expression in ocular surface tissues. The botulinum toxin B-induced dry eye mouse model is potentially useful in evaluating new dry eye treatment. Evaluation of important molecular biomarkers suggests that C-NAC may impart some protective ocular surface properties. However, clinical data did not indicate statistically significant improvement of tear production and corneal staining in any of the groups tested. Topically applied C-NAC might protect the ocular surface in dry eye syndrome, as evidenced by decreased inflammatory cytokine expression.

  13. Evaluation of N-acetylcysteine and methylprednisolone as therapies for oxygen and acrolein-induced lung damage

    SciTech Connect

    Critchley, J.A.J.H.; Beeley, J.M.; Clark, R.J.

    1990-04-01

    Reactive oxidizing species are implicated in the etiology of a range of inhalational pulmonary injuries. Consequently, various free radical scavengers have been tested as potential prophylactic agents. The sulfydryl compound, N-acetylcysteine (NAC) is the only such compound clinically available for use in realistic dosages, and it is well established as an effective antidote for the hepatic and renal toxicity of paracetamol. Another approach in pulmonary injury prophylaxis is methylprednisolone therapy. The authors evaluated NAC and methylprednisolone in two rats models of inhalation injury: 40-hr exposure to >97% oxygen at 1.1 bar and 15-min exposure to acrolein vapor (210 ppm). Themore » increases in lung wet/dry weight ratios, seen with both oxygen and acrolein toxicity were reduced with both treatments. However, with oxygen, NAC therapy was associated with considerably increased mortality and histological changes. Furthermore, IP NAC administration resulted in large volumes of ascitic fluid. With acrolein, IV, NAC had no significant effect on mortality or pulmonary histological damage. Methylprednisolone had no beneficial effects on either the mortality or histological damage observed in either toxicity model. They caution against the ad hoc use of NAC in the management of inhalational pulmonary injury.« less

  14. N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of UV-induced melanoma in mice

    PubMed Central

    Cotter, Murray A.; Thomas, Joshua; Cassidy, Pamela; Robinette, Kyle; Jenkins, Noah; Scott, R. Florell; Leachman, Sancy; Samlowski, Wolfram E.; Grossman, Douglas

    2008-01-01

    UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. In melan-a cells, a mouse melanocyte line, NAC (1–10 mM) conferred protection from several UV-induced oxidative sequelae including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine (8-OG), and depletion of free reduced thiols (primarily glutathione). Mice transgenic for hepatocyte growth factor and Survivin, previously shown to develop melanoma following a single neonatal dose of UV irradiation, were administered NAC (7 mg/ml, mother’s drinking water) transplacentally and through nursing until two weeks after birth. Delivery of NAC in this manner reduced thiol depletion and blocked formation of 8-OG in skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared to control mice (21 vs. 14 weeks, p=0.0003). Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma, and suggest that NAC may be useful as a chemopreventive agent. PMID:17908992

  15. N-Acetylcysteine Selectively Antagonizes the Activity of Imipenem in Pseudomonas aeruginosa by an OprD-Mediated Mechanism

    PubMed Central

    Rodríguez-Beltrán, Jerónimo; Cabot, Gabriel; Valencia, Estela Ynés; Costas, Coloma; Bou, German; Oliver, Antonio

    2015-01-01

    The modulating effect of N-acetylcysteine (NAC) on the activity of different antibiotics has been studied in Pseudomonas aeruginosa. Our results demonstrate that, in contrast to previous reports, only the activity of imipenem is clearly affected by NAC. MIC and checkerboard determinations indicate that the NAC-based modulation of imipenem activity is dependent mainly on OprD. SDS-PAGE of outer membrane proteins (OMPs) after NAC treatments demonstrates that NAC does not modify the expression of OprD, suggesting that NAC competitively inhibits the uptake of imipenem through OprD. Similar effects on imipenem activity were obtained with P. aeruginosa clinical isolates. Our results indicate that imipenem-susceptible P. aeruginosa strains become resistant upon simultaneous treatment with NAC and imipenem. Moreover, the generality of the observed effects of NAC on antibiotic activity was assessed with two additional bacterial species, Escherichia coli and Acinetobacter baumannii. Caution should be taken during treatments, as the activity of imipenem may be modified by physiologically attainable concentrations of NAC, particularly during intravenous and nebulized regimes. PMID:25801561

  16. N-acetylcysteine selectively antagonizes the activity of imipenem in Pseudomonas aeruginosa by an OprD-mediated mechanism.

    PubMed

    Rodríguez-Beltrán, Jerónimo; Cabot, Gabriel; Valencia, Estela Ynés; Costas, Coloma; Bou, German; Oliver, Antonio; Blázquez, Jesús

    2015-01-01

    The modulating effect of N-acetylcysteine (NAC) on the activity of different antibiotics has been studied in Pseudomonas aeruginosa. Our results demonstrate that, in contrast to previous reports, only the activity of imipenem is clearly affected by NAC. MIC and checkerboard determinations indicate that the NAC-based modulation of imipenem activity is dependent mainly on OprD. SDS-PAGE of outer membrane proteins (OMPs) after NAC treatments demonstrates that NAC does not modify the expression of OprD, suggesting that NAC competitively inhibits the uptake of imipenem through OprD. Similar effects on imipenem activity were obtained with P. aeruginosa clinical isolates. Our results indicate that imipenem-susceptible P. aeruginosa strains become resistant upon simultaneous treatment with NAC and imipenem. Moreover, the generality of the observed effects of NAC on antibiotic activity was assessed with two additional bacterial species, Escherichia coli and Acinetobacter baumannii. Caution should be taken during treatments, as the activity of imipenem may be modified by physiologically attainable concentrations of NAC, particularly during intravenous and nebulized regimes. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  17. Protective effect of N-acetylcysteine against ethanol-induced gastric ulcer: A pharmacological assessment in mice

    PubMed Central

    Jaccob, Ausama Ayoob

    2015-01-01

    Aim: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-acetylcysteine (NAC) against ethanol-induced gastric ulcer models in mice. Materials and Methods: A total of 41 mice were allocated into six groups consisted of 7 mice each. Groups 1 (normal control) and 2 (ulcer control) received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6th group received ranitidine (50 mg/kg). All drugs administered orally once daily for 7 days, on the 8th day absolute ethanol (7 ml/kg) was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination. Results: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group. Conclusion: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by anti-secretory, cytoprotective, histological and biochemical data, but the molecular mechanisms behind such protection are complex. PMID:26401392

  18. Formation of the thioester, N-acetyl, S-lactoylcysteine, by reaction of N-acetylcysteine with pyruvaldehyde in aqueous solution. [in prebiotic evolution

    NASA Technical Reports Server (NTRS)

    Weber, A. L.

    1982-01-01

    N-acetylcysteine reacts efficiently with pyruvaldehyde (methylglyoxal) in aqueous solution (pH 7.0) in the presence of a weak base, like imidazole or phosphate, to give the thioester, N-acetyl, S-lactoylcysteine. Reactions of 100 mM N-acetylcysteine with 14 mM, 24 mM and 41 mM pyruvaldehyde yield, respectively, 86%, 76% and 59% N-acetyl, S-lactoylcysteine based on pyruvaldehyde. The decrease in the percent yield at higher pyruvaldehyde concentrations suggests that during its formation the thioester is not only consumed by hydrolysis, but also by reaction with some substance in the pyruvaldehyde preparation. Indeed, purified N-acetyl, S-lactoylcysteine disappears much more rapidly in the presence of pyruvaldehyde than in its absence. Presumably, N-acetyl, S-lactoylcysteine synthesis occurs by rearrangement of the hemithioacetal of N-acetylcysteine and pyruvaldehyde. The significance of this pathway of thioester formation to molecular evolution is discussed.

  19. Bewehrte Betonbauteile unter Betriebsbedingungen: Forschungsbericht

    NASA Astrophysics Data System (ADS)

    Eligehausen, Rolf; Kordina, Karl; Schießl, Peter

    2000-09-01

    Vorwort. Teil I: Rißbreiten (Gert König) 1 Ein mechanisches Modell zur Erhöhung der Vorhersagegenauigkeit über die Rißbreiten unter Betriebsbedingungen (Gert König und Michael Fischer). 1.1 Einleitung und Zielsetzung. 1.2 Versuchsprogramm. 1.3 Meßtechnik. 1.4 Belastung und Versuchsdurchführung. 1.5 Literatur. 2 Rißbreiten und Verformungszunahme vorgespannter Bauteile unter wiederholter Last - und Zwangbeanspruchung (Gert König und Michael Fischer). 2.1 Einleitung und Zielsetzung. 2.2 Versuchsprogramm. 2.3 Auswertung. 2.4 Ausblick. 2.5 Literatur. 3 Rißverhalten von Beton bei plötzlicher Abkühlung (Viktor Mechtcherine und Harald S. Müller). 3.1 Einleitung. 3.2 Experimentelle Untersuchungen. 3.3 Formulierung eines Stoffgesetzes für thermisch beanspruchten Beton. 3.4 Riß entwicklung in einer Betonplatte unter Temperaturschock. 3.5 Zusammenfassung. 3.6 Literatur. 4 Stahlfaserbeton unter Betriebsbedingungen bei Dauerbeanspruchung (Bo Soon Kang, Bernd Schnütgen und Friedhelm Stangenberg). 4.1 Einleitung. 4.2 Wirkung von Stahlfasern im Beton. 4.3 Versuchsprogramm. 4.4 Untersuchungen zum Verbundverhalten. 4.5 Untersuchungen zum Verhalten unter Biegebeanspruchung. 4.6 Theoretische Untersuchungen. 4.7 Literatur. 5 Experimentelle Untersuchungen an Stahlbeton-Zugkörpern unter wiederholter Belastung zur Ermittlung des versteifenden Einflusses der Mitwirkung des Betons zwischen den Rissen (Petra Seibel und Gerhard Mehlhorn). 5.1 Einleitung. 5.2 Ansatz zur Bestimmung der Mitwirkung des Betons zwischen den Rissen nach Eurocode 2, Model Code 90 und Günther. 5.3 Experimentelle Untersuchungen. 5.4 Ergebnisse. 5.5 Zusammenfassung. 5.6 Literatur. 6 Riß- und Verformungsverhalten von vorgefertigten Spannbetonträgern unter Betriebsbedingungen bei besonderer Berücksichtigung des Betonalters (Monika Maske, Heinz Meichsner und Lothar Schubert). 6.1 Einleitung. 6.2 Beschreibung der Fertigteilträger. 6.3 Belastungsversuche. 6.4 Ergebnisse. 6.5 Zusammenfassung. 6

  20. Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy.

    PubMed

    Pinniger, Gavin J; Terrill, Jessica R; Assan, Evanna B; Grounds, Miranda D; Arthur, Peter G

    2017-12-01

    Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a therapeutic intervention for DMD boys, but potential adverse effects of NAC have not been widely investigated. We used young (6 weeks old) growing mdx mice to investigate the capacity of NAC supplementation (2% in drinking water for 6 weeks) to improve dystrophic muscle function and to explore broader systemic effects of NAC treatment. NAC treatment improved normalised measures of muscle function, and decreased inflammation and oxidative stress, but significantly reduced body weight gain, muscle weight and liver weight. Unexpected significant adverse effects of NAC on body and muscle weights indicate that interpretation of muscle function based on normalised force measures should be made with caution and careful consideration is needed when proposing the use of NAC as a therapeutic treatment for young DMD boys. Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease characterised by severe muscle weakness, necrosis, inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a potential therapeutic intervention for DMD boys. We investigated the capacity of NAC to improve dystrophic muscle function in the mdx mouse model of DMD. Young (6 weeks old) mdx and non-dystrophic C57 mice receiving 2% NAC in drinking water for 6 weeks were compared with untreated mice. Grip strength and body weight were measured weekly, before the 12 week old mice were anaesthetised and extensor digitorum longus (EDL) muscles were excised for functional analysis and tissues were sampled for biochemical analyses. Compared to untreated mice, the mean (SD) normalised grip strength was significantly greater in NAC-treated mdx [3.13 (0.58) vs 4.87 (0.78) g body weight (bw) -1 ; P < 0.001] and C57 mice [3.90 (0.32) vs 5.32 (0.60) g bw -1 ; P

  1. N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis.

    PubMed

    Duailibi, Michel Silvio; Cordeiro, Quirino; Brietzke, Elisa; Ribeiro, Marcelo; LaRowe, Steve; Berk, Michael; Trevizol, Alisson Paulino

    2017-10-01

    Recent neurobiological evidences along with clinical observations justify the use of N-acetylcysteine (NAC) as a medication for craving. The objective of our study was to assess the evidence of efficacy of NAC for craving in substance use disorders in randomized clinical trials (RCTs). Systematic review of the RCTs literature (PROSPERO number 56698) until February, 2017, using MEDLINE, Cochrane Library and clinicaltrials.gov. We included seven RCTs (n = 245); most with small-to-moderate sample sizes. The main outcome was the Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I 2 and the χ 2 test. Publication bias was evaluated using the Begg's funnel plot and the Egger's test. Meta-regression was performed using the random-effects model. Comparing NAC versus placebo, NAC was significantly superior for craving symptoms (Hedges' g = 0.94; 95%CI 0.55-1.33). The funnel plot showed the risk of publication bias was low and between-study heterogeneity was not significant (I 2  = 44.4%, p = 0.07 for the χ 2 test). A subgroup analysis performed using meta-regression showed no particular influence. NAC was superior to placebo for craving reduction in SUDs. The relatively small number of trials and their heterogeneous methodology were possible limitations; however, these positive thrilling results stimulate further studies for clarifying the potential impact of NAC for craving symptoms in SUDs. The safety profile of NAC and favorable tolerability, in addition to being an over-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. The safety profile of NAC and its favorable tolerability, in addition to being anover-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. (Am J Addict 2017;26:660-666). © 2017 American Academy of Addiction Psychiatry.

  2. N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes

    PubMed Central

    Ji, Yan-Li; Wang, Hua; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Xu, De-Xiang

    2013-01-01

    Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd-induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg−1). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd-induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd-induced phosphorylation of testicular eukaryotic translation initiation factor 2α (eIF2α), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes. PMID:23353715

  3. Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd²⁺-induced apoptosis.

    PubMed

    Barajas-Espinosa, Alma; Basye, Ariel; Jesse, Erin; Yan, Haixu; Quan, David; Chen, Chun-An

    2014-09-01

    Redox imbalance is a primary cause of endothelial dysfunction (ED). Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of glutathione (GSH), the primary reducing source in cells, can significantly regulate cell function via reversible protein thiol modification. N-acetylcysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. From HPLC analysis, NAC significantly increases both cellular GSH and tetrahydrobiopterin levels. Immunoblotting of endothelial NO synthase (eNOS) and DUSP4, a dual-specificity phosphatase with a cysteine as its active residue, revealed that both enzymes are upregulated by NAC. EPR spin trapping further demonstrated that NAC enhances NO generation from cells. Long-term exposure to Cd(2+) contributes to DUSP4 degradation and the uncontrolled activation of p38 and ERK1/2, leading to apoptosis. Treatment with NAC prevents DUSP4 degradation and protects cells against Cd(2+)-induced apoptosis. Moreover, the increased DUSP4 expression can redox-regulate the p38 and ERK1/2 pathways from hyperactivation, providing a survival mechanism against the toxicity of Cd(2+). DUSP4 gene knockdown further supports the hypothesis that DUSP4 is an antioxidant gene, critical in the modulation of eNOS expression, and thus protects against Cd(2+)-induced stress. Depletion of intracellular GSH by buthionine sulfoximine makes cells more susceptible to Cd(2+)-induced apoptosis. Pretreatment with NAC prevents p38 overactivation and thus protects the endothelium from this oxidative stress. Therefore, the identification of DUSP4 activation by NAC provides a novel target for future drug design. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. N-acetylcysteine augments adenovirus-mediated gene expression in human endothelial cells by enhancing transgene transcription and virus entry.

    PubMed

    Jornot, L; Morris, M A; Petersen, H; Moix, I; Rochat, T

    2002-01-01

    It has previously been shown that oxidants reduce the efficiency of adenoviral transduction in human umbilical vein endothelial cells (HUVECs). In this study, the effect of the antioxidant N-acetylcysteine (NAC) in adenovirus-mediated gene transfer has been investigated. HUVECs were pretreated or not with NAC, and infected with E1E3-deleted adenovirus (Ad) containing the LacZ gene expressed from the RSV-LTR promoter/enhancer in the presence and absence of NAC. Transgene expression was assessed at the protein level (histochemical staining, measurement of beta-Gal activity, and western blot), mRNA level (real-time RT-PCR) and gene level (nuclear run on) 24 h and 48 h after infection. Adenoviral DNA was quantitated by real-time PCR, and cell surface expression of Coxsackie/adenovirus receptors (CAR) was determined by FACS analysis. Pretreatment of cells with NAC prior to Ad infection enhanced beta-Gal activity by two-fold due to an increase in viral DNA, which was related to increased CAR expression. When NAC was present only during the post-infection period, a five-fold increase in beta-Gal activity and LacZ gene transcriptional activity was observed. When NAC was present during both the pretreatment and the post-infection period, beta-Gal activity was further enhanced, by 15-fold. Augmentation of beta-Gal activity was paralleled by an increase in beta-Gal protein and mRNA levels. NAC did not affect the half-life of LacZ mRNA. Pretreatment with NAC prior to Ad infection enhances virus entry, while treatment with NAC post-infection increases transgene transcription. This strategy permits the use of lower adenoviral loads and thus might be helpful for gene therapy of vascular diseases. Copyright 2001 John Wiley & Sons, Ltd.

  5. N-Acetylcysteine Increases Corneal Endothelial Cell Survival in a Mouse Model of Fuchs Endothelial Corneal Dystrophy

    PubMed Central

    Kim, Eun Chul; Meng, Huan; Jun, Albert S.

    2014-01-01

    The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo® luminescent reagent. Two-month-old homozygous knock-in Col8a2L450W/L450W mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (pitalic>0.01). Corneal endothelial cell density (CD) was higher (p=0.001) and percent polymegathism was lower (p=0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD. PMID:24952277

  6. Indocyanine Green Clearance Varies as a Function of N-Acetylcysteine Treatment in a Murine Model of Acetaminophen Toxicity

    PubMed Central

    Milesi-Hallé, Alessandra; Abdel-Rahman, Susan M.; Brown, Aliza; McCullough, Sandra S.; Letzig, Lynda; Hinson, Jack A.; James, Laura P.

    2011-01-01

    Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment. Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (ClT) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had ClT and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity. PMID:21145883

  7. Effect of N-acetylcysteine on the early expression of inflammatory markers in the retina and plasma of diabetic rats

    PubMed Central

    Tsai, Gina Y; Cui, Jing Z; Syed, Husnain; Xia, Zhengyuan; Ozerdem, Ugur; McNeill, John H; Matsubara, Joanne A

    2014-01-01

    Purpose The aim of this study is to investigate markers of inflammation and oxidative stress in an early model of diabetic retinopathy, correlate retinal and plasma results and evaluate the influence of treatment by N-acetylcysteine (NAC), a free radical scavenger. Methods Four groups were studied: control (C), streptozotocin (STZ)-induced diabetic rats (D), STZ rats following 8 weeks of NAC (DT), and control rats following 8 weeks of NAC (CT). Plasma levels of free 15-F2t-isoprostane (15-F-2t-IsoP), superoxide dismutase (SOD) and tumour necrosis factor-alpha (TNF-α) were obtained. Primary antibodies against macrophages (ED-1), microglia (Ox-42), pericytes (NG-2), endothelial and perivascular cells (IB-4), haem oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF) were used. Results Expression of NG-2 was robust in C, CT, DT, and mild in D. The intensity of IB-4 was higher in D and DT compared with the C and CT. Ox-42 and ED-1 expression was higher in the D than in the DT, C or CT. Expression of VEGF and HO-1 was non-specific across the four groups. Plasma levels of 15-F-2t-IsoP and TNF-α were higher in the D as compared with the C, CT and DT. SOD levels were lower in the D when compared with the C, CT and D. Conclusions Macrophage/microglia activation, pericyte loss and endothelial/perivascular cell changes occur early in the pathogenesis of DR. These changes are associated with an increase in plasma markers of oxidative stress and inflammation and are minimized by treatment with NAC. The results suggest that therapies that reduce free radicals will help minimize the early events in diabetic retinopathy in the STZ model. PMID:19723131

  8. Effect of N-acetylcysteine on the early expression of inflammatory markers in the retina and plasma of diabetic rats.

    PubMed

    Tsai, Gina Y; Cui, Jing Z; Syed, Husnain; Xia, Zhengyuan; Ozerdem, Ugur; McNeill, John H; Matsubara, Joanne A

    2009-03-01

    The aim of this study is to investigate markers of inflammation and oxidative stress in an early model of diabetic retinopathy, correlate retinal and plasma results and evaluate the influence of treatment by N-acetylcysteine (NAC), a free radical scavenger. Four groups were studied: control (C), streptozotocin (STZ)-induced diabetic rats (D), STZ rats following 8 weeks of NAC (DT), and control rats following 8 weeks of NAC (CT). Plasma levels of free 15-F2t-isoprostane (15-F-2t-IsoP), superoxide dismutase (SOD) and tumour necrosis factor-alpha (TNF-alpha) were obtained. Primary antibodies against macrophages (ED-1), microglia (Ox-42), pericytes (NG-2), endothelial and perivascular cells (IB-4), haem oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF) were used. Expression of NG-2 was robust in C, CT, DT, and mild in D. The intensity of IB-4 was higher in D and DT compared with the C and CT. Ox-42 and ED-1 expression was higher in the D than in the DT, C or CT. Expression of VEGF and HO-1 was non-specific across the four groups. Plasma levels of 15-F-2t-IsoP and TNF-alpha were higher in the D as compared with the C, CT and DT. SOD levels were lower in the D when compared with the C, CT and D. Macrophage/microglia activation, pericyte loss and endothelial/perivascular cell changes occur early in the pathogenesis of DR. These changes are associated with an increase in plasma markers of oxidative stress and inflammation and are minimized by treatment with NAC. The results suggest that therapies that reduce free radicals will help minimize the early events in diabetic retinopathy in the STZ model.

  9. Effects of chronic N-acetylcysteine treatment on the actions of peroxynitrite on aortic vascular reactivity in hypertensive rats.

    PubMed

    Cabassi, A; Dumont, E C; Girouard, H; Bouchard, J F; Le Jossec, M; Lamontagne, D; Besner, J G; de Champlain, J

    2001-07-01

    Peroxynitrite (ONOO-), the product of superoxide and nitric oxide, seems to be involved in vascular alterations in hypertension. To evaluate the effects of ONOO- on endothelium-dependent and independent aortic vascular responsiveness, oxidized/reduced glutathione balance (GSSG/GSH), malondialdehyde aortic content, and the formation of 3-nitrotyrosine (3-NT), a stable marker of ONOO-, in N-acetylcysteine (NAC)-treated normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In SHR only, NAC significantly reduced heart rate and systolic, but not diastolic, blood pressure. It also improved endothelium-dependent aortic relaxation in SHR, but not after exposure to ONOO-. Endothelium-dependent and independent aortic relaxations were markedly impaired by ONOO- in both strains of rat. NAC partially protected SHR against the ONOO- -induced reduction in endothelium-independent relaxation. Aortic GSSG/GSH ratio and malondialdehyde, which were higher in SHR than in WKY rats, showed a greater increase in SHR after exposure to ONOO-. NAC decreased GSSG/GSH and malondialdehyde in both strains of rat before and after exposure to ONOO-. The 3-NT concentration, which was similar in both strains of rat under basal conditions, was greater in SHR than in WKY rats after the addition of ONOO-, with a reduction only in NAC-treated SHR. These findings suggest an increased vulnerability of SHR aortas to the effects of ONOO- as compared with those of WKY rats. The selective improvements produced by NAC, in systolic arterial pressure, heart rate, aortic endothelial function, ONOO- -induced impairment of endothelium-independent relaxation, aortic GSSG/GSH balance, malondialdehyde content and 3-NT formation in SHR suggest that chronic administration of NAC may have a protective effect against aortic vascular dysfunction in the SHR model of hypertension.

  10. Effects of N-acetylcysteine and terbutaline treatment on hemodynamics and regional albumin extravasation in porcine septic shock

    SciTech Connect

    Groeneveld, A.B.; den Hollander, W.; Straub, J.

    We studied the therapeutic effects of continuously infused N-acetylcysteine, an O2 radical scavenger (N, n = 6), and terbutaline, a beta 2-agonist (T, n = 6), versus dextrose (controls C, N = 6) on hemodynamics and regional albumin extravasation in porcine septic shock. After instrumentation, injection of 99mTc-labeled red blood cells, and baseline measurements, pigs received a 90 min infusion of 11 +/- 9 X 10(8).kg-1 live Escherichia coli bacteria. Thereafter, therapy was started, and 131I human serum albumin was injected. Images were obtained hourly using a gamma camera and a computer until 5 hours after baseline. Regions of interestmore » were drawn in the 99mTc images, yielding regional 131I/99mTc radioactivity ratios, with blood samples as reference. From these ratios, an albumin leak index, a rate constant of transvascular albumin transport, was calculated. Control pigs developed pulmonary hypertension, arterial hypotension, hemoconcentration, and lactic acidemia. In spite of tachycardia and unchanged filling pressures, cardiac output fell. In arterial blood, white cell count, PO2, albumin level, and colloid osmotic pressure fell. The albumin leak index (X10(-3).min-1) measured 1.56 +/- 0.59 over the lungs and 2.87 +/- 1.19 over the abdomen in C, confirming previously found increased albumin flux in both lung and abdomen, the latter exceeding the former. Neither N nor T significantly affected hemodynamic and biochemical changes. The drugs neither decreased the regional albumin leak index nor attenuated the formation of albumin-rich ascites found at autopsy. However, the lung albumin index obtained at autopsy was significantly reduced with N (P less than .01 vs. C), at similar gravimetrically determined extravascular lung water (EVLW). EVLW positively correlated with pulmonary albumin extravasation in C and T but not in N.« less

  11. N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury.

    PubMed

    Wang, Qiao; Zhu, Hong; Zhou, Wu-Gang; Guo, Xiao-Can; Wu, Min-Juan; Xu, Zhen-Yu; Jiang, Jun-feng; Shen, Ce; Liu, Hou-Qi

    2013-08-01

    The transplantation of mesenchymal stem cells (MSCs) has been reported to be a promising approach in the treatment of acute lung injury. However, the poor efficacy of transplanted MSCs is one of the serious handicaps in the progress of MSC-based therapy. Therefore, the purpose of this study was to investigate whether the pretreatment of human embryonic MSCs (hMSCs) with an antioxidant, namely N-acetylcysteine (NAC), can improve the efficacy of hMSC transplantation in lung injury. In vitro, the antioxidant capacity of NAC-pretreated hMSCs was assessed using intracellular reactive oxygen species (ROS) and glutathione assays and cell adhesion and spreading assays. In vivo, the therapeutic potential of NAC-pretreated hMSCs was assessed in a bleomycin-induced model of lung injury in nude mice. The pretreatment of hMSCs with NAC improved antioxidant capacity to defend against redox imbalances through the elimination of cellular ROS, increasing cellular glutathione levels, and the enhancement of cell adhesion and spreading when exposed to oxidative stresses in vitro. In addition, the administration of NAC-pretreated hMSCs to nude mice with bleomycin-induced lung injury decreased the pathological grade of lung inflammation and fibrosis, hydroxyproline content and numbers of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid and apoptotic cells, while enhancing the retention and proliferation of hMSCs in injured lung tissue and improving the survival rate of mice compared with results from untreated hMSCs. The pretreatment of hMSCs with NAC could be a promising therapeutic approach to improving cell transplantation and, therefore, the treatment of lung injury.

  12. N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes.

    PubMed

    Ji, Yan-Li; Wang, Hua; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Xu, De-Xiang

    2013-03-01

    Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd-induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg(-1)). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd-induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd-induced phosphorylation of testicular eukaryotic translation initiation factor 2α (eIF2α), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes.

  13. N-acetylcysteine, Ascorbic Acid, and Methylene Blue for the Treatment of Aluminium Phosphide Poisoning: Still Beneficial?

    PubMed Central

    Gheshlaghi, Farzad; Lavasanijou, Mohamad Reza; Moghaddam, Noushin Afshar; Khazaei, Majid; Behjati, Mohaddeseh; Farajzadegan, Ziba; Sabzghabaee, Ali Mohammad

    2015-01-01

    Objectives: Intentional and accidental intoxication with aluminium phosphide (ALP) remains a clinical problem, especially in the Middle East region. Considering the high mortality rate besides lack of any recommended first option drug for its treatment, this study was aimed to compare the therapeutic effects of N-acetylcysteine (NAC), vitamin C (Vit C), and methylene blue; both in isolate and also in combination, for the treatment of ALP intoxication in a rat model. Materials and Methods: In this experimental animal study, 80 male Wistar rats in eight groups were intoxicated with ALP (12.5 mg/kg) and treated with a single dose of NAC (100 mg/kg) or Vit C (500–1,000 mg/kg) or methylene blue (1 mg/kg/5 min, 0.1%) or two of these agents or all three of them (controls were not treated). Rats were monitored regarding the parameters of drug efficacy as increased survival time and reduced morbidity and mortality rate for 3 consecutive days to ensure toxin neutralization. Macroscopic changes were recorded and biopsy sections were taken from brain, cerebellum, kidney, liver, and heart for microscopic evaluation regarding cellular hypoxia. Results: The mean survival times of rats exposed to ALP and treated with VitC + NAC was 210.55±236.22 minutes. In analysis of survival times, there was a significant difference between Group 5 which received VitC + NAC and the other groups (P < 0.01). Serum magnesium levels after death were higher than normal (P = 0.01). Conclusions: Despite the higher survival rate of antioxidant-treated rats compared with controls, this difference was not statistically significant. PMID:26862259

  14. Redox regulation of MMP-3/TIMP-1 ratio in intestinal myofibroblasts: effect of N-acetylcysteine and curcumin.

    PubMed

    Fontani, Filippo; Marcucci, Tommaso; Picariello, Lucia; Tonelli, Francesco; Vincenzini, Maria Teresa; Iantomasi, Teresa

    2014-04-15

    Matrix metalloproteinases (MMPs) play a critical role in inflammation and ulcerations in gut of Crohn׳s disease (CD) patients. Intestinal subepithelial myofibroblasts (ISEMFs) secrete MMPs in response to inflammatory stimuli. Previous data showed in CD-ISEMFs increased oxidative status. The aim of this study was to investigate the role of ISEMFs in modulating the production of MMP-3 and TIMP-1, an inhibitor of MMPs activity. A relationship among oxidative stress, activity of antioxidants and MMP-3/TIMP-1 was also studied. ISEMFs isolated from CD patient colon and human colonic cell line of myofibroblasts (18Co) were used. Oxidative state was modulated by buthionine sulfoximine, an inhibitor of glutathione (GSH) synthesis, and N-acetylcysteine (NAC), GSH precursor. An up-regulation of MMP-3 due to increased oxidative state was found in CD-ISEMFs. Stimulation by tumor necrosis factor (TNF)α increased further MMP-3 levels. On the contrary, no change in TIMP-1 production was determined. NAC treatment decreased MMP-3 production in CD-ISMEFs and removed the enhancement due to TNFα. Similar effects were observed in 18Co cells treated with curcumin, antioxidant with anti-inflammatory properties. The involvement of MAPKs on MMP-3 redox regulation was also shown. This study demonstrates the involvement of ISEMFs and high oxidative state in the increased MMP-3 production found in intestinal mucosa of CD patients. NAC and curcumin normalize MMP-3 levels mainly in TNFα stimulated cells. A modulation of MMP-3 production by NAC and curcumin due to their direct action on transcriptional factors has been also suggested. Therefore, they could have a therapeutic use for the prevention and treatment of fistulaes in CD. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

    PubMed

    Lee, William M; Hynan, Linda S; Rossaro, Lorenzo; Fontana, Robert J; Stravitz, R Todd; Larson, Anne M; Davern, Timothy J; Murray, Natalie G; McCashland, Timothy; Reisch, Joan S; Robuck, Patricia R

    2009-09-01

    N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

  16. Effect of inhaled N-acetylcysteine monotherapy on lung function and redox balance in idiopathic pulmonary fibrosis.

    PubMed

    Muramatsu, Yoko; Sugino, Keishi; Ishida, Fumiaki; Tatebe, Junko; Morita, Toshisuke; Homma, Sakae

    2016-05-01

    An oxidant-antioxidant imbalance is considered to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Therefore, administration of antioxidants, such as N-acetylcysteine (NAC), may represent a potential treatment option for IPF patients. The aim of this study was to evaluate the effect of inhaled NAC monotherapy on lung function and redox balance in patients with IPF. A retrospective observational study was done, involving 22 patients with untreated early IPF (19 men; mean [±S.D.] age, 71.8 [±6.3]y). At baseline and at 6 and 12 months after initiating inhaled NAC monotherapy, we assessed forced vital capacity (FVC) and measured the levels of total glutathione, oxidized glutathione (GSSG), and the ratio of reduced to oxidized glutathione in whole blood (hereafter referred to as the ratio), and of 8-hydroxy-2'-deoxyguanosine in urine. To evaluate response to treatment, we defined disease progression as a decrease in FVC of ≥5% from baseline and stable disease as a decrease in FVC of <5%, over a period of 6 months. Change in FVC in the stable group at 6 and 12 months were 95±170mL and -70±120mL, while those in the progressive group at 6 and 12 months were -210±80mL, -320±350mL, respectively. The serial mean change in GSSG from baseline decreased as the ratio of reduced to oxidized glutathione increased in patients with stable disease, while it increased as this ratio decreased in patients with progressive disease. Receiver operating characteristic curve analysis revealed that a baseline GSSG level of ≥1.579μM was optimal for identifying treatment responders. Inhaled NAC monotherapy was associated with improved redox imbalance in patients with early IPF. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  17. Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and its 6-(N-Acetylcystein-S-yl) Conjugate

    PubMed Central

    Neudörffer, Anne; Mueller, Melanie; Martinez, Claire-Marie; Mechan, Annis; McCann, Una; Ricaurte, George A.; Largeron, Martine

    2011-01-01

    The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, “ecstasy”) or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), plays a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in brains of these animals was not related to the unstable nature of the THMA molecule, because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA, or oxidized cyclic forms (e.g. the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo. PMID:21557581

  18. Contemporary use and effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention.

    PubMed

    Gurm, Hitinder S; Smith, Dean E; Berwanger, Otavio; Share, David; Schreiber, Theodore; Moscucci, Mauro; Nallamothu, Brahmajee K

    2012-01-01

    The aim of this study was to examine the use of and outcomes associated with use of N-acetylcysteine (NAC) in real-world practice. The role of NAC in the prevention of contrast-induced nephropathy (CIN) is controversial, leading to widely varying recommendations for its use. Use of NAC was assessed in consecutive patients undergoing nonemergent percutaneous coronary intervention from 2006 to 2009 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium, a large multicenter quality improvement collaborative. We examined the overall prevalence of NAC use in these patients and then used propensity matching to link its use with clinical outcomes, including CIN, nephropathy-requiring dialysis, and death. Of the 90,578 percutaneous coronary interventions performed during the study period, NAC was used in 10,574 (11.6%) procedures, with its use steadily increasing over the study period. Patients treated with NAC were slightly older and more likely to have baseline renal insufficiency and other comorbidities. In propensity-matched, risk-adjusted models, we found no differences in outcomes between patients treated with NAC and those not receiving NAC for CIN (5.5% vs. 5.5%, p = 0.99), nephropathy-requiring dialysis (0.6% vs. 0.6%, p = 0.69), or death (0.6% vs. 0.8%, p = 0.15). These findings were consistent across many prespecified subgroups. Use of NAC is common and has steadily increased over the study period but does not seem to be associated with improved clinical outcomes in real-world practice. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  19. N-acetylcysteine protects against motor, optomotor and morphological deficits induced by 6-OHDA in zebrafish larvae.

    PubMed

    Benvenutti, Radharani; Marcon, Matheus; Reis, Carlos G; Nery, Laura R; Miguel, Camila; Herrmann, Ana P; Vianna, Monica R M; Piato, Angelo

    2018-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. In addition to its highly debilitating motor symptoms, non-motor symptoms may precede their motor counterparts by many years, which may characterize a prodromal phase of PD. A potential pharmacological strategy is to introduce neuroprotective agents at an earlier stage in order to prevent further neuronal death. N -acetylcysteine (NAC) has been used against paracetamol overdose hepatotoxicity by restoring hepatic concentrations of glutathione (GSH), and as a mucolytic in chronic obstructive pulmonary disease by reducing disulfide bonds in mucoproteins. It has been shown to be safe for humans at high doses. More recently, several studies have evidenced that NAC has a multifaceted mechanism of action, presenting indirect antioxidant effect by acting as a GSH precursor, besides its anti-inflammatory and neurotrophic effects. Moreover, NAC modulates glutamate release through activation of the cystine-glutamate antiporter in extra-synaptic astrocytes. Its therapeutic benefits have been demonstrated in clinical trials for several neuropsychiatric conditions but has not been tested in PD models yet. In this study, we evaluated the potential of NAC to prevent the damage induced by 6-hydroxydopamine (6-OHDA) on motor, optomotor and morphological parameters in a PD model in larval zebrafish. NAC was able to prevent the motor deficits (total distance, mean speed, maximum acceleration, absolute turn angle and immobility time), optomotor response impairment and morphological alterations (total length and head length) caused by exposure to 6-OHDA, which reinforce and broaden the relevance of its neuroprotective effects. NAC acts in different targets relevant to PD pathophysiology. Further studies and clinical trials are needed to assess this agent as a candidate for prevention and adjunctive treatment of PD.

  20. Beneficial Effects of N-acetylcysteine and N-mercaptopropionylglycine on Ischemia Reperfusion Injury in the Heart.

    PubMed

    Bartekova, Monika; Barancik, Miroslav; Ferenczyova, Kristina; Dhalla, Naranjan S

    2018-01-30

    Ischemia-reperfusion (I/R) injury of the heart as a consequence of myocardial infarction or cardiac surgery represents a serious clinical problem. One of the most prominent mechanisms of I/R injury is the development of oxidative stress in the heart. In this regard, I/R has been shown to enhance the production of reactive oxygen/nitrogen species in the heart which lead to the imbalance between the pro-oxidants and antioxidant capacities of the endogenous radical-scavenging systems. Increasing the antioxidant capacity of the heart by the administration of exogenous antioxidants is considered beneficial for the heart exposed to I/R. N-acetylcysteine (NAC) and Nmercaptopropionylglycine (MPG) are two sulphur containing amino acid substances, which belong to the broad category of exogenous antioxidants that have been tested for their protective potential in cardiac I/R injury. Pretreatment of hearts with both NAC and MPG has demonstrated that these agents attenuate the I/R-induced alterations in sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils in addition to improving cardiac function. While experimental studies have revealed promising data suggesting beneficial effects of NAC and MPG in cardiac I/R injury, the results of clinical trials are not conclusive because both positive and no effects of these substances have been reported on the post-ischemic recovery of heart following cardiac surgery or myocardial infarction. It is concluded that both NAC and MPG exert beneficial effects in preventing the I/Rinduced injury; however, further studies are needed to establish their effectiveness in reversing the I/R-induced abnormalities in the heart. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Assessment of phosphamidon-induced apoptosis in human peripheral blood mononuclear cells: protective effects of N-acetylcysteine and curcumin.

    PubMed

    Ahmed, Tanzeel; Tripathi, Ashok K; Ahmed, Rafat S; Banerjee, Basu Dev

    2010-01-01

    The molecular mechanism for noncholinergic toxicity of phosphamidon, an extensively used organophosphate pesticide, is still not clear. The aim of the present study is to find the possible molecular mechanism of this pesticide to induce apoptosis and the role of different drugs for attenuation of such effects. Human peripheral blood mononuclear cells (PBMC) were incubated with increasing concentrations of phosphamidon (0-20 μM) for 6-24 h. The MTT assay reveals that phosphamidon induces cytotoxicity in a dose-dependent manner. Cellular glutathione (GSH) is depleted in a dose-dependent manner from 55% to 70% at concentrations between 10 and 20 μM. The percentage of cells that bind to Annexin-V, which is a representative of cells either undergoing apoptosis or necrosis during 24 h incubation, increases in a dose-dependent manner. Above 5 μM, significant necrosis of cells was observed. DNA fragmentation assay revealed that at low concentration of phosphamidon (1 μM), no appreciable change in DNA fragmentation was seen; however, distinct fragmentation was observed beyond 2.5 μM. Phosphamidon was found to cause significant depletion of GSH, which correlates well with the percentage of cells undergoing apoptosis. An increasing trend in levels of cytochrome c was observed with increasing concentration of phosphamidon, indicating that the apoptotic effect of phosphamidon is mediated through cytochrome c release. Coadministration of the antioxidants N-acetylcysteine and curcumin attenuated phosphamidon-induced apoptosis. This further supports our hypothesis that oxidative stress, as indicated by GSH depletion, results in the induction of apoptosis by release of cytochrome c. Copyright 2010 Wiley Periodicals, Inc.

  2. Update on the pathological processes, molecular biology, and clinical utility of N-acetylcysteine in chronic obstructive pulmonary disease

    PubMed Central

    Tse, Hoi Nam; Tseng, Cee Zhung Steven

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a common and morbid disease characterized by high oxidative stress. Its pathogenesis is complex, and involves excessive oxidative stress (redox imbalance), protease/antiprotease imbalance, inflammation, apoptosis, and autoimmunity. Among these, oxidative stress has a pivotal role in the pathogenesis of COPD by initiating and mediating various redox-sensitive signal transduction pathways and gene expression. The protective physiological mechanisms of the redox balance in the human body, their role in the pathogenesis of COPD, and the clinical correlation between oxidative stress and COPD are reviewed in this paper. N-acetylcysteine (NAC) is a mucolytic agent with both antioxidant and anti-inflammatory properties. This paper also reviews the use of NAC in patients with COPD, especially the dose-dependent properties of NAC, eg, its effects on lung function and the exacerbation rate in patients with the disease. Earlier data from BRONCUS (the Bronchitis Randomized on NAC Cost-Utility Study) did not suggest that NAC was beneficial in patients with COPD, only indicating that it reduced exacerbation in an “inhaled steroid-naïve” subgroup. With regard to the dose-dependent properties of NAC, two recent randomized controlled Chinese trials suggested that high-dose NAC (1,200 mg daily) can reduce exacerbations in patients with COPD, especially in those with an earlier (moderately severe) stage of disease, and also in those who are at high risk of exacerbations. However, there was no significant effect on symptoms or quality of life in patients receiving NAC. Further studies are warranted to investigate the effect of NAC at higher doses in non-Chinese patients with COPD. PMID:25125976

  3. Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.

    PubMed

    Zeren, Sezgin; Bayhan, Zulfu; Koçak, Cengiz; Koçak, Fatma Emel; Metineren, Mehmet Huseyin; Savran, Bircan; Kocak, Havva; Algin, Mustafa Cem; Kahraman, Cuneyt; Kocak, Ahmet; Cosgun, Suleyman

    2017-04-01

    Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP. Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated. Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC. These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

  4. A Double-Blind Randomized Controlled Pilot Trial of N-Acetylcysteine in Veterans with PTSD and Substance Use Disorders

    PubMed Central

    Back, Sudie E.; McCauley, Jenna L.; Korte, Kristina J.; Gros, Daniel F.; Leavitt, Virginia; Gray, Kevin M.; Hamner, Mark B.; DeSantis, Stacia M.; Malcolm, Robert; Brady, Kathleen T.; Kalivas, Peter W.

    2016-01-01

    Objective The antioxidant N-Acetylcysteine (NAC) is being increasingly investigated as a therapeutic agent in the treatment of substance use disorders. Preclinical and clinical findings suggest that NAC normalizes extracellular glutamate by restoring the activity of glutamate transporters and antiporters in the nucleus accumbens. This study explored the efficacy of NAC in the treatment of post-traumatic stress disorder (PTSD), which frequently co-occurs with substance use disorders (SUD) and shares impaired prefrontal cortex regulation of basal ganglia circuitry, in particular at glutamate synapses in the nucleus accumbens. Method Veterans with current PTSD and SUD (N=35) were randomly assigned to receive a double-blind, 8-week course of NAC (2400 mg/day) or placebo plus outpatient group cognitive-behavioral therapy for SUD. Primary outcome measures included PTSD symptoms (Clinician Administered PTSD Scale, PTSD Checklist-Military) and craving (Visual Analogue Scale). Depression (Beck Depression Inventory-II) and substance use (Timeline Follow Back, urine drug screens) were also assessed. Results Participants treated with NAC, as compared to placebo, evidenced significant improvements in PTSD symptoms, craving, and depression. Substance use at the start of treatment was low for both the NAC and placebo groups and no significant between-group differences were observed. NAC was well tolerated and retention was high. Conclusions This is the first randomized controlled trial to investigate NAC as a pharmacological treatment for PTSD. The findings show a significant treatment effect on symptoms of PTSD and drug craving, and provide initial support for the use of NAC in combination with cognitive-behavioral therapy among individuals with co-occurring PTSD and SUD. PMID:27736051

  5. N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats.

    PubMed

    Smaga, Irena; Pomierny, Bartosz; Krzyżanowska, Weronika; Pomierny-Chamioło, Lucyna; Miszkiel, Joanna; Niedzielska, Ewa; Ogórka, Agata; Filip, Małgorzata

    2012-12-03

    The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N-acetylcysteine (NAC) - a putative precursor of the most important tissue antioxidant glutathione - in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50-100mg/kg, ip) or IMI (10mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity - TAC and the superoxide dismutase activity - SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. N-acetylcysteine reduces oxidative stress, nuclear factor-κB activity and cardiomyocyte apoptosis in heart failure

    PubMed Central

    WU, XIAO-YAN; LUO, AN-YU; ZHOU, YI-RONG; REN, JIANG-HUA

    2014-01-01

    The roles of oxidative stress on nuclear factor (NF)-κB activity and cardiomyocyte apoptosis during heart failure were examined using the antioxidant N-acetylcysteine (NAC). Heart failure was established in Japanese white rabbits with intravenous injections of doxorubicin, with ten rabbits serving as a control group. Of the rabbits with heart failure, 12 were not treated (HF group) and 13 received NAC (NAC group). Cardiac function was assessed using echocardiography and hemodynamic analysis. Myocardial cell apoptosis, apoptosis-related protein expression, NF-κBp65 expression and activity, total anti-oxidative capacity (tAOC), 8-iso-prostaglandin F2α (8-iso-PGF2α) expression and glutathione (GSH) expression levels were determined. In the HF group, reduced tAOC, GSH levels and Bcl-2/Bax ratios as well as increased 8-iso-PGF2α levels and apoptosis were observed (all P<0.05), which were effects that were attenuated by the treatment with NAC. NF-κBp65 and iNOS levels were significantly higher and the P-IκB-α levels were significantly lower in the HF group; expression of all three proteins returned to pre-HF levels following treatment with NAC. Myocardial cell apoptosis was positively correlated with left ventricular end-diastolic pressure (LVEDP), NF-κBp65 expression and 8-iso-PGF2α levels, but negatively correlated with the maximal and minimal rates of increase in left ventricular pressure (+dp/dtmax and −dp/dtmin, respectively) and the Bcl-2/Bax ratio (all P<0.001). The 8-iso-PGF2α levels were positively correlated with LVEDP and negatively correlated with +dp/dtmax and −dp/dtmin (all P<0.001). The present study demonstrated that NAC increased the antioxidant capacity, decreased the NF-κB activation and reduced myocardial cell apoptosis in an in vivo heart failure model. PMID:24889421

  7. Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein.

    PubMed

    Porcu, Mauro; Urbano, Mariana Ragassi; Verri, Waldiceu A; Barbosa, Decio Sabbatini; Baracat, Marcela; Vargas, Heber Odebrecht; Machado, Regina Célia Bueno Rezende; Pescim, Rodrigo Rossetto; Nunes, Sandra Odebrecht Vargas

    2018-05-01

    Outcomes in a RCTs of 12 weeks of theclinical efficacy of N-acetylcysteine (NAC) as an adjunctive treatment on depression and anxiety symptoms and its effects on high-sensitivity C-reactive protein (hs-CRP) levels. A wide array of measures were made. The 17-item version of the Hamilton Depression Rating Scale (HDRS17); the Hamilton Anxiety Rating Scale (HAM-A); Sheehan Disability Scale; Quality of Life; Clinical Global Impression (CGI); anthropometrics measures; and vital signs and biochemical laboratory. There were no significant differences among the groups regarding demographic, clinical features, use of medication, metabolic syndrome and comorbidities. From baseline to week 12, individuals receiving NAC, versus placebo, had a statistically significant reduction in depressive symptoms on HDRS 17 (p < 0.01) and anxiety symptoms on HAM-A (p = 0.04), but only for individuals with levels of hs-CRP > 3 mg/L at baseline. Individuals receiving NAC with baseline levels of hs-CRP > 3 mg/L, had more significant reduction in uric acid levels compared to individuals with baseline levels of hs-CRP ≤ 3 mg/L on week 12. Participants receiving placebogained significantly more weight during the 12 weeks for baseline levels of hs-CRP ≤ 3 mg/L and hs-CRP > 3 mg/L, and individuals receiving NAC in both groups did not have significant weight change during the 12 weeks. No individuals were withdrawn from the study because of adverse event. NAC group exhibited significantly greater reduction on hs-CRP levels than placebo group from baseline to week 12. clinicaltrials.gov Identifier; NCT02252341. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study.

    PubMed

    Cullen, Kathryn R; Klimes-Dougan, Bonnie; Westlund Schreiner, Melinda; Carstedt, Patricia; Marka, Nicholas; Nelson, Katharine; Miller, Michael J; Reigstad, Kristina; Westervelt, Ana; Gunlicks-Stoessel, Meredith; Eberly, Lynn E

    2018-03-01

    Nonsuicidal self-injury (NSSI) is common in adolescents and young adults, and few evidence-based treatments are available for this significant problem. N-acetylcysteine (NAC) is a widely available nutritional supplement that has been studied in some psychiatric disorders relevant to NSSI including mood and addictive disorders. This pilot study tested the use of NAC as a potential treatment for NSSI in youth. Thirty-five female adolescents and young adults with NSSI aged 13-21 years were enrolled in this study that had an open-label, single-arm study design. All participants were given oral NAC as follows: 600 mg twice daily (weeks 1-2), 1200 mg twice daily (weeks 3-4), and 1800 mg twice daily (weeks 5-8). Patients were seen every 2 weeks throughout the trial, at which time youth reported the frequency of NSSI episodes. Levels of depression, impulsivity, and global psychopathology were measured at baseline and at the end of the trial using the Beck Depression Inventory-II (BDI-II), Barratt Impulsivity Scale, and Symptoms Checklist-90 (SCL-90). About two-thirds of the enrolled female youth completed the trial (24/35). NAC was generally well tolerated in this sample. NAC treatment was associated with a significant decrease in NSSI frequency at visit 6 and visit 8 compared to baseline. We also found that depression scores and global psychopathology scores (but not impulsivity scores) decreased after NAC treatment. Decrease in NSSI was not correlated with decrease in BDI-II or SCL-90 scores, suggesting these might be independent effects. We provide preliminary evidence that NAC may have promise as a potential treatment option for adolescents with NSSI. The current results require follow-up with a randomized, placebo-controlled trial to confirm efficacy.

  9. Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice.

    PubMed

    Pilz, Luísa K; Trojan, Yasmine; Quiles, Caroline L; Benvenutti, Radharani; Melo, Gabriela; Levandovski, Rosa; Hidalgo, Maria Paz L; Elisabetsky, Elaine

    2015-03-01

    Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.

  10. Effect of N-Acetylcysteine Pretreatment of Deceased Organ Donors on Renal Allograft Function: A Randomized Controlled Trial

    PubMed Central

    Orban, Jean-Christophe; Quintard, Hervé; Cassuto, Elisabeth; Jambou, Patrick; Samat-Long, Corine; Ichai, Carole

    2015-01-01

    Background Antioxidant donor pretreatment is one of the pharmacologic strategy proposed to prevent renal ischemia-reperfusion injuries and delayed graft function (DGF). The aim of the study was to investigate whether a donor pretreatment with N-acetylcysteine (NAC) reduces the incidence of DGF in adult human kidney transplant recipients. Methods In this randomized, open-label, monocenter trial, 160 deceased heart-beating donors were allowed to perform 236 renal transplantations from September 2005 to December 2010. Donors were randomized to receive, in a single-blind controlled fashion, 600 mg of intravenous NAC 1 hr before and 2 hr after cerebral angiography performed to confirm brain death. Primary endpoint was DGF defined by the need for at least one dialysis session within the first week or a serum creatinine level greater than 200 μmol/L at day 7 after kidney transplantation. Results The incidence of DGF was similar between donors pretreated with or without NAC (39/118; 33% vs. 30/118; 25.4%; P = 0.19). Requirement for at least one dialysis session was not different between the NAC and No NAC groups (17/118; 14.4% vs. 14/118; 11.8%, P = 0.56). The two groups had comparable serum creatinine levels, estimated glomerular filtration rates, and daily urine output at days 1, 7, 15, and 30 after kidney transplantation as well as at hospital discharge. No difference in recipient mortality nor in 1-year kidney graft survival was observed. Conclusion Donor pretreatment with NAC does not improve delayed graft function after kidney transplantation. PMID:25250647

  11. Managing acute acetaminophen poisoning with oral versus intravenous N-acetylcysteine: a provider-perspective cost analysis.

    PubMed

    Marchetti, Albert; Rossiter, Richard

    2009-01-01

    Acetaminophen (APAP) overdose, which can lead to hepatotoxicity, is the most commonly reported poisoning in the United States and has the highest rate of mortality, with more than 100,000 exposures and 300 deaths reported annually (1) . The treatment of choice, N-acetylcysteine (NAC), is effective in both oral (PO) and intravenous (IV) formulations. The main difference in therapies, other than administration route, is time to complete delivery--72 hours for PO NAC versus 21 hours for IV NAC, according to full prescribing information. This distinction is the primary basis for variation in management costs for hospitalized patients receiving these products. To quantify and compare full treatment costs from the provider perspective to manage acute APAP poisoning with either PO or IV NAC in a standard treatment regimen. A cost model was developed and populated with published data comprising probabilities of potential clinical outcomes and the costs of resources consumed during patient care. For patients who present <10 hours post-ingestion, the estimated total cost of care with PO NAC in the treatment regimen is $5,817 (ICU patients) or $3,850, (ward patients) compared with $3,765 and $2,768 for similar care with IV NAC. Potential cost savings equal - $2,052 (-35%) or -$1,083 (-28%), respectively, in favor of IV NAC. Similar potential savings were estimated for patients presenting 10-24 hours post-ingestion. IV NAC is the less costly therapeutic option for APAP poisonings, based on simulation modeling and retrospective data. The current economic evaluation is restricted by the absence of comparative data from head-to-head, matched-cohort studies and the limitations common to retrospective APAP toxicology datasets. Additional research could refine these results.

  12. Arterial morphology responds differently to Captopril then N-acetylcysteine in a monocrotaline rat model of pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Molthen, Robert; Wu, Qingping; Baumgardt, Shelley; Kohlhepp, Laura; Shingrani, Rahul; Krenz, Gary

    2010-03-01

    Pulmonary hypertension (PH) is an incurable condition inevitably resulting in death because of increased right heart workload and eventual failure. PH causes pulmonary vascular remodeling, including muscularization of the arteries, and a reduction in the typically large vascular compliance of the pulmonary circulation. We used a rat model of monocrotaline (MCT) induced PH to evaluated and compared Captopril (an angiotensin converting enzyme inhibitor with antioxidant capacity) and N-acetylcysteine (NAC, a mucolytic with a large antioxidant capacity) as possible treatments. Twenty-eight days after MCT injection, the rats were sacrificed and heart, blood, and lungs were studied to measure indices such as right ventricular hypertrophy (RVH), hematocrit, pulmonary vascular resistance (PVR), vessel morphology and biomechanics. We implemented microfocal X-ray computed tomography to image the pulmonary arterial tree at intravascular pressures of 30, 21, 12, and 6 mmHg and then used automated vessel detection and measurement algorithms to perform morphological analysis and estimate the distensibility of the arterial tree. The vessel detection and measurement algorithms quickly and effectively mapped and measured the vascular trees at each intravascular pressure. Monocrotaline treatment, and the ensuing PH, resulted in a significantly decreased arterial distensibility, increased PVR, and tended to decrease the length of the main pulmonary trunk. In rats with PH induced by monocrotaline, Captopril treatment significantly increased arterial distensibility and decrease PVR. NAC treatment did not result in an improvement, it did not significantly increase distensibility and resulted in further increase in PVR. Interestingly, NAC tended to increase peripheral vascular density. The results suggest that arterial distensibility may be more important than distal collateral pathways in maintaining PVR at normally low values.

  13. Effects of Antioxidant N-acetylcysteine Against Paraquat-Induced Oxidative Stress in Vital Tissues of Mice

    PubMed Central

    Ortiz, Maricelly Santiago; Forti, Kevin Muñoz; Suárez Martinez, Edu B.; Muñoz, Lenin Godoy; Husain, Kazim

    2016-01-01

    Paraquat (PQ) is a commonly used herbicide that induces oxidative stress via reactive oxygen species (ROS) generation. This study aimed to investigate the effects of the antioxidant N-acetylcysteine (NAC) against PQ-induced oxidative stress in mice. Male Balb/C mice (24) were randomly divided into 4 groups and treated for 3 weeks: 1) control (saline), 2) NAC (0.5% in diet), 3) PQ (20 mg/kg, IP) and 4) combination (PQ + NAC). Afterwards mice were sacrificed and oxidative stress markers were analyzed. Our data showed no significant change in serum antioxidant capacity. PQ enhanced lipid peroxidation (MDA) levels in liver tissue compared to control whereas NAC decreased MDA levels (p<0.05). NAC significantly increased MDA in brain tissue (p<0.05). PQ significantly depleted glutathione (GSH) levels in liver (p=0.001) and brain tissue (p<0.05) but non-significant GSH depletion in lung tissue. NAC counteracted PQ, showing a moderate increase GSH levels in liver and brain tissues. PQ significantly increased 8-oxodeoxyguanosine (8-OH-dG) levels (p<0.05) in liver tissue compared to control without a significant change in brain tissue. NAC treatment ameliorated PQ-induced oxidative DNA damage in the liver tissue. PQ significantly decreased the relative mtDNA amplification and increased the frequency of lesions in liver and brain tissue (p<0.0001), while NAC restored the DNA polymerase activity in liver tissue but not in brain tissue. In conclusion, PQ induced lipid peroxidation, oxidative nuclear DNA and mtDNA damage in liver tissues and depleted liver and brain GSH levels. NAC supplementation ameliorated the PQ-induced oxidative stress response in liver tissue of mice. PMID:27398384

  14. Respiratory Syncytial Virus Inhibits Ciliagenesis in Differentiated Normal Human Bronchial Epithelial Cells: Effectiveness of N-Acetylcysteine

    PubMed Central

    Mata, Manuel; Sarrion, Irene; Armengot, Miguel; Carda, Carmen; Martinez, Isidoro; Melero, Jose A.; Cortijo, Julio

    2012-01-01

    Persistent respiratory syncytial virus (RSV) infections have been associated with the exacerbation of chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). This virus infects the respiratory epithelium, leading to chronic inflammation, and induces the release of mucins and the loss of cilia activity, two factors that determine mucus clearance and the increase in sputum volume. These alterations involve reactive oxygen species-dependent mechanisms. The antioxidant N-acetylcysteine (NAC) has proven useful in the management of COPD, reducing symptoms, exacerbations, and accelerated lung function decline. NAC inhibits RSV infection and mucin release in human A549 cells. The main objective of this study was to analyze the effects of NAC in modulating ciliary activity, ciliagenesis, and metaplasia in primary normal human bronchial epithelial cell (NHBEC) cultures infected with RSV. Our results indicated that RSV induced ultrastructural abnormalities in axonemal basal bodies and decreased the expression of β-tubulin as well as two genes involved in ciliagenesis, FOXJ1 and DNAI2. These alterations led to a decrease in ciliary activity. Furthermore, RSV induced metaplastic changes to the epithelium and increased the number of goblet cells and the expression of MUC5AC and GOB5. NAC restored the normal functions of the epithelium, inhibiting ICAM1 expression, subsequent RSV infection through mechanisms involving nuclear receptor factor 2, and the expression of heme oxygenase 1, which correlated with the restoration of the antioxidant capacity, the intracellular H2O2 levels and glutathione content of NHBECs. The results presented in this study support the therapeutic use of NAC for the management of chronic respiratory diseases, including COPD. PMID:23118923

  15. Cytotoxic Effects of Ochratoxin A in Neuro-2a Cells: Role of Oxidative Stress Evidenced by N-acetylcysteine.

    PubMed

    Bhat, Pratiksha V; Pandareesh; Khanum, Farhath; Tamatam, Anand

    2016-01-01

    Ochratoxin-A (OTA), is toxic secondary metabolite and is found to be a source of vast range of toxic effects like hepatotoxicity, nephrotoxicity. However, the information available currently regarding neurotoxic effects exerted by OTA is scanty. Hence, the present study was aimed to evaluate the neurotoxic effects of OTA and the possible mechanisms of toxicity as well as the role of cytotoxic oxidative stress on neuronal (Neuro-2a) cell line was evaluated in vitro. Results of the MTT and LDH assay showed that, OTA induced dose-dependent cell death in Neuro-2a cells and EC50 value was determined as 500 nM. OTA induced high levels of reactive oxygen species (ROS) and elevated levels of malondialdehyde, also loss of mitochondrial membrane potential was observed in a dose depended manner. Effects of OTA on ROS induced chromosomal DNA damage was assessed by Comet assay and plasmid DNA damage assay in which increase in DNA damage was observed in Neuro-2a cells by increasing the OTA concentration. Further western blotting analysis of OTA treated Neuro-2a cells indicated elevated expression levels of c-Jun, JNK3 and cleaved caspase-3 leading to apoptotic cell death. Other hand realtime-Q-PCR analysis clearly indicates the suppressed expression of neuronal biomarker genes including AChE, BDNF, TH and NOS2. Further N-acetylcysteine (NAC) pretreatment to Neuro-2a cells followed by OTA treatment clearly evidenced that, the significant reversal of toxic effects exerted by OTA on Neuro-2a cells. In the present study, results illustrate that ROS a principle event in oxidative stress was elevated by OTA toxicity in Neuro-2a cells. However, further in vivo, animal studies are in need to conclude the present study reports and the use of NAC as a remedy for OTA induced neuronal stress.

  16. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

    PubMed

    Rogliani, Paola; Calzetta, Luigino; Cavalli, Francesco; Matera, Maria Gabriella; Cazzola, Mario

    2016-10-01

    The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment. RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis. Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events. The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Topical N-Acetylcysteine Accelerates Wound Healing in Vitro and in Vivo via the PKC/Stat3 Pathway

    PubMed Central

    Tsai, Min-Ling; Huang, Hui-Pei; Hsu, Jeng-Dong; Lai, Yung-Rung; Hsiao, Yu-Ping; Lu, Fung-Jou; Chang, Horng-Rong

    2014-01-01

    N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP-1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing. PMID:24798751

  18. The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study.

    PubMed

    Froeliger, B; McConnell, P A; Stankeviciute, N; McClure, E A; Kalivas, P W; Gray, K M

    2015-11-01

    Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which in turn meditates drug seeking. In animal models, N-Acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and would help smokers to maintain abstinence over the study period. The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotine-withdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers (N=16; mean (SD) age 36.5±11.9; cigs/day 15.8±6.1; years/smoking 15.7±8.9) were randomized to a double-blind course of 2400mg N-Acetylcysteine (1200mg b.i.d.) or placebo over the course of 3½ days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon monoxide [CO]). On day 4, participants underwent fMRI scanning. As compared to placebo (n=8), smokers in the N-Acetylcysteine group (n=8) maintained abstinence, reported less craving and higher positive affect (all p's<.01), and concomitantly exhibited stronger rsFC between ventral striatal nodes, medial prefrontal cortex and precuneus-key default mode network nodes, and the cerebellum [p<.025; FWE]). Taken together, these findings suggest that N-Acetylcysteine may positively affect dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence immediately following a quit attempt. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study*

    PubMed Central

    Froeliger, B.; McConnell, P.A.; Stankeviciute, N.; McClure, E.A.; Kalivas, P.W.; Gray, K.M.

    2015-01-01

    BACKGROUND Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which in turn meditates drug seeking. In animal models, N-acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and would help smokers to maintain abstinence over the study period. METHODS The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotine-withdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers (N=16; mean (SD) age 36.5±11.9; cigs/day 15.8±6.1; yrs/smoking 15.7±8.9) were randomized to a double-blind course of 2400 mg N-Acetylcysteine (1200 mg b.i.d.) or placebo over the course of 3 ½ days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected digitally and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon monoxide [CO]). On day 4, participants underwent fMRI scanning. RESULTS As compared to placebo (n=8), smokers in the N-Acetylcysteine group (n=8) maintained abstinence, reported less craving and higher positive affect (all p’s <.01), and concomitantly exhibited stronger rsFC between ventral striatal nodes, medial prefrontal cortex and precuneus—key default mode network nodes, and the cerebellum [p<.025; FWE]). CONCLUSIONS Taken together, these findings suggest that N-Acetylcysteine may positively affect potentially dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence immediately following a quit attempt. PMID:26454838

  20. N-Acetylcysteine and Desferoxamine Reduce Pulmonary Oxidative Stress Caused by Hemorrhagic Shock in a Porcine Model.

    PubMed

    Mani, Alexandra; Staikou, Chryssoula; Karmaniolou, Iosifina; Orfanos, Nikolaos; Mylonas, Anastassios; Nomikos, Tzortzis; Pafiti, Agathi; Papalois, Apostolos; Arkadopoulos, Nikolaos; Smyrniotis, Vassilios; Theodoraki, Kassiani

    2017-02-01

    To investigate the pulmonary oxidative stress and possible protective effect of N-Acetylcysteine (NAC) and Desferoxamine (DFX)in a porcine model subjected to hemorrhagic shock. Twenty-one pigs were randomly allocated to Group-A (sham, n = 5), Group-B (fluid resuscitation, n = 8) and Group-C (fluid, NAC and DFX resuscitation, n = 8). Groups B and C were subjected to a 40-min shock period induced by liver trauma, followed by a 60-min resuscitation period. During shock, the mean arterial pressure (MAP) was maintained at 30-40 mmHg. Resuscitation consisted of crystalloids (35 mL/kg) and colloids (18 mL/kg) targeting to MAP normalization (baseline values ± 10%). In addition, Group-C received pretreatment with NAC 200 mg/kg plus DFX 2 g as intravenous infusions. Thiobarbituric Acid Reactive Substances (TBARS), protein carbonyls and glutathione peroxidase (GPx) activity were determined in lung tissue homogenates. Also, histological examination of pulmonary tissue specimens was performed. TBARS were higher in Group-B than in Group-A or Group-C: 2.90 ± 0.47, 0.57 ± 0.10, 1.78 ± 0.47 pmol/μg protein, respectively (p < 0.05). Protein carbonyls content was higher in Group-B than in Group-A or Group-C: 3.22 ± 0.68, 0.89 ± 0.30, 1.95 ± 0.54 nmol/mg protein, respectively (p > 0.05). GPx activity did not differ significantly between the three groups (p > 0.05). Lung histology was improved in Group-C versus Group-B, with less alveolar collapse, interstitial edema and inflammation. NAC plus DFX prevented the increase of pulmonary oxidative stress markers and protein damage after resuscitated hemorrhagic shock and had beneficial effect on lung histology. NAC/DFX combination may be used in the multimodal treatment of hemorrhagic shock, since it may significantly prevent free radical injury in the lung.

  1. Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl L-arginine, and endothelin-1.

    PubMed

    Lawson, D L; Haught, W H; Mehta, P; Mehta, J L

    1996-09-01

    Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings

  2. N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy.

    PubMed

    Kim, Eun Chul; Meng, Huan; Jun, Albert S

    2014-10-01

    The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo(®) luminescent reagent. Two-month-old homozygous knock-in Col8a2(L450W/L450W) mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (p < 0.01). Corneal endothelial cell density (CD) was higher (p = 0.001) and percent polymegathism was lower (p = 0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. N-Acetylcysteine and Allopurinol Synergistically Enhance Cardiac Adiponectin Content and Reduce Myocardial Reperfusion Injury in Diabetic Rats

    PubMed Central

    Wang, Tingting; Qiao, Shigang; Lei, Shaoqing; Liu, Yanan; Ng, Kwok F. J.; Xu, Aimin; Lam, Karen S. L.; Irwin, Michael G.; Xia, Zhengyuan

    2011-01-01

    Background Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Methodology/Principal Findings Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. Conclusions/Significance NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated e

  4. Spray-dried mucoadhesives for intravesical drug delivery using N-acetylcysteine- and glutathione-glycol chitosan conjugates.

    PubMed

    Denora, Nunzio; Lopedota, Angela; Perrone, Mara; Laquintana, Valentino; Iacobazzi, Rosa M; Milella, Antonella; Fanizza, Elisabetta; Depalo, Nicoletta; Cutrignelli, Annalisa; Lopalco, Antonio; Franco, Massimo

    2016-10-01

    This work describes N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential platform useful to formulate micro-(MP) and nano-(NP) particles via spray-drying techniques. These conjugates are mucoadhesive over the range of urine pH, 5.0-7.0, which makes them advantageous for intravesical drug delivery and treatment of local bladder diseases. NAC- and GSH-GC conjugates were generated with a synthetic approach optimizing reaction times and purification in order to minimize the oxidation of thiol groups. In this way, the resulting amount of free thiol groups immobilized per gram of NAC- and GSH-GC conjugates was 6.3 and 3.6mmol, respectively. These polymers were completely characterized by molecular weight, surface sulfur content, solubility at different pH values, substitution and swelling degree. Mucoadhesion properties were evaluated in artificial urine by turbidimetric and zeta (ζ)-potential measurements demonstrating good mucoadhesion properties, in particular for NAC-GC at pH 5.0. Starting from the thiolated polymers, MP and NP were prepared using both the Büchi B-191 and Nano Büchi B-90 spray dryers, respectively. The resulting two formulations were evaluated for yield, size, oxidation of thiol groups and ex-vivo mucoadhesion. The new spray drying technique provided NP of suitable size (<1μm) for catheter administration, low degree of oxidation, and sufficient mucoadhesion property with 9% and 18% of GSH- and NAC-GC based NP retained on pig mucosa bladder after 3h of exposure, respectively. The aim of the present study was first to optimize the synthesis of NAC-GC and GSH-GC, and preserve the oxidation state of the thiol moieties by introducing several optimizations of the already reported synthetic procedures that increase the mucoadhesive properties and avoid pH-dependent aggregation. Second, starting from these optimized thiomers, we studied the feasibility of manufacturing MP and NP by spray

  5. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats

    PubMed Central

    da Silva, Karolline S.; Pinto, Paula R.; Fabre, Nelly T.; Gomes, Diego J.; Thieme, Karina; Okuda, Ligia S.; Iborra, Rodrigo T.; Freitas, Vanessa G.; Shimizu, Maria H. M.; Teodoro, Walcy R.; Marie, Suely K. N.; Woods, Tom; Brimble, Margaret A.; Pickford, Russell; Rye, Kerry-Anne; Okamoto, Maristela; Catanozi, Sergio; Correa-Giannela, Maria L.; Machado, Ubiratan F.; Passarelli, Marisa

    2017-01-01

    Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and

  6. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats.

    PubMed

    da Silva, Karolline S; Pinto, Paula R; Fabre, Nelly T; Gomes, Diego J; Thieme, Karina; Okuda, Ligia S; Iborra, Rodrigo T; Freitas, Vanessa G; Shimizu, Maria H M; Teodoro, Walcy R; Marie, Suely K N; Woods, Tom; Brimble, Margaret A; Pickford, Russell; Rye, Kerry-Anne; Okamoto, Maristela; Catanozi, Sergio; Correa-Giannela, Maria L; Machado, Ubiratan F; Passarelli, Marisa

    2017-01-01

    Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara . CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf , Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and

  7. Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.

    PubMed

    Kopke, Richard; Slade, Martin D; Jackson, Ronald; Hammill, Tanisha; Fausti, Stephen; Lonsbury-Martin, Brenda; Sanderson, Alicia; Dreisbach, Laura; Rabinowitz, Peter; Torre, Peter; Balough, Ben

    2015-05-01

    Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc

  8. Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: multicenter randomized clinical trial.

    PubMed

    Ahmadi, Farrokhlaga; Abbaszadeh, Mahsa; Razeghi, Effat; Maziar, Sima; Khoidaki, Simin Dashti; Najafi, Mohammad Taghi; Lessan-Pezeshki, Mahboob

    2017-04-01

    To investigate the efficacy and safety of oral N-acetylcysteine (NAC) for preserving residual renal function in patients undergoing hemodialysis. Randomized, multi-center, parallel-group, open-label clinical trial (Registration No. IRCT 2014071418482N1). 54 patients who have been undergoing hemodialysis for at least 3 months and had residual urine volume >100 ml/24 h were randomly allocated to NAC or no medication. Residual renal function evaluated by (1) estimated glomerular filtration rate (GFR), (2) 24 h urine volume, and (3) renal Kt/V. GFR and Kt/V was determined at baseline and after 3 months. 24 h urine volume was measured at baseline, after 1, 2, and 3 months. Intention-to-treat analysis was performed on 47 patients (NAC = 26, control = 21). GFR in patients receiving NAC improved, whereas in the control arm a decline of 1.0 ml/min/1.73 m 2 was recorded (3.59 vs. 2.11 ml/min/1.73 m 2 , effect size = 17.0 %, p = 0.004). For 24 h urine volume, the between-group difference after 1 month was significant (669 vs. 533 ml/24 h, effect size = 15.4 %, p = 0.004). After 3 months, 24 h urine volume in the NAC arm was on average 137 ml higher than in the control group, and the difference reached near significance (673 vs. 536 ml/24 h, p = 0.072). In the follow-up visit, Kt/V was higher in the NAC arm but the difference did not reach statistical significance (0.81 vs. 0.54, p = 0.152). Three months treatment with NAC appears to be effective in preserving renal function in patients undergoing hemodialysis and the medication is generally well-tolerated.

  9. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial.

    PubMed

    Berk, Michael; Dean, Olivia M; Cotton, Sue M; Jeavons, Susan; Tanious, Michelle; Kohlmann, Kristy; Hewitt, Karen; Moss, Kirsteen; Allwang, Christine; Schapkaitz, Ian; Robbins, Jenny; Cobb, Heidi; Ng, Felicity; Dodd, Seetal; Bush, Ashley I; Malhi, Gin S

    2014-06-01

    Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression. Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011. The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F₁,₅₂₀.₉ = 1.98, P = .067), and the groups did not separate at week 12 (t₃₆₀.₃ = -1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score ≥ 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t₂₂₁.₀₃ = -2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events. Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by

  10. The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial.

    PubMed

    Skvarc, David R; Dean, Olivia M; Byrne, Linda K; Gray, Laura J; Ives, Kathryn; Lane, Stephen E; Lewis, Matthew; Osborne, Cameron; Page, Richard; Stupart, Douglas; Turner, Alyna; Berk, Michael; Marriott, Andrew J

    2016-08-09

    Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting. This is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress. The PANACEA trial aims to examine

  11. Effect of N-acetylcysteine combined with infliximab on toxic epidermal necrolysis. A proof-of-concept study.

    PubMed

    Paquet, Philippe; Jennes, Serge; Rousseau, Anne Françoise; Libon, Florence; Delvenne, Philippe; Piérard, Gérald E

    2014-12-01

    The pathophysiology of toxic epidermal necrolysis (TEN) is thought to be related to a drug-induced oxidative stress combined with TNFα overexpression by keratinocytes. None of the current treatments for TEN including systemic corticosteroids, cyclosporine and intravenous administration of immunoglobulins has proven superior over supportive care only. A total of 10 TEN patients were enrolled to be treated at admission in burn units with the antioxidant N-acetylcysteine [NAC, 150mg/kg in a 20-h intravenous (IV) administration], or the combination of the same IV NAC perfusion with the anti-TNFα antibody infliximab (Remicade(®)), administered at a 5mg/kg dosage as a single 2-h IV administration. TEN was confirmed by a skin biopsy taken from a bullous lesion. At entry in the trial and 48h later, the illness auxiliary score (IAS) of clinical severity was determined and the extent in altered skin area (erythema and blisters) was assessed as a relative body area. Skin biopsies of both clinically uninvolved and erythematous areas were collected and immunohistochemistry was performed for assessing the density of inflammatory cells (CD8+ T cells, CD68+ macrophages) and keratinocytes enriched in intracellular calcium (Ca(++)) identified by the Mac387 anti-calprotectin antibody. No unexpected drug-induced adverse event was noticed. After 48h of both treatment modalities, improvements were not observed in the extent of skin involvement and in IAS. Immunohistopathology showed the absence of reduction in the amount of intraepidermal inflammatory cells. An increased intracellular Ca(++) load in clinically uninvolved keratinocytes and in erythematous epidermis was noticed. This latter finding suggested the progression in the way of the apoptotic process. On burn unit discharge, the survival in each modality of treatment was not improved compared to the expected outcomes determined from the IAS at admission. In this proof-to-concept attempt, NAC treatment or its combination with

  12. N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats.

    PubMed

    Licks, Francielli; Hartmann, Renata Minuzzo; Marques, Camila; Schemitt, Elizângela; Colares, Josieli Raskopf; Soares, Mariana do Couto; Reys, Juliana; Fisher, Camila; da Silva, Juliana; Marroni, Norma Possa

    2015-11-21

    To evaluate the antioxidant effect of N-acetylcysteine (NAC) on the stomach of rats with portal hypertension. Twenty-four male Wistar rats weighing ± 250 g were divided into four experimental groups (n = 6 each): Sham-operated (SO), SO + NAC, partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC in a dose of 10 mg/kg (i.p.) diluted in 0.6 mL of saline solution was administered daily for 7 d starting 8 d after the surgery. Animals from the PPVL and SO group received saline solution (0.6 mL) for the same period of time as the PPVL + NAC and SO + NAC group. On the 15(th) day the animals were anesthetized and we evaluated portal pressure by cannulating mesenteric artery. After, we removed the stomach for further analysis. We performed immunohistochemical analysis for endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and nitrotirosine (NTT) proteins in stomach. We also evaluated eNOS and VEGF by Western blot analysis and assessed DNA damage in blood samples by the comet assay. The portal hypertension group exhibited increases in portal pressure when compared to SO group (29.8 ± 1.8 vs 12.0 ± 0.3 mmHg) (P < 0.001). The same was observed when we compared the eNOS (56.8 ± 3.7 vs 13.46 ± 2.8 pixels) (P < 0.001), VEGF (34.9 ± 4.7 vs 17.46 ± 2.6 pixels) (P < 0.05), and NTT (39.01 ± 4.0 vs 12.77 ± 2.3 pixels) (P < 0.05) expression by immunohistochemistry of the PPVL animals with the SO group. The expression of eNOS (0.39 ± 0.03 vs 0.25 ± 0.03 a.μ) (P < 0.01) and VEGF (0.38 ± 0.04 vs 0.26 ± 0.04 a.μ) (P < 0.01) were also evaluated by Western blot analysis, and we observed an increase of both proteins on PPVL animals. We also evaluated the DNA damage by comet assay, and observed an increase on damage index and damage frequency on those animals. NAC decreased portal pressure values in PPVL + NAC animals (16.46 ± 2 vs 29.8 ± 1.8 mmHg) (P < 0.001) when compared to PPVL. The expression of eNOS (14.60 ± 4.1 vs 56

  13. Effects of N-acetylcysteine and glutathione ethyl ester drops on streptozotocin-induced diabetic cataract in rats.

    PubMed

    Zhang, Shu; Chai, Fei-Yan; Yan, Hong; Guo, Yong; Harding, J J

    2008-05-12

    To evaluate the effect of N-acetylcysteine (NAC) and glutathione ethyl ester (GSH-EE) eye drops on the progression of diabetic cataract formation induced by streptozotocin (STZ). One hundred and thirty Sprague-Dawley (SD) rats were selected, and diabetes was induced by streptozotocin (65 mg/kg bodyweight) in a single intraperitoneal injection. The control group (group I) received only vehicle. Then, 78 rats with random blood glucose above 14 mmol/l were divided into four groups (group II-V). The drug-treated rats received NAC and GSH-EE eye drops five days before STZ injection. Group I and V animals received sodium phosphate buffer drops (pH 7.4), and those in groups II, III, and IV received 0.01% NAC, 0.05% NAC, and 0.1% GSH-EE drops, respectively. Lens transparency was monitored with a slit lamp biomicroscope and classified into six stages. At the end of four weeks, eight weeks, and 13 weeks, animals were killed and components involved in the pathogenesis of diabetic cataract including thiols (from glutathione and protein), glutathione reductase (GR), catalase (CAT), and glycated proteins were investigated in the lens extracts. Blood glucose, urine glucose, and bodyweight were also determined. The progression in lens opacity induced by diabetes showed a biphasic pattern in which an initial slow increase in the first seven weeks after STZ injection was followed by a rapid increase in the next six weeks. The progression of lens opacity in the treated groups (group II-IV) was slower than that of the untreated group (group V) in the earlier period and especially in the fourth week. There were statistically significant differences between the treated groups and the untreated group (p<0.05). However, these differences became insignificant after the sixth week, and the progression of lens opacification in all diabetic groups became aggravated. The content of thiol (from glutathione and protein), glutathione reductase (GR), and catalase (CAT) were lower in the lens

  14. Effect of N-acetylcysteine administration on the expression and activities of antioxidant enzymes and the malondialdehyde level in the blood of lead-exposed workers.

    PubMed

    Kasperczyk, Sławomir; Dobrakowski, Michał; Kasperczyk, Aleksandra; Machnik, Grzegorz; Birkner, Ewa

    2014-03-01

    We investigated whether treatment with N-acetylcysteine (NAC) reduces oxidative stress intensity and restores the expression and activities of superoxide dismutase (Sod1, SOD), catalase (Cat, CAT) and glutathione peroxidase (Gpx1, GPx) in lead-exposed workers. The exposed population was divided randomly into two groups. Workers in the first group (reference group, n=49) were not administered any drugs, while workers in the second group (n=122) were treated with NAC at three doses for 12 weeks (200 mg, 400 mg, 800 mg/day). NAC administered orally to lead-exposed workers normalized antioxidant enzyme activities in blood cells. Oxidative stress intensity measured as malondialdehyde (MDA) levels in serum, leukocytes and erythrocytes significantly decreased after NAC administration. NAC may be an alternative therapy for chronic lead intoxication. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Use of N-acetylcysteine plus simethicone to improve mucosal visibility during upper GI endoscopy: a double-blind, randomized controlled trial.

    PubMed

    Monrroy, Hugo; Vargas, Jose Ignacio; Glasinovic, Esteban; Candia, Roberto; Azúa, Emilio; Gálvez, Camila; Rojas, Camila; Cabrera, Natalia; Vidaurre, Josefa; Álvarez, Natalia; González, Jessica; Espino, Alberto; González, Robinson; Parra-Blanco, Adolfo

    2018-04-01

    Upper GI endoscopy (UGE) is essential for the diagnosis of gastrointestinal diseases. Mucus and bubbles may decrease mucosal visibility. The use of mucolytics could improve visualization. Our aim was to determine whether premedication with simethicone or simethicone plus N-acetylcysteine is effective in improving visibility during UGE. This was a randomized, double-blinded, placebo-controlled trial with 2 control groups: no intervention and water 100 mL (W); and 3 intervention groups: simethicone 200 mg (S); S + N-acetylcysteine (NAC) 500 mg (S+NAC500); and S + NAC 1000 mg (S+NAC1000). The solution was ingested 20 minutes before UGE. Gastric visibility was evaluated in 4 segments with a previously described scale. A score of less than 7 points was defined as adequate visibility (AV). Water volume was used to improve visibility, and adverse reactions were evaluated as a secondary outcome. Multiple group comparison was performed using non-parametric one-way analysis of variance (ANOVA). Two hundred thirty patients were included in the study, 68% female, mean age 49 years. The most common indication for UGE was epigastric pain/dyspepsia (33%). AV was more frequent in the S+NAC500 and S+NAC1000 groups (65% and 67%) compared with no intervention (44%, P = .044) and water (41%, P = .022). The gastric total visibility scale (TVS) was significantly better in the S+NAC500 and S+NAC1000 groups compared with water (P = .03 and P = .008). Simethicone was not different from no intervention and water. S+NAC1000 required less water volume to improve visibility. No adverse reactions from the study drugs were observed. Premedication with S+NAC500 and S+NAC1000 improves visibility during UGE. The use of simethicone did not show improvements in gastric visibility. TVS was worse in patients using water alone. (Clinical trial registration number: NCT 01653171.). Copyright © 2018 American Society for Gastrointestinal Endoscopy. All rights reserved.

  16. N-Acetylcysteine in the Treatment of Pediatric Trichotillomania: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial

    PubMed Central

    Bloch, Michael H.; Panza, Kaitlyn E.; Grant, Jon E.; Pittenger, Christopher; Leckman, James F.

    2013-01-01

    Objective To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. Method A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of hairpulling as measured by the Massachusetts General Hospital–Hairpulling Scale (MGH-HPS). Secondary measures assessed hairpulling severity, automatic versus focused pulling, clinician-rated improvement, and comorbid anxiety and depression. Outcomes were examined using linear mixed models to test the treatment × time interaction in an intention-to-treat population. Results No significant difference between N-acetylcysteine and placebo was found on any of the primary or secondary outcome measures. On several measures of hairpulling, subjects significantly improved with time regardless of treatment assignment. In the NAC group, 25% of subjects were judged as treatment responders, compared to 21% in the placebo group. Conclusions We observed no benefit of NAC for the treatment of children with trichotillomania. Our findings stand in contrast to a previous, similarly designed trial in adults with TTM, which demonstrated a very large, statistically significant benefit of NAC. Based on the differing results of NAC in pediatric and adult TTM populations, the assumption that pharmacological interventions demonstrated to be effective in adults with TTM will be as effective in children, may be inaccurate. This trial highlights the importance of referring children with TTM to appropriate behavioral therapy before initiating pharmacological interventions, as behavioral therapy has demonstrated efficacy in both children and adults with trichotillomania. PMID:23452680

  17. N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial.

    PubMed

    Bloch, Michael H; Panza, Kaitlyn E; Grant, Jon E; Pittenger, Christopher; Leckman, James F

    2013-03-01

    To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study. A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of hairpulling as measured by the Massachusetts General Hospital-Hairpulling Scale (MGH-HPS). Secondary measures assessed hairpulling severity, automatic versus focused pulling, clinician-rated improvement, and comorbid anxiety and depression. Outcomes were examined using linear mixed models to test the treatment×time interaction in an intention-to-treat population. No significant difference between N-acetylcysteine and placebo was found on any of the primary or secondary outcome measures. On several measures of hairpulling, subjects significantly improved with time regardless of treatment assignment. In the NAC group, 25% of subjects were judged as treatment responders, compared to 21% in the placebo group. We observed no benefit of NAC for the treatment of children with trichotillomania. Our findings stand in contrast to a previous, similarly designed trial in adults with TTM, which demonstrated a very large, statistically significant benefit of NAC. Based on the differing results of NAC in pediatric and adult TTM populations, the assumption that pharmacological interventions demonstrated to be effective in adults with TTM will be as effective in children, may be inaccurate. This trial highlights the importance of referring children with TTM to appropriate behavioral therapy before initiating pharmacological interventions, as behavioral therapy has demonstrated efficacy in both children and adults with trichotillomania. Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. A randomized controlled trial of pre-procedure simethicone and N-acetylcysteine to improve mucosal visibility during gastroscopy – NICEVIS

    PubMed Central

    Basford, Peter John; Brown, James; Gadeke, Lisa; Fogg, Carole; Haysom-Newport, Ben; Ogollah, Reuben; Bhattacharyya, Rupam; Longcroft-Wheaton, Gaius; Thursby-Pelham, Fergus; Neale, James R.; Bhandari, Pradeep

    2016-01-01

    Background and study aims: Mucosal views can be impaired by residual bubbles and mucus during gastroscopy. This study aimed to determine whether a pre-gastroscopy drink containing simethicone and N-acetylcysteine improves mucosal visualisation. Patients and methods: We conducted a randomized controlled trial recruiting 126 subjects undergoing routine gastroscopy. Subjects were randomized 1:1:1 to receive: A—pre-procedure drink of water, simethicone and N-acetylcysteine (NAC); B—water alone; or C—no preparation. Study endoscopists were blinded to group allocation. Digital images were taken at 4 locations (lower esophagus/upper gastric body/antrum/fundus), and rated for mucosal visibility (MV) using a 4-point scale (1 = best, 4 = worst) by 4 separate experienced endoscopists. The primary outcome measure was mean mucosal visibility score (MVS). Secondary outcome measures were procedure duration and volume of fluid flush required to achieve adequate mucosal views. Results: Mean MVS for Group A was significantly better than for Group B (1.35 vs 2.11, P < 0.001) and Group C (1.35 vs 2.21, P < 0.001). Mean flush volume required to achieve adequate mucosal views was significantly lower in Group A than Group B (2.0 mL vs 31.5 mL, P = 0.001) and Group C (2.0 mL vs 39.2 mL P < 0.001). Procedure duration did not differ significantly between any of the 3 groups. MV scores at each of the 4 locations demonstrated significantly better mucosal visibility in Group A compared to Group B and Group C (P < 0.0025 for all comparisons). Conclusions: A pre-procedure drink containing simethicone and NAC significantly improves mucosal visibility during gastroscopy and reduces the need for flushes during the procedure. Effectiveness in the lower esophagus demonstrates potential benefit in Barrett’s oesophagus surveillance gastroscopy. PMID:27853746

  19. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice.

    PubMed

    Farr, Susan A; Poon, H Fai; Dogrukol-Ak, Dilek; Drake, Jeniffer; Banks, William A; Eyerman, Edward; Butterfield, D Allan; Morley, John E

    2003-03-01

    Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

  20. Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice

    PubMed Central

    Korou, Laskarina-Maria; Agrogiannis, George; Koros, Christos; Kitraki, Efthimia; Vlachos, Ioannis S.; Tzanetakou, Irene; Karatzas, Theodore; Pergialiotis, Vasilios; Dimitroulis, Dimitrios; Perrea, Despina N.

    2014-01-01

    Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis. PMID:25348324

  1. Impact of combined C1 esterase inhibitor/coagulation factor XIII or N-acetylcysteine/tirilazad mesylate administration on leucocyte adherence and cytokine release in experimental endotoxaemia.

    PubMed

    Birnbaum, J; Klotz, E; Spies, C D; Mueller, J; Vargas Hein, O; Feller, J; Lehmann, C

    2008-01-01

    We determined the effects of combinations of C1 esterase inhibitor (C1-INH) with factor XIII and of N-acetylcysteine (NAC) with tirilazad mesylate (TM) during lipo-polysaccharide (LPS)-induced endotoxaemia in rats. Forty Wistar rats were divided into four groups: the control (CON) group received no LPS; the LPS, C1-INH + factor XIII and NAC + TM groups received endotoxin infusions (5 mg/kg per h). After 30 min of endotoxaemia, 100 U/kg C1-INH + 50 U/kg factor XIII was administered to the C1-INH + factor XIII group, and 150 mg/kg NAC + 10 mg/kg TM was administered in the NAC + TM group. Administration of C1-INH + factor XIII and NAC + TM both resulted in reduced leucocyte adherence and reduced levels of interleukin-1beta (IL-1beta). The LPS-induced increase in IL-6 levels was amplified by both drug combinations. There was no significant effect on mesenteric plasma extravasation. In conclusion, the administration of C1-INH + factor XIII and NAC + TM reduced endothelial leucocyte adherence and IL-1beta plasma levels, but increased IL-6 levels.

  2. The effect of L-cysteine and N-acetylcysteine on porphyrin/heme biosynthetic pathway in cells treated with 5-aminolevulinic acid and exposed to radiation.

    PubMed

    He, D; Behar, S; Roberts, J E; Lim, H W

    1996-10-01

    The effects of L-cysteine (LC) and N-acetylcysteine (NAC) on porphyrin accumulation in a human dermal microvascular endothelial cell line (HMEC-1) and a human epidermoid carcinoma cell line (A431) loaded with 5-aminolevulinic acid (ALA) and exposed to ultraviolet A (UVA) and blue light radiation were determined. Porphyrin accumulation was decreased in the presence of 0.1-7.5 mM LC (24.8%-31.4% suppression in HMEC-1 cell; 35.8%-48.9% suppression in A431 cells), and in the presence of 0.1-10.0 mM NAC (30.9%-58.0% suppression in HMEC-1 cells; 8.5%-45.3% in A431 cells). The suppression occurred in a LC or NAC dose-dependent fashion. The above was associated with partial reversal of suppression of ferrochelatase (FeC) activity in HMEC-1 cells and in A431 cells. As compared to FeC activity in cells treated with ALA and irradiation, enzyme activity was higher (by 31.9%-62.1%) in the presence of LC (1.0 mM or 5.0 mM) and in the presence of NAC (1.0 mM or 5.0 mM). These data indicate that LC and NAC have protective effects on porphyrin- and irradiation-induced diminution of FeC activity in HMEC-1 cells and A341 cells in vitro.

  3. Evaluating the Effect of Intracoronary N-Acetylcysteine on Platelet Activation Markers After Primary Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction.

    PubMed

    Eshraghi, Azadeh; Talasaz, Azita Hajhossein; Salamzadeh, Jamshid; Salarifar, Mojtaba; Pourhosseini, Hamidreza; Nozari, Yones; Bahremand, Mostafa; Jalali, Arash; Boroumand, Mohammad Ali

    2016-01-01

    During percutaneous coronary intervention (PCI), trauma occurs in the arterial endothelium, resulting in platelet activation and aggregation. As platelet aggregation may lead to coronary thrombosis, antiplatelet agents are essential adjunctive therapies in patients undergoing PCI. The aim of this study was to determine the effect of the intracoronary administration of high-dose N-acetylcysteine (NAC) for the evaluation of its antiplatelet effects in human subjects. In this triple-blind trial, 147 patients undergoing primary PCI were enrolled. Finally, 100 patients were randomized to receive high-dose intracoronary NAC (100 mg/kg bolus, followed by 10 mg·kg⁻¹·h⁻¹ intracoronary continued intravenously for 12 hours) (n = 50) or dextrose solution (n = 50). Platelet activation biomarkers were measured before and 24 hours after the procedure. Secondary end points, comprising all-cause death, reinfarction, and target-vessel revascularization, were assessed at 30 days and 2 years. In comparison with the placebo, NAC could not reduce the level of platelet activation biomarkers within a 24-hour period after its prescription. Major adverse clinical events at 30 days and 2 years were infrequent and not statistically different between the 2 groups. Our results revealed that NAC, compared with the placebo, did not provide an additional clinical benefit as an effective antiplatelet agent after PCI.

  4. HIV proteins (gp120 and Tat) and methamphetamine in oxidative stress-induced damage in the brain: Potential role of the thiol antioxidant N-acetylcysteine amide

    PubMed Central

    Banerjee, Atrayee; Zhang, Xinsheng; Manda, Kalyan Reddy; Banks, William A; Ercal, Nuran

    2010-01-01

    An increased risk of HIV-1 associated dementia (HAD) has been observed in patients abusing methamphetamine (METH). Since both HIV viral proteins (gp120, Tat) and METH induce oxidative stress, drug abusing patients are at a greater risk of oxidative stress-induced damage. The objective of this study was to determine if N-acetylcysteine amide (NACA) protects the blood brain barrier (BBB) from oxidative stress-induced damage in animals exposed to gp120, Tat and METH. To study this, CD-1 mice pre-treated with NACA/saline, received injections of gp120, Tat, gp120 + Tat or saline for 5 days, followed by three injections of METH/saline on the fifth day, and sacrificed 24 h after the final injection. Various oxidative stress parameters were measured, and animals treated with gp120+Tat+Meth were found to be the most challenged group, as indicated by their GSH and MDA levels. Treatment with NACA significantly rescued the animals from oxidative stress. Further, NACA-treated animals had significantly higher expression of TJ proteins and BBB permeability as compared to the group treated with gp120+Tat+METH alone, indicating that NACA can protect the BBB from oxidative stress-induced damage in gp120, Tat and METH exposed animals, and thus could be a viable therapeutic option for patients with HAD. PMID:20188164

  5. [Antagonistic effect of N-acetylcysteine on apoptosis of L-02 hepatocyte induced by Cr(VI) with or without caspase inhibitor].

    PubMed

    Chen, Jing; Zhong, Caigao; Zeng, Ming; Liu, Xinmin; Deng, Yuanyuan; Xiao, Fang

    2010-11-01

    To explore the antagonistic effect of N-acetylcysteine (NAC) on hexevalent chromium (Cr(VI))-induced apoptosis in L-02 hepatocytes with or without caspase inhibitors. L-02 hepatocytes were randomly divided into a control group, and Cr( VI), Z-VAD-fmk + Cr(VI), NAC + Cr(VI), Z-VAD-fmk + NAC + Cr (VI) four treatment groups, in which L-02 hepatocytes were cultured with Cr (VI) at the dose of 20 micromol/L for 6h. The rates of apoptosis in all groups were detected by flow cytometry (FC) after staining with propidium iodide (PI). The changes of mitochondrial membrane potential (deltapsim) and permeability transition pore (PTP) were determined by fluorescent spectrometer. The DNA damages in hepatocytes were observed by the single cell gel electrophoresis (SCGE). Cr(VI) significantly induced apoptosis of L-02 hepatocytes at the dose of 20 micromol/L for 6 hours (P < 0.05). However, NAC significantly decreased the rates of apoptosis of L-02 hepatocytes and alleviated the damages to mitochondria and DNA caused by Cr(VI) in L-02 hepatocytes with or without caspase (P < 0.05). However, in comparition with the non caspase-inhibited group, the protective effects of NAC decreased in the caspase-inhibited group (P < 0.05). NAC could protect the apoptosis of L-02 hepatocyte induced with Cr(VI) with or without caspase inhibitor, and caspase could not play a decisive role in this process.

  6. N-acetylcysteine improves redox status, mitochondrial dysfunction, mucin-depleted crypts and epithelial hyperplasia in dextran sulfate sodium-induced oxidative colitis in mice.

    PubMed

    Amrouche-Mekkioui, Ilhem; Djerdjouri, Bahia

    2012-09-15

    The effect of N-acetylcysteine (NAC), a pharmacological antioxidant was investigated in a murine model of chronic colitis. Male NMRI mice were given 5% dextran sulfate sodium (DSS) in drinking water for 5 days followed by 10 days of water, three times. Compared to control mice given water, DSS-treated mice displayed severe imbalanced redox status with decreased glutathione and catalase, but increased malondialdehyde, protein carbonyls, nitric oxide and myeloperoxidase levels, at days 35th (active colitis) and 45th (recovery period). It also resulted in mitochondrial dysfunction, mucosal ulcers, mucin-depleted crypts and epithelial cell apoptosis. Crypt abscesses and glandular hyperplasia occurred selectively in distal colon. NAC (150 mg/kg) given in drinking water for 45 days along with 3 DSS cycles improved the hallmarks of DSS-colitis. Interestingly, the moderate impact of NAC on lipids and proteins oxidation correlated with myeloperoxidase and nitric oxide levels.NAC as a mucoregulator and a thiol restoring agent is protective on oxidative crypt alterations, mucin depletion, epithelial cell hyperplasia and apoptosis. Taken together, our results highlight the role of NAC as a scavenger of phagocytes-derived reactive oxygen species in mice DDS-colitis, suggesting that a long term NAC diet might be beneficial in inflammatory bowel diseases and colorectal cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: changes in urinary pyrroles levels and motor activity performance.

    PubMed

    Torres, M Edite; dos Santos, A P Marreilha; Gonçalves, Luísa L; Andrade, Vanda; Batoréu, M Camila; Mateus, M Luísa

    2014-11-01

    The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC-MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC. Wistar rats were treated with 4 doses of: 400mg 2,5-HD/kg bw (group I), 400mg 2,5-HD/kg bw+200mg NAC/kg bw (group II), 200mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p<0.01) in urinary DMPN and free 2,5-HD, a significant increase (p<0.01) in DMPN NAC excretion, and a significant recovery (p<0.01) on motor activity in rats co-exposed to 2,5-HD+NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome.

    PubMed

    Maged, Ahmed M; Elsawah, Heba; Abdelhafez, Aly; Bakry, Ahmed; Mostafa, Walaa Ai

    2015-01-01

    To assess the adjuvant effect of metformin and N-acetylcysteine (NAC) to clomiphene citrate (CC) in induction of ovulation in Polycystic Ovary Syndrome (PCOS) patients. 120 women with PCOS were randomly divided into three equal groups: group I received CC only, group II received CC plus NAC and group III received CC plus metformin. There was a significant difference between group II and other two groups regarding average number of ovulatory follicles >18 mm (2.25 versus 1.75 and 1.89, respectively), but no significant difference between the three study groups regarding number of intermediate follicles 14-18 mm (4, 10 and 4, respectively). There was no significant difference between the three study groups regarding occurrence and laterality of ovulation, pregnancy rate per cycle but a significant difference between group II and other two groups regarding pregnancy rate per patient (20% versus 10% and 10%, respectively, p value 0.05). There was a highly statistically significant difference between group II and other two groups regarding peak endometrial thickness (7.3 ± 1.1 versus 5.4 ± 0.6 and 5.3 ± 0.6, respectively). NAC as an adjuvant to CC for induction of ovulation improves ovulation and pregnancy rates in PCOS patients with beneficial impacts on endometrial thickness.

  9. Effects of guaifenesin, N-acetylcysteine, and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells.

    PubMed

    Seagrave, Jeanclare; Albrecht, Helmut H; Hill, David B; Rogers, Duncan F; Solomon, Gail

    2012-10-31

    Therapeutic intervention in the pathophysiology of airway mucus hypersecretion is clinically important. Several types of drugs are available with different possible modes of action. We examined the effects of guaifenesin (GGE), N-acetylcysteine (NAC) and ambroxol (Amb) on differentiated human airway epithelial cells stimulated with IL-13 to produce additional MUC5AC. After IL-13 pre-treatment (3 days), the cultures were treated with GGE, NAC or Amb (10-300 μM) in the continued presence of IL-13. Cellular and secreted MUC5AC, mucociliary transport rates (MTR), mucus rheology at several time points, and the antioxidant capacity of the drugs were assessed. IL-13 increased MUC5AC content (~25%) and secretion (~2-fold) and decreased MTR, but only slightly affected the G' (elastic) or G" (viscous) moduli of the secretions. GGE significantly inhibited MUC5AC secretion and content in the IL-13-treated cells in a concentration-dependent manner (IC50s at 24 hr ~100 and 150 μM, respectively). NAC or Amb were less effective. All drugs increased MTR and decreased G' and G" relative to IL-13 alone. Cell viability was not affected and only NAC exhibited antioxidant capacity. Thus, GGE effectively reduces cellular content and secretion of MUC5AC, increases MTR, and alters mucus rheology, and may therefore be useful in treating airway mucus hypersecretion and mucostasis in airway diseases.

  10. Preclinical High-Dose Acetaminophen With N-Acetylcysteine Rescue Enhances the Efficacy of Cisplatin Chemotherapy in Atypical Teratoid Rhabdoid Tumors

    PubMed Central

    Neuwelt, Alexander J.; Nguyen, Tam; Wu, Y. Jeffrey; Donson, Andrew M.; Vibhakar, Rajeev; Venkatamaran, Sujatha; Amani, Vladimir; Neuwelt, Edward A.; Rapkin, Louis B.; Foreman, Nicholas K.

    2016-01-01

    Background Atypical teratoid rhabdoid tumors (AT-RT) are pediatric tumors of the central nervous system with limited treatment options and poor survival rate. We investigated whether enhancing chemotherapy toxicity by depleting intracellular glutathione (GSH; a key molecule in cisplatin resistance) with high dose acetaminophen (AAP), may improve therapeutic efficacy in AT-RT in vitro. Procedure BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidant N-acetylcysteine (NAC). Cell viability, GSH and peroxide concentrations, mitochondrial damage, and apoptosis were evaluated in vitro. Results AAP enhanced cisplatin cytotoxicity in cisplatin-resistant BT16 cells but not cisplatin-sensitive BT12 cells. Baseline GSH levels were elevated in BT16 cells compared to BT12 cells, and AAP decreased GSH to a greater magnitude in BT16 cells than BT12 cells. Unlike BT12 cells, BT16 cells did not have elevated peroxide levels upon treatment with cisplatin alone, but did have elevated levels when treated with AAP + cisplatin. Both cell lines had markedly increased mitochondrial injury when treated with AAP + cisplatin relative to either drug treatment alone. The enhanced toxic effects were partially reversed with concurrent administration of NAC. Conclusions Our results suggest that AAP could be used as a chemo-enhancement agent to potentiate cisplatin chemotherapeutic efficacy particularly in cisplatin-resistant AT-RT tumors with high GSH levels in clinical settings. PMID:23956023

  11. Effects of guaifenesin, N-acetylcysteine, and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells

    PubMed Central

    2012-01-01

    Background Therapeutic intervention in the pathophysiology of airway mucus hypersecretion is clinically important. Several types of drugs are available with different possible modes of action. We examined the effects of guaifenesin (GGE), N-acetylcysteine (NAC) and ambroxol (Amb) on differentiated human airway epithelial cells stimulated with IL-13 to produce additional MUC5AC. Methods After IL-13 pre-treatment (3 days), the cultures were treated with GGE, NAC or Amb (10–300 μM) in the continued presence of IL-13. Cellular and secreted MUC5AC, mucociliary transport rates (MTR), mucus rheology at several time points, and the antioxidant capacity of the drugs were assessed. Results IL-13 increased MUC5AC content (~25%) and secretion (~2-fold) and decreased MTR, but only slightly affected the G’ (elastic) or G” (viscous) moduli of the secretions. GGE significantly inhibited MUC5AC secretion and content in the IL-13-treated cells in a concentration-dependent manner (IC50s at 24 hr ~100 and 150 μM, respectively). NAC or Amb were less effective. All drugs increased MTR and decreased G’ and G” relative to IL-13 alone. Cell viability was not affected and only NAC exhibited antioxidant capacity. Conclusions Thus, GGE effectively reduces cellular content and secretion of MUC5AC, increases MTR, and alters mucus rheology, and may therefore be useful in treating airway mucus hypersecretion and mucostasis in airway diseases. PMID:23113953

  12. Application of novel Ni(II) complex and ZrO2 nanoparticle as mediators for electrocatalytic determination of N-acetylcysteine in drug samples.

    PubMed

    Karimi-Maleh, Hassan; Salehi, Mehdi; Faghani, Fatemeh

    2017-10-01

    The electrooxidation of N-acetylcysteine (N-AC) was studied by a novel Ni(II) complex modified ZrO 2 nanoparticle carbon paste electrode [Ni(II)/ZrO 2 /NPs/CPE] using voltammetric methods. The results showed that Ni(II)/ZrO 2 /NPs/CPE had high electrocatalytic activity for the electrooxidation of N-AC in aqueous buffer solution (pH = 7.0). The electrocatalytic oxidation peak currents increase linearly with N-AC concentrations over the concentration ranges of 0.05-600μM using square wave voltammetric methods. The detection limit for N-AC was equal to 0.009μM. The catalytic reaction rate constant, k h , was calculated (7.01 × 10 2  M -1  s -1 ) using the chronoamperometry method. Finally, Ni(II)/ZrO 2 /NPs/CPE was also examined as an ultrasensitive electrochemical sensor for the determination of N-AC in real samples such as tablet and urine. Copyright © 2017. Published by Elsevier B.V.

  13. Individual and combined effects of Fusarium toxins on apoptosis in PK15 cells and the protective role of N-acetylcysteine.

    PubMed

    Zhang, Wei; Zhang, Shihua; Zhang, Meiling; Yang, Lige; Cheng, Baojing; Li, Jianping; Shan, Anshan

    2018-01-01

    Deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B 1 (FB 1 ) are among the most toxicologically important Fusarium toxins commonly found in nature that lead to nephrotoxicity in animals. The present study investigated that the individual and combined effects of subcytotoxic DON (0.25 μM), ZEN (20 μM) and FB 1 (10 μM) on oxidative stress and apoptosis in porcine kidney cells (PK15). In addition, the protective effect of N-acetylcysteine (NAC) against the toxicity of Fusarium toxins was also evaluated. Our results showed that the activities of glutathione reductase (GR) and total superoxide dismutase (SOD) were affected by DON, ZEN and FB 1 , and this change in activity induced reactive oxygen species (ROS) and malondialdehyde (MDA) production, increased apoptosis and regulated the mRNA expression of Bax, Bcl-2, caspase-3, caspase-9, cytochrome c (cyto c) and P53. This study demonstrated the complexity of combined mycotoxin infection since the combination of toxins exhibited more profound defects in the oxidative stress responses and apoptosis. Moreover, NAC reduced the oxidative damage and inhibited the apoptosis induced by Fusarium toxins. It was concluded that oxidative damage and apoptosis through the mitochondria-dependent channel were the mechanisms of Fusarium toxin mediated toxicity, and NAC reversed these damages to some extent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. High post-natal mortality associated with defects in lung maturation and reduced adiposity in mice with gestational exposure to high fat and N-acetylcysteine.

    PubMed

    Williams, Lyda; Charron, Maureen J; Sellers, Rani S

    2017-10-01

    Studies have demonstrated that maternal consumption of a high fat diet (HFD) increases offspring susceptibility to metabolic disease. This study was initiated to identify the mechanistic contribution of oxidative stress on this phenomenon. Two weeks prior to mating, dams were fed either HFD or Control diet with or without supplementation with the anti-oxidant N-acetylcysteine (NAC). Pups born to HFD dams had reduced crown rump length (CRL) at birth and higher neonatal mortality compared to pups from Control dams. Supplementation with NAC normalized CRL in pups from HFD dams, but notably increased mortality. Histological examination of the lungs postnatally and prenatally, revealed normal branching morphogenesis but delayed alveolarization in pups from dams fed HFD+NAC. Discontinuation of NAC at ED17.5 with re-introduction at PD3 improved offspring survival and lung maturation. Additionally, interscapular brown adipose tissue (BAT) was reduced in ED18.5 embryos from HFD dams. These findings suggest that increased mortality in offspring from dams fed HFD+NAC during pregnancy may in part be the result of delayed pulmonary alveolarization and decreased BAT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. N-acetylcysteine a possible protector against indomethacin-induced peptic ulcer: crosstalk between antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

    PubMed

    Soliman, Nema Ali; Zineldeen, Doaa Hussein; Katary, Mohamed Alaa; Ali, Darin Abd

    2017-04-01

    This study investigated the gastroprotective effects of N-acetylcysteine (NAC) against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg). 50 male albino rats were allocated into 5 equal groups: control group received normal saline orally, indomethacin group rats received normal saline orally for 5 days and indomethacin (50 mg/kg) on the last day, ranitidine group received ranitidine (reference drug) orally for 5 days (50 mg/kg) before receiving indomethacin (50 mg/kg) on the last day, and NAC groups received NAC orally at 300 and 500 mg/kg, respectively, for 5 days before receiving indomethacin (50 mg/kg) on the last day. Gastric tissue interleukin-1β (IL-1β), interferon-γ (IFN-γ), and caspase-3 levels were immunoassayed. Total thiol (T-SH), myeloperoxidase (MPO), and glucose-6-phosphate dehydrogenase (G6PD) were determined by spectrophotometry. Cytokine-induced neutrophil chemoattractant 2α (CINC-2α) gene expression was evaluated in addition to Bcl-2 immunohistochemistry. Pretreatment with NAC improved the inflammatory, apoptotic, and redox status in a dose-dependent manner particularly in NAC 500 mg/kg pretreated group. These results show a role for NAC in improving indomethacin-induced gastric ulceration via antioxidative, antiapoptotic, and anti-inflammatory interactive mechanisms.

  16. Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats.

    PubMed

    Arent, Camila O; Réus, Gislaine Z; Abelaira, Helena M; Ribeiro, Karine F; Steckert, Amanda V; Mina, Francielle; Dal-Pizzol, Felipe; Quevedo, João

    2012-12-01

    A growing body of evidence has pointed to a relationship between oxidative stress and depression. Thus, the present study was aimed at evaluating the effects of the antioxidants n-acetylcysteine (NAC), deferoxamine (DFX) or their combination on sweet food consumption and oxidative stress parameters in rats submitted to 40days of exposure to chronic mild stress (CMS). Our results showed that in stressed rats treated with saline, there was a decrease in sweet food intake and treatment with NAC or NAC in combination with DFX reversed this effect. Treatment with NAC and DFX decreased the oxidative damage, which include superoxide and TBARS production in submitochondrial particles, and also thiobarbituric acid reactive substances (TBARS) levels and carbonyl proteins in the prefrontal cortex, amygdala and hippocampus. Treatment with NAC and DFX also increased the activity of the antioxidant enzymes, superoxide dismutase and catalase in the same brain areas. Even so, a combined treatment with NAC and DFX produced a stronger increase of antioxidant activities in the prefrontal cortex, amygdala and hippocampus. The results described here indicate that co-administration may induce a more pronounced antidepressant activity than each treatment alone. In conclusion, these results suggests that treatment with NAC or DFX alone or in combination on oxidative stress parameters could have positive effects against neuronal damage caused by oxidative stress in major depressive disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity.

    PubMed

    Gibson, Kyle R; Neilson, Ilene L; Barrett, Fiona; Winterburn, Tim J; Sharma, Sushma; MacRury, Sandra M; Megson, Ian L

    2009-10-01

    N-Acetylcysteine (NAC) is a frequently used "antioxidant" in vitro, but the concentrations applied rarely correlate with those encountered with oral dosing in vivo. Here, we investigated the in vitro antioxidant and antiplatelet properties of NAC at concentrations (10-100 microM) that are achievable in plasma with tolerable oral dosing. The impact of NAC pretreatment (2 hours) on aggregation of platelets from healthy volunteers in response to thrombin and adenosine diphosphate and on platelet-derived nitric oxide (NO) was examined. NAC was found to be a weak reducing agent and a poor antioxidant compared with glutathione (reduced form) (GSH). However, platelets treated with NAC showed enhanced antioxidant activity and depression of reactive oxygen species generation associated with increases in intraplatelet GSH levels. An approximately 2-fold increase in NO synthase-derived nitrite was observed with 10 microM NAC treatment, but the effect was not concentration dependent. Finally, NAC significantly reduced both thrombin-induced and adenosine diphosphate-induced platelet aggregation. NAC should be considered a weak antioxidant that requires prior conversion to GSH to convey antioxidant and antithrombotic benefit at therapeutically relevant concentrations. Our results suggest that NAC might be an effective antiplatelet agent in conditions where increased oxidative stress contributes to heightened risk of thrombosis but only if the intraplatelet machinery to convert it to GSH is functional.

  18. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder.

    PubMed

    Berk, Michael; Dodd, Seetal; Dean, Olivia M; Kohlmann, Kristy; Berk, Lesley; Malhi, Gin S

    2010-10-01

    Berk M, Dodd S, Dean OM, Kohlmann K, Berk L, Malhi GS. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder. The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder. The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75). A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750). The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.

  19. Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats.

    PubMed

    Xia, Zhengyuan; Nagareddy, Prabhakara R; Guo, Zhixin; Zhang, Wei; McNeill, John H

    2006-02-01

    Increased oxidative stress and reduced nitric oxide (NO) bioactivity are key features of diabetes mellitus that eventually result in cardiovascular abnormalities. We assessed whether N-acetylcysteine (NAC), an antioxidant and glutathione precursor, could prevent the hyperglycaemia induced increase in oxidative stress, restore NO availability and prevent depression of arterial blood pressure and heart rate in vivo in experimental diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were treated or not treated with NAC in drinking water for 8 weeks, initiated 1 week after induction of diabetes. At termination, plasma levels of free 15-F2t-isoprostane, a specific marker of oxygen free radical induced lipid peroxidation, was increased while the plasma total antioxidant concentration was decreased in untreated diabetic rats as compared to control rats (P<0.05). This was accompanied by a significant reduction of plasma levels of nitrate and nitrite, stable metabolites of NO, (P<0.05, D vs. C) and a reduced endothelial NO synthase protein expression in the heart and in aortic and mesenteric artery tissues. Systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP) and heart rate (HR) were reduced in diabetic rats (P<0.05 vs. C) and NAC normalised the changes that occurred in the diabetic rats. The protective effects may be attributable to restoration of NO bioavailability in the circulation.

  20. Role of reactive oxygen intermediates in the interferon-mediated depression of hepatic drug metabolism and protective effect of N-acetylcysteine in mice.

    PubMed

    Ghezzi, P; Bianchi, M; Gianera, L; Landolfo, S; Salmona, M

    1985-08-01

    Interferon (IFN) and IFN inducers are known to depress hepatic microsomal cytochrome P-450 levels, and the liver toxicity of IFN was reported to be lethal in newborn mice. We have observed that administration to mice of IFN and IFN inducers caused a marked increase in liver xanthine oxidase activity. Because this enzyme is well known to produce reactive oxygen intermediates and cytochrome P-450 was reported to be sensitive to the oxidative damage, we have tested the hypothesis that a free radical mechanism could mediate the depression of cytochrome P-450 levels by IFN. Administration to mice of the IFN inducer polyinosinic-polycytidylic acid (2 mg/kg i.p.) caused a 29 to 52% decrease in liver cytochrome P-450. Concomitant p.o. administration of the free radical scavenger, N-acetylcysteine (as a 2.5% solution in drinking water), or the xanthine oxidase inhibitor, allopurinol (100 mg/kg), protected against the IFN-mediated depression of P-450 kg), protected against the IFN-mediated depression of P-450 levels. The results suggest that an increased endogenous generation of free radicals, possibly due to the induction of xanthine oxidase, is implicated in the IFN-mediated depression of liver drug metabolism. The relevance of these data also extends to cases in which this side effect is observed in pathological situations (e.g., viral diseases and administration of vaccines) associated with an induction of IFN.

  1. N-acetylcysteine fails to modulate the in vitro function of sarcoplasmic reticulum of diaphragm in the final phase of fatigue.

    PubMed

    Mishima, T; Yamada, T; Matsunaga, S; Wada, M

    2005-07-01

    In the present study, we tested the hypothesis whether N-acetylcysteine (NAC), a non-specific antioxidant, might influence fatigue by modulating Ca2+-handling capacity by the sarcoplasmic reticulum (SR). In the presence (10 mm) or absence of NAC, bundles of rat diaphragm were stimulated with tetanic trains (350 ms, 30-40 Hz) at 1 train every 2 s for 300 s. SR functions, as assessed by SR Ca2+-uptake and release rates and SR Ca2+-ATPase activity, were measured in vitro on muscle homogenates. Following the 300-s stimulation, the force developed by NAC-treated muscles is approximately 1.8-fold higher (P < 0.05) than that of muscles without NAC treatment. Stimulation elicited an 18-30% depression in SR function (P < 0.05). Despite the differing degrees of fatigue between NAC-treated and non-treated muscles, SR functions in these muscles were reduced to similar extents. These results suggest that modulation of SR function measured in vitro may not be a major contributor to inhibition of diaphragmic fatigue with antioxidant, at least, in the final phase of fatigue where force output is remarkably reduced.

  2. N-acetylcysteine supplementation controls total antioxidant capacity, creatine kinase, lactate, and tumor necrotic factor-alpha against oxidative stress induced by graded exercise in sedentary men.

    PubMed

    Leelarungrayub, Donrawee; Khansuwan, Raphiphat; Pothongsunun, Prapas; Klaphajone, Jakkrit

    2011-01-01

    Aim of this study was to evaluate the effects of short-term (7 days) N-acetylcysteine (NAC) at 1,200 mg daily supplementation on muscle fatigue, maximal oxygen uptake (VO(2max)), total antioxidant capacity (TAC), lactate, creatine kinase (CK), and tumor necrotic factor-alpha (TNF-α). Twenty-nine sedentary men (13 controls; 16 in the supplement group) from a randomized control were included. At before and after supplementation, fatigue index (FI) was evaluated in the quadriceps muscle, and performed a graded exercise treadmill test to induce oxidative stress, and as a measure of VO(2max). Blood samples were taken before exercise and 20 minutes after it at before and after supplementation, to determine TAC, CK, lactate, and TNF-α levels. Results showed that FI and VO(2max) increased significantly in the supplement group. After exercise decreased the levels of TAC and increased lactate, CK, and TNF-α of both groups at before supplementation. After supplementation, lactate, CK, and TNF-α levels significantly increased and TAC decreased after exercise in the control group. Whereas the TAC and lactate levels did not change significantly, but CK and TNF-α increased significantly in the supplement group. Therefore, this results showed that NAC improved the muscle fatigue, VO(2max), maintained TAC, controlled lactate production, but had no influence on CK and TNF-α.

  3. Colonic and Hepatic Modulation by Lipoic Acid and/or N-Acetylcysteine Supplementation in Mild Ulcerative Colitis Induced by Dextran Sodium Sulfate in Rats

    PubMed Central

    Moura, Fabiana Andréa; de Andrade, Kívia Queiroz; de Araújo, Orlando Roberto Pimentel; Santos, Juliana Célia de Farias

    2016-01-01

    Lipoic acid (LA) and N-acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg·kg·day−1, each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex®). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H2O2), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H2O2, tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage. PMID:27957238

  4. Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice

    PubMed Central

    Durieux, Alice M. S.; Fernandes, Cathy; Murphy, Declan; Labouesse, Marie Anais; Giovanoli, Sandra; Meyer, Urs; Li, Qi; So, Po-Wah; McAlonan, Grainne

    2015-01-01

    An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span. PMID:26696857

  5. The effects of N-acetylcysteine and epigallocatechin-3-gallate on liver tissue protein oxidation and antioxidant enzyme levels after the exposure to radiofrequency radiation.

    PubMed

    Ozgur, Elcin; Sahin, Duygu; Tomruk, Arin; Guler, Goknur; Sepici Dinçel, Aylin; Altan, Nilgun; Seyhan, Nesrin

    2015-02-01

    The widespread and sustained use of mobile and cordless phones causes unprecedented increase of radiofrequency radiation (RFR). The aim of this experimental study was to investigate the effect of 900 MHz Global System for Mobile Communications (GSM)-modulated RFR (average whole body Specific Absorption Rate (SAR) of 0.4 W/kg, 10 or 20 min daily for consecutive 7 days) to the liver tissue of guinea pigs and the protective effects of antioxidant treatments. Adult male guinea pigs were randomly divided into nine groups as: Group I (sham/saline), Group II (sham/EGCG), Group III (sham/NAC), Group IV (10-min RF-exposure/saline), Group V (20-min RF-exposure/saline), Group VI (10-min RF-exposure/EGCG), Group VII (20-min RF-exposure/EGCG), Group VIII (10-min RF-exposure/NAC), and Group IX (20-min RF-exposure/NAC). Protein oxidation (PCO), advanced oxidation protein products (AOPP) and antioxidant enzyme activities of superoxide dismutase (SOD) were evaluated after the exposure and the treatments with N-acetylcysteine (NAC) and (-)-epigallocatechin-3-gallate (EGCG). Significant decreases in the activities of SOD were observed in the liver of guinea pigs after RFR exposure. Protein damage did not change due to RFR exposure. On the other hand, only NAC treatment induced increased PCO levels, whereas EGCG treatment alone elevated the level of AOPP. Due to antioxidants having pro-oxidant behavior, the well decided doses and treatment timetables of NAC and ECGC are needed.

  6. Effect of N-acetylcysteine supplementation on oxidative stress status and alveolar inflammation in people exposed to asbestos: a double-blind, randomized clinical trial.

    PubMed

    Alfonso, Helman; Franklin, Peter; Ching, Simon; Croft, Kevin; Burcham, Phil; Olsen, Nola; Reid, Alison; Joyce, David; de Klerk, Nick; Musk, Aw Bill

    2015-10-01

    Many of the pathological consequences in the lung following inhalation of asbestos fibres arise as a consequence of persistent oxidative stress and inflammation. Inflammatory responses can be observed in asymptomatic asbestos-exposed individuals. There are currently no interventions to reduce inflammatory or oxidative responses to asbestos before disease develops. We investigated the effects of oral N-acetylcysteine (NAC) on indicators of inflammation or oxidative stress in asymptomatic people previously exposed to asbestos. A double-blind, randomized, placebo-controlled study was conducted to assess the effectiveness and safety of 1800 mg of NAC given orally over a period of 4 months. This was a proof of principle study. Effectiveness was assessed using indicators of inflammation or oxidation as primary end-points. Serum levels of total combined thiols (cysteine, cysteinylglycine, glutathione and homocysteine) were used to monitor the NAC supplementation. Thirty-four subjects were randomly allocated to NAC and 32 to placebo. Serum levels of total combined thiols were similar between the groups after intervention. There were no differences in levels of inflammatory or oxidative stress end-points between the groups. No adverse effects were identified. No evidence was found that NAC supplementation replenishes total combined thiols in the blood of healthy subjects with a history of asbestos exposure. There was also no evidence of reduced indicators of inflammation or oxidative stress. Further studies should determine the conditions required to increase levels of total anti-oxidant capacity in the blood and in the lungs of subjects with either asbestos-related diseases or subclinical lung inflammation. © 2015 Asian Pacific Society of Respirology.

  7. The effect of N-acetylcysteine on the incidence of contrast-induced kidney injury: A systematic review and trial sequential analysis.

    PubMed

    Wang, Nelson; Qian, Pierre; Kumar, Shejil; Yan, Tristan D; Phan, Kevin

    2016-04-15

    There have been a myriad of studies investigating the effectiveness of N-acetylcysteine (NAC) in the prevention of contrast induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) with or without percutaneous coronary intervention (PCI). However the consensus is still out about the effectiveness of NAC pre-treatment due to vastly mixed results amongst the literature. The aim of this study was to conduct a meta-analysis and trial sequential analysis to determine the effects of pre-operative NAC in lowering the incidence of CIN in patients undergoing CAG and/or PCI. A systematic literature search was performed to include all randomized controlled trials (RCTs) comparing NAC versus control as pretreatment for CAG and/or PCI. A traditional meta-analysis and several subgroup analyses were conducted using traditional meta-analysis with relative risk (RR), trial sequential analysis, and meta-regression analysis. 43 RCTs met our inclusion criteria giving a total of 3277 patients in both control and treatment arms. There was a significant reduction in the risk of CIN in the NAC treated group compared to control (OR 0.666; 95% CI, 0.532-0.834; I2=40.11%; p=0.004). Trial sequential analysis, using a relative risk reduction threshold of 15%, indicates that the evidence is firm. The results of the present paper support the use of NAC in the prevention of CIN in patients undergoing CAG±PCI. Future studies should focus on the benefits of NAC amongst subgroups of high-risk patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. N-Acetylcysteine-induced vasodilatation is modulated by KATP channels, Na+/K+-ATPase activity and intracellular calcium concentration: An in vitro study.

    PubMed

    Vezir, Özden; Çömelekoğlu, Ülkü; Sucu, Nehir; Yalın, Ali Erdinç; Yılmaz, Şakir Necat; Yalın, Serap; Söğüt, Fatma; Yaman, Selma; Kibar, Kezban; Akkapulu, Merih; Koç, Meryem İlkay; Seçer, Didem

    2017-08-01

    In this study, we aimed to investigate the role of ATP-sensitive potassium (K ATP ) channel, Na + /K + -ATPase activity, and intracellular calcium levels on the vasodilatory effect of N-acetylcysteine (NAC) in thoracic aorta by using electrophysiological and molecular techniques. Rat thoracic aorta ring preparations and cultured thoracic aorta cells were divided into four groups as control, 2mM NAC, 5mM NAC, and 10mM NAC. Thoracic aorta rings were isolated from rats for measurements of relaxation responses and Na + /K + -ATPase activity. In the cultured thoracic aorta cells, we measured the currents of K ATP channel, the concentration of intracellular calcium and mRNA expression level of K ATP channel subunits (KCNJ8, KCNJ11, ABCC8 and ABCC9). The relaxation rate significantly increased in all NAC groups compared to control. Similarly, Na + /K + - ATPase activity also significantly decreased in NAC groups. Outward K ATP channel current significantly increased in all NAC groups compared to the control group. Intracellular calcium concentration decreased significantly in all groups with compared control. mRNA expression level of ABCC8 subunit significantly increased in all NAC groups compared to the control group. Pearson correlation analysis showed that relaxation rate was significantly associated with K ATP current, intracellular calcium concentration, Na + /K + -ATPase activity and mRNA expression level of ABCC8 subunit. Our findings suggest that NAC relaxes vascular smooth muscle cells through a direct effect on K ATP channels, by increasing outward K+ flux, partly by increasing mRNA expression of K ATP subunit ABCC8, by decreasing in intracellular calcium and by decreasing in Na + /K + -ATPase activity. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  9. N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway

    PubMed Central

    Xia, Yujing; Dai, Weiqi; Wang, Fan; Shen, Miao; Cheng, Ping; Wang, Junshan; Lu, Jie; Zhang, Yan; Yang, Jing; Zhu, Rong; Zhang, Huawei; Li, Jingjing; Zheng, Yuanyuan; Zhou, Yingqun; Guo, Chuanyong

    2014-01-01

    Background Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved. Methods A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM). Results We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice. Conclusion NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2. PMID:25264893

  10. Ameliorative Effects of Dimetylthiourea and N-Acetylcysteine on Nanoparticles Induced Cyto-Genotoxicity in Human Lung Cancer Cells-A549

    PubMed Central

    Srivastava, Ritesh Kumar; Rahman, Qamar; Kashyap, Mahendra Pratap; Lohani, Mohtashim; Pant, Aditya Bhushan

    2011-01-01

    We study the ameliorative potential of dimetylthiourea (DMTU), an OH• radical trapper and N-acetylcysteine (NAC), a glutathione precursor/H2O2 scavenger against titanium dioxide nanoparticles (TiO2-NPs) and multi-walled carbon nanotubes (MWCNTs) induced cyto-genotoxicity in cultured human lung cancer cells-A549. Cytogenotoxicity was induced by exposing the cells to selected concentrations (10 and 50 µg/ml) of either of TiO2-NPs or MWCNTs for 24 h. Anti-cytogenotoxicity effects of DMTU and NAC were studied in two groups, i.e., treatment of 30 minutes prior to toxic insult (short term exposure), while the other group received DMTU and NAC treatment during nanoparticles exposure, i.e., 24 h (long term exposure). Investigations were carried out for cell viability, generation of reactive oxygen species (ROS), micronuclei (MN), and expression of markers of oxidative stress (HSP27, CYP2E1), genotoxicity (P53) and CYP2E1 dependent n- nitrosodimethylamine-demethylase (NDMA-d) activity. In general, the treatment of both DMTU and NAC was found to be effective significantly against TiO2-NPs and MWCNTs induced cytogenotoxicity in A549 cells. Long-term treatment of DMTU and NAC during toxic insults has shown better prevention than short-term pretreatment. Although, cells responded significantly to both DMTU and NAC, but responses were chemical specific. In part, TiO2-NPs induced toxic responses were mediated through OH• radicals generation and reduction in the antioxidant defense system. While in the case of MWCNTs, adverse effects were primarily due to altering/hampering the enzymatic antioxidant system. Data indicate the applicability of human lung cancer cells-A549 as a pre-screening tool to identify the target specific prophylactic and therapeutic potential of drugs candidate molecules against nanoparticles induced cellular damages. PMID:21980536

  11. High concentration of antioxidants N-acetylcysteine and mitoquinone-Q induces intercellular adhesion molecule 1 and oxidative stress by increasing intracellular glutathione.

    PubMed

    Mukherjee, Tapan K; Mishra, Anurag K; Mukhopadhyay, Srirupa; Hoidal, John R

    2007-02-01

    In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF-alpha-induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-alpha. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IkappaB kinase (IKK), a phosphorylation-dependent regulator of NF-kappaB, plays an important regulatory role in the TNF-alpha-mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKKalpha and IKKbeta), low concentrations of NAC and mito-Q activated IKKalpha activity, thereby inhibiting the downstream NF-kappaB and ICAM-1 induction by TNF-alpha. High concentrations of NAC and mito-Q instead caused glutathionylation of IKKalpha, thereby inhibiting its activity that in turn enhanced the downstream NF-kappaB activation and ICAM-1 expression by TNF-alpha. Thus, establishing IKKalpha as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKKalpha activity, and up-regulation of ICAM-1expression.

  12. Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine

    SciTech Connect

    Molina-Jimenez, Maria Francisca; Sanchez-Reus, Maria Isabel; Cascales, Maria

    2005-12-15

    Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Recently, it has been shown that fraxetin (coumarin) and myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced by rotenone, increase the total glutathione levels in vitro, and inhibit lipid peroxidation. Thus, these considerations prompted us to investigate the way in which fraxetin and myricetin affect the endogenous antioxidant defense system, such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a comparative agent. Also,more » the expression and protein levels of HSP70 by Northern and Western blot analysis were assayed in SH-SY5Y cells. After incubation for 16 h, rotenone significantly increased the expression and activity of MnSOD, GPx, and catalase. When cells were preincubated with fraxetin, there was a decrease in the protein levels and activity of both MnSOD and catalase, in comparison with the rotenone treatment. The myricetin effect was less pronounced. Activity and expression of GPx were increased by rotenone and pre-treatment with fraxetin did not modify significantly these levels. The significant enhancement in HSP70 expression at mRNA and protein levels induced by fraxetin was observed by pre-treatment of cells 0.5 h before rotenone insult. These data suggest that major features of rotenone-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that fraxetin partially protects against rotenone toxicity affecting the main protection system of the cells against oxidative injury.« less

  13. Chlorambucil (nitrogen mustard) induced impairment of early vascular endothelial cell migration - effects of α-linolenic acid and N-acetylcysteine.

    PubMed

    Steinritz, Dirk; Schmidt, Annette; Simons, Thilo; Ibrahim, Marwa; Morguet, Christian; Balszuweit, Frank; Thiermann, Horst; Kehe, Kai; Bloch, Wilhelm; Bölck, Birgit

    2014-08-05

    Alkylating agents (e.g. sulfur and nitrogen mustards) cause a variety of cell and tissue damage including wound healing disorder. Migration of endothelial cells is of utmost importance for effective wound healing. In this study we investigated the effects of chlorambucil (a nitrogen mustard) on early endothelial cells (EEC) with special focus on cell migration. Chlorambucil significantly inhibited migration of EEC in Boyden chamber and wound healing experiments. Cell migration is linked to cytoskeletal organization. We therefore investigated the distribution pattern of the Golgi apparatus as a marker of cell polarity. Cells are polarized under control conditions, whereas chlorambucil caused an encircling perinuclear position of the Golgi apparatus, indicating non-polarized cells. ROS are discussed to be involved in the pathophysiology of alkylating substances and are linked to cell migration and cell polarity. Therefore we investigated the influence of ROS-scavengers (α-linolenic acid (ALA) and N-acetylcysteine (NAC)) on the impaired EEC migration. Both substances, in particular ALA, improved EEC migration. Notably ALA restored cell polarity. Remarkably, investigations of ROS and RNS biomarkers (8-isoprostane and nitrotyrosine) did not reveal a significant increase after chlorambucil exposure when assessed 24h post exposure. A distinct breakdown of mitochondrial membrane potential (measured by TMRM) that recovered under ALA treatment was observed. In conclusion our results provide compelling evidence that the alkylating agent chlorambucil dramatically impairs directed cellular migration, which is accompanied by perturbations of cell polarity and mitochondrial membrane potential. ALA treatment was able to reconstitute cell polarity and to stabilize mitochondrial potential resulting in improved cell migration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation

    PubMed Central

    Rocksén, D; Lilliehöök, B; Larsson, R; Johansson, T; Bucht, A

    2000-01-01

    Inhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1α, IL-1β, IL-6, IL-12p40, and MIP-1α mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed. PMID:11091282

  15. Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease.

    PubMed

    Yilmaz, Hale; Sahin, Sinan; Sayar, Nurten; Tangurek, Burak; Yilmaz, Mehmet; Nurkalem, Zekeriya; Onturk, Ebru; Cakmak, Nazmiye; Bolca, Osman

    2007-12-01

    Hyperhomocysteinaemia is related with premature coronary artery disease and adverse cardiac events in patients with coronary artery disease (CAD). It is assumed that hyper-homocysteinaemia causes endothelial dysfunction. In this study, the effect of folic acid and oral N-acetylcysteine (NAC) therapies on plasma homocysteine levels and endothelial function were evaluated in hyperhomocysteinaemic patients with CAD. 60 patients were randomized to either folic acid 5 mg or NAC 600 mg or placebo daily for eight weeks. Brachial artery endothelial functions were studied by using high-resolution ultrasound and assessed by measuring endothelium-dependent dilation (EDD) and endothelium-independent dilation (NEDD). Folic acid and NAC therapies decreased plasma homocysteine (from 21.7 +/- 8.7 micromol/l to 12.5 +/- 2.5 micromol/l, P < 0.001; from 20.9 +/- 7.6 micromol/l to 15.6 +/- 4.3 micromol/l, P = 0.03, respectively), and increased EDD (6.7 +/- 6.1% P = 0.002, 4.4 +/- 2.6% P < 0.001, respectively) compared with placebo. There was no significant difference in improving EDD between the folic acid and the NAC group (6.7 +/- 6.1%, 4.4 +/- 2.6%, P = 0. 168). In the univariate analyses there was an inverse correlation between the post-treatment homocysteine level and the percent change in EDD with folic acid therapy (r= -0.490, P = 0.028), but there was no correlation with the NAC therapy (r = 0.259, P = 0.333) In patients with hyperhomocysteinaemic CAD, folic acid and NAC lowered plasma homocysteine levels and improved endothelial function. The effects of both treatments in improvement of EDD were similar.

  16. Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase.

    PubMed

    Sury, Matthias D; Frese-Schaper, Manuela; Mühlemann, Miranda K; Schulthess, Fabienne T; Blasig, Ingolf E; Täuber, Martin G; Shaw, Sidney G; Christen, Stephan

    2006-11-01

    N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation.

  17. Potentiation of lead-induced cell death in PC12 cells by glutamate: Protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant

    SciTech Connect

    Penugonda, Suman; Mare, Suneetha; Lutz, P.

    2006-10-15

    Oxidative stress has been implicated as an important factor in many neurological diseases. Oxidative toxicity in a number of these conditions is induced by excessive glutamate release and subsequent glutamatergic neuronal stimulation. This, in turn, causes increased generation of reactive oxygen species (ROS), oxidative stress, excitotoxicity, and neuronal damage. Recent studies indicate that the glutamatergic neurotransmitter system is involved in lead-induced neurotoxicity. Therefore, this study aimed to (1) investigate the potential effects of glutamate on lead-induced PC12 cell death and (2) elucidate whether the novel thiol antioxidant N-acetylcysteine amide (NACA) had any protective abilities against such cytotoxicity. Our results suggestmore » that glutamate (1 mM) potentiates lead-induced cytotoxicity by increased generation of ROS, decreased proliferation (MTS), decreased glutathione (GSH) levels, and depletion of cellular adenosine-triphosphate (ATP). Consistent with its ability to decrease ATP levels and induce cell death, lead also increased caspase-3 activity, an effect potentiated by glutamate. Exposure to glutamate and lead elevated the cellular malondialdehyde (MDA) levels and phospholipase-A{sub 2} (PLA{sub 2}) activity and diminished the glutamine synthetase (GS) activity. NACA protected PC12 cells from the cytotoxic effects of glutamate plus lead, as evaluated by MTS assay. NACA reduced the decrease in the cellular ATP levels and restored the intracellular GSH levels. The increased levels of ROS and MDA in glutamate-lead treated cells were significantly decreased by NACA. In conclusion, our data showed that glutamate potentiated the effects of lead-induced PC12 cell death by a mechanism involving mitochondrial dysfunction (ATP depletion) and oxidative stress. NACA had a protective role against the combined toxic effects of glutamate and lead by inhibiting lipid peroxidation and scavenging ROS, thus preserving intracellular GSH.« less

  18. Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes.

    PubMed

    Martina, Valentino; Masha, Andi; Gigliardi, Valentina Ramella; Brocato, Loredana; Manzato, Enzo; Berchio, Arrigo; Massarenti, Paola; Settanni, Fabio; Della Casa, Lara; Bergamini, Stefania; Iannone, Anna

    2008-05-01

    Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation. A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months. The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed. NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.

  19. N-acetylcysteine is able to reduce the oxidation status and the endothelial activation after a high-glucose content meal in patients with Type 2 diabetes mellitus.

    PubMed

    Masha, A; Brocato, L; Dinatale, S; Mascia, C; Biasi, F; Martina, V

    2009-04-01

    Post-prandial hyperglycemia seems to play a pivotal role in the pathogenesis of the cardiovascular complications of diabetes mellitus, as it leads to an oxidative stress which in turn causes a reduced NO bioavailability. These conditions produce an endothelial activation. The aim of this study was to assure that the administration of N-acetylcysteine (NAC), thiolic antioxidant, is able to decrease the oxidation status and endothelial activation after a high-glucose content meal. Ten patients with Type 2 diabetes mellitus (DMT2) (Group 1) and 10 normal subjects (Group 2) were studied. They assumed a high-glucose content meal without (phase A) or after (phase B) the administration of NAC. Glycemia, insulinemia, intercellular adhesion molecule 1, vascular adhesion molecule 1 (VCAM-1), E-selectin, malonaldehyde (MDA), and 4-hydroxynonenal (HNE) were assessed at -30, 0, +30, +60, +90, +120, and +180 min with respect to the meal consumption. During the phase A in Group 1, only HNE and MDA levels increased after the meal assumption; all parameters remained unchanged in Group 2. During the phase B, in Group 1, HNE, MDA, VCAM-1, and E-selectin levels after the meal were lower than those in phase A, while no change for all variables were observed in Group 2. A high-glucose meal produces an increase in oxidation parameters in patients with DMT2. The administration of NAC reduces the oxidative stress and, by doing so, reduces the endothelial activation. In conclusion, NAC could be efficacious in the slackening of the progression of vascular damage in DMT2.

  20. Double-blinded, randomized controlled trial of N-acetylcysteine for prevention of acute kidney injury in high risk patients undergoing off-pump coronary artery bypass.

    PubMed

    Song, Jong Wook; Shim, Jae Kwang; Soh, Sarah; Jang, Jaewon; Kwak, Young Lan

    2015-02-01

    The aim of this study was to investigate the influence of perioperative N-acetylcysteine (NAC) administration, a known antioxidant, on the incidence of acute kidney injury (AKI) after off-pump coronary bypass surgery (OPCAB) in patients with known risk factors of AKI. One hundred and seventeen patients with ≥1 of the following risk factors of AKI were randomized into either the control (n = 57) or the NAC (n = 60) group; (i) preoperative serum creatinine >1.4 mg/dL; (ii) left ventricular ejection fraction <35% or congestive heart failure (iii) age >70 years (iv) diabetes or (v) re-operation. Patients in the NAC group received 150 mg/kg of NAC IV bolus at anaesthetic induction followed by a continuous infusion at 150 mg/kg per day for 24 h. AKI was diagnosed based on Acute Kidney Injury Network criteria during 48 h postoperatively. The incidence of AKI was 32% (19/60) and 35% (20/57) in the control and the NAC group, respectively (P = 0.695). The serum concentrations of creatinine and cystatin C were similar between the groups throughout the study period. Fluid balance including the amount of blood loss and transfusion requirement were similar between the groups except the amount of postoperative urine output, which was higher in the control group compared with the NAC group (5528 ± 1247 mL vs. 4982 ± 1185 mL, control vs. NAC, P = 0.017). Perioperative administration of NAC did not prevent the development of postoperative AKI after OPCAB in highly susceptible patients to AKI. © 2014 Asian Pacific Society of Nephrology.

  1. N-Acetylcysteine added to volume expansion with sodium bicarbonate does not further prevent contrast-induced nephropathy: results from the cardiac angiography in renally impaired patients study.

    PubMed

    Staniloae, Cezar S; Doucet, Serge; Sharma, Samin K; Katholi, Richard E; Mody, Kanika R; Coppola, John T; Solomon, Richard

    2009-06-01

    We reviewed data from the multicenter CARE (Cardiac Angiography in Renally Impaired Patients) study to see if benefit could be shown for N-acetylcysteine (NAC) in patients undergoing cardiac angiography who all received intravenous bicarbonate fluid expansion. Four hundred fourteen patients with moderate-to-severe chronic kidney disease were randomized to receive intra-arterial administration of iopamidol-370 or iodixanol-320. All patients were prehydrated with isotonic sodium bicarbonate solution. Each site chose whether or not to administer NAC 1,200 mg twice daily to all patients. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2-5 days after receiving contrast. The primary outcome was a postdose SCr increase 0.5 mg/dL (44.2 mumol/L) over baseline. Secondary outcomes were a postdose SCr increase 25% and the mean peak change in SCr. The NAC group received significantly less hydration (892 +/- 236 mL vs. 1016 +/- 328 mL; P < 0.001) and more contrast volume (146 +/- 74 mL vs. 127 +/- 71 mL; P = 0.009) compared with no-NAC group. SCr increases 0.5 mg/dL occurred in 4.2% (7 of 168 patients) in NAC group and 6.5% (16 of 246 patients) in no-NAC group (P = 0.38); rates of SCr increases 25% were 11.9% and 10.6%, respectively (P = 0.75); mean post-SCr increases were 0.07 mg/dL in NAC group versus 0.11 mg/dL in no-NAC group (P = 0.14). In conclusion, addition of NAC to fluid expansion with sodium bicarbonate failed to reduce the rate of contrast-induced nephropathy (CIN) after the intra-arterial administration of iopamidol or iodixanol to high-risk patients with chronic kidney disease.

  2. Ex Vivo and in Vivo Evaluation of the Effect of Coating a Coumarin-6-Labeled Nanostructured Lipid Carrier with Chitosan-N-acetylcysteine on Rabbit Ocular Distribution.

    PubMed

    Liu, Dandan; Li, Jinyu; Cheng, Bingchao; Wu, Qingyin; Pan, Hao

    2017-08-07

    This study is focused on further understanding the characteristics of chitosan-N-acetylcysteine surface-modified nanostructured lipid carriers (CS-NAC-NLCs) in their interaction with ocular mucosa. Coumarin-6 (C6)-labeled NLCs, including uncoated NLCs, chitosan hydrochloride (CH)-, and CS-NAC-coated NLCs, were developed using a melt-emulsification technique and subsequently decorated with different types or portions of chitosan derivatives. Mucoadhesion was evaluated ex vivo using a flow-through process with fluorescence detection. The results demonstrated that the presence of CS-NAC on the C6-NLC surface provided the most obvious enhancement in adhesion due to the formation of both noncovalent (ionic) and covalent (disulfide bridges) interactions with mucus chains. Meanwhile, the concentration of CS-NAC in the formulation positively influenced the viscosity of the nanoparticles and hence prolonged their retention in the ocular tissue. Transcorneal penetration studies revealed that CS-NAC-NLC particles were able to penetrate through the entire corneal epithelium primarily via a transcellular route. The transport depth and velocity strongly relied on the modification material and the particle size. Ex vivo fluorescence imaging and in vivo ocular distribution investigations showed that C6 was broadly distributed in rabbit eye tissues and absorbed by aqueous humor after CS-NAC-NLC instillation. In relation to C6 eye drops, CS-NAC-NLCs achieved considerably higher C max (4.01-fold), MRT 0-∞ (1.87-fold), and AUC 0-∞ (16.29-fold) in the aqueous humor. Moreover, the increase in drug absorption was greater in the cornea than in the conjunctiva. Thereby, it is possible to draw a conclusion that CS-NAC-NLCs presented great potential for drug application to the front portion of the eye.

  3. N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis

    PubMed Central

    Conus, Philippe; Seidman, Larry J; Fournier, Margot; Xin, Lijing; Cleusix, Martine; Baumann, Philipp S; Ferrari, Carina; Cousins, Ann; Alameda, Luis; Gholam-Rezaee, Mehdi; Golay, Philippe; Jenni, Raoul; Woo, T -U Wilson; Keshavan, Matcheri S; Eap, Chin B; Wojcik, Joanne; Cuenod, Michel; Buclin, Thierry; Gruetter, Rolf

    2018-01-01

    Abstract Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment. PMID:29462456

  4. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

    PubMed Central

    Hanczko, Robert; Fernandez, David R.; Doherty, Edward; Qian, Yueming; Vas, Gyorgy; Niland, Brian; Telarico, Tiffany; Garba, Adinoyi; Banerjee, Sanjay; Middleton, Frank A.; Barrett, Donna; Barcza, Maureen; Banki, Katalin; Landas, Steve K.; Perl, Andras

    2009-01-01

    Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1–/– and Taldo1+/– mice spontaneously developed HCC, and Taldo1–/– mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1–/– livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1–/– livers reflected adaptation to oxidative stress. Taldo1–/– hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1–/– mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency. PMID:19436114

  5. Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage

    PubMed Central

    de Bragança, Ana C.; Moreau, Regina L. M.; de Brito, Thales; Shimizu, Maria H. M.; Canale, Daniele; de Jesus, Denise A.; Silva, Ana M. G.; Gois, Pedro H.; Seguro, Antonio C.

    2017-01-01

    Background Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used. Methods Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.). Results Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo. Conclusion Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia. PMID:28678861

  6. A Controlled, Randomized Double-Blind Study to Evaluate the Safety and Efficacy of Chitosan-N-Acetylcysteine for the Treatment of Dry Eye Syndrome.

    PubMed

    Schmidl, Doreen; Werkmeister, René; Kaya, Semira; Unterhuber, Angelika; Witkowska, Katarzyna J; Baumgartner, Renate; Höller, Sonja; O'Rourke, Maria; Peterson, Ward; Wolter, Annika; Prinz, Martin; Schmetterer, Leopold; Garhöfer, Gerhard

    2017-06-01

    This study was designed to evaluate the effect of chitosan-N-acetylcysteine (C-NAC) eye drops on tear film thickness (TFT) in patients with dry eye syndrome (DES). This was a controlled, randomized, double-blind clinical investigation with patients assigned to 2 cohorts. In Cohort I, 21 patients were randomized to receive 1 instillation of C-NAC eye drops in 1 eye and placebo (normal saline solution) in the contralateral eye. In Cohort II, 17 patients were randomized to receive C-NAC eye drops once (QD) or twice (BID) daily for 5 days. TFT was assessed with a custom-built ultrahigh-resolution optical coherence tomography system. In Cohort I, mean TFT increased from 3.9 ± 0.5 μm predose to 4.8 ± 1.1 μm 10 min postdose after treatment with C-NAC. The increase was significantly different from placebo over time (P < 0.0001) and remained stable until 24 h postdose. In Cohort II, TFT increased with QD and BID instillation, with no significant difference between regimens. In both groups, Ocular Surface Disease Index scores improved, fewer patients presented with corneal damage, and symptoms of ocular discomfort/conjunctival redness were reduced. A single instillation of C-NAC significantly increased mean TFT in patients with DES as early as 10 min after instillation and lasted for 24 h. The magnitude of the increase in TFT following a single instillation was comparable with that after instillation twice daily over 5 days. Corneal damage improved in >60% of patients. C-NAC could be a viable treatment option for DES.

  7. N-acetylcysteine in agriculture, a novel use for an old molecule: focus on controlling the plant-pathogen Xylella fastidiosa.

    PubMed

    Muranaka, Lígia S; Giorgiano, Thais E; Takita, Marco A; Forim, Moacir R; Silva, Luis F C; Coletta-Filho, Helvécio D; Machado, Marcos A; de Souza, Alessandra A

    2013-01-01

    Xylella fastidiosa is a plant pathogen bacterium that causes diseases in many different crops. In citrus, it causes Citrus Variegated Chlorosis (CVC). The mechanism of pathogenicity of this bacterium is associated with its capacity to colonize and form a biofilm in the xylem vessels of host plants, and there is not yet any method to directly reduce populations of this pathogen in the field. In this study, we investigated the inhibitory effect of N-Acetylcysteine (NAC), a cysteine analogue used mainly to treat human diseases, on X. fastidiosa in different experimental conditions. Concentrations of NAC over 1 mg/mL reduced bacterial adhesion to glass surfaces, biofilm formation and the amount of exopolysaccharides (EPS). The minimal inhibitory concentration of NAC was 6 mg/mL. NAC was supplied to X. fastidiosa-infected plants in hydroponics, fertigation, and adsorbed to organic fertilizer (NAC-Fertilizer). HPLC analysis indicated that plants absorbed NAC at concentrations of 0.48 and 2.4 mg/mL but not at 6 mg/mL. Sweet orange plants with CVC symptoms treated with NAC (0.48 and 2.4 mg/mL) in hydroponics showed clear symptom remission and reduction in bacterial population, as analyzed by quantitative PCR and bacterial isolation. Experiments using fertigation and NAC-Fertilizer were done to simulate a condition closer to that normally is used in the field. For both, significant symptom remission and a reduced bacterial growth rate were observed. Using NAC-Fertilizer the lag for resurgence of symptoms on leaves after interruption of the treatment increased to around eight months. This is the first report of the anti-bacterial effect of NAC against a phytopathogenic bacterium. The results obtained in this work together with the characteristics of this molecule indicate that the use of NAC in agriculture might be a new and sustainable strategy for controlling plant pathogenic bacteria.

  8. Calcium-dependent nitric oxide production is involved in the cytoprotective properties of n-acetylcysteine in glycochenodeoxycholic acid-induced cell death in hepatocytes

    SciTech Connect

    Gonzalez-Rubio, Sandra; Linares, Clara I.; Bello, Rosario I.

    The intracellular oxidative stress has been involved in bile acid-induced cell death in hepatocytes. Nitric oxide (NO) exerts cytoprotective properties in glycochenodeoxycholic acid (GCDCA)-treated hepatocytes. The study evaluated the involvement of Ca{sup 2+} on the regulation of NO synthase (NOS)-3 expression during N-acetylcysteine (NAC) cytoprotection against GCDCA-induced cell death in hepatocytes. The regulation of Ca{sup 2+} pools (EGTA or BAPTA-AM) and NO (L-NAME or NO donor) production was assessed during NAC cytoprotection in GCDCA-treated HepG2 cells. The stimulation of Ca{sup 2+} entrance was induced by A23187 in HepG2. Cell death, Ca{sup 2+} mobilization, NOS-1, -2 and -3 expression, AP-1 activation,more » and NO production were evaluated. GCDCA reduced intracellular Ca{sup 2+} concentration and NOS-3 expression, and enhanced cell death in HepG2. NO donor prevented, and L-NAME enhanced, GCDCA-induced cell death. The reduction of Ca{sup 2+} entry by EGTA, but not its release from intracellular stores by BAPTA-AM, enhanced cell death in GCDCA-treated cells. The stimulation of Ca{sup 2+} entrance by A23187 reduced cell death and enhanced NOS-3 expression in GCDCA-treated HepG2 cells. The cytoprotective properties of NAC were related to the recovery of intracellular Ca{sup 2+} concentration, NOS-3 expression and NO production induced by GCDCA-treated HepG2 cells. The increase of NO production by Ca{sup 2+}-dependent NOS-3 expression during NAC administration reduces cell death in GCDCA-treated hepatocytes.« less

  9. N-acetylcysteine and meso-2,3-dimercaptosuccinic acid alleviate oxidative stress and hepatic dysfunction induced by sodium arsenite in male rats.

    PubMed

    Abu El-Saad, Ahmed M; Al-Kahtani, Mohammed A; Abdel-Moneim, Ashraf M

    2016-01-01

    Environmental exposure to arsenic represents a serious challenge to humans and other animals. The aim of the present study was to test the protective effect of antioxidant N-acetylcysteine (NAC) either individually or in combination with a chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), against sodium arsenite oral toxicity in male rats. Five groups were used: control; arsenic group (orally administrated in a concentration of 2 mg/kg body weight [b.w.]); the other three groups were orally administrated sodium arsenite in a concentration of 2 mg/kg b.w. followed by either NAC (10 mg/kg b.w., intraperitoneally [i.p.]), DMSA (50 mg/kg b.w., i.p.) or NAC plus DMSA. Arsenic toxicity caused significant rise in serum aspartate aminotransferase, alanine aminotransferase and total bilirubin, and a significant decrease in total protein (TP) and albumin levels after 3 weeks of experimental period. In addition, arsenic-treated rats showed significantly higher arsenic content in liver and significant rise in hepatic malondialdehyde level. By contrast, sharp decreases in glutathione content and catalase and glutathione reductase activities were discernible. NAC and/or DMSA counteracted most of these physiologic and biochemical defects. NAC monotherapy was more effective than DMSA in increasing TP, while DMSA was more effective in decreasing alanine aminotransferase. The combined treatment was superior over monotherapies in recovery of TP and glutathione. Biochemical data were well supported by histopathological and ultrastructural findings. In conclusion, the combination therapy of NAC and DMSA may be an ideal choice against oxidative insult induced by arsenic poisoning.

  10. Activated carbon N-acetylcysteine microcapsule protects against nonalcoholic fatty liver disease in young rats via activating telomerase and inhibiting apoptosis

    PubMed Central

    Zhou, Hongping; Xi, Jianjun; Sun, Jingjing; Ke, Yunling; Zhang, Jiankang; Shao, Yidan; Jiang, Xiaojie; Pan, Xuwang; Liu, Shourong; Zhuang, Rangxiao

    2018-01-01

    Non-alcoholic fatty liver disease (NAFLD) is becoming one of the world's most common chronic liver diseases in childhood, yet no therapy is available that has been approved by the food and drug administration (FDA). Previous studies have reported that telomere and telomerase are involved the development and progression of NAFLD. This study was designed to investigate the potential beneficial effects of activated carbon N-acetylcysteine (ACNAC) microcapsules on the development of NAFLD in young rats as well as the underlying mechanism(s) involved. Three-week old male Sprague Dawley rats were given high-fat diet (HFD) with/without ACNAC treatment for 7 consecutive weeks. Liver pathologies were determined by hematoxylin and eosin (H&E) and Oil Red O staining, as well as by changes in biochemical parameters of plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, respectively. Glucose homeostasis was evaluated by the glucose tolerance test and the liver telomere length and activity were measured by real time PCR and telomeric repeat amplification protocol (TRAP). Western blot analysis was performed to determine the expression level of Bcl-2, Bax and Caspase-3. Our results demonstrated that ACNAC supplementation improved liver pathologies of rats that received long-term HFD feeding. ACNAC supplementation prevented HFD-induced telomere shortening and improved telomerase activity. Moreover, in comparison to HFD-fed rats, ACNAC supplementation markedly increased the expression of Bcl-2, but significantly decreased the expression of Bax and Caspase-3 in juvenile rats. Together, these results indicate that ACNAC may be a promising choice for preventing and treating NAFLD among children. PMID:29324774

  11. A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo.

    PubMed

    Cassidy, Pamela B; Liu, Tong; Florell, Scott R; Honeggar, Matthew; Leachman, Sancy A; Boucher, Kenneth M; Grossman, Douglas

    2017-01-01

    Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1-2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36-44. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

    PubMed Central

    Wright, D J; Renoir, T; Smith, Z M; Frazier, A E; Francis, P S; Thorburn, D R; McGee, S L; Hannan, A J; Gray, L J

    2015-01-01

    Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy. PMID:25562842

  13. Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder.

    PubMed

    Costa, Daniel L C; Diniz, Juliana B; Requena, Guaraci; Joaquim, Marinês A; Pittenger, Christopher; Bloch, Michael H; Miguel, Euripedes C; Shavitt, Roseli G

    2017-07-01

    To evaluate the efficacy of serotonin reuptake inhibitor (SRI) augmentation with N-acetylcysteine (NAC), a glutamate modulator and antioxidant medication, for treatment-resistant obsessive-compulsive disorder (OCD). We conducted a randomized, double-blind, placebo-controlled, 16-week trial of NAC (3,000 mg daily) in adults (aged 18-65 years) with treatment-resistant OCD, established according to DSM-IV criteria. Forty subjects were recruited at an OCD-specialized outpatient clinic at a tertiary hospital (May 2012-October 2014). The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores. To evaluate the variables group, time, and interaction effects for Y-BOCS scores at all time points, we used nonparametric analysis of variance with repeated measures. Secondary outcomes were the severity scores for anxiety, depression, specific OCD symptom dimensions, and insight. Both groups showed a significant reduction of baseline Y-BOCS scores at week 16: the NAC group had a reduction of 4.3 points (25.6 to 21.3), compared with 3.0 points (24.8 to 21.8) for the placebo group. However, there were no significant differences between groups (P = .92). Adding NAC was superior to placebo in reducing anxiety symptoms (P = .02), but not depression severity or specific OCD symptom dimensions. In general, NAC was well tolerated, despite abdominal pain being more frequently reported in the NAC group (n [%]: NAC = 9 [60.0], placebo = 2 [13.3]; P < .01). Our trial did not demonstrate a significant benefit of NAC in reducing OCD severity in treatment-resistant OCD adults. Secondary analysis suggested that NAC might have some benefit in reducing anxiety symptoms in treatment-resistant OCD patients. ClinicalTrials.gov identifier: NCT01555970. © Copyright 2017 Physicians Postgraduate Press, Inc.

  14. N-Acetylcysteine in the Treatment of Pediatric Tourette Syndrome: Randomized, Double-Blind, Placebo-Controlled Add-On Trial.

    PubMed

    Bloch, Michael H; Panza, Kaitlyn E; Yaffa, Alisa; Alvarenga, Pedro G; Jakubovski, Ewgeni; Mulqueen, Jilian M; Landeros-Weisenberger, Angeli; Leckman, James F

    2016-05-01

    Current pharmacological treatments for Tourette Syndrome (TS), such as antipsychotic agents and α-2 agonists, are moderately effective in the treatment of tics, but have substantial side effects that limit their use. N-acetylcysteine (NAC) modulates glutamatergic systems, and has been used safely as an antioxidant agent with minimal side effects for decades. NAC has been increasingly studied for the treatment of other obsessive-compulsive spectrum disorders. We aim to examine the efficacy of NAC for the treatment of pediatric TS in a double-blind, placebo-controlled, add-on study. Thirty-one children and adolescents 8-17 years of age with TS were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of tics as measured by the Yale Global Tic Severity Scale (YGTSS), Total tic score. Secondary measures assessed comorbid obsessive-compulsive disorder (OCD), depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD). Linear mixed models in SAS were used to examine differences between NAC and placebo. Of 31 randomized subjects, 14 were assigned to placebo (two females; 11.5 + 2.8 years) and 17 to active NAC (five females; 12.4 + 1.4 years) treatment. No significant difference between NAC and placebo was found in reducing tic severity or any secondary outcomes. We found no evidence for efficacy of NAC in treating tic symptoms. Our findings stand in contrast to studies suggesting benefits of NAC in the treatment of other obsessive-compulsive spectrum disorders in adults, including OCD and trichotillomania, but are similar to a recent placebo-controlled trial of pediatric trichotillomania that found no benefit of NAC.

  15. A phase II randomized placebo-controlled trial of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress in vivo

    PubMed Central

    Cassidy, Pamela B.; Liu, Tong; Florell, Scott R.; Honeggar, Matthew; Leachman, Sancy A.; Boucher, Kenneth M.; Grossman, Douglas

    2016-01-01

    Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1–2 MED) using a solar simulator. One day later, the MED was re-determined and the irradiated nevus and a control un-irradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared to unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and post-intervention MED between those patients receiving NAC vs. placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type vs. loss of function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 h before nevus irradiation. Thus a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. PMID:27920018

  16. Protective role of L-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in zebrafish.

    PubMed

    Wu, Chia-Yen; Lee, Han-Jung; Liu, Chi-Fang; Korivi, Mallikarjuna; Chen, Hwei-Hsien; Chan, Ming-Huan

    2015-03-01

    Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L-ascorbic acid, N-acetylcysteine (NAC) and apocynin on neomycin-induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1-43FX observed under a microscope. Co-administration with L-ascorbic acid, NAC and apocynin protected neomycin-induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the neuromasts were labeled with specific fluorescent dye Texas-red conjugated with neomycin to detect neomycin uptake. Interestingly, the uptake of neomycin into hair cells was not influenced by these three antioxidant compounds. These data imply that prevention of hair cell damage against neomycin by L-ascorbic acid, NAC and apocynin might be associated with inhibition of excessive ROS production, but not related to modulating neomycin uptake. Our findings conclude that L-ascorbic acid, NAC and apocynin could be used as therapeutic drugs to protect aminoglycoside-induced listening impairment after further confirmatory studies. Copyright © 2014 John Wiley & Sons, Ltd.

  17. N-Acetylcysteine in Agriculture, a Novel Use for an Old Molecule: Focus on Controlling the Plant–Pathogen Xylella fastidiosa

    PubMed Central

    Muranaka, Lígia S.; Giorgiano, Thais E.; Takita, Marco A.; Forim, Moacir R.; Silva, Luis F. C.; Coletta-Filho, Helvécio D.; Machado, Marcos A.; de Souza, Alessandra A.

    2013-01-01

    Xylella fastidiosa is a plant pathogen bacterium that causes diseases in many different crops. In citrus, it causes Citrus Variegated Chlorosis (CVC). The mechanism of pathogenicity of this bacterium is associated with its capacity to colonize and form a biofilm in the xylem vessels of host plants, and there is not yet any method to directly reduce populations of this pathogen in the field. In this study, we investigated the inhibitory effect of N-Acetylcysteine (NAC), a cysteine analogue used mainly to treat human diseases, on X. fastidiosa in different experimental conditions. Concentrations of NAC over 1 mg/mL reduced bacterial adhesion to glass surfaces, biofilm formation and the amount of exopolysaccharides (EPS). The minimal inhibitory concentration of NAC was 6 mg/mL. NAC was supplied to X. fastidiosa-infected plants in hydroponics, fertigation, and adsorbed to organic fertilizer (NAC-Fertilizer). HPLC analysis indicated that plants absorbed NAC at concentrations of 0.48 and 2.4 mg/mL but not at 6 mg/mL. Sweet orange plants with CVC symptoms treated with NAC (0.48 and 2.4 mg/mL) in hydroponics showed clear symptom remission and reduction in bacterial population, as analyzed by quantitative PCR and bacterial isolation. Experiments using fertigation and NAC-Fertilizer were done to simulate a condition closer to that normally is used in the field. For both, significant symptom remission and a reduced bacterial growth rate were observed. Using NAC-Fertilizer the lag for resurgence of symptoms on leaves after interruption of the treatment increased to around eight months. This is the first report of the anti-bacterial effect of NAC against a phytopathogenic bacterium. The results obtained in this work together with the characteristics of this molecule indicate that the use of NAC in agriculture might be a new and sustainable strategy for controlling plant pathogenic bacteria. PMID:24009716

  18. Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advanced idiopathic pulmonary fibrosis: a case-control study.

    PubMed

    Sakamoto, Susumu; Muramatsu, Yoko; Satoh, Keita; Ishida, Fumiaki; Kikuchi, Naoshi; Sano, Go; Sugino, Keishi; Isobe, Kazutoshi; Takai, Yujiro; Homma, Sakae

    2015-04-01

    Treatment with pirfenidone may slow the decline in vital capacity and increase progression-free survival (PFS) in idiopathic pulmonary fibrosis (IPF). The effects of combination therapy with inhaled N-acetylcysteine (NAC) and pirfenidone are unclear. We assessed the effects of this combination therapy in patients with advanced IPF. Patients with a diagnosis of advanced IPF (Japanese Respiratory Society stage III/IV IPF) and a relative decline in forced vital capacity (FVC) of ≥ 10% within the previous 6 (± 2) months were enrolled. Outcomes were evaluated in a 12-month follow-up pulmonary function test. Treatment was considered ineffective if the decline in FVC was ≥ 10% and effective if the decline was <10%. We compared clinical characteristics, effectiveness and PFS between patients receiving inhaled NAC plus pirfenidone (n = 24) and those receiving pirfenidone alone (control; n = 10). Data from 34 IPF patients (age range, 59-82 years) were analysed. At the 12-month follow-up examination, treatment was deemed effective in 8 of 17 (47%) patients receiving NAC plus pirfenidone and in 2 of 10 (20%) receiving pirfenidone alone. The annual rate of change in FVC was -610 mL in the NAC plus pirfenidone group and -1320 mL in the pirfenidone group (P < 0.01). PFS was longer (304 days) in the NAC plus pirfenidone group than in the pirfenidone group (168 days; P = 0.016). Combination treatment with inhaled NAC and oral pirfenidone reduced the rate of annual FVC decline and improved PFS in patients with advanced IPF. © 2015 Asian Pacific Society of Respirology.

  19. Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers.

    PubMed

    Kasperczyk, Sławomir; Dobrakowski, Michał; Kasperczyk, Aleksandra; Romuk, Ewa; Rykaczewska-Czerwińska, Monika; Pawlas, Natalia; Birkner, Ewa

    2016-09-01

    N-Acetylcysteine (NAC) could be included in protocols designed for the treatment of lead toxicity. Therefore, in this study, we decided to investigate the influence of NAC administration on homocysteine (Hcy) levels, oxidative damage to proteins, and the levels of iron (Fe), transferrin (TRF), and haptoglobin (HPG) in lead (Pb)-exposed workers. The examined population (n = 171) was composed of male employees who worked with Pb. They were randomized into four groups. Workers who were not administered any antioxidants, drugs, vitamins, or dietary supplements were classified as the reference group (n = 49). The remaining three groups consisted of workers who were treated orally with NAC at three different doses (1 × 200, 2 × 200, or 2 × 400 mg) for 12 weeks. After the treatment, blood Pb levels significantly decreased in the groups receiving NAC compared with the reference group. The protein concentration was not affected by NAC administration. In contrast, Hcy levels significantly decreased or showed a strong tendency toward lower values depending on the NAC dose. Levels of the protein carbonyl groups were significantly decreased in all of the groups receiving NAC. Conversely, glutamate dehydrogenase activity was significantly elevated in all of the groups receiving NAC, while the level of protein thiol groups was significantly elevated only in the group receiving 200 mg of NAC. Treatment with NAC did not significantly affect Fe and TRF levels, whereas HPG levels showed a tendency toward lower values. Treatment with NAC normalized the level of Hcy and decreased oxidative stress as measured by the protein carbonyl content; this effect occurred in a dose-dependent manner. Moreover, small doses of NAC elevated the levels of protein thiol groups. Therefore, NAC could be introduced as an alternative therapy for chronic Pb toxicity in humans. © The Author(s) 2015.

  20. N-acetylcysteine for the prevention of stricture after circumferential endoscopic submucosal dissection of the esophagus: a randomized trial in a porcine model.

    PubMed

    Barret, Maximilien; Batteux, Frédéric; Beuvon, Frédéric; Mangialavori, Luigi; Chryssostalis, Ariane; Pratico, Carlos; Chaussade, Stanislas; Prat, Frédéric

    2012-05-28

    Circumferential endoscopic submucosal dissection (CESD) of the esophagus would allow for both the eradication of Barrett's esophagus and its related complications, such as advanced neoplasia. However, such procedures generally induce inflammatory repair resulting in a fibrotic stricture. N-acetylcysteine (NAC) is an antioxidant that has shown some efficacy against pulmonary and hepatic fibrosis. The aim of our study was to evaluate the benefit of NAC in the prevention of esophageal cicatricial stricture after CESD in a swine model. Two groups of six pigs each were subjected to general anesthesia and CESD: after randomization, a first group received an oral NAC treatment regimen of 100 mg/kg/day, initiated one week before the procedure, whereas a second group was followed without any prophylactic treatment. Follow-up endoscopies took place seven, fourteen, twenty-one, and twenty-eight days after CESD. Necropsy, histological assessment of esophageal inflammation, and fibrosis were performed on day 28. The median esophageal lumen diameter on day 21 (main judgment criterion) was 4 mm (range 2 to 5) in group 1 and 3 mm (range 1 to 7) in group 2 (P = 0.95). No significant difference was observed between the two groups regarding clinical evaluation (time before onset of clinically significant esophageal obstruction), number of dilations, esophageal inflammation and fibrosis, or oxidative stress damage on immunohistochemistry. Despite its antioxidant effect, systemic administration of NAC did not show significant benefit on esophageal fibrosis in our animal model of esophageal wound healing within the experimental conditions of this study. Since the administered doses were relatively high, it seems unlikely that NAC might be a valuable option for the prevention of post-endoscopic esophageal stricture.

  1. N-acetylcysteine for the prevention of stricture after circumferential endoscopic submucosal dissection of the esophagus: a randomized trial in a porcine model

    PubMed Central

    2012-01-01

    Background Circumferential endoscopic submucosal dissection (CESD) of the esophagus would allow for both the eradication of Barrett’s esophagus and its related complications, such as advanced neoplasia. However, such procedures generally induce inflammatory repair resulting in a fibrotic stricture. N-acetylcysteine (NAC) is an antioxidant that has shown some efficacy against pulmonary and hepatic fibrosis. The aim of our study was to evaluate the benefit of NAC in the prevention of esophageal cicatricial stricture after CESD in a swine model. Animals and methods Two groups of six pigs each were subjected to general anesthesia and CESD: after randomization, a first group received an oral NAC treatment regimen of 100 mg/kg/day, initiated one week before the procedure, whereas a second group was followed without any prophylactic treatment. Follow-up endoscopies took place seven, fourteen, twenty-one, and twenty-eight days after CESD. Necropsy, histological assessment of esophageal inflammation, and fibrosis were performed on day 28. Results The median esophageal lumen diameter on day 21 (main judgment criterion) was 4 mm (range 2 to 5) in group 1 and 3 mm (range 1 to 7) in group 2 (P = 0.95). No significant difference was observed between the two groups regarding clinical evaluation (time before onset of clinically significant esophageal obstruction), number of dilations, esophageal inflammation and fibrosis, or oxidative stress damage on immunohistochemistry. Conclusions Despite its antioxidant effect, systemic administration of NAC did not show significant benefit on esophageal fibrosis in our animal model of esophageal wound healing within the experimental conditions of this study. Since the administered doses were relatively high, it seems unlikely that NAC might be a valuable option for the prevention of post-endoscopic esophageal stricture. PMID:22640979

  2. N-Acetylcysteine Attenuates Hexavalent Chromium-Induced Hypersensitivity through Inhibition of Cell Death, ROS-Related Signaling and Cytokine Expression

    PubMed Central

    Huang, Chien-Cheng; Sheu, Hamm-Ming; Tsai, Jui-Chen; Lin, Chia-Ho; Wang, Ying-Jan; Wang, Bour-Jr

    2014-01-01

    Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression. PMID:25248126

  3. Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine.

    PubMed

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Liauw, Winston; Morris, David L

    2015-10-20

    Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin.

  4. Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine

    PubMed Central

    Amini, Afshin; Masoumi-Moghaddam, Samar; Ehteda, Anahid; Liauw, Winston; Morris, David L.

    2015-01-01

    Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin. PMID:26436698

  5. The relaxation induced by S-nitroso-glutathione and S-nitroso-N-acetylcysteine in rat aorta is not related to nitric oxide production.

    PubMed

    Ceron, P I; Cremonez, D C; Bendhack, L M; Tedesco, A C

    2001-08-01

    S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine (NACysNO) are nitrosothiols that release nitric oxide (NO) and mimic the effects of endogenous NO. This study investigated the relaxation induced by GSNO and NACysNO in rat aorta and the relation between relaxation and NO formation. Both compounds at concentrations from 10(-9) M to 10(-4) M relaxed the rat aorta in a concentration-dependent manner. However, NO production depended on the concentration of nitrosothiols present and was detected only above 100 microM GSNO or NACysNO. To determine whether K+ channels are involved in the relaxation induced by nitrosothiols, the contractions were induced with KCl at concentrations of 30, 60, or 90 mM. The concentration-effect curves for the relaxation induced by nitrosothiols were shifted to the right for all the K+ concentrations compared with aortas precontracted with phenylephrine. These results indicate the participation of K+ channels in the relaxation induced by GSNO and NACysNO. A selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, significantly inhibited the relaxation induced by the nitrosothiols. The relaxation induced by GSNO and NACysNO was inhibited by the K+ channel blockers glibenclamide, selective K(ATP) channels, and apamin, selective for low-conductance Ca2+-activated K+ channels in rat aorta, but was not inhibited by charybdotoxin, a potent and selective Ca2+-activated K+ channel blocker, or by 4-aminopyridine, a voltage-gated K+ channel blocker. These results indicate that relaxation induced by GSNO and NACysNO is partially due to activation of K(ATP) channels and partially due to activation of low-conductance Ca2+-activated K+ channels. However, the ability of the nitrosothiol compounds to overcome the inhibitory effect of high extracellular K+ concentrations suggests another mechanism of relaxation contributing to the nitrosothiol response. The most intriguing finding is that relaxation is not

  6. N-Acetylcysteine and Allopurinol Confer Synergy in Attenuating Myocardial Ischemia Injury via Restoring HIF-1α/HO-1 Signaling in Diabetic Rats

    PubMed Central

    Mao, Xiaowen; Wang, Tingting; Liu, Yanan; Irwin, Michael G.; Ou, Jing-song; Liao, Xiao-long; Gao, Xia; Xu, Yuan; Ng, Kwok F. J.; Vanhoutte, Paul M.; Xia, Zhengyuan

    2013-01-01

    Objectives To determine whether or not the antioxidants N-acetylcysteine (NAC) and allopurinol (ALP) confer synergistic cardioprotection against myocardial ischemia/reperfusion (MI/R) injury by stabilizing hypoxia inducible factor 1α (HIF-1α)/heme oxygenase 1 (HO-1) signaling in diabetic myocardium. Methods Control or diabetic [streptozotocin (STZ)-induced] Sprague Dawley rats received vehicle or NAC, ALP or their combination for four weeks starting one week after STZ injection. The animals were then subjected to thirty minutes of coronary artery occlusion followed by two hours reperfusion in the absence or presence of the selective HO-1 inhibitor, tin protoporphyrin-IX (SnPP-IX) or the HIF-1α inhibitor 2-Methoxyestradiol (2ME2). Cardiomyocytes exposed to high glucose were subjected to hypoxia/re-oxygenation in the presence or absence of HIF-1α and HO-1 achieved by gene knock-down with related siRNAs. Results Myocardial and plasma levels of 15-F2t-isoprostane, an index of oxidative stress, were significantly increased in diabetic rats while cardiac HO-1 protein and activity were reduced; this was accompanied with reduced cardiac protein levels of HIF-1α, and increased post-ischemic myocardial infarct size and cellular injury. NAC and ALP given alone and in particular their combination normalized cardiac levels of HO-1 and HIF-1α protein expression and prevented the increase in 15-F2t-isoprostane, resulting in significantly attenuated post-ischemic myocardial infarction. NAC and ALP also attenuated high glucose-induced post-hypoxic cardiomyocyte death in vitro. However, all the above protective effects of NAC and ALP were cancelled either by inhibition of HO-1 or HIF-1α with SnPP-IX and 2ME2 in vivo or by HO-1 or HIF-1α gene knock-down in vitro. Conclusion NAC and ALP confer synergistic cardioprotection in diabetes via restoration of cardiac HIF-1α and HO-1 signaling. PMID:23874823

  7. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children

    PubMed Central

    Empey, Philip E.; Bayır, Hülya; Rosario, Bedda L.; Poloyac, Samuel M.; Kochanek, Patrick M.; Nolin, Thomas D.; Au, Alicia K.; Horvat, Christopher M.; Wisniewski, Stephen R.; Bell, Michael J.

    2017-01-01

    Background There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. Methods IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1–96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. Results There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. Conclusions Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable

  8. Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer.

    PubMed

    Monti, Daniel; Sotgia, Federica; Whitaker-Menezes, Diana; Tuluc, Madalina; Birbe, Ruth; Berger, Adam; Lazar, Melissa; Cotzia, Paolo; Draganova-Tacheva, Rossitza; Lin, Zhao; Domingo-Vidal, Marina; Newberg, Andrew; Lisanti, Michael P; Martinez-Outschoorn, Ubaldo

    2017-06-01

    High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer. Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens. The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated. NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer

  9. Attention Deficit and Hyperactivity Disorder Scores Are Elevated and Respond to N-Acetylcysteine Treatment in Patients With Systemic Lupus Erythematosus

    PubMed Central

    Garcia, Ricardo J.; Francis, Lisa; Dawood, Maha; Lai, Zhi-wei; Faraone, Stephen V.; Perl, Andras

    2014-01-01

    Objective To investigate whether attention deficit hyperactivity disorder (ADHD) may serve as a marker of neuropsychiatric disease and as a target for N-acetylcysteine (NAC) treatment in patients with systemic lupus erythematosus (SLE). Methods The ADHD Self-Report Scale (ASRS) was used to assess 49 patients with SLE and 46 matched healthy control subjects. Twenty-four of the patients with SLE were randomized to receive either placebo, NAC at a dosage of 2.4 gm/day, or NAC at a dosage of 4.8 gm/day. Disease activity was evaluated monthly using the British Isles Lupus Assessment Group (BILAG) index, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Fatigue Assessment Scale (FAS), and the ASRS, before and during the 3-month treatment period and after a 1-month washout period. Results The cognitive/inattentive (ASRS part A), hyperactivity/impulsive (ASRS part B), and combined (total) ASRS scores were increased in patients with SLE compared with control subjects (mean ± SEM 17.37 ± 1.03 [P = 3 × 10−7], 14.51 ± 0.89 [P = 2 × 10−4], and 31.92 ± 1.74 [P = 8 × 10−7], respectively, versus 10.41 ± 1.02, 9.61 ± 1.21, and 20.02 ± 1.98, respectively. ASRS part A scores correlated with SLEDAI (r = 0.53, P < 0.0001) and BILAG scores (r = 0.36, P = 0.011). ASRS total scores also correlated with SLEDAI (r = 0.45, P = 0.0009) and BILAG scores (r = 0.31, P = 0.025). ASRS part A (r = 0.73, P < 0.0001), ASRS part B (r = 0.47, P = 0.0006), and ASRS total scores (r = 0.67, P < 0.0001) correlated with the FAS score. Relative to the scores in placebo-treated patients, ASRS total scores were reduced in SLE patients treated with NAC dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.037). ASRS part A scores were reduced by NAC dosages of 2.4 gm/day (P = 0.001) and 4.8 gm/day (P < 0.0001) as well as by NAC at dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.001). Conclusion In patients with SLE, elevated ASRS scores reveal previously unrecognized and

  10. Hypoxic resistance of KRAS mutant tumor cells to 3-Bromopyruvate is counteracted by Prima-1 and reversed by N-acetylcysteine.

    PubMed

    Orue, Andrea; Chavez, Valery; Strasberg-Rieber, Mary; Rieber, Manuel

    2016-11-18

    The metabolic inhibitor 3-bromopyruvate (3-BrPA) is a promising anti-cancer alkylating agent, shown to inhibit growth of some colorectal carcinoma with KRAS mutation. Recently, we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation. Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring (Q61L)-mutant NRAS and wt BRAF, C8161 melanoma with (G12D)-mutant KRAS (G464E)-mutant BRAF, and A549 lung carcinoma with a KRAS (G12S)-mutation. Since hypoxia increases the toxicity of the p53 activator, Prima-1 against breast cancer cells irrespective of their p53 status, we also investigated whether Prima-1 reversed hypoxic resistance to 3-BrPA. In contrast to the high susceptibility of hypoxic mutant NRAS MelJuso cells to 3-BrPA or Prima-1, KRAS mutant C8161 and A549 cells revealed hypoxic resistance to 3-BrPA counteracted by Prima-1. In A549 cells, Prima-1 increased p21CDKN1mRNA, and reciprocally inhibited mRNA expression of the SLC2A1-GLUT1 glucose transporter-1 and ALDH1A1, gene linked to detoxification and stem cell properties. 3-BrPA lowered CAIX and VEGF mRNA expression. Death from joint Prima-1 and 3-BrPA treatment in KRAS mutant A549 and C8161 cells seemed mediated by potentiating oxidative stress, since it was antagonized by the anti-oxidant and glutathione precursor N-acetylcysteine. This report is the first to show that Prima-1 kills hypoxic wt p53 KRAS-mutant cells resistant to 3-BrPA, partly by decreasing GLUT-1 expression and exacerbating pro-oxidant stress.

  11. Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.

    PubMed Central

    Bernard, G R; Lucht, W D; Niedermeyer, M E; Snapper, J R; Ogletree, M L; Brigham, K L

    1984-01-01

    Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out. PMID:6725559

  12. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children.

    PubMed

    Clark, Robert S B; Empey, Philip E; Bayır, Hülya; Rosario, Bedda L; Poloyac, Samuel M; Kochanek, Patrick M; Nolin, Thomas D; Au, Alicia K; Horvat, Christopher M; Wisniewski, Stephen R; Bell, Michael J

    2017-01-01

    There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. Clinical

  13. Low Pretreatment Impulsivity and High Medication Adherence Increase the Odds of Abstinence in a Trial of N-Acetylcysteine in Adolescents with Cannabis Use Disorder

    PubMed Central

    Bentzley, Jessica P.; Tomko, Rachel L.; Gray, Kevin M.

    2016-01-01

    Background In light of recent progress toward pharmacologic interventions to treat adolescent cannabis use disorder, it is important to consider which adolescent characteristics may be associated with a favorable response to treatment. This study presents secondary analyses from a parent randomized controlled trial of N-acetylcysteine (NAC) in adolescents with cannabis use disorder. We hypothesized high pretreatment impulsivity and medication non-adherence would be associated with reduced abstinence rates. Methods Participants were treatment-seeking adolescents (N = 115) who met criteria for cannabis use disorder and were assessed for pretreatment impulsivity. They received 1200 mg NAC or placebo orally twice daily for 8 weeks. An intent-to-treat analysis using a repeated-measures logistic regression model was used to relate pretreatment impulsivity (Barratt Impulsiveness Scale) and treatment group to abstinence rates, measured by urine cannabinoid tests. To explore mechanisms by which NAC may reduce cannabis use, relationships between impulsivity, adherence, and abstinence were assessed in a second statistical model using data from participants with recorded adherence and urine cannabinoid test results (n = 54). Results In the intent-to-treat analysis, low pretreatment impulsivity, NAC treatment, and negative baseline urine cannabinoid test results independently increased the odds of having negative urine cannabinoid tests during treatment (OR = 2.1, 2.3, 5.3 respectively). In the sample of participants with adherence data (n = 54), adherence tripled the odds of abstinence. Notably, the effect of adherence on abstinence was only observed in the NAC treatment group. Lastly, although the highly impulsive participants had reduced rates of abstinence, highly impulsive individuals adherent to NAC treatment had increased abstinence rates compared to non-adherent individuals. Conclusion Low impulsivity, NAC treatment, medication adherence, and baseline negative

  14. A double-blind, randomized, controlled trial on N-acetylcysteine for the prevention of acute kidney injury in patients undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Ataei, Sara; Hadjibabaie, Molouk; Moslehi, Amirhossein; Taghizadeh-Ghehi, Maryam; Ashouri, Asieh; Amini, Elham; Gholami, Kheirollah; Hayatshahi, Alireza; Vaezi, Mohammad; Ghavamzadeh, Ardeshir

    2015-06-01

    Acute kidney injury (AKI) is one of the complications of hematopoietic stem cell transplantation and is associated with increased mortality. N-acetylcysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties that has been investigated for the prevention of AKI in several clinical settings. In the present study, we evaluated the effects of intravenous NAC on the prevention of AKI in allogeneic hematopoietic stem cell transplantation patients. A double-blind randomized placebo-controlled trial was conducted, and 80 patients were recruited to receive 100 mg/kg/day NAC or placebo as intermittent intravenous infusion from day -6 to day +15. AKI was determined on the basis of the Risk-Injury-Failure-Loss-End-stage renal disease and AKI Network criteria as the primary outcome. We assessed urine neutrophil gelatinase-associated lipocalin (uNGAL) on days -6, -3, +3, +9 and +15 as the secondary outcome. Moreover, transplant-related outcomes and NAC adverse reactions were evaluated during the study period. Statistical analysis was performed using appropriate parametric and non-parametric methods including Kaplan-Meier for AKI and generalized estimating equation for uNGAL. At the end of the trial, data from 72 patients were analysed (NAC: 33 patients and placebo: 39 patients). Participants of each group were not different considering baseline characteristics. AKI was observed in 18% of NAC recipients and 15% of placebo group patients, and the occurrence pattern was not significantly different (p = 0.73). Moreover, no significant difference was observed between groups for uNGAL measures (p = 0.10). Transplant-related outcomes were similar for both groups, and all patients had successful engraftment. Three patients did not tolerate NAC because of abdominal pain, shortness of breath and rash with pruritus and were dropped from the intervention group before transplantation. However, the frequency of adverse reactions was not significantly different between

  15. Metabolomic Analysis of N-acetylcysteine Protection of Injury from Gadolinium-DTPA Contrast Agent in Rats with Chronic Renal Failure.

    PubMed

    Wan, Chuanling; Xue, Rong; Zhan, Youyang; Wu, Yijie; Li, Xiaojing; Pei, Fengkui

    2017-09-01

    Gadolinium-based contrast agents (GBCAs) are frequently used to enhance the diagnostic efficacy of magnetic resonance imaging. On the other hand, the association between GBCA administration in patients with advanced renal disease and nephrogenic systemic fibrosis (NSF) was also noted. NSF is a systemic disorder characterized by widespread tissue fibrosis that may lead to death. N-acetylcysteine (NAC) protects rats from injury induced by gadolinium-based contrast agents, but the underlying mechanisms remain unclear. In this study, a nuclear magnetic resonance-based metabolomic approach was used to systematically investigate the protective effects of NAC on Gd-DTPA-induced injury. Thirty-two male Sprague-Dawley rats were given adenine (200 mg·kg -1 body weight) by oral gavage once a day for 3 weeks to induce chronic renal failure (CRF). NAC (600 mg/L in drinking water for 9 days) pretreatment was initiated 2 days before Gd-DTPA injection (a single tail vein injection, 2 mmol/kg body weight). Serum and liver samples were collected on day 7 after Gd-DTPA injection. By study design, the serum and hepatic metabolic changes of rats were measured in four groups of eight each: CRF, CRF-Gd, CRF-Gd-NAC, and CRF-NAC. Gd-DTPA administration to rats with CRF resulted in disturbances of several metabolic pathways, including glucose, lipid, glutamate, choline, gut microbiota, one-carbon, and purine metabolism. NAC pretreatment reversed the abundance changes of high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, glutamate, glutamine, oxidized glutathione, choline, phosphocholine, glycerophosphocholine, trimethylamine, and trimethylamine-N-oxide induced by Gd-DTPA. It is noteworthy, however, that the ameliorating effects of NAC on the disturbance of glutamate, choline, and gut microbiota metabolism may be specific to Gd-DTPA. In all, these findings could be potentially useful to decipher the underlying mechanisms of NAC protective effects from the

  16. N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

    PubMed

    Polyak, Erzsebet; Ostrovsky, Julian; Peng, Min; Dingley, Stephen D; Tsukikawa, Mai; Kwon, Young Joon; McCormack, Shana E; Bennett, Michael; Xiao, Rui; Seiler, Christoph; Zhang, Zhe; Falk, Marni J

    2018-04-01

    Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major

  17. Effects of N-acetylcysteine and tirilazad mesylate on intestinal functional capillary density, leukocyte adherence, mesenteric plasma extravasation and cytokine levels in experimental endotoxemia in rats.

    PubMed

    Birnbaum, J; Lehmann, Ch; Klotz, E; Hein, O Vargas; Blume, A; Jubin, F; Polze, N; Luther, D; Spies, C D

    2008-01-01

    The study's objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental endotoxemia in rats. In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body weight NAC was administered after the first 30 minutes of endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of endotoxemia intravenously. Animals of the series 1 underwent studies of leukocyte adherence on submucosal venular endothelium of the small bowel wall and intestinal functional capillary density (FCD) in the intestinal mucosa and the circular as well as the longitudinal muscle layer by intravital fluorescence microscopy (IVM). Plasma levels of interleukin 1beta (IL-1beta), interferone gamma (IFN-gamma) and soluble intercellular adhesion molecule1 (s-ICAM 1) as well as white blood cell count (WBC) were estimated. In the animals of the series 2 mesenteric plasma extravasation was determined by IVM and plasma levels of tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, IL-10 and malondialdehyde (MDA) were estimated. After LPS administration, FCD in the villi intestinales was unchanged and in the longitudinal muscularis layer it was increased. There was no effect of NAC or TM administration on FCD.Although the plasma extravasation was not significantly influenced by LPS administration, TM administration resulted in a lower plasma extravasation in the TM group compared to the other groups. After endotoxin challenge, the firmly adherence of leukocytes to vascular endothelium as a parameter

  18. [The effect of prophylactically administered n-acetylcysteine on clinical indicators for tissue oxygenation during hyperoxic ventilation in cardiac risk patients].

    PubMed

    Spies, C; Giese, C; Meier-Hellmann, A; Specht, M; Hannemann, L; Schaffartzik, W; Reinhart, K

    1996-04-01

    Hyperoxic ventilation, used to prevent hypoxia during potential periods of hypoventilation, has been reported to paradoxically decrease whole-body oxygen consumption (VO2). Reduction in nutritive blood flow due to oxygen radical production is one possible mechanism. We investigated whether pretreatment with the sulfhydryl group donor and O2 radical scavenger N-acetylcysteine (NAC) would preserve VO2 and other clinical indicators of tissue oxygenation in cardiac risk patients. Thirty patients, requiring hemodynamic monitoring (radial and pulmonary artery catheters) because of cardiac risk factors, were included in this randomized investigation. All patients exhibited stable clinical conditions (hemodynamics, body temperature, hemoglobin, F1O2 < 0.5). Cardiac output was determined by thermodilution and VO2 by cardiovascular Fick. After baseline measurements, patients randomly received either 150 mg kg-1 NAC (n = 15) or placebo (n = 15) in 250 ml 5% dextrose i.v. over a period of 30 min. Measurements were repeated 30 min after starting NAC or placebo infusion, 30 min after starting hyperoxia (F1O2 = 1.0), and 30 min after resetting the original F1O2. There were no significant differences between groups in any of the measurements before treatment and after the return to baseline F1O2 at the end of the study, respectively. NAC, but not placebo infusion, caused a slight but not significant increase in cardiac index (CI), left ventricular stroke work index (LVSWI) and a decrease in systemic vascular resistance. Significant differences between groups during hyperoxia were: VO2 (NAC: 108 +/- 38 ml min-1m-2 vs placebo: 79 +/- 22 ml min-1m-2; P < or = 0.05), CI (NAC: 4.6 +/- 1.0 vs placebo: 3.7 +/- 1.11 min-1m-2; P < or = 0.05) and LVSWI (NAC: 47 +/- 12 vs placebo: 38 +/- 9; P < or = 0.05). The mean decrease of VO2 was 22% in the NAC group vs 47% in the placebo group (P < or = 0.05) and the mean difference between groups in venoarterial carbon dioxide gradient (PvaCO2) was 14

  19. Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal NG-Nitro-L-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring.

    PubMed

    Tain, You-Lin; Lee, Chien-Te; Chan, Julie Y H; Hsu, Chien-Ning

    2016-11-01

    Pregnancy is a critical time for fetal programming of hypertension. Nitric oxide deficiency during pregnancy causes hypertension in adult offspring. We examined whether maternal melatonin or N-acetylcysteine therapy can prevent N G -nitro-L-arginine-methyl ester-induced fetal programming of hypertension in adult offspring. Next, we aimed to identify potential gatekeeper pathways that contribute to N G -nitro-L-arginine-methyl ester -induced programmed hypertension using the next generation RNA sequencing technology. Pregnant Sprague-Dawley rats were assigned to 4 groups: control, N G -nitro-L-arginine-methyl ester, N G -nitro-L-arginine-methyl ester +melatonin, and N G -nitro-L-arginine-methyl ester+N-acetylcysteine. Pregnant rats received N G -nitro-L-arginine-methyl ester administration at 60 mg/kg/d subcutaneously during pregnancy alone, with additional 0.01% melatonin in drinking water, or with additional 1% N-acetylcysteine in drinking water during the entire pregnancy and lactation. Male offspring (n=8/group) were killed at 12 weeks of age. N G -nitro-L-arginine-methyl ester exposure during pregnancy induced programmed hypertension in adult male offspring, which was prevented by maternal melatonin or N-acetylcysteine therapy. Protective effects of melatonin and N-acetylcysteine against N G -nitro-L-arginine-methyl ester-induced programmed hypertension were associated with an increase in hydrogen sulfide-generating enzymes and hydrogen sulfide synthesis in the kidneys. Nitric oxide inhibition by N G -nitro-L-arginine-methyl ester in pregnancy caused >2000 renal transcripts to be modified during nephrogenesis stage in 1-day-old offspring kidney. Among them, genes belong to the renin-angiotensin system, and arachidonic acid metabolism pathways were potentially involved in the N G -nitro-L-arginine-methyl ester-induced programmed hypertension. However, melatonin and N-acetylcysteine reprogrammed the renin-angiotensin system and arachidonic acid pathway

  20. The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection -- a pilot study.

    PubMed

    Skov, Marianne; Pressler, Tacjana; Lykkesfeldt, Jens; Poulsen, Henrik Enghusen; Jensen, Peter Østrup; Johansen, Helle Krogh; Qvist, Tavs; Kræmer, Dorthe; Høiby, Niels; Ciofu, Oana

    2015-03-01

    Patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection have increased oxidative stress as a result of an imbalance between the production of reactive oxygen species caused by inflammation and their inactivation by the impaired antioxidant systems. Supplementation with anti-oxidants is potentially beneficial for CF patients. The effect of 4 weeks of oral N-acetylcysteine (NAC) treatment (2400 mg/day divided into two doses) on biochemical parameters of oxidative stress was investigated in an open-label, controlled, randomized trial on 21 patients; 11 patients in the NAC group and 10 in the control group. Biochemical parameters of oxidative burden and plasma levels of antioxidants were assessed at the end of the study and compared to the baseline values in the two groups. A significant increase in the plasma levels of the antioxidant ascorbic acid (p=0.037) and a significant decrease in the levels of the oxidized form of ascorbic acid (dehydroascorbate) (p=0.004) compared to baseline were achieved after NAC treatment. No significant differences were observed in the control group. The parameters of oxidative burden did not change significantly compared to baseline in either of the groups. A better lung function was observed in the NAC treated group with a mean (SD) change compared to baseline of FEV1% predicted of 2.11 (4.6), while a decrease was observed in the control group (change -1.4 (4.6)), though not statistically significant. Treatment with N-acetylcysteine 1200 mg×2/day for 30 days significantly decreased the level of oxidized vitamin C and increased the level of vitamin C (primary end-points) and a not statistically significant improvement of lung function was observed in this group of patients. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  1. REACTIONS OF MERCAPTANS. I. FORMATION OF 2-METHYL-2-THIAZOLINE-4- CARBOXYLIC ACID FROM N-ACETYLCYSTEINE. II. A SPECTROPHOTOMETRIC METHOD FOR STUDY OF THE REACTION OF RADIATION-PROTECTIVE MERCAPTANS WITH ARYL DISULFIDES

    SciTech Connect

    Smith, H.A. Jr.

    1962-08-01

    I. Methyl 2-methyl-2-thiazoline-4-carboxylate was synthesized and converted to the corresponding acid. The behavior of the carboxythiazoline in various concentrations of mineral acids was studied spectrophotometrically. The cyclization of N-acetylcysteine to form a thiazoline-ring compound in concentrated mineral acids was also studied by this means. N-Acetylcysteine in concentrated mineral acid solutions yielded 2-methyl-2-thiazoline-4-carboxylic acid, which also was obtained by controlied hydrolysis of the corresponding methyl ester. Hydrolysis of methyl 2-methyl2-thiazoline-4-carboxylate, pK 3.05, in 0.1M sodium hydroxide yielded the corresponding carboxythiazoline in solution, pK 2.20 and 4.95. The carboxythiazoline was hydrolyzed very slowly in 7M hydrochloric acid, but the velocity of reactionmore » increased with decreasing acid concentration to a maximum at about pH 1.7; the products were N- and Sacetylcysteine, as well as cysteine and acetic acid. At acid concentrations below 0.2M, the last two products were formed slowly, and a pseudo-equilibrium could be established between thiazolinium ion, N-, and S-acetylcysteine. Equilibrium constants were determined. II. 4,4'-Dithiobis (benzenesulfonic acid) (I) and 4,4'-dithiobis(1-naphthalenesulfonic acid) (II) were synthesized from sulfanilic and naphthionic acids, respectively. The absorption spectra of I and II and of the corresponding mercaptans were determined. The thiol-disuifide interchange reactions were studied by spectrophotometric means for the reactions of cysteine with I and with II, and the equilibrium constants were determined. The systems had spectra very similar to those of the respective mixed disuifides with cysteine, and it was not possible to determine the concentrations from absorbancy measurements. On the other hand, the mercaptide ions had spectra different from the other species, with maxima at 285 and 348 m mu , respectively, and the concentrations of the corresponding mercaptans could

  2. Protective influences of N-acetylcysteine against alcohol abstinence-induced depression by regulating biochemical and GRIN2A, GRIN2B gene expression of NMDA receptor signaling pathway in rats.

    PubMed

    Yawalkar, Rutuja; Changotra, Harish; Gupta, Girdhari Lal

    2018-04-25

    Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague-Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1, GRIN2A, GRIN2B genes for the N-methyl d-aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The

  3. The add-on N-acetylcysteine is more effective than dimethicone alone to eliminate mucus during narrow-band imaging endoscopy: a double-blind, randomized controlled trial.

    PubMed

    Chen, Ming-Jen; Wang, Horng-Yuan; Chang, Chen-Wang; Hu, Kuang-Chun; Hung, Chien-Yuan; Chen, Chih-Jen; Shih, Shou-Chuan

    2013-02-01

    Recent studies have shown that pronase can improve mucosal visibility, but this agent is not uniformly available for human use worldwide. This study aimed to assess the efficacy of N-acetylcysteine (NAC), a mucolytic agent, in improving mucus elimination as measured by decreased endoscopic water flushes during narrow-band imaging (NBI) endoscopy. A consecutive series of patients scheduled for upper gastrointestinal endoscopy at outpatient clinics were enrolled in this double-blind, randomized controlled trial. The control group drank a preparation of 100 mg dimethicone (5 ml at 20 mg/ml) plus water up to 100 ml, and the NAC group drank 300 mg NAC plus 100 mg dimethicone and water up to 100 ml. During the endoscopy, the endoscopist used as many flushes of water as deemed necessary to produce a satisfactory NBI view of the entire gastric mucosa. In all, 177 patients with a mean age of 51 years were evaluated in this study. Significantly lesser water was used for flushing during NBI endoscopy for the NAC group than the control group; 40 ml (30-70, 0-120) versus 50 ml (30-100, 0-150) (median (interquartile range, range), p = 0.0095). Considering the safety profile of NAC, decreasing the number of water flushes for optimal vision and unavailability of pronase in some areas, the authors suggest the use of add-on NAC to eliminate mucus during NBI endoscopy.

  4. Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine.

    PubMed

    Nematbakhsh, Mehdi; Pezeshki, Zahra

    2013-01-01

    Background. Nitric oxide (NO) concentration in serum is altered by cisplatin (CP), and NO influences CP-induced nephrotoxicity. The effect of nephroprotectant agent supplementation (vitamin E, human recombinant erythropoietin (EPO), or n-acetylcysteine (NAC)) on the NO metabolites levels after CP administration in the two genders was determined. Methods. Sixty-four adult Wistar rats were randomly divided into 10 groups. Male and female rats in different groups received vehicle (saline), CP (7 mg/kg) alone, CP plus EPO (100 IU/kg), CP plus vitamin E (250 mg/kg), and CP plus NAC (600 mg/kg). CP was administrated as a single dose, but the supplementations were given for a period of 7 days. Results. In male rats, the serum levels of total NO metabolites (NO x ) and nitrite were increased significantly (P < 0.05) by CP. However, vitamin E significantly reduced the serum levels of these metabolites, which was increased by administration of CP (P < 0.05), and such findings were not observed for female rats. The EPO or NAC did not influence NO metabolites neither in male rats nor in female rats. Conclusion. Although vitamin E, EPO, and NAC are reported to be nephroprotectant agents against CP-induced nephrotoxicity, only vitamin E could reduce the level of all NO metabolites only in male rats.

  5. Development and utilization of extracorporeal regional complexing hemodialysis as a means of mobilizing and enhancing the excretion of methylmercury in the dog. [N-acetylcysteine; N-acetylpenicillamine; 2,3-dimercaptosuccinic acid

    SciTech Connect

    Kostyniak, P.J.

    1975-01-01

    The present investigation was directed at developing and testing a new procedure for increasing methylmercury excretion in the dog. The procedure utilizes hemodialysis in conjunction with the extracorporeal reversal of protein binding of methylmercury in blood by the presence of low molecular weight sulfhydryl containing complexing agents (cysteine, N-acetylcysteine, penicillamine, N-acetylpenicillamine, 2,3-dimercaptosuccinic acid) having a high chemical affinity for methylmercury. Using such a procedure, the complexed methylmercury and the free complexing agent were found to be readily removed from blood by the dialyzer. Unlike chelation therapy, this procedure does not rely on the attainment of high systemic concentrations of complexingmore » agent in order to attain enhanced excretion by normal routes. It rather introduces into the circulatory system a shunt designed specifically for methylmercury extraction from blood. In vitro testing of this procedure revealed that methylmercury removal from blood was dependent upon the concentration of complexing agent in blood and the dialyzer blood flow rate. In vivo testing of the procedure in the dog utilized a standard hemodialyzer with infusion of complexing agent into the arterial dialyzer blood line. The rate of methylmercury removal from the dog during the treatment procedures were as high as 400 times the excretion rate of mercury in untreated dogs.« less

  6. N-acetylcysteine attenuates TNF-α-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells

    PubMed Central

    Hashimoto, Shu; Gon, Yasuhiro; Matsumoto, Ken; Takeshita, Ikuko; Horie, Takashi

    2001-01-01

    We have previously shown that tumour necrosis factor-α (TNF-α) activates p38 mitogen-activated protein (MAP) kinase to produce interleukin-8 (IL-8) by human pulmonary vascular endothelial cells. Reactive oxygen species (ROS) including H2O2 generated by TNF-α can act as signalling intermediates for cytokine induction; therefore, scavenging ROS by anti-oxidants is important for the regulation of cytokine production. However, the effect of N-acetylcysteine (NAC), which acts as a precursor of glutathione (GSH) synthesis, on TNF-α-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells has not been determined. To clarify these issues, we examined the effect of NAC on TNF-α-induced activation of p38 MAP kinase, MAP kinase kinase (MKK) 3 and MKK6 which are upstream regulators of p38 MAP kinase, and p38 MAP kinase-mediated IL-8 production. Human pulmonary vascular endothelial cells that had been preincubated with NAC were stimulated with TNF-α and then the activation of p38 MAP kinase and MKK3/MKK6 in the cells and IL-8 concentrations in the culture supernatants were determined. Intracellular GSH levels increased in NAC-treated cells. NAC attenuated TNF-α-induced activation of p38 MAP kinase and MKK3/MKK6. NAC attenuated p38 MAP kinase-mediated IL-8 production by TNF-α-stimulated cells. These results indicate that the cellular reduction and oxidation (redox) regulated by intracellular GSH is critical for TNF-α-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells, and we emphasize that anti-oxidant therapy is an important strategy for the treatment of acute lung injury. PMID:11156586

  7. Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial.

    PubMed

    Camuglia, Anthony C; Maeder, Micha T; Starr, Jennifer; Farrington, Catherine; Kaye, David M

    2013-04-01

    Both heart and renal failure are characterised by increased systemic oxidative stress and endothelial dysfunction and occur in the cardiorenal syndrome (CRS). The aim of the present study was to assess the impact of N-acetylcysteine (NAC), a potent antioxidant, on endothelial function, B-type natriuretic peptide (BNP) and renal function in patients with CRS. In a double blind, placebo controlled manner, we randomised nine stable outpatients with both heart failure (LVEF<40% and NYHA class II or III) and renal failure (Cockroft Gault clearance of 20-60ml/min) to placebo or NAC (500mg orally twice daily) for 28 days followed by a wash out period (>7 days) and crossover to the other treatment. Eight patients completed the study and all data (N=9) was used in the analysis. Mean forearm blood flow improved significantly with NAC with mean ratio of improvement of 1.99 (SEM: ±0.49) for NAC and 0.73 (SEM: ±0.23) for placebo with a p-value of 0.047. There was no significant difference in BNP (p=0.25), renal function (p=0.71) or NYHA class (p=0.5). No deaths occurred during the trial. In this pilot trial of patients with CRS, NAC therapy was associated with improved forearm blood flow. This may represent a general improvement in endothelial function and warrants further investigation of antioxidant therapy in these patients. Copyright © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  8. A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation

    SciTech Connect

    Oh, Seon-Hee; Lim, Sung-Chul

    2006-05-01

    Although reactive oxygen species (ROS) have been implicated in cadmium (Cd)-induced hepatotoxicity, the role of ROS in this pathway remains unclear. Therefore, we attempted to determine the molecular mechanisms relevant to Cd-induced cell death in HepG2 cells. Cd was found to induce apoptosis in the HepG2 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis and TUNEL staining. In the early stages, both rapid and transient ROS generation triggered apoptosis via Fas activation and subsequent caspase-8-dependent Bid cleavage, as well as by calpain-mediated mitochondrial Bax cleavage. The timing of Bid activation was coincided with the timingmore » at which the mitochondrial transmembrane potential (MMP) collapsed as well as the cytochrome c (Cyt c) released into the cytosol. Furthermore, mitochondrial permeability transition (MPT) pore inhibitors, such as cyclosporin A (CsA) and bongkrekic acid (BA), did not block Cd-induced ROS generation, MMP collapse and Cyt c release. N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of the Cd-induced apoptosis via catalase upregulation and subsequent Fas downregulation. NAC treatment also completely blocked the Cd-induced intracellular ROS generation, MMP collapse and Cyt c release, indicating that Cd-induced mitochondrial dysfunction may be regulated indirectly by ROS-mediated signaling pathway. Taken together, a rapid and transient ROS generation by Cd triggers apoptosis via caspase-dependent pathway and subsequent mitochondrial pathway. NAC inhibits Cd-induced apoptosis through the blocking of ROS generation as well as the catalase upregulation.« less

  9. N-acetylcysteine attenuates TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells.

    PubMed

    Hashimoto, S; Gon, Y; Matsumoto, K; Takeshita, I; Horie, T

    2001-01-01

    1. We have previously shown that tumour necrosis factor-alpha (TNF-alpha) activates p38 mitogen-activated protein (MAP) kinase to produce interleukin-8 (IL-8) by human pulmonary vascular endothelial cells. Reactive oxygen species (ROS) including H(2)O(2) generated by TNF-alpha can act as signalling intermediates for cytokine induction; therefore, scavenging ROS by anti-oxidants is important for the regulation of cytokine production. However, the effect of N-acetylcysteine (NAC), which acts as a precursor of glutathione (GSH) synthesis, on TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells has not been determined. To clarify these issues, we examined the effect of NAC on TNF-alpha-induced activation of p38 MAP kinase, MAP kinase kinase (MKK) 3 and MKK6 which are upstream regulators of p38 MAP kinase, and p38 MAP kinase-mediated IL-8 production. 2. Human pulmonary vascular endothelial cells that had been preincubated with NAC were stimulated with TNF-alpha and then the activation of p38 MAP kinase and MKK3/MKK6 in the cells and IL-8 concentrations in the culture supernatants were determined. 3. Intracellular GSH levels increased in NAC-treated cells. 4. NAC attenuated TNF-alpha-induced activation of p38 MAP kinase and MKK3/MKK6. 5. NAC attenuated p38 MAP kinase-mediated IL-8 production by TNF-alpha-stimulated cells. 6. These results indicate that the cellular reduction and oxidation (redox) regulated by intracellular GSH is critical for TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells, and we emphasize that anti-oxidant therapy is an important strategy for the treatment of acute lung injury.

  10. Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study.

    PubMed

    Sherman, Brian J; McRae-Clark, Aimee L; Baker, Nathaniel L; Sonne, Susan C; Killeen, Therese K; Cloud, Kasie; Gray, Kevin M

    2017-03-01

    Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n = 86) and men (n = 216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site, randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network. Women reported greater withdrawal intensity (p = .001) and negative impact of withdrawal (p = .001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = .038) and current agoraphobia (p = .022), and reported more days of poor physical health (p = .006) and cannabis-related medical problems (p = .023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p = .006). Men and women did not differ on any measures of baseline cannabis use. Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.(Am J Addict 2017;26:136-144). © 2017 American Academy of Addiction Psychiatry.

  11. The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

    PubMed

    Zhao, Shi-Jie; Zhong, Zhao-Shuang; Qi, Guo-Xian; Tian, Wen

    2016-10-15

    The efficacy of combining use of N-acetylcysteine (NAC) and sodium bicarbonate (SOB) in the prevention of contrast-induced nephropathy (CIN) after cardiac catheterization and percutaneous coronary intervention (PCI) is unclear. All relevant studies that compared the effect of combining the use of NAC and SOB with individual use on CIN in patients undergoing cardiac catheterization and PCI were identified by searching the databases including Pubmed, Embase, Cochrane Library, and Web of Science without time and language limitation. Only randomized controlled trials (RCTs) with full-text published were considered. Sixteen RCTs involving 4432 cases were included into this meta-analysis. The results showed there were no additional benefit in reduction of CIN in COM group (COM versus NAC: RR 0.85, 95% CI 0.70-1.03, P=0.103; COM versus SOB: RR 0.91, 95% CI 0.71-1.16, P=0.449), even in patients with diabetes mellitus (COM versus NAC: RR 1.11, 95% CI 0.71-1.75, P=0.646; COM versus SOB: RR 1.06, 95% CI 0.45-2.47, P=0.893), undergoing PCI procedure (COM versus NAC: RR0.76, 95% CI 0.39-1.47, P=0.411; COM versus SOB: RR0.96, 95% CI 0.65-1.40, P=0.814), or with baseline renal dysfunction (COM versus NAC: RR 0.89, 95% CI 0.70-1.14, P=0.366; COM versus SOB: RR 0.95, 95% CI 0.67-1.36, P=0.788). The present study demonstrated combining use of NAC and SOB was not significantly superior to individual use method in the prevention of CIN after cardiac catheterization and PCI. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the Achieving Cannabis Cessation – Evaluating N-acetylcysteine Treatment (ACCENT) study

    PubMed Central

    Sherman, Brian J.; McRae-Clark, Aimee L.; Baker, Nathaniel L.; Sonne, Susan C.; Killeen, Therese K.; Cloud, Kasie; Gray, Kevin M.

    2017-01-01

    Background and Objectives Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. Methods The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n = 86) and men (n = 216) entering the Achieving Cannabis Cessation – Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site, randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network. Results Women reported greater withdrawal intensity (p = 0.001) and negative impact of withdrawal (p = 0.001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = 0.038) and current agoraphobia (p = 0.022), and reported more days of poor physical health (p = 0.006) and cannabis-related medical problems (p = 0.023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p = 0.006). Men and women did not differ on any measures of baseline cannabis use. Discussion and Conclusion Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. Scientific Significance Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome. PMID:28152236

  13. Add-on treatment with N-acetylcysteine for bipolar depression: a 24-week randomized double-blind parallel group placebo-controlled multicentre trial (NACOS-study protocol).

    PubMed

    Ellegaard, Pernille Kempel; Licht, Rasmus Wentzer; Poulsen, Henrik Enghusen; Nielsen, René Ernst; Berk, Michael; Dean, Olivia May; Mohebbi, Mohammadreza; Nielsen, Connie Thuroee

    2018-04-05

    Oxidative stress and inflammation may be involved in the development and progression of mood disorders, including bipolar disorder. Currently, there is a scarcity of useful treatment options for bipolar depressive episodes, especially compared with the efficacy of treatment for acute mania. N-Acetylcysteine (NAC) has been explored for psychiatric disorders for some time given its antioxidant and anti-inflammatory properties. The current trial aims at testing the clinical effects of adjunctive NAC treatment (compared to placebo) for bipolar depression. We will also explore the biological effects of NAC in this context. We hypothesize that adjunctive NAC treatment will reduce symptoms of depression, which will be reflected by changes in selected markers of oxidative stress. In the study, we will include adults diagnosed with bipolar disorder, in a currently depressive episode. Participants will undertake a 20-week, adjunctive, randomized, double-blinded, parallel group placebo-controlled trial comparing 3 grams of adjunctive NAC daily with placebo. The primary outcome is the mean change over time from baseline to end of study on the Montgomery-Asberg Depression Rating Scale (MADRS). Among the secondary outcomes are mean changes from baseline to end of study on the Bech-Rafaelsen Melancholia Scale (MES), the Young Mania Rating Scale (YMRS), the WHO-Five Well-being Index (WHO-5), the Global Assessment of Functioning scale (GAF-F), the Global Assessment of Symptoms scale (GAF-S) and the Clinical Global Impression-Severity scale (CGI-S). The potential effects on oxidative stress by NAC treatment will be measured through urine and blood samples. DNA will be examined for potential polymorphisms related to oxidative defences. Registered at The European Clinical Trials Database, ClinicalTrials.gov: NCT02294591 and The Danish Data Protection Agency: 2008-58-0035.

  14. Achieving cannabis cessation -- evaluating N-acetylcysteine treatment (ACCENT): design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network.

    PubMed

    McClure, Erin A; Sonne, Susan C; Winhusen, Theresa; Carroll, Kathleen M; Ghitza, Udi E; McRae-Clark, Aimee L; Matthews, Abigail G; Sharma, Gaurav; Van Veldhuisen, Paul; Vandrey, Ryan G; Levin, Frances R; Weiss, Roger D; Lindblad, Robert; Allen, Colleen; Mooney, Larissa J; Haynes, Louise; Brigham, Gregory S; Sparenborg, Steve; Hasson, Albert L; Gray, Kevin M

    2014-11-01

    Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18-50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging

    PubMed Central

    Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

    2017-01-01

    Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4. PMID:28915583

  16. N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging.

    PubMed

    Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

    2017-08-22

    Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ( 89 Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity ( 89 Zr-Trastuzumab HER2-immunoPET) and glucose metabolism ( 18 F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

  17. Achieving Cannabis Cessation - Evaluating N-acetylcysteine Treatment (ACCENT): Design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network

    PubMed Central

    McClure, Erin A.; Sonne, Susan C.; Winhusen, Theresa; Carroll, Kathleen M.; Ghitza, Udi E.; McRae-Clark, Aimee L.; Matthews, Abigail G.; Sharma, Gaurav; Van Veldhuisen, Paul; Vandrey, Ryan G.; Levin, Frances R.; Weiss, Roger D.; Lindblad, Robert; Allen, Colleen; Mooney, Larissa J.; Haynes, Louise; Brigham, Gregory S.; Sparenborg, Steve; Hasson, Albert L.; Gray, Kevin M.

    2014-01-01

    Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18–50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders. PMID:25179587

  18. High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial.

    PubMed

    Johnson, Kara; McEvoy, Charlene E; Naqvi, Sakina; Wendt, Chris; Reilkoff, Ronald A; Kunisaki, Ken M; Wetherbee, Erin E; Nelson, David; Tirouvanziam, Rabindra; Niewoehner, Dennis E

    2016-01-01

    Clinical outcomes are worse in patients with COPD and chronic bronchitis. N-acetylcysteine (NAC) is commonly prescribed for such patients but with uncertain clinical benefits. We postulated that oral NAC, at much larger doses than those ordinarily prescribed, would improve clinical outcomes in a subset of patients with COPD and chronic bronchitis. The aim of this study was to determine whether very high-dose NAC would improve respiratory health status in patients with COPD and chronic bronchitis. Patients with COPD and chronic bronchitis were enrolled in a randomized, controlled, double-blinded trial. Patients received oral NAC (1,800 mg) or matching placebo twice daily for 8 weeks in addition to their usual respiratory medications. The primary outcome, respiratory health status, was assessed by changes in the St George's Respiratory Questionnaire. The effects of NAC on lung function and circulating markers of oxidative stress and inflammation were also evaluated. We terminated the study prematurely because new external information suggested the possibility of a safety issue. Of the planned 130 patients, 51 were randomized and 45 (22 in the placebo arm and 23 in the NAC arm) completed the study. There was no statistically significant difference between changes in the St George's Respiratory Questionnaire total score, comparing NAC to placebo (adjusted mean difference, 0.1 U; 95% CI, -7.8 to 8.18 U; P=0.97). There were also no significant NAC-related improvements in any of the secondary outcomes. In this 8-week trial, we were unable to show any clinical benefit from a very high dose of NAC in patients with COPD and chronic bronchitis.

  19. Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs.

    PubMed

    Pan, Xiaoqi; Wu, Xu; Yan, Dandan; Peng, Cheng; Rao, Chaolong; Yan, Hong

    2018-05-15

    Acrylamide (ACR) is a classic neurotoxin in animals and humans. However, the mechanism underlying ACR neurotoxicity remains controversial, and effective prevention and treatment measures against this condition are scarce. This study focused on clarifying the crosstalk between the involved signaling pathways in ACR-induced oxidative stress and inflammatory response and investigating the protective effect of antioxidant N-acetylcysteine (NAC) against ACR in PC12 cells. Results revealed that ACR exposure led to oxidative stress characterized by significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and glutathione (GSH) consumption. Inflammatory response was observed based on the dose-dependently increased levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). NAC attenuated ACR-induced enhancement of MDA and ROS levels and TNF-α generation. In addition, ACR activated nuclear transcription factor E2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling pathways. Knockdown of Nrf2 by siRNA significantly blocked the increased NF-κB p65 protein expression in ACR-treated PC12 cells. Down-regulation of NF-κB by specific inhibitor BAY11-7082 similarly reduced ACR-induced increase in Nrf2 protein expression. NAC treatment increased Nrf2 expression and suppressed NF-κB p65 expression to ameliorate oxidative stress and inflammatory response caused by ACR. Further results showed that mitogen-activated protein kinases (MAPKs) pathway was activated prior to the activation of Nrf2 and NF-κB pathways. Inhibition of MAPKs blocked Nrf2 and NF-κB pathways. Collectively, ACR activated Nrf2 and NF-κB pathways which were regulated by MAPKs. A crosstalk between Nrf2 and NF-κB pathways existed in ACR-induced cell damage. NAC protected against oxidative damage and inflammatory response induced by ACR by activating Nrf2 and inhibiting NF-κB pathways in PC12 cells. Copyright © 2018 Elsevier B

  20. Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

    PubMed

    Dósa, Edit; Heltai, Krisztina; Radovits, Tamás; Molnár, Gabriella; Kapocsi, Judit; Merkely, Béla; Fu, Rongwei; Doolittle, Nancy D; Tóth, Gerda B; Urdang, Zachary; Neuwelt, Edward A

    2017-10-03

    Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached

  1. Synthesis of the 3-sulfates of N-acetylcysteine conjugated bile acids (BA-NACs) and their transient formation from BA-NACs and subsequent hydrolysis by a rat liver cytosolic fraction as shown by liquid chromatography/electrospray ionization-mass spectrometry.

    PubMed

    Mitamura, Kuniko; Sakai, Toshihiro; Nakai, Risa; Wakamiya, Tateaki; Iida, Takashi; Hofmann, Alan F; Ikegawa, Shigeo

    2011-06-01

    Previous work from this laboratory has reported the chemical synthesis of N-acetylcysteine (NAC) conjugates of natural bile acids (BAs) and shown that such novel conjugates can be formed in vivo in rats to which NAC has been administered. The subsequent fate of such novel conjugates is not known. One possible biotransformation is sulfation, a major pathway for BAs N-acylamidates in patients with cholestatic liver disease. Here, we report the chemical synthesis of the 3-sulfates of the S-acyl NAC conjugates of five natural BAs (cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, and lithocholic). We also measured the sulfation of N-acetylcysteine-natural bile acid (BA-NAC) conjugates when they were incubated with a rat liver cytosolic fraction. The chemical structures of the BA-NAC 3-sulfates were confirmed by proton nuclear magnetic resonance, as well as by means of electrospray ionization-linear ion trap mass spectrometry with negative-ion detection. Upon collision-induced dissociation of singly and doubly charged deprotonated molecules, structurally informative product ions were observed. Using a triple-stage quadrupole instrument, selected reaction monitoring analyses by monitoring characteristic transition ions allowed the achievement of a highly sensitive and specific assay. When BA-NACs were incubated with a rat liver cytosolic fraction to which 3'-phosphoadenosine 5'-phosphosulfate was added, sulfation occurred, but the dominant reaction was hydrolysis of the S-acyl linkage to form the unconjugated BAs. Subsequent sulfation occurred at C-3 on the unconjugated BAs that had been formed from the BA-NACs. Such sulfation was proportional to the hydrophobicity of the unconjugated bile acid. Thus, NAC conjugates of BAs as well as their C-3 sulfates if formed in vivo are rapidly hydrolyzed by cytosolic enzymes.

  2. N-acetylcysteine and endothelial cell injury by sulfur mustard.

    PubMed

    Atkins, K B; Lodhi, I J; Hurley, L L; Hinshaw, D B

    2000-12-01

    Understanding the underlying mechanisms of cell injury and death induced by the chemical warfare vesicant sulfur mustard (HD) will be extremely helpful in the development of effective countermeasures to this weapon of terror. We have found recently that HD induces both apoptosis and necrosis in endothelial cells (Toxicol. Appl. Pharmacol. 1996; 141: 568-583). Pretreatment of the endothelial cells for 20 h with the redox-active agent N-acetyl-L-cysteine (NAC) selectively prevented apoptotic death induced by HD. In this study, we tested the hypotheses that pretreatment with NAC acts through two different pathways to minimize endothelial injury by HD: NAC pretreatment acts via a glutathione (GSH)-dependent pathway; and NAC pretreatment acts to suppress HD-induced activation of the nuclear transcription factor NFkappaB. We used a fluorescence microscopic assay of apoptotic nuclear features to assess viability and electrophoretic mobility shift assays (EMSAs) to assess the activity of NFkappaB following exposure to HD. The cells were treated with 0-10 mM GSH for 1 h prior to and during exposure to 0 or 500 microM HD for 5-6 h. Cells were also treated with 50 mM NAC or 200 microM buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, alone or in combination overnight prior to exposure to 0 or 500 microM HD for 5-6 h. Externally applied GSH up to a concentration of 5 mM had no toxic effect on the cells. Mild toxicity was associated with 10 mM GSH alone. There was a dose-related enhancement of viability when 2.5 and 5 mM GSH were present during the HD exposure. Pretreatment with BSO alone had no discernible toxicity. However, pretreatment with this inhibitor of GSH synthesis potentiated the toxicity of HD. Pretreatment with 50 mM NAC, as previously reported, provided substantial protection. Combining pretreatment with both BSO and NAC eliminated the protective effect of NAC pretreatment alone on HD injury. These observations are highly suggestive that NAC enhances endothelial survival via GSH-dependent effects and confirms and extends the work of others with different models that externally supplied GSH alone may be a fairly effective countermeasure against HD injury of endothelium. We next examined the hypothesis that HD may activate the nuclear transcription factor NFkappaB by performing EMSAs with nuclear extracts of endothelial cells following exposure to 0, 250 or 500 microM HD. This demonstrated an up to 2.5-fold increase (scanning densitometry) in activation of NFkappaB binding to its consensus sequence induced by 500 microM HD after 5 h of HD exposure. Paradoxically, treatment of the endothelial cells alone with 50 mM NAC activated NFkappaB, although HD-induced activation of NFkappaB was partially suppressed by NAC at 5 h. Factor NFkappaB is an important transcription factor for a number of cytokine genes (e.g. tumor necrosis factor, TNF), which can be activated following stress in endothelial cells. Taken together, these observations suggest that the protective effects of NAC may be mediated by enhanced GSH synthesis. The increased GSH may act to scavenge HD and also prevent oxidative activation of NFkappaB. Under some conditions, NAC may act as an oxidizing agent and thus increase NFkappaB activity. The NFkappaB-dependent gene expression may be important in inducing endothelial cell death as well as in generating a local inflammatory reaction associated with the release of endothelial-derived cytokines.

  3. Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents

    PubMed Central

    McClure, Erin A.; Baker, Nathaniel L.; Gray, Kevin M.

    2014-01-01

    Background and Objectives Tobacco and cannabis use are both highly prevalent worldwide. Their co-use is also common in adults and adolescents. Despite this frequent co-occurrence, cessation from both substances is rarely addressed in randomized clinical trials. Given evidence that tobacco use may increase during cannabis cessation attempts, and additionally that tobacco users have poorer cannabis cessation outcomes, we explored tobacco outcomes, specifically cigarette smoking, from an adolescent cannabis cessation trial that tested the efficacy of N-acetylesteine (NAC). Methods Cannabis-dependent adolescents (ages 15–21; n=116) interested in cannabis treatment were randomized to NAC (1200 mg bid) or matched placebo for 8 weeks. Participants did not need to be cigarette smokers or be interested in smoking cessation to qualify for inclusion. Results Approximately 59% of enrolled participants were daily and non-daily cigarette smokers, and only differed from non-smoking participants on the compulsion sub-scale of the Marijuana Craving Questionnaire. Among cigarette smokers who were retained in the study, there was no change in cigarettes per day for either NAC or placebo groups during the 8-week treatment phase. Being a cigarette smoker did not appear to influence the effects of NAC on cannabis abstinence, though there was a trend in the placebo group of poorer cannabis outcomes for cigarette smokers vs. non-smokers. Conclusions No evidence was found of compensatory cigarette smoking during this cannabis cessation trial in adolescents. Further work assessing interventions to reduce both cannabis and tobacco use in this population is greatly needed. PMID:24720376

  4. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

    SciTech Connect

    Santra, Amal; Chowdhury, Abhijit; Ghatak, Subhadip

    2007-04-15

    Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology.more » Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects.« less