Dataset Information

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

ABSTRACT: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (??m) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC).A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls.NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased ??m (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4-CD8- T cells (mean ± SEM 1.35 ± 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049).This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

SUBMITTER: Lai ZW

PROVIDER: S-EPMC3411859 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

Lai Zhi-Wei ZW Hanczko Robert R Bonilla Eduardo E Caza Tiffany N TN Clair Brandon B Bartos Adam A Miklossy Gabriella G Jimah John J Doherty Edward E Tily Hajra H Francis Lisa L Garcia Ricardo R Dawood Maha M Yu Jianghong J Ramos Irene I Coman Ioana I Faraone Stephen V SV Phillips Paul E PE Perl Andras A

Arthritis and rheumatism 20120901 9

<h4>Objective</h4>Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC).<h4>Methods</h4>A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. ...[more]

PMID: 22549432

Similar Datasets

Project description:IntroductionEndothelial function is significantly impaired in patients with SLE compared to healthy controls. Elevated activation of the mammalian target of rapamycin complex 1 (mTORC1) is reported in humans and mice with SLE. However, it is unclear if elevated mTORC1 in SLE contributes to impaired mitophagy and endothelial dysfunction. Therefore, we tested the hypothesis that inhibiting mTORC1 with rapamycin would increase mitophagy and attenuate endothelial dysfunction and inflammatory responses in SLE.MethodsNine-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned into rapamycin treatment (lpr_Rapamycin and MpJ_Rapamycin) or control (lpr_Control and MpJ_Control) groups. Rapamycin was injected i.p. 3 days per week for 8 weeks. After 8 weeks, endothelium-dependent vasorelaxation to acetylcholine (ACh) and endothelium-independent vasorelaxation to sodium nitroprusside (SNP) were measured in thoracic aortas using a wire myograph.ResultsMTORC1 activity was increased in aorta from lpr mice as demonstrated by increased phosphorylation of s6rp and p70s6k and significantly inhibited by rapamycin (s6rp, p < 0.0001, p70s6k, p = 0.04, respectively). Maximal responses to Ach were significantly impaired in lpr_Control (51.7% ± 6.6%) compared to MpJ_Control (86.7% ± 3.6%) (p < 0.0001). Rapamycin prevented endothelial dysfunction in the thoracic aorta from lupus mice (lpr_Rapamycin) (79.6% ± 4.2%) compared to lpr_Control (p = 0.002). Maximal responses to SNP were not different across groups. Phosphorylation of endothelial nitric oxide synthase also was 42% lower in lpr_Control than MpJ_Control and 46% higher in lpr_Rapamycin than lpr_Control. The inflammatory marker, vascular cell adhesion protein 1 (Vcam 1), was elevated in aorta from lupus mice compared with healthy mice (p = 0.001), and significantly reduced with Rapamycin treatment (p = 0.0021). Mitophagy markers were higher in lupus mice and reduced by rapamycin treatment, suggesting altered mitophagy in lpr mice.ConclusionCollectively, these results demonstrate the beneficial effects of inhibiting mTORC1 on endothelial function in SLE mice and suggest inflammation and altered mitophagy contribute to endothelial dysfunction in SLE.

Dataset Information

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

Publications

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets