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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

OBJECTIVE

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).

METHODS

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.

RESULTS

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 Δψm (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).

CONCLUSION

This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

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  • Authors+Show Affiliations

    ,

    State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York 13210, USA.

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    Source

    Arthritis and rheumatism 64:9 2012 Sep pg 2937-46

    MeSH

    Acetylcysteine
    Adult
    Double-Blind Method
    Female
    Free Radical Scavengers
    Humans
    Lupus Erythematosus, Systemic
    Male
    Membrane Potential, Mitochondrial
    Middle Aged
    Pilot Projects
    Placebos
    Severity of Illness Index
    T-Lymphocytes
    TOR Serine-Threonine Kinases
    Treatment Outcome

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22549432

    Citation

    Lai, Zhi-Wei, et al. "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." Arthritis and Rheumatism, vol. 64, no. 9, 2012, pp. 2937-46.
    Lai ZW, Hanczko R, Bonilla E, et al. 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. Arthritis Rheum. 2012;64(9):2937-46.
    Lai, Z. W., Hanczko, R., Bonilla, E., Caza, T. N., Clair, B., Bartos, A., ... Perl, A. (2012). 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. Arthritis and Rheumatism, 64(9), pp. 2937-46. doi:10.1002/art.34502.
    Lai ZW, et al. 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. Arthritis Rheum. 2012;64(9):2937-46. PubMed PMID: 22549432.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Lai,Zhi-Wei, AU - Hanczko,Robert, AU - Bonilla,Eduardo, AU - Caza,Tiffany N, AU - Clair,Brandon, AU - Bartos,Adam, AU - Miklossy,Gabriella, AU - Jimah,John, AU - Doherty,Edward, AU - Tily,Hajra, AU - Francis,Lisa, AU - Garcia,Ricardo, AU - Dawood,Maha, AU - Yu,Jianghong, AU - Ramos,Irene, AU - Coman,Ioana, AU - Faraone,Stephen V, AU - Phillips,Paul E, AU - Perl,Andras, PY - 2012/5/3/entrez PY - 2012/5/3/pubmed PY - 2012/12/10/medline SP - 2937 EP - 46 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 64 IS - 9 N2 - OBJECTIVE: 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). METHODS: 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. RESULTS: 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 Δψm (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). CONCLUSION: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes. SN - 1529-0131 UR - https://www.unboundmedicine.com/medline/citation/22549432/full_citation L2 - https://doi.org/10.1002/art.34502 DB - PRIME DP - Unbound Medicine ER -