Cystine levels, cystine flux, and protein catabolism in cancer cachexia, HIV/SIV infection, and senescence

Hack, Volker; Schmid, Daniel; Breitkreutz, Raoul; Stahl-Henning, C; Drings, P.; Kinscherf, Ralf; Taut, Friedemann; Holm, Eggert; Dröge, Wulf

doi:10.1096/fasebj.11.1.9034170

Cited by 61 publications

(44 citation statements)

References 9 publications

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“…To ameliorate these changes and their immunological consequences, we (Dröge, 1989;Dröge et al 1992) proposed treatment with a cysteine derivative such as N-acetyl-cysteine. Subsequently, the abnormal cysteine status of HIV-infected patients and simian immunodeficiency virus-infected macaques has been confirmed by other research groups (Eck et al 1991;Staal et al 1992;Hortin et al 1994;Akerlund et al 1996;Hack et al 1997;Walmsley et al 1997). Several groups also reported a significant decrease in the intracellular glutathione level of the peripheral-blood mononuclear cells from HIV-infected patients (Eck et al 1989; Roederer et al Herzenberg et al 1997;Jahoor et al 1999) and simian immunodeficiency virus-infected rhesus macaques (Eck et al 1991).…”

Section: Massive Loss Of Cysteine In Human Immunodeficiency Virus Infmentioning

confidence: 75%

Glutathione and immune function

2000

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The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. This factor has been studied most extensively in the case of human immunodeficiency virus (HIV)-infected patients who were found to experience, on average, a massive loss of S equivalent to a net loss of approximately 4 g cysteine/d. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions.

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Section: Massive Loss Of Cysteine In Human Immunodeficiency Virus Infmentioning

confidence: 75%

Glutathione and immune function

2000

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“…Depletion of branched chain amino acids has been implicated in muscle shrinkage observed in HD (5). Similarly, a pathogenic role for cysteine deficiency in HD is supported by the beneficial effects of N-acetylcysteine (8,27) and couples with evidence for cysteine disturbances in other conditions of oxidative stress including aging, neurodegeneration, AIDS, and insulin resistance syndrome (28)(29)(30)(31)(32). Disturbances of cysteine disposition in multiple diseases may reflect a form of "cysteine stress" with widespread impact.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

Sbodio

Snyder

Paul

2016

Proc. Natl. Acad. Sci. U.S.A.

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Disturbances in amino acid metabolism, which have been observed in Huntington’s disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.

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“…Franklin et al have reported that the peak GSH-induced proliferation is consistently fourfold greater in splenocytes from old rats as compared to young rats when cells are stimulated with concanavalin A. The low plasma levels of cystine, one of the precursors of GSH, in old age [15] may result in high responsiveness to exogenous cystine. Although the precise mechanisms responsible for this difference are obscure, our results suggest that the GSH peroxidase-dependent detoxification system is defective in T lymphocytes from aged animals and that exogenous GSH is more effective in augmenting proliferation of splenocytes from aged animals than of those from young animals [8].…”

Section: Discussionmentioning

confidence: 99%

“…Regulation of the plasma cystine level is disrupted in conditions with progressive skeletal muscle catabolism, including cancer, HIV infection and old age [15]. Virtually all diseases in which abnormally low Open and closed bars indicate data for the control and combined administration groups, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Combined Administration L-Cystine and L-Theanine Enhances Immune Functions and Protects against Influenza Virus Infection in Aged Mice

et al. 2010

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ABSTRACT. Cell-mediated and humoral immune responses are attenuated with aging. Intracellular glutathione (GSH) levels also decrease with aging. Previously, we have reported that combined administration of L -cystine and L -theanine enhances antigen-specific IgG production, partly through augmentation of GSH levels and T helper 2-mediated responses in 12-week-old mice. These findings suggest that combined administration of L -cystine and L -theanine to aged mice improves immune responses via increase of GSH synthesis. Here, we examined the effects of combined administration of L -cystine and L -theanine on antigen-specific antibody production and influenza virus infection in aged mice. Combined administration of these amino acids for 14 days before primary immunization significantly enhanced the serum antigen-specific IgM and IgG levels in 24-month-old mice. Furthermore, 13-month-old mice co-treated with these amino acids orally for 10 days had significantly lower lung viral titers than controls at 6 days after influenza virus infection. In addition, this co-treatment also significantly prevented the weight loss associated with infection. Enhancement of anti-influenza-virus IgG antibodies by combined administration of L -cystine and L -theanine was seen 10 days after infection. The significantly elevated serum interleukin-10/interferon- ratio and -glutamylcysteine synthetase mRNA expression, which is the rate-limiting enzyme of GSH synthesis, in the spleen 3 days after infection may have contributed to the observed beneficial effects. These results suggest that combined administration of L -cystine and L -theanine enhances immune function and GSH synthesis which are compromised with advanced age, and may become a useful strategy in healthy aging. With aging, the human body's defense capability weakens, including production of antibodies and cytotoxic T lymphocytes (CTL) and cellular immune function [12,28]. These age-related alterations seem to result from oxidative stress [9]. Diet supplementation with antioxidants has been used to prevent or delay the onset of age-related immune impairment [7]. For example, a diet that contains the antioxidant 2-mercaptoethanol, which reduces cystine to cysteine and increases the intracellular concentration of glutathione (GSH; L --glutamyl-L -cysteinyl-glycine), improves several types of immune response in aged mice [17]. Dietary supplementation with GSH, another antioxidant, has also been shown to increase cell-mediated immunity in aged mice [11]. In addition, GSH levels and the gene expression of -glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, are known to decrease with aging [24]. These results suggest that GSH antioxidant therapy may aid in preventing or delaying the onset of age-related immune impairment.A recent study we performed indicated that combined administration of L -cystine and L -theanine (-glutamylethylamide, a specific amino acid found in green tea) to young mice increases the GSH level in the liver and also enhances the s...

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Cystine levels, cystine flux, and protein catabolism in cancer cachexia, HIV/SIV infection, and senescence

Cited by 61 publications

References 9 publications

Glutathione and immune function

Glutathione and immune function

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

Combined Administration L-Cystine and L-Theanine Enhances Immune Functions and Protects against Influenza Virus Infection in Aged Mice

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