Safety assessment of gamma-glutamylcysteine sodium salt

Chandler, S.D.; Zarka, Martin; Babu, Subramanian; Suhas, Yelshetty; Reddy, Kandula Ravindra; Bridge, Wallace

doi:10.1016/j.yrtph.2012.05.008

Cited by 19 publications

(11 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A series of therapies and adjunctive drugs, such as glucocorticoids, insulin, and recombinant activated protein C, have been used for clinical treatment for sepsis [38] , [39] , [40] , however, these drugs induce several side effects ranging from potentially life-threatening (e.g., cardiovascular events and infections) to those less clinically serious (e.g., sleep disturbances, stomach upset during the treatment period) [41] , [42] , [43] . γ-GC is a relatively unexplored option for sepsis treatment, despite its exhibiting anti-inflammatory effects with little or no side effects [44] .…”

Section: Discussionmentioning

confidence: 99%

γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level

Yang

Hang

et al. 2019

Redox Biology

View full text Add to dashboard Cite

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection and characterized by redox imbalance and severe oxidative stress. Glutathione (GSH) serves several vital functions, including scavenging free radicals and maintaining intracellular redox balance. Extracellular GSH is unable to be taken into the majority of human cells, and the GSH prodrug N-acetyl-l-cysteine (NAC) does not exhibit promising clinical effects. γ-glutamylcysteine (γ-GC), an intermediate dipeptide of the GSH-synthesis pathway and harboring anti-inflammatory properties, represents a relatively unexplored option for sepsis treatment. The anti-inflammatory efficiency of γ-GC and the associated molecular mechanism need to be explored. In vivo investigation showed that γ-GC reduced sepsis lethality and attenuated systemic inflammatory responses in mice, as well as inhibited lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), high-mobility group box 1 (HMGB1), and nitric oxide (NO) and the expression of inducible NO synthase and cyclooxygenase 2 in RAW264.7 cells. Moreover, both in vivo and in vitro experiments demonstrated that γ-GC exhibited better therapeutic effects against inflammation compared with N-acetyl-L-cysteine (NAC) and GSH. Mechanistically, γ-GC suppressed LPS-induced reactive oxygen species accumulation and GSH depletion. Inflammatory stimuli, such as LPS treatment, upregulated the expression of glutathione synthetase via activating nuclear factor-erythroid 2-related factor (Nrf2) and nuclear factor kappa B (NF-κB) pathways, thereby promoting synthesis of GSH from γ-GC. These findings suggested that γ-GC might represent a potential therapeutic agent for sepsis treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level

Yang

Hang

et al. 2019

Redox Biology

View full text Add to dashboard Cite

show abstract

“…With regards to GGC, the 2000 μM equate to 17.5 g of an in vivo dose. Animal safety trials have demonstrated that GGC is safe at repeated doses at a limit dosage of 1000 mg/kg over a 90-day period [12]. No adverse effect was observed in a human clinical trial of healthy, non-fasting subjects [13].…”

Section: Discussionmentioning

confidence: 99%

“…The immediate precursor to glutathione, γ -glutamylcysteine (GGC), a dietary supplement has shown superior efficacy in increasing intracellular GSH levels in cardiac [9], liver [10] and neural [11] cells in vitro. Animal safety trials have demonstrated that GGC is safe at repeated doses at a limit dosage of 1000 mg/kg over a 90-day period [12]. A randomised human pilot study found that single doses of oral administered GGC at 2 g and 4 g significantly increased GSH levels in lymphocytes within 3h, with a return to normal homeostatic levels by 5h [13].…”

Section: Introductionmentioning

confidence: 99%

Novel antioxidant therapy with the immediate precursor to glutathione, γ-glutamylcysteine (GGC), ameliorates LPS-induced cellular stress in anin vitrocystic fibrosis model

Hewson

Capraro

Wong

et al. 2020

Preprint

View full text Add to dashboard Cite

IntroductionGlutathione deficiency and chronic bacterial inflammation exacerbates the oxidative stress damage to airways in cystic fibrosis. Improvements to current antioxidant therapeutic strategies are needed. Dietary supplement, γ-glutamylcysteine (GGC), the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against Pseudomonas aeruginosa derived lipopolysaccharide (LPS), a prominent factor in mediating both bacterial virulence and host responses, in CF remains unassessed.MethodsPrimary F508del/F508del mucociliary differentiated bronchial and nasal epithelial cells were created to model LPS-induced oxidative stress and inflammation of CF. The proteomic signature of GGC treated cells was resolved by qLC-MS/MS. Parameters including cell redox state (glutathione, ROS), anti-inflammatory mediators (IL-8, IDO-1) and cellular health (membrane integrity, stress granule formation and cell viability) were assayed.ResultsProteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced ROS and stress granule formation, while significantly increasing intracellular glutathione levels and improving epithelial cell barrier integrity. Moreover, we compared the effect of GGC with thiols NAC and glutathione on cell viability. GGC was the only thiol that increased cell viability; protecting cells against LPS induced cell death. Both therapeutic and prophylactic treatments were successful.ConclusionTogether, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress related damage to airways in Cystic Fibrosis.

show abstract

“…Alternatively, GGC can be taken up by cells intact where it is converted to glutathione [16][17][18]. Furthermore, GGC itself is an antioxidant by acting as a cofactor for GPx where it is effectively comparable to GSH for hydrogen peroxide detoxification [19] Animal safety trials have demonstrated that GGC is safe at a repeated limit dosage of 1000 mg/kg/day over a 90-day period [20]. Exogenous supply of GGC, which is sold as a dietary supplement in the USA, has been reported to suppress oxidative injury and improve mitochondrial function both in in vitro and in vivo animal models of oxidative stress-induced tissue damage [18,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells

et al. 2020

View full text Add to dashboard Cite

Systemic glutathione deficiency, inflammation, and oxidative stress are hallmarks of cystic fibrosis (CF), an inherited disease that causes persistent lung infections and severe damage to the respiratory system and many of the body organs. Improvements to current antioxidant therapeutic strategies are needed. The dietary supplement, γ-glutamylcysteine (GGC), which is the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against oxidative stress induced by Pseudomonas aeruginosa, which is a common and chronic pathogen infecting lungs of CF patients, remains unassessed. Primary mucocilliary differentiated airway (bronchial and/or nasal) epithelial cells were created from four individuals with CF. Airway oxidative stress and inflammation was induced by P. aeruginosa lipopolysaccharide (LPS). Parameters including global proteomics alterations, cell redox state (glutathione, oxidative stress), pro-inflammatory mediators (IL-8, IDO-1), and cellular health (membrane integrity, stress granule formation, cell metabolic viability) were assayed under six experimental conditions: (1) Mock, (2) LPS-challenged (3) therapeutic, (4) prophylactic (5) therapeutic and prophylactic and (6) GGC alone. Proteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced oxidative stress and stress granule formation, while significantly increasing total intracellular glutathione levels, metabolic viability and improving epithelial cell barrier integrity. Both therapeutic and prophylactic treatments were successful. Together, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress-related damage to airways in cystic fibrosis.

show abstract

Safety assessment of gamma-glutamylcysteine sodium salt

Cited by 19 publications

References 17 publications

γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level

γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level

Novel antioxidant therapy with the immediate precursor to glutathione, γ-glutamylcysteine (GGC), ameliorates LPS-induced cellular stress in anin vitrocystic fibrosis model

Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells

Contact Info

Product

Resources

About