Gamma-glutamylcysteine

Gamma-glutamylcysteine (γ-Glu-Cys) is an orally active, blood-brain barrier permeable dipeptide. Gamma-glutamylcysteine activates AMPK, SIRT1, IL-4/STAT6, AC/cAMP/PI3K, IGF-1R/IRS1/PI3K, and Nrf2 signaling pathways; it inhibits NF-κB, JAK1/STAT1/3, MAPKs, cadmium-induced p38 MAPK, JNK, and PI3K/Akt signaling pathways. Gamma-glutamylcysteine regulates macrophage polarization, modulates the trafficking of CD36 and GLUT4, induces glutathione synthesis, improves metabolic dysfunction, reduces lipid deposition, ameliorates glucose homeostasis, inhibits apoptosis (Apoptosis), stabilizes mitochondria, suppresses lipid peroxidation, iron accumulation and ferroptosis (Ferroptosis), reduces ds-HMGB1 levels, reverses mechanical hyperalgesia, and alleviates hepatic lipid droplet formation. Gamma-glutamylcysteine is applicable to research related to inflammatory bowel disease, type 2 diabetes, cadmium-induced neurotoxicity, Alzheimer's disease, cerebral ischemia/reperfusion injury, neuropathy, and alcoholic liver disease^{[1][2][3][4][5][6][8][9]}. In Vitro:Gamma-glutamylcysteine (0-80 μM; 24 h) inhibits M1 polarization of Raw264.7 macrophages by suppressing the JAK1/STAT1/3, AKT, MAPKs and NF-κB signaling pathways, while activating the AMPK/SIRT1 axis^[1].
Gamma-glutamylcysteine (0-80 μM; 24 h) promotes M2 polarization of Raw264.7 macrophages, and drives their repolarization from M1 to M2 via activation of the IL-4/STAT6 and AMPK/SIRT1 signaling pathways^[1].
Gamma-glutamylcysteine (20-80 μM; 24 h) induces the polarization of human Jurcat CD4⁺ T lymphocytes toward Th2 by promoting IL-4 secretion^[1].
Gamma-glutamylcysteine (2 mM; 6 h) activates the Nrf2 signaling pathway via nuclear translocation and upregulates the expression of antioxidant target genes and proteins in primary intestinal epithelial cells (IECs) of chicken embryos^[2].
Gamma-glutamylcysteine (2 mM; 6 h) inhibits oxidative stress induced by Salmonella typhimurium in primary wild-type chicken embryonic intestinal epithelial cells (IECs) by maintaining Nrf2 activation^[2].
Gamma-glutamylcysteine (2 mM; 6 h) protects primary intestinal epithelial cells (IECs) from wild-type chicken embryos against intestinal barrier disruption and inflammatory injury induced by Salmonella typhimurium, and this protective effect depends on the Nrf2 signaling pathway^[2].
Gamma-glutamylcysteine (20-80 μM; administered for 24 h after 24 h of pre-treatment with insulin + PA) dose-dependently activates the IGF-1R/IRS1/PI3K/Akt signaling pathway in insulin-resistant HepG2 cells, primary mouse hepatocytes and C2C12 myotubes induced by Insulin (HY-P701240) + Palmitic acid (HY-N0830) (PA), by increasing the phosphorylation levels of key pathway proteins^[3].
Gamma-glutamylcysteine (2-4 mM; 2 h pretreatment followed by 12 h cadmium exposure) inhibits the activation of JNK/p38 MAPK and PI3K/Akt signaling pathways in cadmium-treated cells by downregulating the expression of pro-apoptotic markers and normalizing the Bax/Bcl-2 ratio. This consequently suppresses cadmium-induced changes in apoptosis-related proteins, inhibits cadmium-induced cell apoptosis, and prevents cadmium-induced mitochondrial transmembrane potential depolarization in PC12 cells^[4].
Gamma-glutamylcysteine (2-4 mM; 2 h pretreatment followed by 12 h cadmium exposure) dose-dependently inhibits cadmium-induced oxidative stress in PC12 cells by reducing ROS and lipid peroxidation levels, restoring antioxidant enzyme activity, and maintaining intracellular GSH homeostasis^[4].
Gamma-glutamylcysteine (0.25-16 mM; 24 h) shows no toxicity to BV-2 cells at concentrations up to 4 mM after 24 h of incubation, while higher concentrations (8, 16 mM) reduce cell viability in a dose-dependent manner^[5].
Gamma-glutamylcysteine (2-4 mM; 30 min pretreatment, 24 h AβO exposure) dose-dependently inhibits the release of proinflammatory mediators (TNF-α, IL-1β, NO) and the expression of proinflammatory proteins (iNOS, COX-2) induced by AβO in BV-2 cells, suppresses AβO-induced oxidative stress, and restores the antioxidant capacity of cells^[5].
Gamma-glutamylcysteine (4 mM; 30 min pretreatment, followed by 6-24 h of AβO exposure) inhibits AβO-induced activation of the NF-κB signaling pathway in BV-2 cells, upregulates and maintains the expression of Nurr1 mRNA and protein, and thereby exerts anti-inflammatory effects by suppressing the binding of NF-κB p65 to the iNOS promoter induced by AβO in BV-2 cells^[5].
Gamma-glutamylcysteine (2-4 mM; 30 min pretreatment, followed by 24 h AβO exposure) dose-dependently inhibits the release of proinflammatory mediators (TNF-α, IL-1β, NO) induced by AβO in primary mouse microglia, suppresses oxidative stress, and restores the antioxidant capacity of cells^[5].
Gamma-glutamylcysteine (0.25-2 mM; 12 h) increases GSH levels, GSH/GSSG ratio, GPX activity, and cell viability in primary cortical neurons treated with OGD/R, with the strongest effect observed at 2 mM for 12 h^[6].
Gamma-glutamylcysteine (0.85-7 mM; 12 h) increases GSH level, GSH/GSSG ratio, GPX activity and cell viability in PC12 cells treated with oxygen-glucose deprivation/reoxygenation (OGD/R)^[6].
Gamma-glutamylcysteine (1.7-7 mM; 0-12 h, time-course 0-12 h) regulates the mRNA and protein levels of GSS in OGD/R-treated PC12 cells, promotes nuclear translocation of Nrf2 in cells, reduces the interaction between Nrf2 and Keap1, inhibits the upregulation of Keap1, decreases MDA and Fe²⁺ levels, improves cell viability, and thereby inhibits ferroptosis in cells^[6].
Gamma-glutamylcysteine (3.5 mM; 12 h, time-course 0-12 h) activates Nrf2 in OGD/R-treated PC12 cells by increasing the level of phosphorylated PKC-ε^[6].
Gamma-glutamylcysteine (200 μM; 15 min pre-incubation, 24 h co-incubation with oligomeric Aβ₄₀) protects primary human astrocytes against oligomeric Aβ₄₀-induced cytotoxicity, apoptosis, oxidative stress, neuroinflammation, and dysregulated metalloproteinase activity, while restoring antioxidant status and GSH levels^[7].
Gamma-glutamylcysteine (20-80 μM; 2 h pretreatment followed by 24 h ethanol exposure; 400 μM; 24 h single treatment) protects human L02 hepatocytes against ethanol-induced injury by dose-dependently increasing cell viability, reducing hepatic enzyme release, inhibiting cell apoptosis, suppressing oxidative stress and mitochondrial damage, and attenuating the activation of pro-inflammatory signaling pathways^[9]. In Vivo:Gamma-glutamylcysteine (600-1200 mg/kg; p.o.; daily; ~3 days) significantly increases the survival rate of mice with TNBS-induced inflammatory bowel disease, alleviates colon damage, and shifts macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, with both doses exhibiting therapeutic efficacy^[1].
Gamma-glutamylcysteine (250-500 mg/kg; p.o.; daily; 8 weeks) dose-dependently improves glycemic control, insulin sensitivity, β-cell function and hepatic steatosis, while alleviating diabetes-related organ damage in db/db mice^[3].
Gamma-glutamylcysteine (100-400 mg/kg/d; p.o.; daily; 20 days) dose-dependently inhibits AβO-induced neuroinflammation in male ICR mice^[5].
Gamma-glutamylcysteine (688 mg/kg; p.o.; single dose) upregulates GSH by activating the PKC-ε/Nrf2/GSS pathway, and significantly reduces cerebral infarction volume, neurological dysfunction, and neuronal ferroptosis induced by cerebral ischemia/reperfusion injury in male Sprague-Dawley rats^[6].
Gamma-glutamylcysteine (600 mg/kg; p.o.; once) significantly reduces the level of ds-HMGB1 in DRG of OIPN mice and reverses oxaliplatin-induced mechanical hyperalgesia^[8].
Gamma-glutamylcysteine (700-1200 mg/kg; p.o.; daily; 7 days) alleviates acute ethanol-induced hepatotoxicity in male C57BL/6JNifdc mice in a dose-dependent manner by reducing hepatic enzyme release, restoring hepatic antioxidant levels, alleviating histopathological damage, and inhibiting inflammatory signaling pathways^[9].