{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe glutamate‐cysteine ligase catalytic subunit (GCLC) is the rate‐limiting enzyme in the de novo synthesis of glutathione (GSH), a key cellular antioxidant. Multiple studies have demonstrated that under conditions of oxidative stress—from schizophrenia‐related redox imbalances to xenobiotic challenges—GCLC expression and activity are crucial for maintaining intracellular GSH levels and redox homeostasis. For example, fibroblasts from schizophrenia patients exhibit reduced GCLC protein expression associated with a diminished ability to synthesize GSH, while cystine deprivation can trigger a non‐canonical activity of GCLC that produces γ–glutamyl peptides to protect against ferroptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGCLC expression is finely tuned by various extracellular stimuli and intracellular signaling pathways. Melatonin can stimulate GCLC gene expression through Nrf2 translocation in keratinocytes, whereas vitamin D is reported to upregulate GCLC in monocytes. Moreover, insulin signaling in human brain endothelial cells promotes GCLC expression via the PI3K/Akt/mTOR/Nrf2 cascade, further enhancing GSH recovery during oxidative challenge. Inflammatory mediators such as TNF‑α, acting through transcriptional coactivators like LEDGF, also increase GCLC expression. In addition, posttranslational modifications—such as 4‑hydroxynonenal adduction of specific cysteine residues—can alter the enzymatic activity and assembly of the GCLC-containing holoenzyme, while hydrogen sulfide (H₂S) upregulates GCLC to boost GSH levels and inhibit proinflammatory cytokine release."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its regulation by stress signals, genetic variations in the GCLC gene have been repeatedly linked to disease susceptibility. Polymorphisms—such as GAG‐repeat variants—are associated with altered GCLC expression and GSH production in disorders including schizophrenia, where high‐risk genotypes correlate with lower fibroblast GSH and altered plasma thiol profiles. Similar genetic associations have been observed with coronary vasomotor dysfunction, non‐alcoholic fatty liver disease, and even in conditions related to metal detoxification (e.g. methylmercury retention). In addition, studies in patients with endometriosis, diabetic nephropathy, and stroke have implicated GCLC polymorphisms in the modulation of redox balance and vascular health, while mutations leading to deficiency of the catalytic subunit can result in clinical manifestations such as hemolytic anemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_fs", "start_ref": "16", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of oncology, aberrant regulation of GCLC has been implicated in the development of drug resistance and tumor progression. Elevated GCLC expression driven by factors such as hypoxia inducible Nrf2 activation, antiestrogen treatments, or oncogenic regulators (e.g. MYCN and epigenetic modifiers like G9a) results in enhanced GSH synthesis that can protect cancer cells from chemotherapeutic agents. This has been observed in breast, ovarian, head and neck, colon, and neuroblastoma tumors, where GCLC‐mediated increases in antioxidant capacity contribute to a chemoresistant phenotype. Moreover, microRNA regulation of GCLC may further modulate GSH levels and influence the response to oxidative stress in various tumor types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "René Gysin, Rudolf Kraftsik, Julie Sandell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0706778104"}], "href": "https://doi.org/10.1073/pnas.0706778104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17921251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17921251"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yun Pyo Kang, Andrea Mockabee-Macias, Chang Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2020.12.007"}], "href": "https://doi.org/10.1016/j.cmet.2020.12.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33357455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33357455"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Dale A Dickinson, Anna-Liisa Levonen, Douglas R Moellering, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human glutamate cysteine ligase gene regulation through the electrophile response element."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2004.06.011"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2004.06.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15451055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15451055"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Shun-ichi Koide, Kiyotaka Kugiyama, Seigo Sugiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Coll Cardiol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0735-1097(02)02866-8"}], "href": "https://doi.org/10.1016/s0735-1097(02"}, {"type": "t", "text": "02866-8) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12598062"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12598062"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Alessandra Rinna, Henry Jay Forman "}, {"type": "b", "children": [{"type": "t", "text": "SHP-1 inhibition by 4-hydroxynonenal activates Jun N-terminal kinase and glutamate cysteine ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2007-0371OC"}], "href": "https://doi.org/10.1165/rcmb.2007-0371OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18276794"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18276794"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "David Hamilton, Jian Hui Wu, Moulay Alaoui-Jamali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2002-11-3622"}], "href": "https://doi.org/10.1182/blood-2002-11-3622"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12663448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12663448"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Konrad Kleszczyński, Detlef Zillikens, Tobias W Fischer "}, {"type": "b", "children": [{"type": "t", "text": "Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pineal Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jpi.12338"}], "href": "https://doi.org/10.1111/jpi.12338"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27117941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27117941"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sushil K Jain, David Micinski "}, {"type": "b", "children": [{"type": "t", "text": "Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2013.06.004"}], "href": "https://doi.org/10.1016/j.bbrc.2013.06.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23770363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23770363"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Masahiro Okouchi, Naotsuka Okayama, Jonathan Steven Alexander, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NRF2-dependent glutamate-L-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia- induced brain endothelial cell apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Neurovasc Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/156720206778792876"}], "href": "https://doi.org/10.2174/156720206778792876"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17109620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17109620"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "William Langston, Magdalena L Circu, Tak Yee Aw "}, {"type": "b", "children": [{"type": "t", "text": "Insulin stimulation of gamma-glutamylcysteine ligase catalytic subunit expression increases endothelial GSH during oxidative stress: influence of low glucose."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2008.09.013"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2008.09.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18926903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18926903"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yoshihiro Takamura, Nigar Fatma, Eri Kubo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of heavy subunit chain of gamma-glutamylcysteine synthetase by tumor necrosis factor-alpha in lens epithelial cells: role of LEDGF/p75."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00398.2005"}], "href": "https://doi.org/10.1152/ajpcell.00398.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16403949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16403949"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Donald S Backos, Kristofer S Fritz, James R Roede, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2010.10.694"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2010.10.694"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20970495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20970495"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Sushil K Jain, Laura Huning, David Micinski "}, {"type": "b", "children": [{"type": "t", "text": "Hydrogen sulfide upregulates glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione and inhibits interleukin-1β secretion in monocytes exposed to high glucose levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Metab Syndr Relat Disord (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/met.2014.0022"}], "href": "https://doi.org/10.1089/met.2014.0022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24665821"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24665821"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Lijing Xin, Ralf Mekle, Margot Fournier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Bull (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/schbul/sbw038"}], "href": "https://doi.org/10.1093/schbul/sbw038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27069063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27069063"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "René Gysin, Rudolf Kraftsik, Olivier Boulat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Antioxid Redox Signal (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/ars.2010.3463"}], "href": "https://doi.org/10.1089/ars.2010.3463"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20673128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20673128"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Claudia Pinto Marques Souza Oliveira, José Tadeu Stefano, Ana Mercedes Cavaleiro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes in non-alcoholic fatty liver disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gastroenterol Hepatol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1440-1746.2009.06001.x"}], "href": "https://doi.org/10.1111/j.1440-1746.2009.06001.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19817962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19817962"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Fernando Augusto de Lima Marson, Carmen Sílvia Bertuzzo, Rodrigo Secolin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic interaction of GSH metabolic pathway genes in cystic fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-14-60"}], "href": "https://doi.org/10.1186/1471-2350-14-60"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23758905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23758905"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Sailendra N Nichenametla, Irina Ellison, Ana Calcagnotto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of gamma-glutamylcysteine ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2008.05.012"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2008.05.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18549827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18549827"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "B L Man, L Baum, Y P Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic polymorphisms of Chinese patients with ischemic stroke and concurrent stenoses of extracranial and intracranial vessels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jocn.2010.01.050"}], "href": "https://doi.org/10.1016/j.jocn.2010.01.050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20615707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20615707"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Hipolito M Custodio, Karin Broberg, Maria Wennberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in glutathione-related genes affect methylmercury retention."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Environ Health (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00039890409603438"}], "href": "https://doi.org/10.1080/00039890409603438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16599007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16599007"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Karin Schläwicke Engström, Ulf Strömberg, Thomas Lundh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic variation in glutathione-related genes and body burden of methylmercury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Environ Health Perspect (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1289/ehp.10804"}], "href": "https://doi.org/10.1289/ehp.10804"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18560528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18560528"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "L Marcellin, P Santulli, S Chouzenoux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2017.04.362"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2017.04.362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28457937"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28457937"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Suzana M Vieira, Maria B Monteiro, Tatiana Marques, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-12-129"}], "href": "https://doi.org/10.1186/1471-2350-12-129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21962117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21962117"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Saravanabavan Sayanthooran, Dhammika N Magana-Arachchi, Lishanthe Gunerathne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potential diagnostic biomarkers for chronic kidney disease of unknown etiology (CKDu) in Sri Lanka: a pilot study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Nephrol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12882-017-0440-x"}], "href": "https://doi.org/10.1186/s12882-017-0440-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28103909"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28103909"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Jhih-Pu Syu, Jen-Tsan Chi, Hsiu-Ni Kung "}, {"type": "b", "children": [{"type": "t", "text": "Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.7406"}], "href": "https://doi.org/10.18632/oncotarget.7406"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26894974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26894974"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Monica M Montano, Huayun Deng, Min Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1207358"}], "href": "https://doi.org/10.1038/sj.onc.1207358"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14676828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14676828"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Marco Fiorillo, Federica Sotgia, Diego Sisci, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial \"power\" drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15852"}], "href": "https://doi.org/10.18632/oncotarget.15852"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28411284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28411284"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Filipa Lopes-Coelho, Sofia Gouveia-Fernandes, Luís G Gonçalves, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-015-4290-5"}], "href": "https://doi.org/10.1007/s13277-015-4290-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26520442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26520442"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Chia-Wen Liu, Kuo-Tai Hua, Kai-Chun Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-16-0567-T"}], "href": "https://doi.org/10.1158/1535-7163.MCT-16-0567-T"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28265008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28265008"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Areum Daseul Kim, Rui Zhang, Xia Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2015.3902"}], "href": "https://doi.org/10.3892/mmr.2015.3902"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26059756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26059756"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Gokul C Das, Attila Bacsi, Meena Shrivastav, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.20184"}], "href": "https://doi.org/10.1002/mc.20184"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16491484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16491484"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Miguel Veas-Perez de Tudela, María Delgado-Esteban, Julia Cuende, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human neuroblastoma cells with MYCN amplification are selectively resistant to oxidative stress by transcriptionally up-regulating glutamate cysteine ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2010.06648.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2010.06648.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20180881"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20180881"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Cristina Espinosa-Diez, Marta Fierro-Fernández, Francisco Sánchez-Gómez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-β-Dependent Fibrogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Antioxid Redox Signal (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/ars.2014.6025"}], "href": "https://doi.org/10.1089/ars.2014.6025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25353619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25353619"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Jie Li, Aiguo Dai, Ruicheng Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Positive correlation between PPARgamma/PGC-1alpha and gamma-GCS in lungs of rats and patients with chronic obstructive pulmonary disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmq071"}], "href": "https://doi.org/10.1093/abbs/gmq071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20732852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20732852"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Phuong Oanh T Tran, Sarah M Parker, Eric LeRoy, et al. 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