The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates.

Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1-5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS.

Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape.

Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer.

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells.

Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of -target mutagenicity. Other transfection platforms have thus been proposed, such the in vitro transcribed (IVT)-mRNAs.

Glutathione-Hemin/Hematin Adduct Formation to Disintegrate Cytotoxic Oxidant Hemin/Hematin in Human K562 Cells and Red Blood Cells' Hemolysates: Impact of Glutathione on the Hemolytic Disorders and Homeostasis.

Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and proposed to scavenge cytotoxic free heme, which is released from hemoglobin of damaged red blood cells (RBCs) during different hemolytic disorders. In the present study, we aimed to uncover the molecular mechanism by which GSH inhibits hemin-induced cytotoxicity (HIC) by affecting hemin's structural integrity in K562 cells and in RBC hemolysates.

Hemin accumulation and identification of a heme-binding protein clan in K562 cells by proteomic and computational analysis.

Heme (iron protoporphyrin IX) is an essential regulator conserved in all known organisms. We investigated the kinetics of intracellular accumulation of hemin (oxidized form) in human transformed proerythroid K562 cells using [ C]-hemin and observed that it is time and temperature-dependent, affected by the presence of serum proteins, as well as the amphipathic/hydrophobic properties of hemin. Hemin-uptake exhibited saturation kinetics as a function of the concentration added, suggesting the involvement of a carrier-cell surface receptor-mediated process.

Formation of novel N-acetylcysteine-hemin adducts abrogates hemin-induced cytotoxicity and suppresses the NRF2-driven stress response in human pro-erythroid K562 cells.

Heme (iron protoporphyrin IX), as the prosthetic group in hemoproteins, regulates vital cellular functions in human tissues. However, free heme released during hemolysis events promotes severe complications to millions of people worldwide. Over the years, thiols like glutathione (GSH) were known to antagonize heme toxicity.

Activation of KEAP1/NRF2 stress signaling involved in the molecular basis of hemin-induced cytotoxicity in human pro-erythroid K562 cells.

During hemolysis, free heme released from damaged RBCs impairs adjacent cells. As a response, heme induces its metabolic degradation via heme oxygenase-1 (HO-1), activated by NF-E2-related factor 2 (NRF2), the master stress response transcription factor. Heme is well considered a signaling molecule, but how heme does activate NRF2 is not well understood.