Roles of the NFκB and glutathione pathways in mature human erythrocytes

Abstract

Abbreviations used: Ca 2+ -calcium; ERK2 -extracellular signal-regulated kinase 2; GPIIb/IIIa -glycoprotein IIb/IIIa; GSH -reduced glutathione; ICAM-1 -inter-cellular adhesion molecule; IFN-γ -interferon-γ; IκB-α -inhibitor of kappaB; IKK-α -IκB kinase-α; IL-6 -interleukin-6; IL-8 -interleukin-8; JNK1 -c-Jun N-terminal kinase 1; NFκB -nuclear factor κB; PS -phosphatidylserine; R -putative phosphatidylserine receptor Abstract: Anucleated erythrocytes were long considered as oxygen-transporting cells with limited regulatory functions. Components of different nuclear signaling pathways have not been investigated in those cells, yet. Surprisingly, we repeatedly found significant amounts of transcription factors in purified erythrocyte preparations, i.e. nuclear factor κB (NFκB), and major components of the canonical NFκB signaling pathway. To investigate the functional role of NFκB signaling, the effects of the preclinical compounds Bay 11-7082 and parthenolide on the survival of highly purified erythrocytes were investigated. Interestingly, both inhibitors of the NFκB pathway triggered erythrocyte programmed cell death as demonstrated by enhanced phospholipid scrambling Unauthenticated Download Date | 5/12/18 7:51 PM

Glutathionylation: a regulatory role of glutathione in physiological processes

“…Even in erythrocytes, NF-κB and major components of the canonical NF-κB signalling pathway interfere with the antioxidative system. Challenged by its inhibitors, compounds such as Bay 11-7082 and parthenolide, GSH levels drop, and so does erythrocyte survival (74). The examples of responses of NF-κB to GSH in vivo are numerous and specific (9,19,35,64).…”

The impact of erythrocyte age on eryptosis

“…Also, Ca 2+ stimulates cell membrane scrambling, leading to exposure of phosphatidylserine at the cell surface (Lang et al , ). The Ca 2+ ‐permeable cation channels are activated by oxidation (Duranton et al , ), and eryptosis is thus sensitive to oxidative stress (Bhavsar et al , ; Ghashghaeinia et al , , , ; Lang et al , ; Calderon‐Salinas et al , ; Maellaro et al , ). So far, all published studies concerning eryptosis were performed with unfractionated erythrocyte concentrates containing a mixture of cells with different ages.…”

Sustained Release of Metformin via Red Blood Cell Accumulated Sulfenamide Prodrug

“…It is rapidly and efficiently accumulated into the RBCs, where it is converted to metformin by free thiols that exist with high amounts in the RBCs. 15 We have previously reported that the conversion of the cyclohexyl sulfenamide prodrug is very fast, half-life being less than 5 min in 1 mM GSH solution, and it liberates metformin quantitatively. 14 Because the RBSs contain high levels of GSH, it can be assumed that the conversion of the sulfenamide prodrug is relatively fast also in vivo.…”

“…Overall, the cyclohexyl prodrug of metformin seems to have ideal properties for sustained‐release purposes. It is rapidly and efficiently accumulated into the RBCs, where it is converted to metformin by free thiols that exist with high amounts in the RBCs . We have previously reported that the conversion of the cyclohexyl sulfenamide prodrug is very fast, half‐life being less than 5 min in 1 mM GSH solution, and it liberates metformin quantitatively .…”