Early studies have shown that erythrocytes have caspase-3 and caspase-8 and are capable of dying through an apoptotic-like cell death triggered by Ca2+ ionophores. This cell death is associated with apoptosis-like morphological signs, including cell shrinkage, membrane blebbing, and phosphatidylserine externalization. To emphasize that mature erythrocytes don't have the apoptotic mitochondrial machinery and distinguish this unique cell death modality from apoptosis, it was named "eryptosis". Over recent decades, our knowledge of eryptosis has been significantly expanded, providing more insights into the uniqueness of cell death pathways in erythrocytes. In this review, we aim to summarize our current understanding of eryptosis, formulate the nomenclature and guidelines to interpret results of eryptosis studies, provide a synopsis of morphological and biochemical features of eryptosis, and highlight the role of eryptosis in health and disease, including its druggability.

• MeSH
• apoptóza MeSH
• eryptóza * účinky léků   fyziologie   MeSH
• erytrocyty * metabolismus   účinky léků   cytologie   MeSH
• lidé MeSH
• terminologie jako téma MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• vápník MeSH

Costunolide, a natural sesquiterpene lactone, has multiple pharmacological activities such as neuroprotection or induction of apoptosis and eryptosis. However, the effects of costunolide on pro-survival factors and enzymes in human erythrocytes, e.g. glutathione and glucose-6-phosphate dehydrogenase (G6PDH) respectively, have not been studied yet. Our aim was to determine the mechanisms underlying costunolide-induced eryptosis and to reverse this process. Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry, and intracellular glutathione [GSH]i from high performance liquid chromatography. The oxidized status of intracellular glutathione and enzyme activities were measured by spectrophotometry. Treatment of erythrocytes with costunolide dose-dependently enhanced the percentage of annexin-V-binding cells, decreased the cell volume, depleted [GSH]i and completely inhibited G6PDH activity. The effects of costunolide on annexin-V-binding and cell volume were significantly reversed by pre-treatment of erythrocytes with the specific PKC-α inhibitor chelerythrine. The latter, however, had no effect on costunolide-induced GSH depletion. Costunolide induces eryptosis, depletes [GSH]i and inactivates G6PDH activity. Furthermore, our study reveals an inhibitory effect of chelerythrine on costunolide-induced eryptosis, indicating a relationship between costunolide and PKC-α. In addition, chelerythrine acts independently of the GSH depletion. Understanding the mechanisms of G6PDH inhibition accompanied by GSH depletion should be useful for development of anti-malarial therapeutic strategies or for synthetic lethality-based approaches to escalate oxidative stress in cancer cells for their sensitization to chemotherapy and radiotherapy.

• Klíčová slova
• Chelerythrine, Costunolide, Eryptosis, Glucose-6-phosphate dehydrogenase (G6PDH), Glutathione, Phosphatidylserine exposure,
• MeSH
• apoptóza účinky léků   MeSH
• benzofenantridiny farmakologie   MeSH
• eryptóza účinky léků   genetika   MeSH
• erytrocyty účinky léků   patologie   MeSH
• glukosa-6-fosfátdehydrogenasa antagonisté a inhibitory   genetika   MeSH
• glutathion genetika   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• oxidační stres účinky léků   MeSH
• proteinkinasa C-alfa antagonisté a inhibitory   genetika   MeSH
• reaktivní formy kyslíku MeSH
• seskviterpeny farmakologie   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzofenantridiny MeSH
• chelerythrine MeSH Prohlížeč
• costunolide MeSH Prohlížeč
• G6PD protein, human MeSH Prohlížeč
• glukosa-6-fosfátdehydrogenasa MeSH
• glutathion MeSH
• inhibitory enzymů MeSH
• PRKCA protein, human MeSH Prohlížeč
• proteinkinasa C-alfa MeSH
• reaktivní formy kyslíku MeSH
• seskviterpeny MeSH
• vápník MeSH