Alexey Vereninov and collaborators pioneered the application of mathematical models of cellular homeostasis with ground-breaking contributions to the understanding of the mechanisms behind the dynamics of homeostatic changes in a variety of different cell types. As part of an issue dedicated to Vereninov’s memory, I thought that an example of the predictive potential of such models would be a fitting tribute to his work and achievements. The “Gardos effect” is the example chosen from our modelling experience.
{"title":"The Predictive Power of Cellular Homeostasis Models Illustrated with a Study of the Gardos Effect","authors":"V. Lew","doi":"10.33594/000000593","DOIUrl":"https://doi.org/10.33594/000000593","url":null,"abstract":"Alexey Vereninov and collaborators pioneered the application of mathematical models of cellular homeostasis with ground-breaking contributions to the understanding of the mechanisms behind the dynamics of homeostatic changes in a variety of different cell types. As part of an issue dedicated to Vereninov’s memory, I thought that an example of the predictive potential of such models would be a fitting tribute to his work and achievements. The “Gardos effect” is the example chosen from our modelling experience.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46623787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdulla Al Mamun Bhuyana, Kousi Alzoubib, A. Fazioc, Marilena Brigliad, Caterina Faggioe, F. Langb
Background/Aims: Pentostatin (2'-deoxycoformycin), a purine analog, is used for the treatment of diverse B and T-cell malignancies as well as for immunosuppression. Pentostatin is at least in part effective by triggering apoptosis. Pentostatin sensitive mechanisms leading to apoptosis include accumulation of DNA strand breaks, altered transcription and mitochondrial depolarization. Erythrocytes lack nuclei and mitochondria but nevertheless may enter eryptosis, an apoptosis-like suicidal cell death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), ceramide formation and energy depletion. The present study tested, whether and how pentostatin induces eryptosis. Methods: The phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies, and cytosolic ATP concentration utilizing a luciferin–luciferase assay kit. Results: A 48 hours exposure of human erythrocytes to pentostatin (≥5 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Pentostatin significantly increased [Ca2+]i, and significantly decreased cytosolic ATP, but did not significantly modify ceramide abundance. The effect of pentostatin on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusion: Pentostatin triggers erythrocyte shrinkage and phospholipid scrambling of the erythrocyte cell membrane, effects paralleled by and at least partially due to entry of extracellular Ca2+ and cellular energy depletion.
{"title":"Suicidal Death of Human Erythrocytes Following Exposure to Pentostatin","authors":"Abdulla Al Mamun Bhuyana, Kousi Alzoubib, A. Fazioc, Marilena Brigliad, Caterina Faggioe, F. Langb","doi":"10.33594/000000576","DOIUrl":"https://doi.org/10.33594/000000576","url":null,"abstract":"Background/Aims: Pentostatin (2'-deoxycoformycin), a purine analog, is used for the treatment of diverse B and T-cell malignancies as well as for immunosuppression. Pentostatin is at least in part effective by triggering apoptosis. Pentostatin sensitive mechanisms leading to apoptosis include accumulation of DNA strand breaks, altered transcription and mitochondrial depolarization. Erythrocytes lack nuclei and mitochondria but nevertheless may enter eryptosis, an apoptosis-like suicidal cell death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i), ceramide formation and energy depletion. The present study tested, whether and how pentostatin induces eryptosis. Methods: The phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies, and cytosolic ATP concentration utilizing a luciferin–luciferase assay kit. Results: A 48 hours exposure of human erythrocytes to pentostatin (≥5 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Pentostatin significantly increased [Ca2+]i, and significantly decreased cytosolic ATP, but did not significantly modify ceramide abundance. The effect of pentostatin on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusion: Pentostatin triggers erythrocyte shrinkage and phospholipid scrambling of the erythrocyte cell membrane, effects paralleled by and at least partially due to entry of extracellular Ca2+ and cellular energy depletion.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44503562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The positive charge on the major intracellular inorganic cations (K+, Na+, and Mg2+) significantly exceeds the combined negative charge on Cl- and HCO3-. This so-called anion gap must be balanced by organic anions. From the analysis of published data, we conclude that organic phosphorus-containing compounds (Po) are responsible for the neutralization of much of the anion gap. Importantly, many of them are large polymers, such as DNA, RNA, or polyphosphate, that undergo regular synthesis and degradation. That produces a variable average valency z associated with organic anions. It follows from theory that an increase in z should lead to membrane hyperpolarization and accumulation of cations: this result has been known before, and here we further confirm it by an analysis based on different cellular and computational models. Furthermore, we show that inhibition of potassium channels is expected to reduce the uptake of phosphorus through sodium-coupled transporters. This suggests a simple explanation to two long-established experimental facts about DNA synthesis: namely, that it is accompanied by cell hyperpolarization and that it requires functional potassium channels.
{"title":"Nucleic Acids Regulate Intracellular Ions and Membrane Potential","authors":"","doi":"10.33594/000000613","DOIUrl":"https://doi.org/10.33594/000000613","url":null,"abstract":"The positive charge on the major intracellular inorganic cations (K+, Na+, and Mg2+) significantly exceeds the combined negative charge on Cl- and HCO3-. This so-called anion gap must be balanced by organic anions. From the analysis of published data, we conclude that organic phosphorus-containing compounds (Po) are responsible for the neutralization of much of the anion gap. Importantly, many of them are large polymers, such as DNA, RNA, or polyphosphate, that undergo regular synthesis and degradation. That produces a variable average valency z associated with organic anions. It follows from theory that an increase in z should lead to membrane hyperpolarization and accumulation of cations: this result has been known before, and here we further confirm it by an analysis based on different cellular and computational models. Furthermore, we show that inhibition of potassium channels is expected to reduce the uptake of phosphorus through sodium-coupled transporters. This suggests a simple explanation to two long-established experimental facts about DNA synthesis: namely, that it is accompanied by cell hyperpolarization and that it requires functional potassium channels.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45767532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoarthritis (OA) is a major cause of pain and disability in adults, affecting approximately 150 million people worldwide. It is most prevalent in knees and hips. Major risk factors are age, female sex, prior joint injury, and obesity. OA causes significant personal and steeply rising socio-economical costs in ageing populations. OA is characterized by progressive cartilage damage and inflammation. In later stages, it affects the subchondral bone, bone marrow, ligaments, tendons, and nerves und eventually leads to joint failure. Symptoms include pain, joint swelling, and stiffness. Therapies are symptomatic and focus on pain relief and measures to improve mobility, or, ultimately, joint replacement. So far, no drugs that could prevent or slow down disease progression are available. Based on promising in vitro and preclinical studies, recombinant fibroblast growth factor (FGF) 18 (sprifermin; Merck Serono) has come into focus as a potential disease-modifying OA drug (DMOAD). Three randomized controlled trials (RCTs) investigating the safety and efficacy of intraarticularly (i.a.) injected sprifermin application in patients with knee OA have been completed so far. Data from these trials, post hocanalyses and follow-ups provide have evidenced that i.a. sprifermin induced a significant and sustained increase in cartilage thickness and volume without specific adverse effects, but in terms of clinical symptoms or physical joint function sprifermin did not cause significant improvements compared to placebo treatment in whole study populations. However, significant pain reduction was observed in a “subgroup at risk” of patients with more severe disease states, indicating that under certain disease conditions the structural benefit improvements could translate into clinical benefit. This calls for larger RCTs allowing e.g., for disease state or risk factor-specific stratification of patients and longer follow-ups to substantiate the efficacy of sprifermin as a possible DMOAD. This review gives an overview on the prevalence, etiology and socio-economic burden of OA, its pathogenesis as well as the current treatment options of the disease. It summarizes the role of FGF-18 in chondrocyte and cartilage (patho)physiology and addresses the question of evidence for the efficacy and safety of i.a. sprifermin injection in patients with knee OA based on trial outcomes and literature data.
{"title":"Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug","authors":"","doi":"10.33594/000000612","DOIUrl":"https://doi.org/10.33594/000000612","url":null,"abstract":"Osteoarthritis (OA) is a major cause of pain and disability in adults, affecting approximately 150 million people worldwide. It is most prevalent in knees and hips. Major risk factors are age, female sex, prior joint injury, and obesity. OA causes significant personal and steeply rising socio-economical costs in ageing populations. OA is characterized by progressive cartilage damage and inflammation. In later stages, it affects the subchondral bone, bone marrow, ligaments, tendons, and nerves und eventually leads to joint failure. Symptoms include pain, joint swelling, and stiffness. Therapies are symptomatic and focus on pain relief and measures to improve mobility, or, ultimately, joint replacement. So far, no drugs that could prevent or slow down disease progression are available. Based on promising in vitro and preclinical studies, recombinant fibroblast growth factor (FGF) 18 (sprifermin; Merck Serono) has come into focus as a potential disease-modifying OA drug (DMOAD). Three randomized controlled trials (RCTs) investigating the safety and efficacy of intraarticularly (i.a.) injected sprifermin application in patients with knee OA have been completed so far. Data from these trials, post hocanalyses and follow-ups provide have evidenced that i.a. sprifermin induced a significant and sustained increase in cartilage thickness and volume without specific adverse effects, but in terms of clinical symptoms or physical joint function sprifermin did not cause significant improvements compared to placebo treatment in whole study populations. However, significant pain reduction was observed in a “subgroup at risk” of patients with more severe disease states, indicating that under certain disease conditions the structural benefit improvements could translate into clinical benefit. This calls for larger RCTs allowing e.g., for disease state or risk factor-specific stratification of patients and longer follow-ups to substantiate the efficacy of sprifermin as a possible DMOAD. This review gives an overview on the prevalence, etiology and socio-economic burden of OA, its pathogenesis as well as the current treatment options of the disease. It summarizes the role of FGF-18 in chondrocyte and cartilage (patho)physiology and addresses the question of evidence for the efficacy and safety of i.a. sprifermin injection in patients with knee OA based on trial outcomes and literature data.","PeriodicalId":74396,"journal":{"name":"Paracelsus proceedings of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42034896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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