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5. COVID-19 therapy target discovery with context-aware literature mining

Author

Martinc, Matej, Škrlj, Blaž, Pirkmajer, Sergej, Lavrač, Nada, Cestnik, Bojan, Marzidovšek, Martin, and Pollak, Senja

Subjects
Computer Science - Computation and Language, Computer Science - Digital Libraries, Computer Science - Information Retrieval
Abstract

The abundance of literature related to the widespread COVID-19 pandemic is beyond manual inspection of a single expert. Development of systems, capable of automatically processing tens of thousands of scientific publications with the aim to enrich existing empirical evidence with literature-based associations is challenging and relevant. We propose a system for contextualization of empirical expression data by approximating relations between entities, for which representations were learned from one of the largest COVID-19-related literature corpora. In order to exploit a larger scientific context by transfer learning, we propose a novel embedding generation technique that leverages SciBERT language model pretrained on a large multi-domain corpus of scientific publications and fine-tuned for domain adaptation on the CORD-19 dataset. The conducted manual evaluation by the medical expert and the quantitative evaluation based on therapy targets identified in the related work suggest that the proposed method can be successfully employed for COVID-19 therapy target discovery and that it outperforms the baseline FastText method by a large margin., Comment: Accepted to the 23rd International Conference on Discovery Science (DS 2020)

Published
2020
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8. Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells

Author

Zandona Antonio, Zorbaz Tamara, Miš Katarina, Pirkmajer Sergej, and Katalinić Maja

Subjects
antidotes, calcium signalling, cell viability, fura-2 am, receptor, kinase, kinaza, protuotrovi, signalizacija kalcijem, vijabilnost stanica, Toxicology. Poisons, RA1190-1270
Abstract

Current research has shown that several imidazolium and chlorinated bispyridinium oximes are cytotoxic and activate different mechanisms or types of cell death. To investigate this further, we analysed interactions between these oximes and acetylcholine receptors (AChRs) and how they affect several signalling pathways to find a relation between the observed toxicities and their effects on these specific targets. Chlorinated bispyridinium oximes caused time-dependent cytotoxicity by inhibiting the phosphorylation of STAT3 and AMPK without decreasing ATP and activated ERK1/2 and p38 MAPK signal cascades. Imidazolium oximes induced a time-independent and significant decrease in ATP and inhibition of the ERK1/2 signalling pathway along with phosphorylation of p38 MAPK, AMPK, and ACC. These pathways are usually triggered by a change in cellular energy status or by external signals, which suggests that oximes interact with some membrane receptors. Interestingly, in silico analysis also indicated that the highest probability of interaction for all of our oximes is with the family of G-coupled membrane receptors (GPCR). Furthermore, our experimental results showed that the tested oximes acted as acetylcholine antagonists for membrane AChRs. Even though oxime interactions with membrane receptors need further research and clarification, our findings suggest that these oximes make promising candidates for the development of specific therapies not only in the field of cholinesterase research but in other fields too, such as anticancer therapy via altering the Ca2+ flux involved in cancer progression.

Published
2022
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13. Terminologija klinične prehrane: Načrt prehranskih ukrepov in organizacija prehranske oskrbe v zdravstvenih in negovalnih ustanovah

Author

Rotovnik Kozjek, Nada, primary, Tonin, Gašper, primary, Puzigaća, Luka, primary, Veninšek, Gregor, primary, Pirkmajer, Sergej, primary, Košir Božič, Tajda, primary, Mlakar Mastnak, Denis, primary, Košir, Jurij Aleš, primary, Petrica, Laura, primary, Berlec, Karla, primary, Kogovšek, Katja, primary, Marš, Tomaž, primary, Jordan, Taja, primary, Lainščak, Mitja, primary, Farkaš Lainščak, Jerneja, primary, Poličnik, Rok, primary, Peklaj, Eva, primary, Majdič, Neža, primary, Brecelj, Erik, primary, Marič Cevzar, Alenka, primary, Škoberne, Andrej, primary, Korošec, Barbara, primary, Franko, Rada, primary, Brumen Avramović, Brigita, primary, Hribar, Renata, primary, Jelovčan, Ana, primary, Stubelj, Mojca, primary, Bratina, Nataša, primary, Sernec, Karin, primary, Povhe Jemec, Katja, primary, Stražišar, Branka, primary, Kozar, Sergeja, primary, Jensterle, Mojca, primary, Šarc, Irena, primary, Strel, Jaka, primary, Schara, Klemen, primary, Gabrijelčič, Mojca, primary, Kerin Povšič, Milena, primary, Lipovec, Neža, primary, Benedik, Evgen, primary, Klen, Jasna, primary, and Blaž Kovač, Milena, primary

Published
2024
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14. AMPK and glucose deprivation exert an isoform-specific effect on the expression of Na+,K+-ATPase subunits in cultured myotubes.

Author

Vidović, Anja, Dolinar, Klemen, Chibalin, Alexander V., and Pirkmajer, Sergej

Abstract

In skeletal muscle, Na+,K+-ATPase (NKA), a heterodimeric (α/β) P-type ATPase, has an essential role in maintenance of Na+ and K+ homeostasis, excitability, and contractility. AMP-activated protein kinase (AMPK), an energy sensor, increases the membrane abundance and activity of NKA in L6 myotubes, but its potential role in regulation of NKA content in skeletal muscle, which determines maximum capacity for Na+ and K+ transport, has not been clearly delineated. We examined whether energy stress and/or AMPK affect expression of NKA subunits in rat L6 and primary human myotubes. Energy stress, induced by glucose deprivation, increased protein content of NKAα1 and NKAα2 in L6 myotubes, while decreasing the content of NKAα1 in human myotubes. Pharmacological AMPK activators (AICAR, A-769662, and diflunisal) modulated expression of NKA subunits, but their effects only partially mimicked those that occurred in response to glucose deprivation, indicating that AMPK does not mediate all effects of energy stress on NKA expression. Gene silencing of AMPKα1/α2 increased protein levels of NKAα1 in L6 myotubes and NKAα1 mRNA levels in human myotubes, while decreasing NKAα2 protein levels in L6 myotubes. Collectively, our results suggest a role for energy stress and AMPK in modulation of NKA expression in skeletal muscle. However, their modulatory effects were not conserved between L6 myotubes and primary human myotubes, which suggests that coupling between energy stress, AMPK, and regulation of NKA expression in vitro depends on skeletal muscle cell model. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Markers of Mitochondrial Injury and Neurological Outcomes of Comatose Patients after Cardiac Arrest.

Author

Živanović, Ina, Miš, Katarina, Pirkmajer, Sergej, Marić, Ivica, and Goslar, Tomaž

Subjects
CYTOCHROME c, CARDIAC arrest, MITOCHONDRIAL DNA, CARDIAC patients, ENOLASE
Abstract

Background and Objectives: Most patients who are successfully resuscitated from cardiac arrest remain comatose, and only half regain consciousness 72 h after the arrest. Neuroprognostication methods can be complex and even inconclusive. As mitochondrial components have been identified as markers of post-cardiac-arrest injury and associated with survival, we aimed to investigate cytochrome c and mtDNA in comatose patients after cardiac arrest to compare neurological outcomes and to evaluate the markers' neuroprognostic value. Materials and Methods: This prospective observational study included 86 comatose post-cardiac-arrest patients and 10 healthy controls. Cytochrome c and mtDNA were determined at admission. Neuron-specific enolase (NSE) was measured after 72 h. Additional neuroprognostication methods were performed when patients remained unconscious. Cerebral performance category (CPC) was determined. Results: Cytochrome c was elevated in patients compared to healthy controls (2.029 [0.85–4.97] ng/mL vs. 0 [0.0–0.16], p < 0.001) but not mtDNA (95,228 [52,566–194,060] vs. 41,466 [28,199–104,708] copies/μL, p = 0.074). Compared to patients with CPC 1–2, patients with CPC 3–5 had higher cytochrome c (1.735 [0.717–3.40] vs. 4.109 [1.149–8.457] ng/mL, p = 0.011), with no differences in mtDNA (87,855 [47,598–172,464] vs. 126,452 [69,447–260,334] copies/μL, p = 0.208). Patients with CPC 1–2 and CPC 3–5 differed in all neuroprognostication methods. In patients with good vs. poor neurological outcome, ROC AUC was 0.664 (p = 0.011) for cytochrome c, 0.582 (p = 0.208) for mtDNA, and 0.860 (p < 0.001) for NSE. The correlation between NSE and cytochrome c was moderate, with a coefficient of 0.576 (p < 0.001). Conclusions: Cytochrome c was higher in comatose patients after cardiac arrest compared to healthy controls and higher in post-cardiac-arrest patients with poor neurological outcomes. Although cytochrome c correlated with NSE, its neuroprognostic value was poor. We found no differences in mtDNA. [ABSTRACT FROM AUTHOR]

Published
2024
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21. List of contributors

Author

Anadón, Arturo, primary, Andrys, Rudolf, additional, Avdonin, Pavel, additional, Bajgar, Jiri, additional, Balali-Mood, Mahdi, additional, Balszuweit, Frank, additional, Banerjee, Atrayee, additional, Bast, Cheryl B., additional, Belinskaia, Daria, additional, Bharti, Vijay K., additional, Bollinger, Claire E., additional, Casillas, Robert P., additional, Clark, Ryan, additional, Clarkson, Edward D., additional, Cole, Toby B., additional, Cope, Rhian B., additional, Coppock, Robert W., additional, Costa, Lucio G., additional, Dettbarn, Wolf-D., additional, Dlabkova, Alzbeta, additional, Doss, Robin B., additional, Dziwenka, Margitta M., additional, Estevez, Jorge, additional, Evans, Tim J., additional, Fink, John K., additional, Flora, Swaran J.S., additional, Furlong, Clement E., additional, Fusek, Josef, additional, Garrick, Jacqueline, additional, Gearhart, Jeffery M., additional, Gerecke, Donald R., additional, Glass-Mattie, Dana F., additional, Goel, Saryu, additional, Goncharov, Nikolay, additional, Gordon, Richard K., additional, Gray, Joshua P., additional, Grubic, Zoran, additional, Gulati, Kavita, additional, Gupta, Ramesh C., additional, Gwaltney-Brant, Sharon M., additional, Hamilton, Tracey A., additional, Harris, Kenneth J., additional, Hood, Darryl B., additional, Jakubowski, Edward M., additional, Jenkins, Richard, additional, Jett, David A., additional, Jiao, Yuqin, additional, John, Harald, additional, Johnson, Nathan H., additional, Jokanović, Milan, additional, Jun, Daniel, additional, Karakashev, Georgy, additional, Kassa, Jiri, additional, Katalinic, Maja, additional, Kehe, Kai, additional, Khlebnikova, Natalia, additional, Kodavanti, Urmila P., additional, Korf, Ekaterina, additional, Koryagina, Nadezhda, additional, Kovač, Bojan, additional, Krishna, Gopala, additional, Krishna, Mayur, additional, Kuca, Kamil, additional, Kumar, Dinesh, additional, Kuroiwa, Yukio, additional, Kuznetsov, Sergey, additional, Kuča, Kamil, additional, Larsen, Joseph C., additional, Leninskiy, Mikhail, additional, Liu, Jing, additional, Lochotzki, Heather, additional, Lockridge, Oksana, additional, Lockwich, Jordana, additional, Loganathan, Bommanna G., additional, Lončar-Stojiljković, Dragana, additional, Lushchekina, Sofya V., additional, Lyman, Megan E., additional, Maguire, Mark, additional, Makhaeva, Galina F., additional, Malik, Jitendra K., additional, Malinak, David, additional, Mars, Tomaz, additional, Marsillach, Judit, additional, Martínez-Larrañaga, María-Rosa, additional, Masson, Patrick, additional, Masunaga, Shigeki, additional, McCallister, Monique, additional, McCauley, Linda A., additional, McClellan, Roger O., additional, McNutt, Patrick M., additional, Meek, Edward C., additional, Merrill, Elaine, additional, Milanez, Sylvia, additional, Mindukshev, Igor, additional, Mis, Katarina, additional, Misik, Jan, additional, Murphy, Michael J., additional, Musilek, Kamil, additional, Nakajima, Tamie, additional, Nelson, Marian R., additional, Nepovimova, Eugenie, additional, Okumura, Tetsu, additional, Patocka, Jiri, additional, Pegan, Katarina, additional, Pejchal, Jaroslav, additional, Pirkmajer, Sergej, additional, Pita, René, additional, Pitt, Jason, additional, Pitt, Yiuka, additional, Platoff, Gennady E., additional, Pope, Carey N., additional, Radilov, Andrey, additional, Rahal, Anu, additional, Ramesh, Aramandla, additional, Ray, Arunabha, additional, Rembovskiy, Vladimir, additional, Rhoades, Raina, additional, Richardson, Rudy J., additional, Ristić, Dragana, additional, Robinson, Peter J., additional, Romero, Alejandro, additional, Ruark, Chris, additional, Salem, Harry, additional, Samchenko, Natalia, additional, Satoh, Tetsuo, additional, Savage, Russell E., additional, Savelieva, Elena, additional, Schopfer, Lawrence M., additional, Sciuto, Alfred M., additional, Seto, Yasuo, additional, Shakarjian, Michael P., additional, Shmurak, Vladimir, additional, Skarka, Adam, additional, Škrbić, Ranko, additional, Sogorb, Miguel, additional, Spriggs, Shardell M., additional, Srivastava, Sakshi, additional, Steinritz, Dirk, additional, Stojiljković, Miloš P., additional, Tewari-Singh, Neera, additional, Thiermann, Horst, additional, Thokchom, Suresh Kumar, additional, Thompson, Larry J., additional, Ukolov, Anton, additional, Valerio, Luis G., additional, van der Schans, M.J., additional, Varma, Daya R., additional, Vilanova, Eugenio, additional, Watson, Annetta, additional, Wijeyesakere, Sanjeeva J., additional, Wismer, Tina, additional, Worden, R. Mark, additional, Worek, Franz, additional, Wright, Linzzi K., additional, Yamasue, Hidenori, additional, Yoshida, Takemi, additional, Yoshioka, Toshiharu, additional, Young, Robert A., additional, Zaja-Milatovic, Snjezana, additional, Zinchenko, Valeriy, additional, and Zoltani, Csaba K., additional

Published
2020
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28. Characterization of lysophospholipase PNPLA7 as a potential target for drug development

Author

Lulić, Ana-Marija, Miš, Katarina, Pirkmajer, Sergej, Dulić, Morana, Lončar, Jovica, and Katalinić, Maja

Subjects
NRE, NTE, hepatocytes, kinetics
Abstract

Lysophospholipase PNPLA7 is a member of the PNPLA (patatin-like phospholipase domain containing proteins) family of nine enzymes sharing a patatin-like catalytic domain. It has been shown that PNPLA7 is highly expressed in the insulin targeted tissues where it can be associated with endoplasmic reticulum and lipid droplets, however, its physiological and molecular roles are not described well. Crystal structure of PNPLA7 is not known, but according to the sequence analysis and homology modelling, it consists of a transmembrane segment near the N-terminal end, three cyclic nucleotide binding sites, and patatin domain where the active site with catalytic dyad Ser-Asp is located. As the first aim of this study, we investigated the physiological role of this enzyme in the cultured human skeletal muscle cells. Our study confirms that human skeletal muscle cells express PNPLA7 mRNA and protein and that it is regulated by metabolic signals, implicating a role for PNPLA7 in skeletal muscle energy metabolism. Gene silencing of PNPLA7 in myoblasts reduced the phosphorylation of S6RP and p70, activators of protein translation, as well as the abundance of α1-subunit of Na+, K+- ATPase and acetyl-CoA carboxylase, indirectly suggesting that PNPLA7 is functionally important for these cells. As for the second objective of this study, we have tried to express a truncated PNPLA7 enzyme using Escherichia coli as a host. Our results showed that the majority of this enzyme remains in the membrane fractions hence, we are currently working on the optimization of the expression and purification conditions, in order to get the PNPLA7 for possible kinetic characterization. This research was supported by the Croatian Science Foundation, grant number HrZZ-UIP-2017-05- 7260, Slovenian Research Agency (J3-9263 and J3-2523, P3-0043 and J7-8276) and Croatian-Slovenian Bilateral grant 2020-2022 (BI- HR/20-21-041).

Published
2023

37. Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells

Author

Zandona, Antonio, Zorbaz, Tamara, Miš, Katarina, Pirkmajer, Sergej, Katalinić, Maja, Zandona, Antonio, Zorbaz, Tamara, Miš, Katarina, Pirkmajer, Sergej, and Katalinić, Maja

Abstract

Current research has shown that several imidazolium and chlorinated bispyridinium oximes are cytotoxic and activate different mechanisms or types of cell death. To investigate this further, we analysed interactions between these oximes and acetylcholine receptors (AChRs) and how they affect several signalling pathways to find a relation between the observed toxicities and their effects on these specific targets. Chlorinated bispyridinium oximes caused time-dependent cytotoxicity by inhibiting the phosphorylation of STAT3 and AMPK without decreasing ATP and activated ERK1/2 and p38 MAPK signal cascades. Imidazolium oximes induced a time-independent and significant decrease in ATP and inhibition of the ERK1/2 signalling pathway along with phosphorylation of p38 MAPK, AMPK, and ACC. These pathways are usually triggered by a change in cellular energy status or by external signals, which suggests that oximes interact with some membrane receptors. Interestingly, in silico analysis also indicated that the highest probability of interaction for all of our oximes is with the family of G-coupled membrane receptors (GPCR). Furthermore, our experimental results showed that the tested oximes acted as acetylcholine antagonists for membrane AChRs. Even though oxime interactions with membrane receptors need further research and clarification, our findings suggest that these oximes make promising candidates for the development of specific therapies not only in the field of cholinesterase research but in other fields too, such as anticancer therapy via altering the Ca2+ flux involved in cancer progression., Praćenjem učinka odabranih imidazolijevih i kloriranih bispiridinijevih oksima utvrđeno je da uzrokuju citotoksičnost i aktiviraju različite mehanizme ili tipove stanične smrti. Kako bismo to detaljnije istražili, analizirali smo aktivaciju nekoliko signalnih putova, kao i interakcije acetilkolinskih receptora (AChR) s navedenim oksimima te procijenili može li se opaženi toksični učinak objasniti njihovim utjecajem na ove specifične mete. Rezultati su pokazali da su klorirani bispiridinijevi oksimi prouzročili vremenski-ovisnu citotoksičnost, bez smanjenja razine ATP-a uz aktivaciju ERK1/2 i p38 MAPK-vezanih signalnih kaskada i inhibiciju fosforilacije STAT3 i AMPK proteina. Imidazolijevi oksimi djelovali su vremenski neovisno, uz značajno smanjenje razine ATP-a i inhibiciju ERK1/2 signalnog puta te fosforilaciju p38 MAPK, AMPK i ACC proteina. Navedeni signalni putovi obično se aktiviraju ili promjenom unutarnjega staničnog statusa, osobito energetskoga, ili vanjskim signalima, što upućuje na moguće interakcije oksima s nekim membranskim receptorima. Zanimljivo, in silico analizom procijenjeno je da je najvjerojatnija interakcija testiranih oksima s porodicom G-protein-spregnutih membranskih receptora (GPCR). K tomu, eksperimentalno je potvrđeno da testirani oksimi djeluju kao mogući antagonisti acetilkolina za vezanje na membranske AChR, potvrđujući tako i računalnu in silico procjenu. Iako interakcije ispitanih oksima s membranskim receptorima treba dodatno potvrditi, takve bi ih interakcije učinile kandidatima za razvoj specifičnih terapija u drugim područjima istraživanja, osim u istraživanjima povezanima s kolinesterazama, npr. kao moguće protutumorske lijekove, putem utjecaja na fluks iona Ca2+ uključenoga u progresiju tumora.

Published
2022

38. Neuropathy target esterase-related enzyme and its kinetic characterization

Author

Lulić, Ana-Marija, Miš, Katarina, Pirkmajer, Sergej, Katalinić, Maja, Dulić, Morana, Sinčić, Nino, and Vrhovac Madunić, Ivana

Subjects
NRE, NTE, hepatocytes, kinetics
Abstract

The object of our study was the kinetic characterization of the neuropathy target esterase-related enzyme (NRE, PNPLA7) in different cell lines. NRE enzyme is a member of the PNPLA (patatin-like phospholipase domain containing proteins) family and a membrane protein associated with endoplasmic reticulum or lipids droplets and is highly expressed in insulin-targeted tissues. Its crystal structure has not been resolved, yet, but according to the sequence analysis and homology modelling it consists of an N-terminal domain with a transmembrane segment and three cyclic nucleotide binding sites, and a C-terminal domain where the active site with catalytic dyad Ser-Asp is located. NRE has been identified as a lysophospholipase that hydrolyses sn-1 esters in lysophosphatidylcholine and lysophosphatidic acid, but its physiological roles are not fully understood. NRE enzyme shares high homology with neuropathy target esterase (NTE, PNPLA6), which suggests that NRE might also be a target of highly toxic organophosphorus compounds (OP) implying involvement of NRE in OP caused pathological conditions such as poorly defined intermediate myopathy syndrome. In our research, we used two commercially available donors of human skeletal muscle cells and the liver hepatocellular carcinoma cell line HepG2 to kinetically characterize NRE activity using known substrate p-nitrophenyl valerate (p-NPV). Firstly, we confirmed presence of NRE in myotubes, differentiated human skeletal muscle cells, and HepG2 by Western blot. Afterwards, esterase activity measurement was optimised for cell lysates. In order to confirm esterase activity, we incubated cell lysates with different OP compounds and measured esterase activity with p-NPV. Our results showed a difference in the NRE activity in different donors of human skeletal muscle cells, probably due to difference in the protein expression. Also, we have concluded that optimal p-NPV concentration for activity measurement is 1 mM with the Km value of 0.4827 mM. Since little is known about this enzyme's physiological role and biological relevance, any findings would most certainly contribute to the understanding of the importance of NRE, which still calls for a detailed clarification. This research was supported by the Croatian Science Foundation, grant number HrZZ-UIP-2017-05- 7260, Slovenian Research Agency (J3-9263 and J3- 2523, P3-0043 and J7-8276) and Croatian-Slovenian Bilateral grant 2020-2022 (BI-HR/20-21-041).

Published
2022

39. The effects of vitamin B3-based compounds on neuronal and muscle cells

Author

Madunić, Josip, Zandona, Antonio, Lulić, Ana- Marija, Miš, Katarina, Bušić, Valentina, Gašo- Sokač, Dajana, Pirkmajer, Sergej, Katalinić, Maja, Kovarik, Zrinka, and Primožič, Ines

Subjects
nicotinamide, neuronal cells, muscle cells, cytotoxicity, PI3K, MAPK
Abstract

Compounds based on vitamin B3 active form nicotinamide, have been associated with many targets due to their antitumoral, antibacterial, anti-inflammatory, and various other biological activities. Our previous work has characterized these compounds as inhibitors of human cholinesterases which makes them possible drugs for cholinergic neurotransmission-linked pathologies. Our aim was to assess in more detail the safety of these compounds on target cells. In the present study we evaluated the effects of these nicotinamides on neuronal (SH-SY5Y) and muscle cells, as types of cells involved in neuromuscular junction. Possible cytotoxic effect in both cell types was evaluated by MTS assay and the involvement of several nicotinamide-associated signalling pathways in the mechanism behind observed cellular effects was further analysed using flow cytometry. Results showed that out of nine tested compounds, four have displayed time- dependent cytotoxicity in treated cells. Cytotoxicity profiling revealed that compounds in doses of 100 μM could induce events possibly leading to cell death. These responses likely arise from modulation of nicotinamide-linked pathways such as MAPK-, AMPK-, Akt- and mTOR signalling that have an important role in multiple cellular functions. Nevertheless, the concentration affecting the cells, especially for the potent ChE- inhibitor 1-(4'-phenylphenacyl)-3- carbamoylpyridinium bromide, was far greater than predicted to be used in therapy according to the determined inhibition potency or in the general aspect of drug administration. However, the observed effects on cells should not be neglected in any future detailed studies of nicotinamide derivatives as new drug scaffolds. This research was supported by the Croatian Science Foundation grant UIP-2017-05-7260, Croatian- Slovenian Bilateral project BI-HR/20-21 and Slovenian Research Agency grant P3-0043 in J7-8276.

Published
2022

40. Triggering apoptosis in human cells by 3-hydroxy-2- pyridine oximes

Author

Zandona, Antonio, Madunić, Josip, Miš, Katarina, Pirkmajer, Sergej, Katalinić, Maja, Dulić, Morana, Sinčić, Nino, and Vrhovac Madunić, Ivana

Subjects
cytotoxicity, apoptotis, caspase, oximes
Abstract

Pyridinium core-based oximes are primarily investigated as reactivators of synaptic acetylcholinesterase inhibited by organophosphorus nerve agents and pesticides. In the search for efficient antidotes, numerous structures have been synthesised, but for many of them side-effects and cytotoxicity are observed in their early-stage testing. Therefore, we aimed to investigate what causes this cytotoxicity for one of the oxime series, and whether it could be related to small differences in structural motives. We tested the effect of five 3-hydroxy-2-pyridine oximes on the viability of neuroblastoma SH-SY5Y cells, representing nerves as the main target of oxime antidotes action. The cytotoxic effect was monitored in a time- and dose-dependent manner. The results indicated apoptosis induction via the mitochondrial-dependent pathway by caspase 9 and/or 3 activation, accompanied by DNA damage, increased phosphorylation of MAPK kinase or acetyl-CoA carboxylase (ACC) and decreased phosphorylation of the transcription factor STAT3. We assume that 3-hydroxy-2-pyridine oximes target mitochondria and cellular metabolism of the fatty acids, due to increased phosphorylation of ACC. Furthermore, a hydroisoquinoline moiety in the structure seems to be responsible for triggering apoptosis, where dimethylamino-phenyl group had the most significant effect on cytotoxicity and activation of additional apoptosis initiator - caspase 8. In conclusion, even though these oximes cannot be considered as candidates in organophosphorus antidote research due to such influence on cells, they could be introduced in studies on other specific targets and as potential new drugs for different conditions. This work was supported by the Croatian Science Foundation (HrZZ-UIP-2017- 05-7260), Slovenian Research Agency (J3-9263 and J3-2523, P3-0043 and J7-8276) and Croatian-Slovenian Bilateral grant 2020-2021 (BI-HR/20-21-041).

Published
2022

44. List of Contributors

Author

Anadón, Arturo, primary, Anderson, Jaime, additional, Anzai, Jun-ichi, additional, Aschner, Michael, additional, Avdonin, Pavel, additional, Bajgar, Jiri, additional, Bakshi, Kulbir, additional, Balali-Mood, Mahdi, additional, Balszuweit, Frank, additional, Banerjee, Atrayee, additional, Bast, Cheryl B., additional, Bhattacharya, Rahul, additional, Bollinger, Claire E., additional, Casillas, Robert P., additional, Chemtob, Sylvain, additional, Clark, Ryan, additional, Clarkson, Edward D., additional, Cole, Toby B., additional, Coppock, Robert W., additional, Costa, Lucio G., additional, Dettbarn, Wolf-D., additional, Dobbins, Dorothy L., additional, Dorsey, Russell, additional, Dziwenka, Margitta, additional, Emmett, George, additional, Estévez, Jorge, additional, Evans, Timothy J., additional, Fink, John K., additional, Flora, Swaran J.S., additional, Fonnum, Frode, additional, Furlong, Clement E., additional, Fusek, Josef, additional, Gearhart, Jeffery M., additional, Gerecke, Donald R., additional, Glass-Mattie, Dana F., additional, Goel, Saryu, additional, Goncharov, Nikolay, additional, Gordon, Richard K., additional, Gray, Joshua P., additional, Grubic, Zoran, additional, Gulati, Kavita, additional, Gupta, Ramesh C., additional, Gwaltney-Brant, Sharon M., additional, Hamilton, Tracey L., additional, Hauschild, Veronique, additional, Hein, Nichole D., additional, Hilmas, Corey J., additional, Hilmas, Elora, additional, Hood, Darryl B., additional, Jakubowski, Edward M., additional, Jenkins, Richard O., additional, Jett, David A., additional, Jiang, George C-T, additional, Jiao, Yuqin, additional, John, Harald, additional, Johnson, Nathan H., additional, Jokanović, Milan, additional, Jun, Daniel, additional, Kadakkuzha, Beena M., additional, Kassa, Jiri, additional, Katalinic, Maja, additional, Kehe, Kai, additional, Khlebnikova, Natalia, additional, King, Joseph, additional, Kodavanti, Urmila P., additional, Korabecny, Jan, additional, Krishna, Gopala, additional, Krivorotova, Nadezhda, additional, Kuca, Kamil, additional, Kuroiwa, Yukio, additional, Kuznetsov, Anatoliy, additional, Kuznetsov, Sergey, additional, Larsen, Joseph C., additional, Leung, Yiuka, additional, Liu, Jing, additional, Liu, Xin-an, additional, Lockridge, Oksana, additional, Loganathan, Bommanna G., additional, Lugo, Andres M., additional, Maguire, Mark, additional, Makhaeva, Galina F., additional, Malik, Jitendra K., additional, Mars, Tomaz, additional, Martínez-Larrañaga, Maria Rosa, additional, Masson, Patrick, additional, Masunaga, Shigeki, additional, McCallister, Monique, additional, McCauley, Linda A., additional, McNutt, Patrick M., additional, Meek, Edward, additional, Merrill, Elaine, additional, Milanez, Sylvia, additional, Mindukshev, Igor, additional, Mis, Katarina, additional, Mulay, Shree, additional, Murphy, Michael J., additional, Musilek, Kamil, additional, Myhrer, Trond, additional, Okumura, Tetsu, additional, Opresko, Dennis, additional, Orlova, Tatiana, additional, Pål, Aas, additional, Pan, Xiaoping, additional, Patocka, Jiri, additional, Pirkmajer, Sergej, additional, Pita, Rene, additional, Pitt, Jason, additional, Pope, Carey, additional, Prokofieva, Daria, additional, Radilov, Andrey, additional, Ramaiah, Shashi K., additional, Ramesh, Aramandla, additional, Ray, Arunabha, additional, Ray, Kausik, additional, Rembovskiy, Vladimir, additional, Rhoades, Raina, additional, Richardson, Rudy J., additional, Rizzo, Valerio, additional, Robinson, Peter J., additional, Ruark, Chris, additional, Salem, Harry, additional, Satoh, Tetsuo, additional, Savage, Russell E., additional, Savelieva, Elena, additional, Schopfer, Lawrence M., additional, Sciuto, Alfred M., additional, Seto, Yasuo, additional, Shakarjian, Michael P., additional, Sogorb, Miguel, additional, Soreq, Hermona, additional, Sterri, Sigrun Hanne, additional, Stick, Melissa, additional, Suzuki, Kouichiro, additional, Taki, Kenji, additional, Thiermann, Horst, additional, Thompson, Larry J., additional, Uchea, Chibuzor, additional, Ukolov, Anton, additional, Valerio, Luis G., additional, Van der Merwe, Deon, additional, van der Schans, Marcel J., additional, Varma, Daya R., additional, Vilanova, Eugenio, additional, Vinokurov, Maxim, additional, Voitenko, Natalia, additional, Waiskopf, Nir, additional, Watson, Annetta, additional, Wijeyesakere, Sanjeeva J., additional, Wismer, Tina, additional, Woltjer, Randall L., additional, Mark Worden, R., additional, Worek, Franz, additional, Wright, Linnzi, additional, Yeung, David T., additional, Yoshida, Takemi, additional, Young, Robert A., additional, Zaja-Milatovic, Snjezana, additional, Zinchenko, Valeriy, additional, and Zoltani, Csaba K., additional

Published
2015
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48. HIF-1[alpha] response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle

Author

Pirkmajer, Sergej, Filipovic, Dragana, Mars, Tomaz, Mis, Katarina, and Grubic, Zoran

Subjects
Corticosteroids -- Research, Corticosteroids -- Properties, Muscles -- Research, Hypoxia -- Research, Transcription factors -- Research, Transcription factors -- Properties, Muscles -- Regeneration, Biological sciences
Abstract

Injury of skeletal muscle is followed by muscle regeneration in which new muscle tissue is formed from the proliferating mononuclear myoblasts, and by systemic response to stress that exposes proliferating myoblasts to increased glucocorticoid (GC) concentration. Because of its various causes, hypoxia is a frequent condition affecting skeletal muscle, and therefore both processes, which importantly determine the outcome of the injury, often proceed under hypoxic conditions. It is therefore important to identify and characterize in proliferating human myoblasts: 1) response to hypoxia which is generally organized by hypoxia-inducible factor-1[alpha] (HIF-1[alpha]); 2) response to GCs which is mediated through the isoforms of glucocorticoid receptors (GRs) and 11[beta]-hydroxysteroid dehydrogenases (11[beta]-HSDs), and 3) the response to GCs under the hypoxic conditions and the influence of this combination on the factors controlling myoblast proliferation. Using real-time PCR, Western blotting, and HIF-1[alpha] small-interfering RNA silencing, we demonstrated that cultured human myoblasts possess both, the HIF-1[alpha]-based response to hypoxia, and the GC response system composed of GR[alpha] and types 1 and 2 11[beta]-HSDs. However, using combined dexamethasone and hypoxia treatments, we demonstrated that these two systems operate practically without mutual interactions. A seemingly surprising separation of the two systems that both organize response to hypoxic stress can be explained on the evolutionary basis: the phylogenetically older HIF-1[alpha] response is a protection at the cellular level, whereas the GC stress response protects the organism as a whole. This necessitates actions, like downregulation of IL-6 secretion and vascular endothelial growth factor, that might not be of direct benefit for the affected myoblasts. hypoxia-inducible factor-[alpha]; antisense version of hypoxia-inducible factor; vascular endothelial growth factor; glucocorticoid receptors; 11[beta]-hydroxysteroid dehydrogenases doi: 10.1152/ajpregu.00133.2010

Published
2010

49. Mitochondrial physiology: Gnaiger Erich et al ― MitoEAGLE Task Group

Author

Gnaiger, Erich, Aasander Frostner, Eleonor, Abdul Karim, Norwahidah, Abdel-Rahman, Engy Ali, Abumrad, Nada A, Acuna-Castroviejo, Dario, Adiele, Reginald C, Ahn, Bumsoo, Alencar, MB, Ali, Sameh S, Almeida, Angeles, Alton, Lesley, Alves, Marco G, Amati, Francesca, Amoedo, Nivea Dias, Amorim, Ricardo, Anderson, Ethan J, Andreadou, Ioanna, Antunes, Diana, Arago, Marc, Aral, Cenk, Arandarcikaite, Odeta, Arias-Reyes, Christian, Armand, Anne-Sophie, Arnould, Thierry, Avram, Vlad Florian, Axelrod, Christopher L, Bairam, Aida, Bailey, Damian M, Bajpeyi, Sudip, Bajzikova, Martina, Bakker, Barbara M, Barlow, Jonathan, Bardal, Tora, Banni, A, Bastos Sant'Anna Silva, Ana Carolina, Batterson, Philip, Battino, Maurizio, Bazil, Jason, Beard, Daniel A, Beleza, Jorge, Bednarczyk, Piotr, Bello, Fiona, Ben-Shachar, Dorit, Bento Guida, Jose Freitas, Bergdahl, Andreas, Berge, Rolf K, Bergmeister, Lisa, Bernardi, Paolo, Berridge, Michael V, Bettinazzi, Stefano, Bishop, David, Blier, Pierre U, Blindheim, Dan Filip, Boardman, Neoma T, Boetker, Hans Erik, Borchard, Sabine, Boros, Mihaly, Borsheim, Elisabet, Borras, Consuelo, Borutaite, Vilma, Botella, Javier, Bouillaud, Frederic, Bouitbir, Jamal, Boushel, Robert C, Bovard, Josh, Bravo-Sagua, Roberto, Breton, Sophie, Brown, David A, Brown, Guy C, Brown, Robert A, Brozinick, Joseph T, Buettner, Garry R, Burtscher, Johannes, Bustos, Matilde, Calabria, Elisa, Calbet, Jose A, Calzia, Enrico, Cannon, Daniel T, Cano Sanchez, Maria, Canto Alvarez, Carles, Cardinale, D, Cardoso, Luiza Helena Daltro, Carvalho, Eugenia, Casado Pinna, Marta, Cassar, Samantha, Castelo, Maria P, Castilho, Roger F, Cavalcanti-de-Albuquerque, Joao Paulo, Cecatto, Cristiane, Celen, Murat C, Cervinkova, Zuzana, Chabi, Beatrice, Chakrabarti, Lisa, Chakrabarti, Sasanka, Chaurasia, Bhagirath, Chen, Quan, Chicco, Adam J, Chinopoulos, Christos, Chowdhury, Subir K, Cizmarova, Beata, Clementi, Emilio, Coen, Paul M, Cohen, Bruce H, Coker, Robert H, Collin-Chenot, Anne, Coughlan, Melinda T, Coxito, Petro, Crisostomo, Luis, Crispim, Marcell, Crossland, Hannah, Dahdah, Norma, Dalgaard, Louise T, Dambrova, Maija, Danhelovska, Tereza, Darveau, Charles A, Darwin, Paula M, Das, Anibh M, Dash, Ranjan K, Davidova, Eliska, Davis, Michael S, Dayanidhi, Sudarshan, De Bem, Andreza Fabro, De Goede, Paul, De Palma, Clara, De Pinto, Vito, Dela, F, Dembinska-Kiec, Aldona, Detraux, Damien, Devaux, Yvan, Di Marcello, Marco, Di Paola, Floriana Jessica, Dias, Candida, Dias, Tania R, Diederich, Marc, Distefano, Giovanna, Djafarzadeh, Siamak, Doermann, Niklas, Doerrier, Carolina, Dong, Lan-Feng, Donnelly, Chris, Drahota, Zdenek, Duarte, Filipe Valente, Dubouchaud, Herve, Duchen, Michael R, Dumas, Jean-Francois, Durham, William J, Dymkowska, Dorota, Dyrstad, Sissel E, Dyson, Alex, Dzialowski, Edward M, Eaton, Simon, Ehinger, Johannes, Elmer, Eskil, Endlicher, Rene, Engin, Ayse B, Escames, Germaine, Evinova, Andrea, Ezrova, Zuzana, Falk, Marni Joy, Fell, David A, Ferdinandy, Peter, Ferko, Miroslav, Fernandez-Ortiz, Marisol, Erika, Fernandez-Vizarra, Ferreira, Julio Cesar Batista, Ferreira, Rita, Ferri, Alessandra, Festuccia, WT, Fessel, Joshua P, Filipovska, Aleksandra, Fisar, Zdenek, Fischer, Christine, Fischer, Michael, Fisher, Gordon, Fisher, Joshua J, Fontanesi, Flavia, Forbes-Hernandez, Tamara Y, Ford, Ellen, Fornaro, Mara, Fuertes Agudo, Marina, Fulton, Montana, Galina, Antonio, Galkin, Alexander, Gallee, Leon, Galli, Gina L, Gama Perez, Pau, Gan, Zhenji, Ganetzky, Rebecca, Gao, Yun, Garcia, Geovana S, Garcia-Rivas, Gerardo, Garcia-Roves, Pablo Miguel, Garcia-Souza, Luiz Felipe, Garlid, Keith D, Garrabou, Gloria, Garten, Antje, Gastaldelli, Amalia, Gayen, Jiaur, Genders, Amanda J, Genova, Maria Luisa, Giampieri, Francesca, Glatz, Jan FC, Giovarelli, Matteo, Goikoetxea Usandizaga, Naroa, Goncalo Teixeira da Silva, Rui, Goncalves, Debora Farina, Gonzalez-Armenta, Jenny L, Gonzalez-Francesqua, A, Gonzalez-Freire, Marta, Gonzalo, Hugo, Goodpaster, Bret H, Gorr, Thomas A, Gourlay, Campbell W, Grams, Bente, Granata, Cesare, Grefte, Sander, Grilo, Luis, Guarch, Meritxell Espino, Gueguen, Naig, Gumeni, Sentiljana, Haas, Clarissa B, Haavik, Jan, Hachmo, Yafit, Haendeler, Judith, Haider, Markus, Hajrulahovic, Anesa, Hamann, Andrea, Han, Jin, Han, Woo Hyun, Hancock, Chad R, Hand, Steven C, Handl, Jiri, Hansikova, Hana, Hardee, Justin P, Hargreaves, Ian P, Harper, Mary Ellen, Harrison, David K, Hassan, Hazirah, Hatakova, Zuzana, Hausenloy, Derek J, Heales, Simon JR, Heiestad, Christina, Hellgren, Kim T, Henrique, Alexandrino, Hepple, Russell T, Hernansanz-Agustin, Pablo, Hewakapuge, Sudinna, Hickey, Anthony J, Ho, Dieu Hien, Hoehn, Kyle L, Hoel, Frederik, Holland, Olivia J, Holloway, Graham P, Holzner, Lorenz, Hoppel, Charles L, Hoppeler, H, Hoppel, Florian, Houstek, Josef, Huete-Ortega, Maria, Hyrossova, Petra, Iglesias-Gonzalez, Javier, Indiveri, Cesare, Irving, Brian A, Isola, Raffaella, Iyer, Shilpa, Jackson, Christophe B, Jadiya, Pooja, Jana, Prado Fabian, Jandeleit-Dahm, K, Jang, David H, Jang, Young C, Janowska, Joanna, Jansen, Kirsten, Jansen-Duerr, Pidder, Jansone, Baiba, Jarmuszkiewicz, Wieslawa, Jaskiewicz, Anna, Jaspers, Richard T, Jedlicka, Jan, Jerome, Estaquier, Jespersen, Nichlas R, Jha, Rajan K, Joseph, Vincent, Juhasz, Laszlo, Jurczak, Michael J, Jurk, Diana, Kaambre, Tuuli, Kaczor, Jan J, Kainulainen, Heikki, Kampa, Rafal Pawel, Kandel, Sunil M, Kane, Daniel A, Kapferer, Werner, Kapnick, Senta, Kappler, Lisa, Karabatsiakis, Alexander, Karavaeva, Iuliia, Karkucinska-Wieckowska, Agnieszka, Kaur, Sarbjot, Keijer, Jaap, Keller, Markus A, Keppner, Gloria, Khamoui, Andy V, Kidere, Dita, Kilbaugh, Todd, Kim, Hyoung Kyu, Kim, Julian KS, Kimoloi, Sammy, Klepinin, Aleksandr, Klepinina, Lyudmila, Klingenspor, Martin, Klocker, Helmut, Komlódi, Timea, Kolasa, Iris, Koopman, Werner JH, Kopitar-Jerala, Natasa, Kowaltowski, Alicia J, Kozlov, Andrey V, Krajcova, Adela, Krako Jakovljevic, Nina, Kristal, Bruce S, Krycer, Jamer R, Kuang, Jujiao, Kucera, Otto, Kuka, Janis, Kwak, Hyo Bum, Kwast, Kurt, Kwon, Oh Sung, Laasmaa, Martin, Labieniec-Watala, Magdalena, Lai, Nicola, Lalic, Nebojsa M, Land, John M, Lane, Nick, Laner, Verena, Lanza, Ian R, Laouafa, Sofien, Larsen, Steen, Larsen, Terje S, Lavery, Gareth G, Lazou, Antigone, Ledo, Ana Margarida, Lee, Hong Kyu, Leeuwenburgh, Christiaan, Lehti, Maarit, Lemieux, Helene, Lenaz, Giorgio, Lerfall, Jorgen, Li, Pingan A, Li Puma, Lance, Liang, Liping, Liepins, Edgars, Lin, Chien-Te, Liu, Jiankang, Lopez, Luis C, Lucchinetti, Eliana, Ma, Tao, Macedo, Maria P, Machado, Ivo F, Maciej, Sarah, MacMillan-Crow, Lee Ann, Magalhaes, Jose, Magri, Andrea, Majtnerova, Pavlina, Makarova, Elina, Makrecka-Kuka, Marina, Malik, Afshan N, Marcouiller, Francois, Marechal, Amandine, Markova, Michaela, Markovic, Ivanka, Martin, Daniel S, Martins, Ana Dias, Martins, Joao D, Maseko, Tumisang Edward, Maull, Felicia, Mazat, Jean Pierre, McKenna, Helen T, McKenzie, Matthew, McMillan, Duncan GG, McStay, Gavin P, Menze, Michael A, Mendham, Amy, Mercer, John R, Merz, Tamara, Messina, Angela, Meszaros, Andras T, Methner, Axel, Michalak, Slawomir, Mila Guasch, Maria, Minuzzi, Luciele M, Misirkic Marjanovic, Maja, Moellering, Douglas R, Moisoi, Nicoleta, Molina, Anthony JA, Montaigne, David, Moore, Anthony L, Moore, Christy, Moreau, Kerrie, Moreira, Bruno P, Moreno-Sanchez, Rafael, Mracek, Tomas, Muccini, Anna Maria, Muntane, Jordi, Muntean, Danina M, Murray, Andrew J, Musiol, Eva, Nabben, Miranda, Nair, K Sreekumaran, Nehlin, Jan O, Nemec, Michal, Nesci, Salvatore, Neufer, P Darrell, Neuzil, Jiri, Neviere, Remi, Newsom, Sean A., Norman, Jennifer, Nozickova, Katerina, Nunes, Sara, Nuoffer, Jean-Marc, O'Brien, Kristin, O'Brien, Katie A, O'Gorman, Donal, Olgar, Yusuf, Oliveira, Ben, Oliveira, Jorge, Oliveira, Marcus F, Oliveira, Marcos Tulio, Oliveira, Pedro F, Oliveira, Paulo J, Olsen, Rolf Erik, Orynbayeva, Zulfiya, Osiewacz, Heinz D, Paez, Hector, Pak, Youngmi K, Pallotta, Maria L, Palmeira, Carlos M, Parajuli, Nirmala, Passos, Joao F, Passrugger, Manuela, Patel, Hemal H, Pavlova, Nadia, Pavlovic, Kasja, Pecina, Petr, Pedersen, Tina M, Perales, Jose Carlos, Pereira da Silva Grilo da Silva, Filomena, Pereira, Rita, Perez Valencia, Juan A, Perks, Kara L, Pesta, Dominik, Petit, Patrice X, Pettersen Nitschke, Ina Katrine, Pichaud, Nicolas, Pichler, Irene, Piel, Sarah, Pietka, Terri A, Pinho, Sonia A, Pino, Maria F, Pirkmajer, Sergej, Place, Nicolas, Plangger, Mario, Porter, Craig, Porter, Richard K, Preguica, Ines, Procaccio, Vincent, Prochownik, Edward V, Prola, Alexandre, Pulinilkunnil, Thomas, Puskarich, Michael A, Puurand, Marju, Radenkovic, Filip, Ramzan, Rabia, Rattan, Suresh IS, Reano, Simone, Reboredo, Patricia, Rees, Bernard B, Renner-Sattler, Kathrin, Rial, Eduardo, Robinson, Matthew M, Roden, Michael, Rodrigues, Ana Sofia, Rodriguez, Enrique, Rodriguez-Enriquez, Sara, Roesland, Gro Vatne, Rolo, Anabela Pinto, Ropelle, Eduardo R, Roshanravan, Baback, Rossignol, Rodrigue, Rossiter, Harry B, Rousar, Tomas, Rubelj, Ivica, Rybacka-Mossakowska, Joanna, Saada, Ann, Safaei, Zahra, Sarlak, Saharnaz, Salin, Karine, Salvadego, Desy, Sandi, Carmen, Saner, Nicholas, Santos, Diana, Sanz, Alberto, Sardao, Vilma, Sazanov, Leonid A, Scaife, Paula, Scatena, Roberto, Schartner, Melanie, Scheibye-Knudsen, Morten, Schilling, Jan M, Schlattner, Uwe, Schmitt, Sabine, Schneider Gasser, Edith Mariane, Schoenfeld, Peter, Schots, Pauke C, Schulz, Rainer, Schwarzer, Christoph, Scott, Graham R, Selman, Colin, Sendon, Pamella Marie, Shabalina, Irina G, Sharma, Pushpa, Sharma, Vipin, Shevchuk, Igor, Shirazi, Reza, Shiroma, Jonathan G, Siewiera, Karolina, Silber, Ariel M, Silva, Ana Maria, Sims, Carrie A, Singer, Dominique, Singh, Brijesh Kumar, Skolik, Robert A, Smenes, Benedikte Therese, Smith, James, Soares, Félix Alexandre Antunes, Sobotka, Ondrej, Sokolova, Inna, Solesio Torregrosa, M De la Encarnacion, Soliz, Jorge, Sonkar, Vijay K, Sova, Marina, Sowton, Alice P, Sparagna, Genevieve C, Sparks, Lauren M, Spinazzi, Marco, Stankova, Pavla, Starr, Jonathan, Stary, Creed, Stefan, Eduard, Stelfa, Gundega, Stepto, Nigel K, Stevanovic, Jelena, Stiban, Johnny, Stier, Antoine, Stocker, Roland, Storder, Julie, Sumbalova, Zuzana, Suomalainen, Wartiovaara Anu, Suravajhala, Prashanth, Svalbe, Baiba, Swerdlow, Russel H, Swiniuch, Daria, Szabo, Ildiko, Szewczyk, Adam, Szibor, Marten, Tanaka, Masashi, Tandler, Bernard, Tarnopolsky, Mark A, Tausan, Daniel, Tavernarakis, Nektarios, Tepp, Kersti, Teodoro, J, Thakkar, Himani, Thapa, Maheshwo, Thyfault, John P, Tomar, Dhanendra, Ton, Riccardo, Torp, May-Kristin, Torres-Quesada, Omar, Towheed, Atif, Treberg, Jason R, Tretter, Laszlo, Trewin, Adam J, Trifunovic, Aleksandra, Trivigno, Catherine, Tronstad, Karl Johan, Trougakos, Ioannis P, Truu, Laura, Tuncay, Erkan, Turan, Belma, Tyrrell, Daniel J, Urban, Tomas, Urner, Sofia, Valentine, Joseph Marco, Van Bergen, Nicole J, Van der Ende, Miranda, Varricchio, Frederick, Vaupel, Peter, Vella, Joanna, Vendelin, Marko, Verdaguer, IB, Vercesi, Anibal E, Vernerova, Andrea, Victor, Victor Manuel, Vieira Ligo Teixeira, Camila, Vidimce, Josif, Viel, Christian, Vieyra, Adalberto, Vilks, Karlis, Villena, Joseph A, Vincent, Vinnyfred, Vinogradov, Andrey D, Viscomi, Carlo, Vitorino, Rui Miguel Pinheiro, Vlachaki Walker, Julia, Vogt, Sebastian, Volani, Chiara, Volska, Kristine, Votion, Dominique-Marie, Vujacic-Mirski, Ksenija, Wagner, Brett A, Ward, Marie Louise, Warnsmann, Verena, Wasserman, David H, Watala, Cezary, Wei, Yau-Huei, Weinberger, Klaus M, White, Sarah, Whitfield, Jamie, Wickert, Anika, Wieckowski, Mariusz R, Wiesner, Rudolf J, Williams, Caroline M, Winwood-Smith, Hugh, Wohlgemuth, Stephanie E, Wohlwend, Martin, Wolff, Jonci Nikolai, Wrutniak-Cabello, Chantal, Wuest, Rob C I, Yokota, Takashi, Zablocki, Krzysztof, Zanon, Alessandra, Zanou, Nadege, Zaugg, Kathrin, Zaugg, Michael, Zdrazilova, Lucie, Zhang, Yong, Zhang, Yi Zhu, Zikova, Alena, Zischka, Hans, Zorzano, Antonio, Zujovic, Tijana, Zurmanova, Jitka, Zvejniece, Liga, Lagarrigue, Sylviane, Munro, Daniel, Pereira, Susana, Laranjinha, Joäo, Hecker, Matthias, Jusic, Amela, Prigione, Alessandro, Sommer, Natascha, Weissig, Volkmar, Guida, Bento, G, John G, Jones, JG, AMS - Tissue Function & Regeneration, AMS - Rehabilitation & Development, Physiology, Mito-Eagle - Evolution-Age-Gender-Lifestyle-Environment (Mito-Eagle), Oroboros Instruments, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Gnaiger Erich, Aasander Frostner Eleonor, Abdul Karim Norwahidah, Abdel-Rahman Engy Ali, Abumrad Nada A, Acuna-Castroviejo Dario, Adiele Reginald C, Ahn Bumsoo, Alencar Mayke Bezerra, Ali Sameh S, Almeida Angeles, Alton Lesley, Alves Marco G, Amati Francesca, Amoedo Nivea Dias, Amorim Ricardo, Anderson Ethan J, Andreadou Ioanna, Antunes Diana, Arago Marc, Aral Cenk, Arandarcikaite Odeta, Arias-Reyes Christian, Armand Anne-Sophie, Arnould Thierry, Avram Vlad F, Axelrod Christopher L, Bailey Damian M, Bairam Aida, Bajpeyi Sudip, Bajzikova Martina, Bakker Barbara M, Banni Aml, Bardal Tora, Barlow J, Bastos Sant'Anna Silva Ana Carolina, Batterson Philip M, Battino Maurizio, Bazil Jason N, Beard Daniel A, Bednarczyk Piotr, Beleza Jorge, Bello Fiona, Ben-Shachar Dorit, Bento Guida Jose Freitas, Bergdahl Andreas, Berge Rolf K, Bergmeister Lisa, Bernardi Paolo, Berridge Michael V, Bettinazzi Stefano, Bishop David J, Blier Pierre U, Blindheim Dan Filip, Boardman Neoma T, Boetker Hans Erik, Borchard Sabine, Boros Mihaly, Boersheim Elisabet, Borras Consuelo, Borutaite Vilma, Botella Javier, Bouillaud Frederic, Bouitbir Jamal, Boushel Robert C, Bovard Josh, Bravo-Sagua Roberto, Breton Sophie, Brown David A, Brown Guy C, Brown Robert Andrew, Brozinick Joseph T, Buettner Garry R, Burtscher Johannes, Bustos Matilde, Calabria Elisa, Calbet Jose AL, Calzia Enrico, Cannon Daniel T, Cano Sanchez Maria Consolacion, Canto Alvarez Carles, Cardinale Daniele A, Cardoso Luiza HD, Carvalho Eugenia, Casado Pinna Marta, Cassar Samantha, Castelo Rueda Maria Paulina, Castilho Roger F, Cavalcanti-de-Albuquerque Joao Paulo, Cecatto Cristiane, Celen Murat C, Cervinkova Zuzana, Chabi Beatrice, Chakrabarti Lisa, Chakrabarti Sasanka, Chaurasia Bhagirath, Chen Quan, Chicco Adam J, Chinopoulos Christos, Chowdhury Subir Kumar, Cizmarova Beata, Clementi Emilio, Coen Paul M, Cohen Bruce H, Coker Robert H, Collin-Chenot Anne, Coughlan Melinda T, Coxito Pedro, Crisostomo Luis, Crispim Marcell, Crossland Hannah, Dahdah Norma Ramon, Dalgaard Louise T, Dambrova Maija, Danhelovska Tereza, Darveau Charles-A, Darwin Paula M, Das Anibh Martin, Dash Ranjan K, Davidova Eliska, Davis Michael S, Dayanidhi Sudarshan, De Bem Andreza Fabro, De Goede Paul, De Palma Clara, De Pinto Vito, Dela Flemming, Dembinska-Kiec Aldona, Detraux Damian, Devaux Yvan, Di Marcello Marco, Di Paola Floriana Jessica, Dias Candida, Dias Tania R, Diederich Marc, Distefano Giovanna, Djafarzadeh Siamak, Doermann Niklas, Doerrier Carolina, Dong Lan-Feng, Donnelly Chris, Drahota Zdenek, Duarte Filipe Valente, Dubouchaud Herve, Duchen Michael R, Dumas Jean-Francois, Durham William J, Dymkowska Dorota, Dyrstad Sissel E, Dyson Alex, Dzialowski Edward M, Eaton Simon, Ehinger Johannes K, Elmer Eskil, Endlicher Rene, Engin Ayse Basak, Escames Germaine, Evinova Andrea, Ezrova Zuzana, Falk Marni J, Fell David A, Ferdinandy Peter, Ferko Miroslav, Fernandez-Ortiz Marisol, Fernandez-Vizarra Erika, Ferreira Julio Cesar B, Ferreira Rita Maria P, Ferri Alessandra, Fessel Joshua Patrick, Festuccia William T, Filipovska Aleksandra, Fisar Zdenek, Fischer Christine, Fischer Michael J, Fisher Gordon, Fisher Joshua J, Fontanesi Flavia, Forbes-Hernandez Tamara Y, Ford Ellen, Fornaro Mara, Fuertes Agudo Marina, Fulton Montana, Galina Antonio, Galkin Alexander, Gallee Leon, Galli Gina L J, Gama Perez Pau, Gan Zhenji, Ganetzky Rebecca, Gao Yun, Garcia Geovana S, Garcia-Rivas Gerardo, Garcia-Roves Pablo Miguel, Garcia-Souza Luiz F, Garlid Keith D, Garrabou Gloria, Garten Antje, Gastaldelli Amalia, Gayen Jiaur, Genders Amanda J, Genova Maria Luisa, Giampieri Francesca, Giovarelli Matteo, Glatz Jan FC, Goikoetxea Usandizaga Naroa, Goncalo Teixeira da Silva Rui, Goncalves Debora Farina, Gonzalez- Armenta Jenny L, Gonzalez-Franquesa Alba, Gonzalez-Freire Marta, Gonzalo Hugo, Goodpaster Bret H, Gorr Thomas A, Gourlay Campbell W, Grams Bente, Granata Cesare, Grefte Sander, Grilo Luis, Guarch Meritxell Espino, Gueguen Naig, Gumeni Sentiljana, Haas Clarissa, Haavik Jan, Hachmo Yafit, Haendeler Judith, Haider Markus, Hajrulahovic Anesa, Hamann Andrea, Han Jin, Han Woo Hyun, Hancock Chad R, Hand Steven C, Handl Jiri, Hansikova Hana, Hardee Justin P, Hargreaves Iain P, Harper Mary- Ellen, Harrison David K, Hassan Hazirah, Hatokova Zuzana, Hausenloy Derek J, Heales Simon JR, Hecker 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Ines, Prigione Alessandro, Procaccio Vincent, Prochownik Edward V, Prola Alexandre, Pulinilkunnil Thomas, Puskarich Michael A, Puurand Marju, Radenkovic Filip, Ramzan Rabia, Rattan Suresh IS, Reano Simone, Reboredo-Rodriguez Patricia, Rees Bernard B, Renner-Sattler Kathrin, Rial Eduardo, Robinson Matthew M, Roden Michael, Rodrigues Ana Sofia, Rodriguez Enrique, Rodriguez-Enriquez Sara, Roesland Gro Vatne, Rohlena Jakub, Rolo Anabela Pinto, Ropelle Eduardo R, Roshanravan Baback, Rossignol Rodrigue, Rossiter Harry B, Rousar Tomas, Rubelj Ivica, Rybacka-Mossakowska Joanna, Saada Reisch Ann, Safaei Zahra, Salin Karine, Salvadego Desy, Sandi Carmen, Saner Nicholas, Santos Diana, Sanz Alberto, Sardao Vilma, Sarlak Saharnaz, Sazanov Leonid A, Scaife Paula, Scatena Roberto, Schartner Melanie, Scheibye-Knudsen Morten, Schilling Jan M, Schlattner Uwe, Schmitt Sabine, Schneider Gasser Edith Mariane, Schoenfeld Peter, Schots Pauke C, Schulz Rainer, Schwarzer Christoph, Scott Graham R, Selman Colin, Sendon Pamella Marie, Shabalina Irina G, Sharma Pushpa, Sharma Vipin, Shevchuk Igor, Shirazi Reza, Shiroma Jonathan G, Siewiera Karolina, Silber Ariel M, Silva Ana Maria, Sims Carrie A, Singer Dominique, Singh Brijesh Kumar, Skolik Robert A, Smenes Benedikte Therese, Smith James, Soares Felix Alexandre Antunes, Sobotka Ondrej, Sokolova Inna, Solesio Maria E, Soliz Jorge, Sommer Natascha, Sonkar Vijay K, Sova Marina, Sowton Alice P, Sparagna Genevieve C, Sparks Lauren M, Spinazzi Marco, Stankova Pavla, Starr Jonathan, Stary Creed, Stefan Eduard, Stelfa Gundega, Stepto Nigel K, Stevanovic Jelena, Stiban Johnny, Stier Antoine, Stocker Roland, Storder Julie, Sumbalova Zuzana, Suomalainen Anu, Suravajhala Prashanth, Svalbe Baiba, Swerdlow Russell H, Swiniuch Daria, Szabo Ildiko, Szewczyk Adam, Szibor Marten, Tanaka Masashi, Tandler Bernard, Tarnopolsky Mark A, Tausan Daniel, Tavernarakis Nektarios, Teodoro Joao Soeiro, Tepp Kersti, Thakkar Himani, Thapa Maheshwor, Thyfault John P, Tomar Dhanendra, Ton Riccardo, Torp May-Kristin, Torres-Quesada Omar, Towheed Atif, Treberg Jason R, Tretter Laszlo, Trewin Adam J, Trifunovic Aleksandra, Trivigno Catherine, Tronstad Karl Johan, Trougakos Ioannis P, Truu Laura, Tuncay Erkan, Turan Belma, Tyrrell Daniel J, Urban Tomas, Urner Sofia, Valentine Joseph Marco, Van Bergen Nicole J, Van der Ende Miranda, Varricchio Frederick, Vaupel Peter, Vella Joanna, Vendelin Marko, Vercesi Anibal E, Verdaguer Ignasi Bofill, Vernerova Andrea, Victor Victor Manuel, Vieira Ligo Teixeira Camila, Vidimce Josif, Viel Christian, Vieyra Adalberto, Vilks Karlis, Villena Josep A, Vincent Vinnyfred, Vinogradov Andrey D, Viscomi Carlo, Vitorino Rui Miguel Pinheiro, Vlachaki Walker Julia, Vogt Sebastian, Volani Chiara, Volska Kristine, Votion Dominique-Marie, Vujacic-Mirski Ksenija, Wagner Brett A, Ward Marie Louise, Warnsmann Verena, Wasserman David H, Watala Cezary, Wei Yau-Huei, Weinberger Klaus M, Weissig Volkmar, White Sarah Haverty, Whitfield Jamie, Wickert Anika, Wieckowski Mariusz R, Wiesner Rudolf J, Williams Caroline M, Winwood-Smith Hugh, Wohlgemuth Stephanie E, Wohlwend Martin, Wolff Jonci Nikolai, Wrutniak-Cabello Chantal, Wuest Rob CI, Yokota Takashi, Zablocki Krzysztof, Zanon Alessandra, Zanou Nadege, Zaugg Kathrin, Zaugg Michael, Zdrazilova Lucie, Zhang Yong, Zhang Yizhu, Zikova Alena, Zischka Hans, Zorzano Antonio, Zujovic Tijana, Zurmanova Jitka, Zvejniece Liga

Subjects
uncoupling, MitoPedia: Respiratory states, SI - The International System of Units, IUPAC, Coupling control, Mitochondrial preparations, Protonmotive force, Uncoupling, Oxidative phosphorylation, Phosphorylation efficiency, Electron transfer-pathway, LEAK-respiration, Residual oxygen consumption, Normalization of rate, Flow, Flux, Flux control ratio, Mitochondrial marker, Cell count, Oxygen, [SDV]Life Sciences [q-bio], coupling control, protonmotive force, oxidative phosphorylation, mitochondrial respiratory control, State 4, electron transfer, State 2, State 3, Mitochondrial physiology, residual oxygen consumption, flux, normalization, ion leak and slip compensatory state, efficiency, electron transfer system, flow, mitochondrial physiology, oxygen, mitochondrial preparations, proton leak
Abstract

As the knowledge base and importance of mitochondrial physiology to evolution, health and diseaseexpands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followthe latest SI guidelines and those of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute BEC 2020.1 doi:10.26124/bec:2020-0001.v1www.bioenergetics-communications.org3of 44to reproducibility between laboratories and thussupport the development of datarepositoriesof mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.

Published
2020
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50. Activation of (un)regulated cell death as a new perspective for oxime activity research

Author

Zandona, Antonio, Maraković, Nikola, Miš, Katarina, Dolinar, Klemen, Pirkmajer, Sergej, and Katalinić, Maja

Subjects
cytotoxicity, apoptotis, necrosis, caspase, pharmacophore
Abstract

Compounds known as oximes are tested as antidotes against the toxic effects of organophosphates (OP). Oximes have diverse scaffolds, created with the purpose to fit the active site of the acetylcholinesterase-OP conjugate as their main target in the organism. After primary screening, candidates which meet the in vitro kinetic parameters of action as antidotes are promoted to further evaluation, while others are discarded. Our previous research showed that some of the oximes display toxic effects on cell level which could be explored beyond their main mechanism of action. To investigate this further, we performed an in vitro cell-based evaluation of four structurally diverse groups of oximes at concentrations of up to 0.8 mM, identifying specific biomarkers. We tested the effect of oximes on several in vitro cell models: skeletal muscles, kidneys, liver, and neurons. As our results indicate, the effect of oximes was consistent in all cells tested. Compounds with quinuclidine and imidazolium core induced unregulated cell death caused by cell burst, with increased levels of reactive oxygen species formation, but without antioxidant scavenging activation. On the other hand, oximes with a pyridine or pyridinium core activated apoptosis and specific caspases-3, -8, and/or -9. Interestingly, some of the compounds even had a synergistic effect. We generated a pharmacophore model for each series and identified ligands from public databases that map to generated pharmacophores. Several interesting hits were obtained including well known chemotherapy agents, gene expression modulators, antibiotics, cytochrome P450 modulators, etc. Even though the exact mechanism by which oximes act to trigger observed cell effects needs to be explained, our findings should open up a whole new perspective for oxime research. Acknowledgement: This work was supported by the Croatian Science Foundation under the project UIP-2017-05-7260 and by Croatian-Slovenian bilateral grant 2020-2021

Published
2021

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