medlitГигиена и санитарияHygiene and Sanitation0016-99002412-0650Federal Scientific Center of Hygiene named after F.F. Erisman10.47470/0016-9900-2025-104-6-793-798cyhiihmedlit-5027Research ArticleПРОФИЛАКТИЧЕСКАЯ ТОКСИКОЛОГИЯ И ГИГИЕНИЧЕСКОЕ НОРМИРОВАНИЕPREVENTIVE TOXICOLOGY AND HYGIENIC STANDARTIZATIONНейротоксичность ингаляционного воздействия наночастиц оксида свинца на лабораторных животных на уровне экспрессии генов и метаболомаNeurotoxicity of PbO nanoparticles following subchronic inhalation exposure of laboratory animals studied at the level of gene expression and metabolomehttps://orcid.org/0000-0001-8794-7288КикотьАнна МихайловнаKikotAnna M.

Науч. сотр. отд. молекулярной биологии и электронной микроскопии ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: kikotam@ymrc.ru

Researcher, Department of Molecular Biology and Electron Microscopy, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: kikotam@ymrc.ru

kikotam@ymrc.ruhttps://orcid.org/0000-0002-5576-365XУнесихинаМария СергеевнаUnesikhinaMaria S.

Мл. науч. сотр. отд. молекулярной биологии и электронной микроскопии ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: unesihinams@ymrc.ru

Junior researcher, Department of Molecular Biology and Electron Microscopy, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: unesihinams@ymrc.ru

unesihinams@ymrc.ruhttps://orcid.org/0000-0002-7029-3406ШаиховаДарья РамильевнаShaikhovaDaria R.

Науч. сотр. отд. молекулярной биологии и электронной микроскопии ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: darya.boo@mail.ru

Researcher, Department of Molecular Biology and Electron Microscopy, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: darya.boo@mail.ru

darya.boo@mail.ruhttps://orcid.org/0000-0002-4109-9268БерёзаИван АндреевичBerezaIvan A.

Науч. сотр. отд. молекулярной биологии и электронной микроскопии ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: berezaia@ymrc.ru

Researcher, Department of Molecular Biology and Electron Microscopy, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: berezaia@ymrc.ru

berezaia@ymrc.ruhttps://orcid.org/0000-0002-1871-8593МинигалиеваИльзира АмировнаMinigalievaIlzira A.

Доктор биол. наук, зав. отд. токсикологии и биопрофилактики ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: ilzira-minigalieva@yandex.ru

DSc (Biology), Head of the Department of Toxicology and Bioprophylaxis, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: ilzira@ymrc.ru

ilzira-minigalieva@yandex.ruhttps://orcid.org/0009-0003-0780-5733НикогосянКарен МерсоповичNikogosyanKaren M.

Мл. науч. сотр. отд. токсикологии и биопрофилактики ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: nikoghosyankm@ymrc.ru

Junior researcher, Department of Toxicology and Bioprophylaxis, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: nikoghosyankm@ymrc.ru

nikoghosyankm@ymrc.ruhttps://orcid.org/0000-0002-1743-7642СутунковаМарина ПетровнаSutunkovaMarina P.

Доктор мед. наук, директор ФБУН «ЕМНЦ ПОЗРПП» Роспотребнадзора, 620014, Екатеринбург, Россия

e-mail: sutunkova@ymrc.ru

DSc (Medicine), Director, Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, 620014, Russian Federation

e-mail: sutunkova@ymrc.ru

sutunkova@ymrc.ruФБУН «Екатеринбургский медицинский научный центр профилактики и охраны здоровья рабочих промпредприятий» Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человекаРоссияYekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial WorkersRussian FederationФБУН «Екатеринбургский медицинский научный центр профилактики и охраны здоровья рабочих промпредприятий» Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека; ФГБОУ ВО «Уральский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияYekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers; Ural State Medical UniversityRussian Federation2025150820251046793798Copyright © Кикоть А.М., Унесихина М.С., Шаихова Д.Р., Берёза И.А., Минигалиева И.А., Никогосян К.М., Сутункова М.П., 20252025Кикоть А.М., Унесихина М.С., Шаихова Д.Р., Берёза И.А., Минигалиева И.А., Никогосян К.М., Сутункова М.П.Kikot A.M., Unesikhina M.S., Shaikhova D.R., Bereza I.A., Minigalieva I.A., Nikogosyan K.M., Sutunkova M.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rjhas.ru/jour/article/view/5027Введение

Введение. Изучение токсичности наночастиц оксида свинца (НЧ PbO) является актуальной задачей в связи с их повсеместной распространённостью в окружающей среде и влиянием на здоровье населения. Особое внимание вызывают нейротоксичные эффекты НЧ PbO. Один из возможных механизмов нейротоксичности – апоптотический процесс, вызванный необратимым повреждением ДНК. Для подтверждения данной гипотезы были проведены исследования экспрессии генов ATM, MDM2 и метаболомный анализ.

Цель исследования – изучение нейротоксичности ингаляционного воздействия НЧ PbO на лабораторных животных с помощью анализа экспрессии генов и метаболомики.

Материалы и методы

Материалы и методы. Субхронический эксперимент, заключавшийся в ингаляционном воздействии НЧ PbO в концентрации 1,55 ± 0,06 мг/м3 в течение четырёх недель (за исключением выходных дней), был проведён на 20 белых самках крыс, разделённых на опытную и контрольную группы. Уровень мРНК генов ATM и MDM2 в обонятельной луковице крыс определяли количественной ПЦР в реальном времени. Полуколичественный метаболомный анализ тканей мозга животных проводили с помощью жидкостной хромато-масс-спектрометрии.

Результаты

Результаты. Экспрессия гена ATM в обонятельной луковице была статистически значимо (р < 0,05) выше у животных опытной группы по сравнению с контрольной. Метаболомный анализ выявил у животных из опытной группы изменения в метаболизме лизофосфатидилэтаноламинов, лизофосфатидилхолинов, ацилкарнитинов, омега-3 полиненасыщенных жирных кислот, амида жирной кислоты, фосфорилхолина, инозина и гипоксантина. Для комбинации обнаруженных метаболитов была построена ROC-кривая со значением AUC = 0,903.

Ограничения исследования

Ограничения исследования. Данная работа выполнена на самках крыс породы Wistar и не учитывает возможных межполовых различий.

Заключение

Заключение. В совокупности полученные данные анализа экспрессии генов и метаболомики свидетельствуют о том, что ингаляционное воздействие НЧ PbO в концентрации 1,55 ± 0,06 мг/м3 вызывает опосредованный ATM p53-индуцированный апоптоз в мозге животных.

Соблюдение этических стандартов. Заключение локального этического комитета ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора: содержание, питание, уход за животными и выведение их из эксперимента осуществляли в соответствии с общепринятыми требованиями с учётом ARRIVE guidelines. Исследования были одобрены локальным этическим комитетом ФБУН ЕМНЦ ПОЗРПП Роспотребнадзора (протокол № 5 от 16.10.2023 г.).

Участие авторов

Участие авторов: Кикоть А.М. – обработка данных, статистическая обработка, написание текста, редактирование; Унесихина М.С. – сбор материала и обработка данных, статистическая обработка, написание текста, редактирование; Шаихова Д.Р. – обработка данных, редактирование; Берёза И.А. – сбор материала и обработка данных, редактирование; Никогосян К.М. – сбор материала, редактирование; Минигалиева И.А. – концепция и дизайн исследования, редактирование; Сутункова М.П. – концепция и дизайн исследования. Все соавторы – утверждение окончательного варианта статьи, ответственность за целостность всех её частей.

Конфликт интересов

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов в связи с публикацией данной статьи.

Финансирование

Финансирование. Исследование не имело спонсорской поддержки.

Поступила

Поступила: 28.03.2025 / Принята к печати: 26.06.2025 / Опубликована: 31.07.2025

Introduction

Introduction. The study of toxicity of lead oxide nanoparticles (PbO NPs) is relevant owing to their ubiquity in the environment and human health impact with the focus on their neurotoxic effects. Apoptosis induced by irreversible DNA damage is one of the possible mechanisms of neurotoxicity. To confirm this hypothesis, studies of ATM and MDM2 gene expression and metabolomic analysis were conducted.

The purpose was to establish neurotoxicity of inhalation exposure of laboratory animals to PbO NPs using gene expression analysis and metabolomics.

Materials and methods

Materials and methods. The subchronic experiment with inhalation exposure to PbO NPs at the concentration of 1.55 ± 0.06 mg/m3 was conducted on twenty female albino rats equally divided into exposure and control groups for 5 days a week during 4 weeks. The mRNA level of the ATM and MDM2 genes in olfactory bulbs in the rats was determined by quantitative real-time PCR. Semi-quantitative metabolomic analysis of animal brain tissues was performed using liquid chromatography-mass spectrometry.

Results

Results. ATM gene expression in the olfactory bulb was statistically higher in the exposed animals compared to the controls (p < 0.05). Metabolome analysis revealed changes in the metabolism of lysophosphatidylethanolamines, lysophosphatidylcholines, acylcarnitines, omega-3 polyunsaturated fatty acids, fatty acid amide, phosphorylcholine, inosine, and hypoxanthine in the exposed rodents. For the combination of metabolites detected, a ROC curve with an AUC value of 0.903 was constructed.

Limitations

Limitations. The study was conducted using female Wistar rats with no potential sex differences considered.

Conclusion

Conclusion. Taken together, the obtained gene expression and metabolomics data indicate that inhalation exposure to PbO NPs at the concentration of 1,55 ± 0,06 mg/m3 induces ATM-mediated p53-induced apoptosis in the animal brain.

Compliance with ethical standards. The local Ethics Committee of the Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers concluded that the animals were kept, fed, cared for, and sacrificed in accordance with generally accepted requirements, taking into account the ARRIVE guidelines. Ethics approval was provided by the Ethics Committee of the Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers (protocol No. 5 of October 16, 2023).

Contribution

Contribution: Kikot A.M. — data processing, statistical analysis, draft manuscript preparation, editing; Unesikhina M.S. — data collection and processing, statistical analysis, draft manuscript preparation, editing; Shaikhova D.R. — data processing, editing; Bereza I.A. — data collection and processing, editing; Nikogosyan K.M. — data collection, editing; Minigalieva I.A. — study conception and design, editing; Sutunkova M.P. — study conception and design. All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest

Conflict of interest. The authors declare no conflict of interest.

Funding

Funding. The study had no sponsorship.

Received

Received: March 28, 2025 / Accepted: June 26, 2025 / Published: July 31, 2025

наночастицы свинцаэкспрессия геновметаболитыапоптознейротоксичность наночастицlead nanoparticlesgene expressionmetabolitesapoptosisneurotoxicity of nanoparticlesReferencesSutunkova M.P., Solovyeva S.N., Chernyshov I.N., Klinova S.V., Gurvich V.B., Shur V.Ya., et al. Manifestation of systemic toxicity in rats after a short-time inhalation of lead oxide nanoparticles. Int. J. Mol. Sci. 2020; 21(3): 690. https://doi.org/10.3390/ijms21030690Sutunkova M.P., Solovyeva S.N., Chernyshov I.N., Klinova S.V., Gurvich V.B., Shur V.Ya., et al. Manifestation of systemic toxicity in rats after a short-time inhalation of lead oxide nanoparticles. Int. J. Mol. Sci. 2020; 21(3): 690. https://doi.org/10.3390/ijms21030690Elgharabawy R.M., Alhowail A.H., Emara A.M., Aldubayan M.A., Ahmed A.S. The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats. Biomed. Pharmacother. 2021; 137: 111324. https://doi.org/10.1016/j.biopha.2021.111324Elgharabawy R.M., Alhowail A.H., Emara A.M., Aldubayan M.A., Ahmed A.S. The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats. Biomed. Pharmacother. 2021; 137: 111324. https://doi.org/10.1016/j.biopha.2021.111324Minigaliyeva I.A., Klinova S.V., Sutunkova M.P., Ryabova Y.V., Valamina I.E., Shelomentsev I.G., et al. On the mechanisms of the cardiotoxic effect of lead oxide nanoparticles. Cardiovasc Toxicol. 2024; 24(1): 49–61. https://doi.org/10.1007/s12012-023-09814-5Minigaliyeva I.A., Klinova S.V., Sutunkova M.P., Ryabova Y.V., Valamina I.E., Shelomentsev I.G., et al. On the mechanisms of the cardiotoxic effect of lead oxide nanoparticles. Cardiovasc Toxicol. 2024; 24(1): 49–61. https://doi.org/10.1007/s12012-023-09814-5Ermolin M.S., Fedotov P.S., Ivaneev A.I., Karandashev V.K., Burmistrov A.A., Tatsy Y.G. Assessment of elemental composition and properties of copper smelter-affected dust and its nano- and micron size fractions. Environ. Sci. Pollut. Res. 2016; 23(23): 23781–90. https://doi.org/10.1007/s11356-016-7637-6Ermolin M.S., Fedotov P.S., Ivaneev A.I., Karandashev V.K., Burmistrov A.A., Tatsy Y.G. Assessment of elemental composition and properties of copper smelter-affected dust and its nano- and micron size fractions. Environ. Sci. Pollut. Res. 2016; 23(23): 23781–90. https://doi.org/10.1007/s11356-016-7637-6Ermolin M.S., Shilobreeva S.N., Fedotov P.S. Study of the chemical composition of ash nanoparticles from the volcanoes of Kamchatka. Geochem. Int. 2023; 61(4): 348–58. https://doi.org/10.1134/S0016702923040043Ermolin M.S., Shilobreeva S.N., Fedotov P.S. Study of the chemical composition of ash nanoparticles from the volcanoes of Kamchatka. Geochem. Int. 2023; 61(4): 348–58. https://doi.org/10.1134/S0016702923040043Pal D., Dastoor A., Ariya P.A. Aerosols in an urban cold climate: Physical and chemical characteristics of nanoparticles. Urban Clim. 2020; 34: 100713. https://doi.org/10.1016/j.uclim.2020.100713Pal D., Dastoor A., Ariya P.A. Aerosols in an urban cold climate: Physical and chemical characteristics of nanoparticles. Urban Clim. 2020; 34: 100713. https://doi.org/10.1016/j.uclim.2020.100713Bláhová L., Nováková Z., Večeřa Z., Vrlíková L., Dočekal B., Dumková J., et al. The effects of nano-sized PbO on biomarkers of membrane disruption and DNA damage in a sub-chronic inhalation study on mice. Nanotoxicology. 2020; 14(2): 214–31. https://doi.org/10.1080/17435390.2019.1685696Bláhová L., Nováková Z., Večeřa Z., Vrlíková L., Dočekal B., Dumková J., et al. The effects of nano-sized PbO on biomarkers of membrane disruption and DNA damage in a sub-chronic inhalation study on mice. Nanotoxicology. 2020; 14(2): 214–31. https://doi.org/10.1080/17435390.2019.1685696Tulinska J., Krivosikova Z., Liskova A., Mikusova M.L., Masanova V., Rollerova E., et al. Six-week inhalation of lead oxide nanoparticles in mice affects antioxidant defense, immune response, kidneys, intestine and bones. Environ. Sci. Nano. 2022; 9(2): 751–66. https://doi.org/10.1039/D1EN00957ETulinska J., Krivosikova Z., Liskova A., Mikusova M.L., Masanova V., Rollerova E., et al. Six-week inhalation of lead oxide nanoparticles in mice affects antioxidant defense, immune response, kidneys, intestine and bones. Environ. Sci. Nano. 2022; 9(2): 751–66. https://doi.org/10.1039/D1EN00957EAljelehawy H.A.Q. Effects of the lead, cadmium, manganese heavy metals, and magnesium oxide nanoparticles on nerve cell function in Alzheimer’s and Parkinson’s diseases. Cent. Asian J. Med. Pharm. Sci. Innov. 2022; 2(1): 25–36. https://doi.org/10.22034/CAJMPSI.2022.01.04Aljelehawy H.A.Q. Effects of the lead, cadmium, manganese heavy metals, and magnesium oxide nanoparticles on nerve cell function in Alzheimer’s and Parkinson’s diseases. Cent. Asian J. Med. Pharm. Sci. Innov. 2022; 2(1): 25–36. https://doi.org/10.22034/CAJMPSI.2022.01.04Кикоть А.М., Шаихова Д.Р., Берёза И.А., Минигалиева И.А., Никогосян К.М., Сутункова М.П. Изменение экспрессии генов, вовлечённых в митохондриальный путь апоптоза, при воздействии наночастиц оксида свинца. Гигиена и санитария. 2024; 103(11): 1429–33. https://doi.org/10.47470/0016-9900-2024-103-11-1429-1433 https://elibrary.ru/pkpdpmKikot A.M., Shaikhova D.R., Bereza I.A., Minigalieva I.A., Nikogosyan K.M., Sutunkova M.P. Alterations in the expression of genes involved in the mitochondrial apoptotic pathway upon exposure to lead oxide nanoparticles. Gigiena i Sanitaria (Hygiene and Sanitation, Russian journal). 2024; 103(11): 1429–33. https://doi.org/10.47470/0016-9900-2024-103-11-1429-1433 https://elibrary.ru/pkpdpm (in Russian)Xu D., Liang D., Guo Y., Sun Y. Endosulfan causes the alterations of DNA damage response through ATM-p53 signaling pathway in human leukemia cells. Environ. Pollut. 2018; 238: 1048–55. https://doi.org/10.1016/j.envpol.2018.03.044Xu D., Liang D., Guo Y., Sun Y. Endosulfan causes the alterations of DNA damage response through ATM-p53 signaling pathway in human leukemia cells. Environ. Pollut. 2018; 238: 1048–55. https://doi.org/10.1016/j.envpol.2018.03.044Yin J., Zhou Q., Tan J., Che W., He Y. Inorganic arsenic induces MDM2, p53, and their phosphorylation and affects the MDM2/p53 complex in vitro. Environ. Sci. Pollut. Res. Int. 2022; 29(58): 88078–88. https://doi.org/10.1007/s11356-022-21986-1Yin J., Zhou Q., Tan J., Che W., He Y. Inorganic arsenic induces MDM2, p53, and their phosphorylation and affects the MDM2/p53 complex in vitro. Environ. Sci. Pollut. Res. Int. 2022; 29(58): 88078–88. https://doi.org/10.1007/s11356-022-21986-1Liao J., Yang F., Bai Y., Yu W., Qiao N., Han Q., et al. Metabolomics analysis reveals the effects of copper on mitochondria-mediated apoptosis in kidney of broiler chicken (Gallus gallus). J. Inorg. Biochem. 2021; 224: 111581. https://doi.org/10.1016/j.jinorgbio.2021.111581Liao J., Yang F., Bai Y., Yu W., Qiao N., Han Q., et al. Metabolomics analysis reveals the effects of copper on mitochondria-mediated apoptosis in kidney of broiler chicken (Gallus gallus). J. Inorg. Biochem. 2021; 224: 111581. https://doi.org/10.1016/j.jinorgbio.2021.111581Xia Y., Zhang X., Sun D., Gao Y., Zhang X, Wang L., et al. Effects of water-soluble components of atmospheric particulates from rare earth mining areas in China on lung cancer cell cycle. Part. Fibre. Toxicol. 2021; 18(1): 27. https://doi.org/10.1186/s12989-021-00416-zXia Y., Zhang X., Sun D., Gao Y., Zhang X, Wang L., et al. Effects of water-soluble components of atmospheric particulates from rare earth mining areas in China on lung cancer cell cycle. Part. Fibre. Toxicol. 2021; 18(1): 27. https://doi.org/10.1186/s12989-021-00416-zWang Y., Sun X., Fang L., Li K., Yang P., Du L., et al. Genomic instability in adult men involved in processing electronic waste in Northern China. Environ. Int. 2018; 117: 69–81. https://doi.org/10.1016/j.envint.2018.04.027Wang Y., Sun X., Fang L., Li K., Yang P., Du L., et al. Genomic instability in adult men involved in processing electronic waste in Northern China. Environ. Int. 2018; 117: 69–81. https://doi.org/10.1016/j.envint.2018.04.027Peker N., Gozuacik D. Autophagy as a cellular stress response mechanism in the nervous system. J. Mol. Biol. 2020; 432(8): 2560–88. https://doi.org/10.1016/j.jmb.2020.01.017Peker N., Gozuacik D. Autophagy as a cellular stress response mechanism in the nervous system. J. Mol. Biol. 2020; 432(8): 2560–88. https://doi.org/10.1016/j.jmb.2020.01.017Pal P., Jha N.K., Pal D., Jha S.K., Anand U., Gopalakrishnan A.V., et al. Molecular basis of fluoride toxicities: Beyond benefits and implications in human disorders. Genes Dis. 2022; 10(4): 1470–93. https://doi.org/10.1016/j.gendis.2022.09.004Pal P., Jha N.K., Pal D., Jha S.K., Anand U., Gopalakrishnan A.V., et al. Molecular basis of fluoride toxicities: Beyond benefits and implications in human disorders. Genes Dis. 2022; 10(4): 1470–93. https://doi.org/10.1016/j.gendis.2022.09.004Wu Y., Chen Z., Darwish W.S., Terada K., Chiba H., Hui S.P. Choline and ethanolamine plasmalogens prevent lead-induced cytotoxicity and lipid oxidation in HepG2 cells. J. Agric. Food Chem. 2019; 67(27): 7716–25. https://doi.org/10.1021/acs.jafc.9b02485Wu Y., Chen Z., Darwish W.S., Terada K., Chiba H., Hui S.P. Choline and ethanolamine plasmalogens prevent lead-induced cytotoxicity and lipid oxidation in HepG2 cells. J. Agric. Food Chem. 2019; 67(27): 7716–25. https://doi.org/10.1021/acs.jafc.9b02485Butera A., Roy M., Zampieri C., Mammarella E., Panatta E., Melino G., et al. p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer. Biol. Direct. 2022; 17(1): 6. https://doi.org/10.1186/s13062-022-00319-9Butera A., Roy M., Zampieri C., Mammarella E., Panatta E., Melino G., et al. p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer. Biol. Direct. 2022; 17(1): 6. https://doi.org/10.1186/s13062-022-00319-9Chaurio R.A., Janko C., Muñoz L.E., Frey B., Herrmann M., Gaipl U.S. Phospholipids: key players in apoptosis and immune regulation. Molecules. 2009; 14(12): 4892–914. https://doi.org/10.3390/molecules14124892Chaurio R.A., Janko C., Muñoz L.E., Frey B., Herrmann M., Gaipl U.S. Phospholipids: key players in apoptosis and immune regulation. Molecules. 2009; 14(12): 4892–914. https://doi.org/10.3390/molecules14124892Griffin J.L., Kauppinen R.A. Tumour metabolomics in animal models of human cancer. J. Proteome. Res. 2007; 6(2): 498–505. https://doi.org/10.1021/pr060464hGriffin J.L., Kauppinen R.A. Tumour metabolomics in animal models of human cancer. J. Proteome. Res. 2007; 6(2): 498–505. https://doi.org/10.1021/pr060464hIorio E., Di Vito M., Spadaro F., Ramoni C., Lococo E., Carnevale R., et al. Triacsin C inhibits the formation of 1H NMR-visible mobile lipids and lipid bodies in HuT 78 apoptotic cells. Biochim. Biophys. Acta. 2003; 1634(1–2): 1–14. https://doi.org/10.1016/j.bbalip.2003.07.001Iorio E., Di Vito M., Spadaro F., Ramoni C., Lococo E., Carnevale R., et al. Triacsin C inhibits the formation of 1H NMR-visible mobile lipids and lipid bodies in HuT 78 apoptotic cells. Biochim. Biophys. Acta. 2003; 1634(1–2): 1–14. https://doi.org/10.1016/j.bbalip.2003.07.001Montecillo-Aguado M., Tirado-Rodriguez B., Huerta-Yepez S. The involvement of polyunsaturated fatty acids in apoptosis mechanisms and their implications in cancer. Int. J. Mol. Sci. 2023; 24(14): 11691. https://doi.org/10.3390/ijms241411691Montecillo-Aguado M., Tirado-Rodriguez B., Huerta-Yepez S. The involvement of polyunsaturated fatty acids in apoptosis mechanisms and their implications in cancer. Int. J. Mol. Sci. 2023; 24(14): 11691. https://doi.org/10.3390/ijms241411691Sun Y., Jia X., Hou L., Liu X., Gao Q. Involvement of apoptotic pathways in docosahexaenoic acid-induced benefit in prostate cancer: Pathway-focused gene expression analysis using RT2 Profile PCR Array System. Lipids Health Dis. 2017; 16(1): 59. https://doi.org/10.1186/s12944-017-0442-5Sun Y., Jia X., Hou L., Liu X., Gao Q. Involvement of apoptotic pathways in docosahexaenoic acid-induced benefit in prostate cancer: Pathway-focused gene expression analysis using RT2 Profile PCR Array System. Lipids Health Dis. 2017; 16(1): 59. https://doi.org/10.1186/s12944-017-0442-5Wellner N., Diep T.A., Janfelt C., Hansen H.S. N-acylation of phosphatidylethanolamine and its biological functions in mammals. Biochim. Biophys. Acta. 2013; 1831(3): 652–62. https://doi.org/10.1016/j.bbalip.2012.08.019Wellner N., Diep T.A., Janfelt C., Hansen H.S. N-acylation of phosphatidylethanolamine and its biological functions in mammals. Biochim. Biophys. Acta. 2013; 1831(3): 652–62. https://doi.org/10.1016/j.bbalip.2012.08.019Shadfar S., Parakh S., Jamali M.S., Atkin J.D. Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases. Transl. Neurodegener. 2023; 12(1): 18. https://doi.org/10.1186/s40035-023-00350-4Shadfar S., Parakh S., Jamali M.S., Atkin J.D. Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases. Transl. Neurodegener. 2023; 12(1): 18. https://doi.org/10.1186/s40035-023-00350-4Kim Y.J., Ryu H.M., Choi J.Y., Cho J.H., Kim C.D., Park S.H., et al. Hypoxanthine causes endothelial dysfunction through oxidative stress-induced apoptosis. Biochem. Biophys. Res. Commun. 2017; 482(4): 821–27. https://doi.org/10.1016/j.bbrc.2016.11.119Kim Y.J., Ryu H.M., Choi J.Y., Cho J.H., Kim C.D., Park S.H., et al. Hypoxanthine causes endothelial dysfunction through oxidative stress-induced apoptosis. Biochem. Biophys. Res. Commun. 2017; 482(4): 821–27. https://doi.org/10.1016/j.bbrc.2016.11.119Virág L., Szabó C. Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death. FASEB J. 2001; 15(1): 99–107. https://doi.org/10.1096/fj.00-0299comVirág L., Szabó C. Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death. FASEB J. 2001; 15(1): 99–107. https://doi.org/10.1096/fj.00-0299comSanchez-Macedo N., Feng J., Faubert B., Chang N., Elia A., Rushing E.J., et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ. 2013; 20(4): 659–68. https://doi.org/10.1038/cdd.2012.168Sanchez-Macedo N., Feng J., Faubert B., Chang N., Elia A., Rushing E.J., et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ. 2013; 20(4): 659–68. https://doi.org/10.1038/cdd.2012.168

The authors declare that there are no conflicts of interest present.