rpmjResearch'n Practical Medicine JournalResearch and Practical Medicine Journal2410-1893"QUASAR", LLC10.17709/2410-1893-2025-12-4-5TOJWTFrpmj-1163Research ArticleОригинальные статьиOriginal ArticlesУчастие факторов роста в реализации радиопротекторного эффекта N-ацетилцистеина при радиационном поражении поджелудочной железыRegulatory role of growth factors during N-acetylcysteine administration in the model of radiation-induced pancreatic injuryhttps://orcid.org/0000-0001-8447-2600ДемяшкинГ. А.DemyashkinG. A.

 

Демяшкин Григорий Александрович – д.м.н., заведующий лабораторией гистологии и иммуногистохимии Института трансляционной медицины и биотехнологии ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет), г. Москва, Российская Федерация; заведующий отделом цифровой онкоморфологии Московского научно-исследовательского онкологического института им. П. А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Москва, Российская Федерация

ORCID: http://orcid.org/0000-0001-8447-2600

eLibrary SPIN: 5157-0177, AuthorID: 645433

Scopus Author ID: 57200415197

WoS ResearcherID: ABD-7650-2021

 

Grigory A. Demyashkin – Dr. Sci. (Medicine), pathologist, Head of the Laboratory of Histology and Immunohistochemistry, Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; Head of the Department of Digital Oncomorphology, P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Moscow, Russian Federation

ORCID: http://orcid.org/0000-0001-8447-2600

eLibrary SPIN: 5157-0177, AuthorID: 645433

Scopus Author ID: 57200415197

WoS ResearcherID: ABD-7650-2021

dr.dga@mail.ruhttps://orcid.org/0000-0002-6235-1020ВадюхинМ. А.VadyukhinM. A.

 

Вадюхин Матвей Анатольевич – аспирант Института трансляционной медицины и биотехнологии ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет), г. Москва, Российская Федерация; лаборант-исследователь отдела цифровой онкоморфологии Московского научно-исследовательского онкологического института им. П. А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Москва, Российская Федерация

ORCID: https://orcid.org/0000-0002-6235-1020

eLibrary SPIN: 9485-7722, AuthorID: 1150399

Scopus Author ID: 57539187100

 

Matvey А. Vadyukhin – graduate student of Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; Researcher of the Department of Digital Oncomorphology, P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0002-6235-1020

eLibrary SPIN: 9485-7722, AuthorID: 1150399

Scopus Author ID: 57539187100

vma20@mail.ruhttps://orcid.org/0000-0003-3763-7454ЩекинВ. И.ShchekinV. I.

 

Щекин Владимир Иванович – аспирант Института трансляционной медицины и биотехнологии ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет), г. Москва, Российская Федерация; лаборант-исследователь отдела цифровой онкоморфологии Московского научно-исследовательского онкологического института им. П. А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Москва, Российская Федерация

ORCID: https://orcid.org/0000-0003-3763-7454

eLibrary SPIN: 3664-8044, AuthorID: 1109647

Scopus Author ID: 57222109527

 

Vladimir I. Shchekin – graduate student of Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; Researcher of the Department of Digital Oncomorphology, P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Moscow, Russian Federation

ORCID: https://orcid.org/0000-0003-3763-7454

eLibrary SPIN: 3664-8044, AuthorID: 1109647

Scopus Author ID: 57222109527

dr.shchekin@mail.ruhttps://orcid.org/0009-0006-3746-3924БелокопытовД. В.BelokopytovD. V.

 

Белокопытов Дмитрий Вячеславович – аспирант Института трансляционной медицины и биотехнологии ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет), г. Москва, Российская Федерация; лаборант-исследователь отдела цифровой онкоморфологии Московского научно-исследовательского онкологического института им. П. А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации, г. Москва, Российская Федерация

ORCID: https://orcid.org/0009-0006-3746-3924

 

Dmitriy V. Belokopytov – graduate student of Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; Researcher of the Department of Digital Oncomorphology, P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Moscow, Russian Federation

ORCID: https://orcid.org/0009-0006-3746-3924

 

Beldimbur@gmail.comПервый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет);<p> Московский научно-исследовательский онкологический институт им. П. А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Министерства здравоохранения Российской Федерации <p> г. Москва, Российская ФедерацияSechenov First Moscow State Medical University (Sechenov University);<p> P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre <p> Moscow, Russian Federation2025111220251245667Copyright &#x00A9; Демяшкин Г.А., Вадюхин М.А., Щекин В.И., Белокопытов Д.В., 20252025Демяшкин Г.А., Вадюхин М.А., Щекин В.И., Белокопытов Д.В.Demyashkin G.A., Vadyukhin M.A., Shchekin V.I., Belokopytov D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpmj.ru/rpmj/article/view/1163Цель исследования

Цель исследования. Оценить уровни экспрессии факторов роста IGF‑1, TGF-β и VEGF-A в отдаленные сроки после предлучевого введения N-ацетилцистеина (N-АЦ) и локального облучения поджелудочной железы электронами в суммарной очаговой дозе (СОД) 30 Гр.

Материалы и методы

Материалы и методы. Экспериментальное исследование проведено на 60 самцах крыс линии Вистар, которые были распределены на 4 группы: 1‑я группа (контрольная) (n = 10) – крысы, которым вводили 0,9 % физиологический раствор NaCl без локального облучения электронами; 2‑я группа (n = 20) – интраперитонеальное введение раствора NaCl 0,9 % перед локальным облучением электронами в режиме фракционирования в СОД 30 Гр; 3‑я группа (n = 20) – интраперитонеальное введение N-АЦ в дозе 120 мг/кг перед локальным облучением электронами в режиме фракционирования в СОД 30 Гр; 4‑я группа (n = 10) – интраперитонеальное введение N-АЦ в дозе 120 мг/кг без локального облучения электронами. Через 30 сут. оценивали уровни глюкозы, инсулина и амилазы в крови, гистоархитектонику панкреатических островков, степень фиброза в периваскулярных зонах (при окрашивании по Массону), а также экспрессию IGF‑1, TGF-β и VEGF-A методом подсчета позитивных клеток при иммуногистохимическом исследовании.

Результаты

Результаты. После облучения отмечали повышение концентраций глюкозы и амилазы в крови, снижение уровня инсулина. Развитие признаков радиационно-индуцированного повреждения поджелудочной железы сопровождалось снижением экспрессии IGF‑1 и VEGF-A в островках на 39 % и 56 %, тогда как доля TGF-β+ клеток превышала контрольные значения в 3,4 раза. Предлучевое введение N-АЦ способствовало менее выраженному изменению биохимических показателей на фоне низкой экспрессии TGF-β и повышенного количества IGF‑1+ и VEGF-A+ эндокринных клеток, в 2,5 и 3 раза превышающих аналогичные показатели в группе животных, локально облученных электронами в СОД 30 Гр.

Заключение

Заключение. Предлучевое введение N-АЦ спустя 30 сут. после локального облучения поджелудочной железы электронами приводит к увеличению экспрессии ключевых факторов роста IGF‑1, TGF-β и VEGF-A, вносящих вклад в развитие радиопротекторных механизмов, направленных на сохранение структурной целостности и эндокринной функции органа. Полученные данные позволяют рассматривать N-АЦ как перспективное средство для профилактики отсроченных постлучевых осложнений, включая фиброз, метаболическую и секреторную недостаточность панкреатических островков.

Purpose of the study

Purpose of the study. To evaluate the roles of the growth factors IGF‑1, TGF-β, and VEGF-A in regulating delayed regenerative mechanisms induced by N-acetylcysteine (NAC) administered prior to local pancreatic irradiation with electrons at a total dose of 30 Gy.

Materials and methods

Materials and methods. An experimental study was conducted on 60 male Wistar rats, which were divided into four groups: Group 1 (control, n = 10): rats received an intraperitoneal injection of NaCl solution without local electron irradiation; Group 2 (n = 20): intraperitoneal administration of 0.9 % NaCl solution prior to local electron irradiation in a fractionated mode with a total focal dose (TFD) of 30 Gy; Group 3 (n = 20): intraperitoneal administration of N-AC at a dose of 120 mg/kg prior to local electron irradiation in a fractionated mode with a TFD of 30 Gy; Group 4 (n = 10): intraperitoneal administration of N-AC at a dose of 120 mg/kg without local electron irradiation. Thirty days after irradiation, blood levels of glucose, insulin, and amylase were measured. Histological analysis of pancreatic islet architecture, the degree of perivascular fibrosis (Masson’s trichrome staining), and the expression of IGF‑1, TGF-β, and VEGF-A were assessed by immunohistochemistry through counting positively stained cells.

Results

Results. Irradiation resulted in elevated blood glucose and amylase levels and decreased insulin levels. Signs of radiation-induced pancreatic injury were accompanied by reduced expression of IGF‑1 and VEGF-A in the islets by 39 % and 56 %, respectively, while the proportion of TGF-β-positive cells exceeded the control values by 3.4‑fold. Pre-irradiation administration of NAC partially preserved biochemical parameters within the normal range, suppressed TGF-β expression, and maintained the numbers of IGF‑1- and VEGF-A-positive endocrine cells at levels 2.5 and 3 times higher than those in the irradiation-only group, respectively.

Conclusion

Conclusion. Pre-irradiation administration of NAC exerts a modulatory effect on the expression of growth factors IGF‑1, TGF-β, and VEGF-A in the late period following local electron irradiation of the pancreas, promoting restoration of the organ’s structural integrity and endocrine function. The obtained data suggest that N-AC is a promising agent for the prevention of delayed post-radiation complications, including fibrosis as well as metabolic and secretory insufficiency of the pancreatic islets.

факторы ростарадиопротекцияпоздние эффектыэлектроныфиброгенезангиогенезрепарацияgrowth factorsradioprotectionlate effectselectronsfibrogenesisangiogenesisreparationисследование в полном объеме выполнено за счет средств гранта Российского научного фонда № 25-25-00350 (https://rscf.ru/project/25-25-00350/).the study was fully supported by the Russian Science Foundation Grant No. 25-25-00350, (https://rscf.ru/project/25-25-00350/).ReferencesColeman CN, Buchsbaum JC, Prasanna PGS. Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care. JNCI Cancer Spectr. 2021;5(4):pkab046. https://doi.org/10.1093/jncics/pkab046Coleman CN, Buchsbaum JC, Prasanna PGS. Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care. JNCI Cancer Spectr. 2021;5(4):pkab046. https://doi.org/10.1093/jncics/pkab046Calvo FA, Serrano J, Cambeiro M, et al. Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies. Cancers (Basel). 2022;14(15):3693. https://doi.org/10.3390/cancers14153693Calvo FA, Serrano J, Cambeiro M, et al. Intra-Operative Electron Radiation Therapy: An Update of the Evidence Collected in 40 Years to Search for Models for Electron-FLASH Studies. Cancers (Basel). 2022;14(15):3693. https://doi.org/10.3390/cancers14153693Ronga MG, Cavallone M, Patriarca A, et al. Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy. Cancers (Basel). 2021;13(19):4942. https://doi.org/10.3390/cancers13194942Ronga MG, Cavallone M, Patriarca A, et al. Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy. Cancers (Basel). 2021;13(19):4942. https://doi.org/10.3390/cancers13194942Wydmanski J, Polanowski P, Tukiendorf A, Maslyk B. Radiation-induced injury of the exocrine pancreas after chemoradiotherapy for gastric cancer. Radiother Oncol. 2016;118(3):535-539. https://doi.org/10.1016/j.radonc.2015.11.033Wydmanski J, Polanowski P, Tukiendorf A, Maslyk B. Radiation-induced injury of the exocrine pancreas after chemoradiotherapy for gastric cancer. Radiother Oncol. 2016;118(3):535-539. https://doi.org/10.1016/j.radonc.2015.11.033You SH, Cho MY, Sohn JH, Lee CG. Pancreatic radiation effect in apoptosis-related rectal radiation toxicity. J Radiat Res. 2018;59(5):529–540. https://doi.org/10.1093/jrr/rry043You SH, Cho MY, Sohn JH, Lee CG. Pancreatic radiation effect in apoptosis-related rectal radiation toxicity. J Radiat Res. 2018;59(5):529–540. https://doi.org/10.1093/jrr/rry043Baek JY, Lim DH, Oh D, Nam H, Kim JJ, Lee JH, Min BH, Lee H. Increased Risk of Diabetes after Definitive Radiotherapy in Patients with Indolent Gastroduodenal Lymphoma. Cancer Res Treat. 2022;54(1):294–300. https://doi.org/10.4143/crt.2021.073Baek JY, Lim DH, Oh D, Nam H, Kim JJ, Lee JH, Min BH, Lee H. Increased Risk of Diabetes after Definitive Radiotherapy in Patients with Indolent Gastroduodenal Lymphoma. Cancer Res Treat. 2022;54(1):294–300. https://doi.org/10.4143/crt.2021.073Bacarella N, Ruggiero A, Davis AT, Uberseder B, Davis MA, Bracy DP, et al. Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates. Int J Radiat Oncol Biol Phys. 2020;106(4):878-886. https://doi.org/10.1016/j.ijrobp.2019.11.034Bacarella N, Ruggiero A, Davis AT, Uberseder B, Davis MA, Bracy DP, et al. Whole Body Irradiation Induces Diabetes and Adipose Insulin Resistance in Nonhuman Primates. Int J Radiat Oncol Biol Phys. 2020;106(4):878-886. https://doi.org/10.1016/j.ijrobp.2019.11.034Singh VK, Seed TM. Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert. Opin. Pharmacother. 2020;21(3):317–337. https://doi.org/10.1080/14656566.2019.1702968Singh VK, Seed TM. Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert. Opin. Pharmacother. 2020;21(3):317–337. https://doi.org/10.1080/14656566.2019.1702968Campesi I, Brunetti A, Capobianco G, Galistu A, Montella A, Ieri F, Franconi F. Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine. Antioxidants. 2023;12:77. https://doi.org/10.3390/antiox12010077Campesi I, Brunetti A, Capobianco G, Galistu A, Montella A, Ieri F, Franconi F. Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine. Antioxidants. 2023;12:77. https://doi.org/10.3390/antiox12010077Topcu A, Mercantepe F, Rakici S, Tumkaya L, Uydu HA, Mercantepe T. An investigation of the effects of N-acetylcysteine on radiotherapy-induced testicular injury in rats. Naunyn Schmiedebergs Arch. Pharmacol. 2019;392(2):147–157. https://doi.org/10.1007/s00210-018-1581-6Topcu A, Mercantepe F, Rakici S, Tumkaya L, Uydu HA, Mercantepe T. An investigation of the effects of N-acetylcysteine on radiotherapy-induced testicular injury in rats. Naunyn Schmiedebergs Arch. Pharmacol. 2019;392(2):147–157. https://doi.org/10.1007/s00210-018-1581-6Mantawy EM, Said RS, Kassem DH, Abdel-Aziz AK, Badr AM. Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats. Ecotoxicol Environ Saf. 2020;206:111190. https://doi.org/10.1016/j.ecoenv.2020.111190Mantawy EM, Said RS, Kassem DH, Abdel-Aziz AK, Badr AM. Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats. Ecotoxicol Environ Saf. 2020;206:111190. https://doi.org/10.1016/j.ecoenv.2020.111190Ezeriņa D, Takano Y, Hanaoka K, Urano Y, Dick TP. N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production. Cell Chem Biol. 2018;25(4):447-459.e4. https://doi.org/10.1016/j.chembiol.2018.01.011Ezeriņa D, Takano Y, Hanaoka K, Urano Y, Dick TP. N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production. Cell Chem Biol. 2018;25(4):447-459.e4. https://doi.org/10.1016/j.chembiol.2018.01.011Lu Q, Liang Y, Tian S, Jin J, Zhao Y, Fan H. Radiation-Induced Intestinal Injury: Injury Mechanism and Potential Treatment Strategies. Toxics. 2023;11(12):1011. https://doi.org/10.3390/toxics11121011Lu Q, Liang Y, Tian S, Jin J, Zhao Y, Fan H. Radiation-Induced Intestinal Injury: Injury Mechanism and Potential Treatment Strategies. Toxics. 2023;11(12):1011. https://doi.org/10.3390/toxics11121011Mercantepe F, Topcu A, Rakici S, Tumkaya L, Yilmaz A. The effects of N-acetylcysteine on radiotherapy-induced small intestinal damage in rats. Exp. Biol. Med. (Maywood). 2019;244(5):372–379. https://doi.org/10.1177/1535370219831225Mercantepe F, Topcu A, Rakici S, Tumkaya L, Yilmaz A. The effects of N-acetylcysteine on radiotherapy-induced small intestinal damage in rats. Exp. Biol. Med. (Maywood). 2019;244(5):372–379. https://doi.org/10.1177/1535370219831225Talasaz AH, Khalili H, Jenab Y, Salarifar M, Broumand MA, Darabi F. N-Acetylcysteine effects on transforming growth factor-β and tumor necrosis factor-α serum levels as pro-fibrotic and inflammatory biomarkers in patients following ST-segment elevation myocardial infarction. Drugs R D. 2013;13(3):199–205. https://doi.org/10.1007/s40268-013-0025-5Talasaz AH, Khalili H, Jenab Y, Salarifar M, Broumand MA, Darabi F. N-Acetylcysteine effects on transforming growth factor-β and tumor necrosis factor-α serum levels as pro-fibrotic and inflammatory biomarkers in patients following ST-segment elevation myocardial infarction. Drugs R D. 2013;13(3):199–205. https://doi.org/10.1007/s40268-013-0025-5Wang B, Wang H, Zhang M, Ji R, Wei J, Xin Y, Jiang X. Radiation-induced myocardial fibrosis: Mechanisms underlying its pathogenesis and therapeutic strategies. J Cell Mol Med. 2020;24(14):7717–7729. https://doi.org/10.1111/jcmm.15479Wang B, Wang H, Zhang M, Ji R, Wei J, Xin Y, Jiang X. Radiation-induced myocardial fibrosis: Mechanisms underlying its pathogenesis and therapeutic strategies. J Cell Mol Med. 2020;24(14):7717–7729. https://doi.org/10.1111/jcmm.15479Li P, Zhou H, Yang Y, Wu M, Zhao D, Wang L, et al. Dietary supplementation with N-acetylcysteine confers a protective effect on muscle and liver in lipopolysaccharide-challenged piglets. Front Nutr. 2024;11:1458912. https://doi.org/10.3389/fnut.2024.1458912Li P, Zhou H, Yang Y, Wu M, Zhao D, Wang L, et al. Dietary supplementation with N-acetylcysteine confers a protective effect on muscle and liver in lipopolysaccharide-challenged piglets. Front Nutr. 2024;11:1458912. https://doi.org/10.3389/fnut.2024.1458912Sahasrabudhe SA, Terluk MR, Kartha RV. N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. Antioxidants (Basel). 2023;12(7):1316. https://doi.org/10.3390/antiox12071316Sahasrabudhe SA, Terluk MR, Kartha RV. N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. Antioxidants (Basel). 2023;12(7):1316. https://doi.org/10.3390/antiox12071316Barlaz Us S, Vezir O, Yildirim M, Bayrak G, Yalin S, Balli E, et al. Protective effect of N-acetyl cysteine against radiotherapy-induced cardiac damage. Int J Radiat Biol. 2020;96(5):661–670. https://doi.org/10.1080/09553002.2020.1721605Barlaz Us S, Vezir O, Yildirim M, Bayrak G, Yalin S, Balli E, et al. Protective effect of N-acetyl cysteine against radiotherapy-induced cardiac damage. Int J Radiat Biol. 2020;96(5):661–670. https://doi.org/10.1080/09553002.2020.1721605Kusakabe J, Anderson B, Liu J, Williams GA, Chapman WC, Doyle MMB, et al. Long-Term Endocrine and Exocrine Insufficiency After Pancreatectomy. J Gastrointest Surg. 2019;23(8):1604–1613. https://doi.org/10.1007/s11605-018-04084-xKusakabe J, Anderson B, Liu J, Williams GA, Chapman WC, Doyle MMB, et al. Long-Term Endocrine and Exocrine Insufficiency After Pancreatectomy. J Gastrointest Surg. 2019;23(8):1604–1613. https://doi.org/10.1007/s11605-018-04084-xShiba S, Miyasaka Y, Okamoto M, Komatsu S, Okazaki S, Shibuya K, Ohno T. Deterioration of pancreatic exocrine function in carbon ion radiotherapy for pancreatic cancer. Clin Transl Radiat Oncol. 2021;31:80–85. https://doi.org/10.1016/j.ctro.2021.09.007Shiba S, Miyasaka Y, Okamoto M, Komatsu S, Okazaki S, Shibuya K, Ohno T. Deterioration of pancreatic exocrine function in carbon ion radiotherapy for pancreatic cancer. Clin Transl Radiat Oncol. 2021;31:80–85. https://doi.org/10.1016/j.ctro.2021.09.007Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.Demyashkin G, Vadyukhin M, Shchekin V, Borovaya T, Zavialova O, Belokopytov D, et al. New Cellular Interactions Due to the Radioprotective Effect of N-Acetylcysteine in a Model of Radiation-Induced Pancreatitis. Int J Mol Sci. 2025;26(11):5238. https://doi.org/10.3390/ijms26115238Demyashkin G, Vadyukhin M, Shchekin V, Borovaya T, Zavialova O, Belokopytov D, et al. New Cellular Interactions Due to the Radioprotective Effect of N-Acetylcysteine in a Model of Radiation-Induced Pancreatitis. Int J Mol Sci. 2025;26(11):5238. https://doi.org/10.3390/ijms26115238Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med. 2020;217(3):e20190103. https://doi.org/10.1084/jem.20190103Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med. 2020;217(3):e20190103. https://doi.org/10.1084/jem.20190103Zhang Q, Ye W, Liu Y, Niu D, Zhao X, Li G, et al. S-allylmercapto-N-acetylcysteine ameliorates pulmonary fibrosis in mice via Nrf2 pathway activation and NF-κB, TGF-β1/Smad2/3 pathway suppression. Biomed Pharmacother. 2023;157:114018. https://doi.org/10.1016/j.biopha.2022.114018Zhang Q, Ye W, Liu Y, Niu D, Zhao X, Li G, et al. S-allylmercapto-N-acetylcysteine ameliorates pulmonary fibrosis in mice via Nrf2 pathway activation and NF-κB, TGF-β1/Smad2/3 pathway suppression. Biomed Pharmacother. 2023;157:114018. https://doi.org/10.1016/j.biopha.2022.114018Sisto M, Ribatti D, Lisi S. Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT. Biomolecules. 2021;11(2):310. https://doi.org/10.3390/biom11020310Sisto M, Ribatti D, Lisi S. Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT. Biomolecules. 2021;11(2):310. https://doi.org/10.3390/biom11020310Bignold R, Johnson JR. Effects of cytokine signaling inhibition on inflammation-driven tissue remodeling. Curr Res Pharmacol Drug Discov. 2021;2:100023. https://doi.org/10.1016/j.crphar.2021.100023Bignold R, Johnson JR. Effects of cytokine signaling inhibition on inflammation-driven tissue remodeling. Curr Res Pharmacol Drug Discov. 2021;2:100023. https://doi.org/10.1016/j.crphar.2021.100023Yu XY, Sun Q, Zhang YM, Zou L, Zhao YY. TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis. Front Pharmacol. 2022;13:860588. https://doi.org/10.3389/fphar.2022.860588Yu XY, Sun Q, Zhang YM, Zou L, Zhao YY. TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis. Front Pharmacol. 2022;13:860588. https://doi.org/10.3389/fphar.2022.860588Kim DS, Song L, Gou W, Kim J, Liu B, Wei H, et al. GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes. Cell Death Dis. 2024;15(5):374. https://doi.org/10.1038/s41419-024-06754-yKim DS, Song L, Gou W, Kim J, Liu B, Wei H, et al. GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes. Cell Death Dis. 2024;15(5):374. https://doi.org/10.1038/s41419-024-06754-yFriedman DN, Moskowitz CS, Hilden P, Howell RM, Weathers RE, Smith SA, et al. Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2020;112(5):525–532. https://doi.org/10.1093/jnci/djz152Friedman DN, Moskowitz CS, Hilden P, Howell RM, Weathers RE, Smith SA, et al. Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2020;112(5):525–532. https://doi.org/10.1093/jnci/djz152Aggarwal M, Jayapal N, Mittal D, et al. Risk and mechanism of metabolic syndrome associated with radiation exposure. Radiation Medicine and Protection. 2023;4(2):100048. https://doi.org/10.1016/j.radmp.2023.05.001Aggarwal M, Jayapal N, Mittal D, et al. Risk and mechanism of metabolic syndrome associated with radiation exposure. Radiation Medicine and Protection. 2023;4(2):100048. https://doi.org/10.1016/j.radmp.2023.05.001Tóthová Z, Šemeláková M, Solárová Z, Tomc J, Debeljak N, Solár P. The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization. Int J Mol Sci. 2021;22(14):7682. https://doi.org/10.3390/ijms22147682Tóthová Z, Šemeláková M, Solárová Z, Tomc J, Debeljak N, Solár P. The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization. Int J Mol Sci. 2021;22(14):7682. https://doi.org/10.3390/ijms22147682Handayaningsih AE, Iguchi G, Fukuoka H, Nishizawa H, Takahashi M, Yamamoto M, et al. Reactive oxygen species play an essential role in IGF-I signaling and IGF-I-induced myocyte hypertrophy in C2C12 myocytes. Endocrinology. 2011;152(3):912–921. https://doi.org/10.1210/en.2010-0981Handayaningsih AE, Iguchi G, Fukuoka H, Nishizawa H, Takahashi M, Yamamoto M, et al. Reactive oxygen species play an essential role in IGF-I signaling and IGF-I-induced myocyte hypertrophy in C2C12 myocytes. Endocrinology. 2011;152(3):912–921. https://doi.org/10.1210/en.2010-0981Wiszniak S, Schwarz Q. Exploring the Intracrine Functions of VEGF-A. Biomolecules. 2021;11(1):128. https://doi.org/10.3390/biom11010128Wiszniak S, Schwarz Q. Exploring the Intracrine Functions of VEGF-A. Biomolecules. 2021;11(1):128. https://doi.org/10.3390/biom11010128Han Z, Dong Y, Lu J, Yang F, Zheng Y, Yang H. Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application. Am J Cancer Res. 2021;11(8):3777–3793.Han Z, Dong Y, Lu J, Yang F, Zheng Y, Yang H. Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application. Am J Cancer Res. 2021;11(8):3777–3793.Han C, Barakat M, DiPietro LA. Angiogenesis in Wound Repair: Too Much of a Good Thing? Cold Spring Harb Perspect Biol. 2022;14(10):a041225. https://doi.org/10.1101/cshperspect.a041225Han C, Barakat M, DiPietro LA. Angiogenesis in Wound Repair: Too Much of a Good Thing? Cold Spring Harb Perspect Biol. 2022;14(10):a041225. https://doi.org/10.1101/cshperspect.a041225Bakleh MZ, Al Haj Zen A. The Distinct Role of HIF-1α and HIF-2α in Hypoxia and Angiogenesis. Cells. 2025;14(9):673. https://doi.org/10.3390/cells14090673Bakleh MZ, Al Haj Zen A. The Distinct Role of HIF-1α and HIF-2α in Hypoxia and Angiogenesis. Cells. 2025;14(9):673. https://doi.org/10.3390/cells14090673

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