MorphologyMorphologyМорфология1026-35432949-2556Eco-Vector62941010.17816/morph.629410Original Study ArticlesОригинальные исследованияResearch ArticleRenal proliferation and apoptosis against ascorbic acid administration in a model of acute radiation nephropathyОсобенности пролиферации и апоптоза в клетках сосудистых клубочков и нефроцитов после локального облучения электронами и введения аскорбиновой кислоты局部电子照射和注射抗坏血酸后血管小管和肾小球细胞增殖和凋亡的特点https://orcid.org/0000-0001-8447-26005157-0177DemyashkinGrigory A.ДемяшкинГригорий АлександровичDemyashkinGrigory A.
Russian Federation

MD, Dr. Sci. (Medicine)

д-р мед. наук

MD, Dr. Sci. (Medicine)

dr.dga@mail.ruhttps://orcid.org/0009-0009-2291-3680UruskhanovaZhanna E.УрусхановаЖанна ЭйсаевнаUruskhanovaZhanna E.
Russian Federation
jey.149@yandex.ruhttps://orcid.org/0000-0003-0128-45388153-5789KoryakinSergey N.КорякинСергей НиколаевичKoryakinSergey N.
Russian Federation

Cand. Sci. (Biology)

канд. биол. наук

Cand. Sci. (Biology)

korsernic@mail.ruhttps://orcid.org/0009-0004-7170-8783ParshenkovMikhail A.ПаршенковМихаил АлексеевичParshenkovMikhail A.
Russian Federation
misjakj@gmail.comhttps://orcid.org/0000-0001-7936-180X4254-6082DubovayaTatiana K.ДубоваяТатьяна КлеониковнаDubovayaTatiana K.
Russian Federation

MD, Dr. Sci. (Medicine), Professor

д-р мед. наук, профессор

MD, Dr. Sci. (Medicine), Professor

gusvbr@mail.ruhttps://orcid.org/0000-0002-0536-95905657-9984RodionovaGalina M.РодионоваГалина МихайловнаRodionovaGalina M.
Russian Federation

Cand. Sci. (Pharmacy), Assistant Professor

канд. фарм. наук, доцент

Cand. Sci. (Pharmacy), Assistant Professor

rodionovagalinam@mail.ruhttps://orcid.org/0000-0003-3763-74543664-8044ShchekinVladimir I.ЩекинВладимир ИвановичShchekinVladimir I.
Russian Federation
dr.shchekin@mail.ruhttps://orcid.org/0000-0003-1336-7277IvchenkoYuliya V.ИвченкоЮлия ВалерьевнаIvchenkoYuliya V.
Russian Federation
ivchenko_yu_v@student.sechenov.ruhttps://orcid.org/0009-0007-9137-6597IonovaOlga V.ИоноваОльга ВладиславовнаIonovaOlga V.
Russian Federation
olgaionova99@mail.ruThe First Sechenov Moscow State Medical University (Sechenov University)Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет)The First Sechenov Moscow State Medical University (Sechenov University)National Medical Research Radiological CenterНациональный медицинский исследовательский центр радиологииNational Medical Research Radiological CenterThe Russian National Research Medical University named after N.I. PirogovРоссийский национальный исследовательский медицинский университет имени Н.И. ПироговаThe Russian National Research Medical University named after N.I. Pirogov2907202404092024162116302503202425062024Copyright ©; 2024, Eco-VectorCopyright ©; 2024, Эко-ВекторCopyright ©; 2024,2024Eco-VectorЭко-Векторhttps://j-morphology.com/1026-3543/article/view/629410

BACKGROUND: Radiation exposure, an integral part of the treatment of malignant neoplasms, is associated with a risk of radiation nephropathy because of the high radiosensitivity of the kidneys. The analysis of renal tissue proliferation and apoptosis is important to understand the mechanisms of radiation damage and develop treatment strategies.

AIM: To evaluate endothelial proliferation and apoptosis of vascular tubules and nephrocytes during preradiation administration of ascorbic acid in a model of radiation nephropathy.

MATERIALS AND METHODS: Wistar rats (n=90) were divided into groups: I, control (n=15); II, irradiation, 2 Gy dose (n=15); III, irradiation, 8 Gy dose (n=15); IV, irradiation, 2 Gy dose + ascorbic acid, intraperitoneal injection at 50 mg/kg (n=15); V, irradiation, 8 Gy dose + ascorbic acid, intraperitoneal injection at 50 mg/kg (n=15); VI, ascorbic acid, intraperitoneal injection at 50 mg/kg (n=15). Kidney slides were stained with hematoxylin and eosin. In addition, immunohistochemical evaluation of the expression levels of Ki-67- and Cas-3-positive cells was performed.

RESULTS: The histological study showed that preradiation administration of ascorbic acid (intraperitoneal injection of 50 mg/kg) in the acute radiation nephropathy model induced by local irradiation with electrons at 2 and 8 Gy contributed to the statistical reduction of pathomorphologic changes. According to the results of immunohistochemical evaluation of proliferation and apoptosis, distribution of Ki-67- and Cas-3-positive cells in the tubules, epitheliocytes of proximal and distal tubules of nephrons in mono-irradiation groups revealed the activation of the terminal stage of cell death, which correlated with the electron irradiation dose. Moreover, in the experimental groups with preirradiation administration of ascorbic acid, a significant decrease in the intensity of apoptosis was recorded.

CONCLUSION: Preradiation administration of ascorbic acid reduces the strength of radiation-induced kidney damage and the effect of electron irradiation on the life cycle of tubular cells and epitheliocytes of nephron tubules while increasing the effectiveness of the antioxidant defense.

Обоснование. Радиационное облучение ― один из методов лечения злокачественных новообразований, сопряжённых с риском развития радиационной нефропатии из-за высокой радиочувствительности сосудистых клубочков и эпителия канальцев нефронов. Исследование пролиферации и апоптоза эндотелия сосудистых клубочков и нефроцитов имеет ключевое значение для понимания механизмов радиационного повреждения и разработки способов профилактики.

Цель исследования — оценка пролиферации и апоптоза эндотелия сосудистых клубочков и нефроцитов при предлучевом введении аскорбиновой кислоты в модели лучевой нефропатии.

Материалы и методы. Крысы линии Wistar (n=90) были разделены на группы: I ― контрольная (n=15); II ― облучение, разовая очаговая доза (РОД) 2 Гр (n=15); III ― облучение, РОД 8 Гр (n=15); IV ― облучение, РОД 2 Гр + аскорбиновая кислота, интраперитонеальная инъекция, доза 50 мг/кг (n=15); V ― облучение, РОД 8 Гр + аскорбиновая кислота, интраперитонеальная инъекция, доза 50 мг/кг (n=15); VI ― аскорбиновая кислота, интраперитонеальная инъекция, доза 50 мг/кг (n=15). Образцы окрашивали гематоксилином и эозином, а также проводили иммуногистохимическую оценку количества Ki-67- и каспаза-3-позитивных клеток.

Результаты. При гистологическом исследовании патоморфологические изменения структур почки были менее выражены при предлучевом введении аскорбиновой кислоты в модели острой лучевой нефропатии, индуцированной локальным облучением электронами в РОД 2 Гр и 8 Гр. При иммуногистохимическом исследовании в группах РОД 2 Гр и 8 Гр наблюдали уменьшение Ki-67- и каспаза-3-позитивных клеток в сосудистых клубочках, эпителиоцитах проксимальных и дистальных канальцев нефронов (p >0,05). Напротив, в опытных группах с предлучевым введением аскорбиновой кислоты фиксировали статистически значимое снижение интенсивности апоптоза, а количество Ki-67-позитивных клеток было приближено к контрольным значениям (p >0,05).

Заключение. Предлучевое введение аскорбиновой кислоты снижает степень выраженности радиационно-индуцированного повреждения структур почек, а также воздействие электронов на пролиферацию и апоптоз клеток сосудистых клубочков, эпителиоцитов канальцев нефронов, усиливая эффективность антиоксидантной защиты.

论证。放射线照射是治疗恶性肿瘤的方法之一，由于血管肾小球和肾单位小管上皮的高放射性敏感性，因此存在发生放射性肾病的风险。研究肾小球血管内皮和肾细胞的增殖和凋亡是了解辐射损伤机制和制定预防方法的关键。

本研究旨在评估放射性肾病模型在辐射前注射抗坏血酸期间肾小球血管内皮和肾细胞的增殖和凋亡情况。

材料和方法。将 Wistar 大鼠（n=90）分为几组： I组对照组（n=15）；II组：放射，单灶剂量（single fraction dose, SFD）2 Gy（n=15）；III组：放射，SFD 8 Gy（n=15）；IV组：放射，SFD 2 Gy + 抗坏血酸，腹腔注射，剂量50 mg/kg（n=15）；V组： 第五组：放射射，SFD 8 Gy + 腹腔注射抗坏血酸，剂量 50 mg/kg（n=15）；第六组：腹腔注射抗坏血酸，剂量 50 mg/kg（n=15）。样本用血红素和伊红染色，并对 Ki-67- 和 caspase-3 阳性细胞的数量进行免疫组化评估。

结果。在组织学研究中，在2 Gy和8 Gy SFD局部电子放射诱导的急性放射性肾病模型中，放射前服用抗坏血酸后，肾脏结构的病理形态学变化不太明显。在免疫组化研究中，观察到2 Gy和8 Gy SFD组血管肾小球、肾小管近端和远端上皮细胞中的 Ki-67- 和 caspase-3 阳性细胞减少（p >0.05）。相反，在放射前服用抗坏血酸的实验组中，细胞凋亡强度显著降低，Ki-67阳性细胞数量接近对照组（p>0.05）。

结论。放射前服用抗坏血酸可减轻辐射对肾脏结构造成的损害，以及电子对血管肾小球血管细胞和肾小管上皮细胞增殖和凋亡的影响，提高抗氧化防御的有效性。

radiation nephropathyelectron irradiationkidneysascorbic acidcell cycleproliferationapoptosisлучевая нефропатияоблучение электронамипочкиаскорбиновая кислотаклеточный циклпролиферацияапоптоз放射性肾病电子辐照肾脏抗坏血酸细胞周期增殖凋亡Pinto R, Ardoino L, Villani P, Marino C. In vivo studies on radiofrequency (100 kHz-300 GHz) electromagnetic field exposure and cancer: A systematic review. Int J Environ Res Public Health. 2023;20(3):2071. EDN: UWBDFH doi: 10.3390/ijerph20032071Pinto R., Ardoino L., Villani P., Marino C. In vivo studies on radiofrequency (100 kHz-300 GHz) electromagnetic field exposure and cancer: A systematic review // Int J Environ Res Public Health. 2023. Vol. 20, N 3. P. 2071. EDN: UWBDFH doi: 10.3390/ijerph20032071Pinto R, Ardoino L, Villani P, Marino C. In vivo studies on radiofrequency (100 kHz-300 GHz) electromagnetic field exposure and cancer: A systematic review. Int J Environ Res Public Health. 2023;20(3):2071. EDN: UWBDFH doi: 10.3390/ijerph20032071Wild CP, Espina C, Bauld L, et al. Cancer prevention Europe. Mol Oncol. 2019;13(3):528–534. doi: 10.1002/1878-0261.12455Wild C.P., Espina C., Bauld L., et al. Cancer prevention Europe // Mol Oncol. 2019. Vol. 13, N 3. P. 528–534. doi: 10.1002/1878-0261.12455Wild CP, Espina C, Bauld L, et al. Cancer prevention Europe. Mol Oncol. 2019;13(3):528–534. doi: 10.1002/1878-0261.12455Wei J, Wang B, Wang H, et al. Radiation-induced normal tissue damage: Oxidative stress and epigenetic mechanisms. Oxid Med Cell Longev. 2019;2019:3010342. EDN: CJOKXL doi: 10.1155/2019/3010342Wei J., Wang B., Wang H., et al. Radiation-induced normal tissue damage: Oxidative stress and epigenetic mechanisms // Oxid Med Cell Longev. 2019. Vol. 2019. P. 3010342. EDN: CJOKXL doi: 10.1155/2019/3010342Wei J, Wang B, Wang H, et al. Radiation-induced normal tissue damage: Oxidative stress and epigenetic mechanisms. Oxid Med Cell Longev. 2019;2019:3010342. EDN: CJOKXL doi: 10.1155/2019/3010342Le VH, Kha QH, Minh TN, et al. Development and validation of CT-based radiomics signature for overall survival prediction in multi-organ cancer. J Digit Imaging. 2023;36(3):911–922. EDN: CUARJO doi: 10.1007/s10278-023-00778-0Le V.H., Kha Q.H., Minh T.N., et al. Development and validation of CT-based radiomics signature for overall survival prediction in multi-organ cancer // J Digit Imaging. 2023. Vol. 36, N 3. P. 911–922. EDN: CUARJO doi: 10.1007/s10278-023-00778-0Le VH, Kha QH, Minh TN, et al. Development and validation of CT-based radiomics signature for overall survival prediction in multi-organ cancer. J Digit Imaging. 2023;36(3):911–922. EDN: CUARJO doi: 10.1007/s10278-023-00778-0Dawson L, Kavanagh B, Paulino A, et al. Radiation-associated kidney injury. Int J Radiation Oncol Biol Physics. 2010;76(3):108–115. doi: 10.1016/j.ijrobp.2009.02.089Dawson L., Kavanagh B., Paulino A., et al. Radiation-associated kidney injury // Int J Radiation Oncol Biol Physics. 2010. Vol. 76, N 3. P. 108–115. doi: 10.1016/j.ijrobp.2009.02.089Dawson L, Kavanagh B, Paulino A, et al. Radiation-associated kidney injury. Int J Radiation Oncol Biol Physics. 2010;76(3):108–115. doi: 10.1016/j.ijrobp.2009.02.089Aratani S, Tagawa M, Nagasaka S, et al. Radiation-induced premature cellular senescence involved in glomerular diseases in rats. Sci Rep. 2018;8(1):16812. doi: 10.1038/s41598-018-34893-8Aratani S., Tagawa M., Nagasaka S., et al. Radiation-induced premature cellular senescence involved in glomerular diseases in rats // Sci Rep. 2018. Vol. 8, N 1. P. 16812. doi: 10.1038/s41598-018-34893-8Aratani S, Tagawa M, Nagasaka S, et al. Radiation-induced premature cellular senescence involved in glomerular diseases in rats. Sci Rep. 2018;8(1):16812. doi: 10.1038/s41598-018-34893-8Scholz M, Kraft-Weyrather W, Ritter S, Kraft G. Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells. Int J Radiation Biol. 1994;66(1):59–75. EDN: XYSSVT doi: 10.1080/09553009414550951Scholz M., Kraft-Weyrather W., Ritter S., Kraft G. Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells // Int J Radiation Biol. 1994. Vol. 66, N 1. P. 59–75. EDN: XYSSVT doi: 10.1080/09553009414550951Scholz M, Kraft-Weyrather W, Ritter S, Kraft G. Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells. Int J Radiation Biol. 1994;66(1):59–75. EDN: XYSSVT doi: 10.1080/09553009414550951Mavragani IV, Nikitaki Z, Kalospyros SA, Georgakilas AG. Ionizing radiation and complex DNA damage: From prediction to detection challenges and biological significance. Cancers (Basel). 2019;11(11):1789. EDN: GIFYCB doi: 10.3390/cancers11111789Mavragani I.V., Nikitaki Z., Kalospyros S.A., Georgakilas A.G. Ionizing radiation and complex DNA damage: From prediction to detection challenges and biological significance // Cancers (Basel). 2019. Vol. 11, N 11. P. 1789. EDN: GIFYCB doi: 10.3390/cancers11111789Mavragani IV, Nikitaki Z, Kalospyros SA, Georgakilas AG. Ionizing radiation and complex DNA damage: From prediction to detection challenges and biological significance. Cancers (Basel). 2019;11(11):1789. EDN: GIFYCB doi: 10.3390/cancers11111789Carante MP, Ballarini F. Radiation damage in biomolecules and cells. Int J Mol Sci. 2020;21(21):8188. EDN: CXOOGB doi: 10.3390/ijms21218188Carante M.P., Ballarini F. Radiation damage in biomolecules and cells // Int J Mol Sci. 2020. Vol. 21, N 21. P. 8188. EDN: CXOOGB doi: 10.3390/ijms21218188Carante MP, Ballarini F. Radiation damage in biomolecules and cells. Int J Mol Sci. 2020;21(21):8188. EDN: CXOOGB doi: 10.3390/ijms21218188Sia J, Szmyd R, Hau E, Gee HE. Molecular mechanisms of radiation-induced cancer cell death: A primer. Front Cell Developmental Biol. 2020;(8):41. EDN: IHCCVI doi: 10.3389/fcell.2020.00041Sia J., Szmyd R., Hau E., Gee H.E. Molecular mechanisms of radiation-induced cancer cell death: A primer // Front Cell Developmental Biol. 2020. N 8. P. 41. EDN: IHCCVI doi: 10.3389/fcell.2020.00041Sia J, Szmyd R, Hau E, Gee HE. Molecular mechanisms of radiation-induced cancer cell death: A primer. Front Cell Developmental Biol. 2020;(8):41. EDN: IHCCVI doi: 10.3389/fcell.2020.00041Ashrafizadeh M, Farhood B, Eleojo Musa A, et al. Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol. 2020;(86):106761. EDN: UNXGZM doi: 10.1016/j.intimp.2020.106761Ashrafizadeh M., Farhood B., Eleojo Musa A., et al. Damage-associated molecular patterns in tumor radiotherapy // Int Immunopharmacol. 2020. Vol. 86. P. 106761. EDN: UNXGZM doi: 10.1016/j.intimp.2020.106761Ashrafizadeh M, Farhood B, Eleojo Musa A, et al. Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol. 2020;(86):106761. EDN: UNXGZM doi: 10.1016/j.intimp.2020.106761Nano M, Mondo JA, Harwood J, et al. Cell survival following direct executioner-caspase activation. Proc Natl Acad Sci USA. 2023;120(4): e2216531120. EDN: QFKEAX doi: 10.1073/pnas.2216531120Nano M., Mondo J.A., Harwood J., et al. Cell survival following direct executioner-caspase activation // Proc Natl Acad Sci USA. 2023. Vol. 120, N 4. P. e2216531120. EDN: QFKEAX doi: 10.1073/pnas.2216531120Nano M, Mondo JA, Harwood J, et al. Cell survival following direct executioner-caspase activation. Proc Natl Acad Sci USA. 2023;120(4): e2216531120. EDN: QFKEAX doi: 10.1073/pnas.2216531120Demyashkin GA, Koryakin SN, Stepanova YY, et al. Morphological characteristics of kidneys in rats after targeted irradiation with electrons in a dose of 2, 4 and 6 Gy. Veterinarny vrach. 2021;(5)9–16. EDN: YIAPCK doi: 10.33632/1998-698Х.2021-5-9-16Демяшкин Г.А., Корякин С.Н., Степанова Ю.Ю., и др. Морфологическая характеристика почек крыс после прицельного облучения электронами в дозах 2, 4 и 6 Гр // Ветеринарный врач. 2021. № 5. P. 9–16. EDN: YIAPCK doi: 10.33632/1998-698Х.2021-5-9-16Demyashkin GA, Koryakin SN, Stepanova YY, et al. Morphological characteristics of kidneys in rats after targeted irradiation with electrons in a dose of 2, 4 and 6 Gy. Veterinarny vrach. 2021;(5)9–16. EDN: YIAPCK doi: 10.33632/1998-698Х.2021-5-9-16Bunyatyan ND, Vasiliev AN, Verstakova OL, et al. Manual on conducting preclinical studies of medicines. Part I. Mironov AN, editor.Moscow: Grif i K; 2012. 944 р. (In Russ.).Бунятян Н.Д., Васильев А.Н., Верстакова О.Л., и др. Руководство по проведению доклинических исследований лекарственных средств. Часть первая / отв. ред. А.Н. Миронов. Москва: Гриф и К, 2012. 944 с.Bunyatyan ND, Vasiliev AN, Verstakova OL, et al. Manual on conducting preclinical studies of medicines. Part I. Mironov AN, editor.Moscow: Grif i K; 2012. 944 р. (In Russ.).Yumusak N, Sadic M, Yucel G, et al. Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: An experimental and immunohistochemical study. Nucl Med Commun. 2018;39(2):131–139. EDN: YFTKAP doi: 10.1097/MNM.0000000000000788Yumusak N., Sadic M., Yucel G., et al. Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: An experimental and immunohistochemical study // Nucl Med Commun. 2018. Vol. 39, N 2. P. 131–139. EDN: YFTKAP doi: 10.1097/MNM.0000000000000788Yumusak N, Sadic M, Yucel G, et al. Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: An experimental and immunohistochemical study. Nucl Med Commun. 2018;39(2):131–139. EDN: YFTKAP doi: 10.1097/MNM.0000000000000788Kolina IB, Bobkova IN. Renal damage with malignant neoplasms. Clinician. 2014;(2):7–16. EDN: TIINVPКолина И.Б., Бобкова И.Н. Поражение почек при злокачественных образованиях // Клиницист. 2014. № 2. С. 7–16. EDN: TIINVPKolina IB, Bobkova IN. Renal damage with malignant neoplasms. Clinician. 2014;(2):7–16. EDN: TIINVPZhao W, Zhuang P, Chen Y, et al. “Double-edged sword” effect of reactive oxygen species (ROS) in tumor development and carcinogenesis. Physiol Res. 2023;72(3):301–307. EDN: XLCYPX doi: 10.33549/physiolres.935007Zhao W., Zhuang P., Chen Y., et al. “Double-edged sword” effect of reactive oxygen species (ROS) in tumor development and carcinogenesis // Physiol Res. 2023. Vol. 72, N 3. P. 301–307. EDN: XLCYPX doi: 10.33549/physiolres.935007Zhao W, Zhuang P, Chen Y, et al. “Double-edged sword” effect of reactive oxygen species (ROS) in tumor development and carcinogenesis. Physiol Res. 2023;72(3):301–307. EDN: XLCYPX doi: 10.33549/physiolres.935007McRobb LS, McKay MJ, Gamble JR, et al. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence. Aging (Albany NY). 2017;9(4):1248–1268. EDN: YEVGSZ doi: 10.18632/aging.101225McRobb L.S., McKay M.J., Gamble J.R., et al. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence // Aging (Albany NY). 2017. Vol. 9, N 4. P. 1248–1268. EDN: YEVGSZ doi: 10.18632/aging.101225McRobb LS, McKay MJ, Gamble JR, et al. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence. Aging (Albany NY). 2017;9(4):1248–1268. EDN: YEVGSZ doi: 10.18632/aging.101225Fujino S, Sun J, Nakayama S, et al. A combination of iohexol treatment and ionizing radiation exposure enhances kidney injury in contrast-induced nephropathy by increasing DNA damage. Radiat Res. 2022;197(4):384–395. EDN: YNXLII doi: 10.1667/RADE-21-00178.1Fujino S., Sun J., Nakayama S., et al. A combination of iohexol treatment and ionizing radiation exposure enhances kidney injury in contrast-induced nephropathy by increasing DNA damage // Radiat Res. 2022. Vol. 197, N 4. P. 384–395. EDN: YNXLII doi: 10.1667/RADE-21-00178.1Fujino S, Sun J, Nakayama S, et al. A combination of iohexol treatment and ionizing radiation exposure enhances kidney injury in contrast-induced nephropathy by increasing DNA damage. Radiat Res. 2022;197(4):384–395. EDN: YNXLII doi: 10.1667/RADE-21-00178.1Finkelman BS, Zhang H, Hicks DG, Turner BM. The evolution of Ki-67 and breast carcinoma: Past observations, present directions, and future considerations. Cancers (Basel). 2023;15(3):808. EDN: RKJHIR doi: 10.3390/cancers15030808Finkelman B.S., Zhang H., Hicks D.G., Turner B.M. The evolution of Ki-67 and breast carcinoma: Past observations, present directions, and future considerations // Cancers (Basel). 2023. Vol. 15, N 3. P. 808. EDN: RKJHIR doi: 10.3390/cancers15030808Finkelman BS, Zhang H, Hicks DG, Turner BM. The evolution of Ki-67 and breast carcinoma: Past observations, present directions, and future considerations. Cancers (Basel). 2023;15(3):808. EDN: RKJHIR doi: 10.3390/cancers15030808Chrabańska M, Rynkiewicz M, Kiczmer P, Drozdzowska B. Immunohistochemical expression of CD44, MMP-2, MMP-9, and Ki-67 as the prognostic markers in non-clear cell renal cell carcinomas: A prospective cohort study. J Clin Med. 2022;11(17):5196. EDN: YDLFYK doi: 10.3390/jcm11175196Chrabańska M., Rynkiewicz M., Kiczmer P., Drozdzowska B. Immunohistochemical expression of CD44, MMP-2, MMP-9, and Ki-67 as the prognostic markers in non-clear cell renal cell carcinomas: A prospective cohort study // J Clin Med. 2022. Vol. 11, N 17. P. 5196. EDN: YDLFYK doi: 10.3390/jcm11175196Chrabańska M, Rynkiewicz M, Kiczmer P, Drozdzowska B. Immunohistochemical expression of CD44, MMP-2, MMP-9, and Ki-67 as the prognostic markers in non-clear cell renal cell carcinomas: A prospective cohort study. J Clin Med. 2022;11(17):5196. EDN: YDLFYK doi: 10.3390/jcm11175196Li Z, Li F, Pan C, et al. Tumor cell proliferation (Ki-67) expression and its prognostic significance in histological subtypes of lung adenocarcinoma. Lung Cancer. 2021;(154):69–75. EDN: CIWVOU doi: 10.1016/j.lungcan.2021.02.009Li Z., Li F., Pan C., et al. Tumor cell proliferation (Ki-67) expression and its prognostic significance in histological subtypes of lung adenocarcinoma // Lung Cancer. 2021. N 154. P. 69–75. EDN: CIWVOU doi: 10.1016/j.lungcan.2021.02.009Li Z, Li F, Pan C, et al. Tumor cell proliferation (Ki-67) expression and its prognostic significance in histological subtypes of lung adenocarcinoma. Lung Cancer. 2021;(154):69–75. EDN: CIWVOU doi: 10.1016/j.lungcan.2021.02.009Kim DH, Park JS, Choi HI, et al. The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. Cell Death Disease. 2021;12(4):320. EDN: MEBYNA doi: 10.1038/s41419-021-03620-zKim D.H., Park J.S., Choi H.I., et al. The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD // Cell Death Disease. 2021. Vol. 12, N 4. P. 320. EDN: MEBYNA doi: 10.1038/s41419-021-03620-zKim DH, Park JS, Choi HI, et al. The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. Cell Death Disease. 2021;12(4):320. EDN: MEBYNA doi: 10.1038/s41419-021-03620-zLi G, Wang S, Fan Z. Oxidative stress in intestinal ischemia-reperfusion. Front Med (Lausanne). 2022;(8):750731. EDN: TCFEIW doi: 10.3389/fmed.2021.750731Li G., Wang S., Fan Z. Oxidative stress in intestinal ischemia-reperfusion // Front Med (Lausanne). 2022. N 8. P. 750731. EDN: TCFEIW doi: 10.3389/fmed.2021.750731Li G, Wang S, Fan Z. Oxidative stress in intestinal ischemia-reperfusion. Front Med (Lausanne). 2022;(8):750731. EDN: TCFEIW doi: 10.3389/fmed.2021.750731Wang Q, Zhou Y, Wang X, Evers BM. Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase. Oncogene. 2006;25(1):43–50. doi: 10.1038/sj.onc.1209004Wang Q., Zhou Y., Wang X., Evers B.M. Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase // Oncogene. 2006. Vol. 25, N 1. P. 43–50. doi: 10.1038/sj.onc.1209004Wang Q, Zhou Y, Wang X, Evers BM. Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase. Oncogene. 2006;25(1):43–50. doi: 10.1038/sj.onc.1209004Okunieff P, Suit HD. Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas. J Natl Cancer Inst. 1987;79(2):377–381. doi: 10.1093/JNCI/79.2.377Okunieff P., Suit H.D. Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas // J Natl Cancer Inst. 1987. Vol. 79, N 2. P. 377–381. doi: 10.1093/JNCI/79.2.377Okunieff P, Suit HD. Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas. J Natl Cancer Inst. 1987;79(2):377–381. doi: 10.1093/JNCI/79.2.377González E, Cruces MP, Pimentel E, Sánchez P. Evidence that the radioprotector effect of ascorbic acid depends on the radiation dose rate. Environ Toxicol Pharmacol. 2018;62:210–214. doi: 10.1016/j.etap.2018.07.015González E., Cruces M.P., Pimentel E., Sánchez P. Evidence that the radioprotector effect of ascorbic acid depends on the radiation dose rate // Environ Toxicol Pharmacol. 2018. Vol. 62. P. 210–214. doi: 10.1016/j.etap.2018.07.015González E, Cruces MP, Pimentel E, Sánchez P. Evidence that the radioprotector effect of ascorbic acid depends on the radiation dose rate. Environ Toxicol Pharmacol. 2018;62:210–214. doi: 10.1016/j.etap.2018.07.015Jagetia GC, Rajanikant GK, Rao SK, Baliga MS. Alteration in the glutathione, glutathione peroxidase, superoxide dismutase and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation. Clin Chim Acta. 2003;332(1–2):111–121. doi: 10.1016/S0009-8981(03)00132-3Jagetia G.C., Rajanikant G.K., Rao S.K., Baliga M.S. Alteration in the glutathione, glutathione peroxidase, superoxide dismutase and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation // Clin Chim Acta. 2003. Vol. 332, N 1–2. P. 111–121. doi: 10.1016/S0009-8981(03)00132-3Jagetia GC, Rajanikant GK, Rao SK, Baliga MS. Alteration in the glutathione, glutathione peroxidase, superoxide dismutase and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation. Clin Chim Acta. 2003;332(1–2):111–121. doi: 10.1016/S0009-8981(03)00132-3Mikirova N, Ichim TE, Riordan NH. Anti-angiogenic effect of high doses of ascorbic acid. J Transl Med. 2008;6:50. doi: 10.1186/1479-5876-6-50Mikirova N., Ichim T.E., Riordan N.H. Anti-angiogenic effect of high doses of ascorbic acid // J Transl Med. 2008. Vol. 6. P. 50. doi: 10.1186/1479-5876-6-50Mikirova N, Ichim TE, Riordan NH. Anti-angiogenic effect of high doses of ascorbic acid. J Transl Med. 2008;6:50. doi: 10.1186/1479-5876-6-50Morel C, Carlson SM, White FM, Davis RJ. Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol. 2009;29(14):3845–3852. doi: 10.1128/MCB.00279-09Morel C., Carlson S.M., White F.M., Davis R.J. Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis // Mol Cell Biol. 2009. Vol. 29, N 14. P. 3845–3852. doi: 10.1128/MCB.00279-09Morel C, Carlson SM, White FM, Davis RJ. Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol. 2009;29(14):3845–3852. doi: 10.1128/MCB.00279-09Allum AJ, Mussallem JT, Froning CE, et al. Ascorbic acid 2-glucoside pretreatment protects cells from ionizing radiation, UVC, and short wavelength of UVB. Genes (Basel). 2020;11(3):238. doi: 10.3390/genes11030238Allum A.J., Mussallem J.T., Froning C.E., et al. Ascorbic acid 2-glucoside pretreatment protects cells from ionizing radiation, UVC, and short wavelength of UVB // Genes (Basel). 2020. Vol. 11, N 3. P. 238. doi: 10.3390/genes11030238Allum AJ, Mussallem JT, Froning CE, et al. Ascorbic acid 2-glucoside pretreatment protects cells from ionizing radiation, UVC, and short wavelength of UVB. Genes (Basel). 2020;11(3):238. doi: 10.3390/genes11030238Petruk G, del Giudice R, Rigano MM, Monti DM. Antioxidants from plants protect against skin photoaging. Oxidat Med Cell Longev. 2018;2018:1454936. EDN: VJFAYU doi: 10.1155/2018/1454936Petruk G., del Giudice R., Rigano M.M., Monti D.M. Antioxidants from plants protect against skin photoaging // Oxidat Med Cell Longev. 2018. Vol. 2018. P. 1454936. EDN: VJFAYU doi: 10.1155/2018/1454936Petruk G, del Giudice R, Rigano MM, Monti DM. Antioxidants from plants protect against skin photoaging. Oxidat Med Cell Longev. 2018;2018:1454936. EDN: VJFAYU doi: 10.1155/2018/1454936El-Sonbaty SM, Moawed FS, Elbakry MM. Amphora algae with low-level ionizing radiation exposure ameliorate D-galactosamine-induced inflammatory impairment in rat kidney. Environ Toxicol. 2021;36(4):451–459. EDN: RANHHY doi: 10.1002/tox.23050El-Sonbaty S.M., Moawed F.S., Elbakry M.M. Amphora algae with low-level ionizing radiation exposure ameliorate D-galactosamine-induced inflammatory impairment in rat kidney // Environ Toxicol. 2021. Vol. 36, N 4. P. 451–459. EDN: RANHHY doi: 10.1002/tox.23050El-Sonbaty SM, Moawed FS, Elbakry MM. Amphora algae with low-level ionizing radiation exposure ameliorate D-galactosamine-induced inflammatory impairment in rat kidney. Environ Toxicol. 2021;36(4):451–459. EDN: RANHHY doi: 10.1002/tox.23050