Nuclear-nucleolar relationships and nucleolar stress in hepatocytes in hyperhomocysteinemia



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Abstract

Hyperhomocysteinemia causes stress of the endoplasmic reticulum, which suggests the formation of nucleolar stress. The purpose of this work is to clarify the relationship between structural changes in the nucleus and the region of the nucleolar organizer in hyperhomocysteinemia to prove nucleolar stress in hyperhomo-cysteinemia, which can serve as an additional diagnostic marker of the disease. The object of the study was white mongrel rats with methionine-induced hyperhomocysteinemia. Histologic sections of the liver were stained with hematoxylin and eosin (to assess the histological structure of the organ, hepatocyte nuclei), ammonia silver (to analyze the areas of the nucleolar organizer - AgNORs). Morphometry has allowed to establish that hyperhomocysteinemia decreases the number of nuclei (1,86 times, p<0,05) and the total area occupied by nuclear material (1,69 times, p<0,05); decreases AgNORs (1,71 times, p<0,05) and the total area of the nucleolar organizer (2,31 times, p<0,05). In the hepatocytes of experimental animals, a class of nuclei with one nucleolus appears, but nuclei with 7 or more nucleoluses disappear, nucleolus of the inactive phenotype decreases (5,45 times, p<0,05), active (compact) AgNORs increases (2,15 times, p<0,05). The total number of argyrophilic granules, which characterize the number of RNA polymerases functioning in the cell, is also reduced, mainly due to silver granules localized extranuclearly. The detected changes in the AgNORs region can be characterized as nucleolar stress, the formation of which is caused by an increase in homocysteine levels and liver cell dysfunction. Thus, methionine-induced hyperhomocysteinemia leads to disorganization of nuclear-nucleolar relationships, is accompanied by nucleolar stress, and disrupts the nuclear stage of protein biosynthesis, which can exacerbate the existing pathology.

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About the authors

N. N Chuchkova

Izhevsk state medical Academy

K. A Pazinenko

Izhevsk state medical Academy

M. V Smetanina

Izhevsk state medical Academy

N. V Kormilina

Izhevsk state medical Academy

References

  1. Skovierova H., Vidomanova E., Mahmood S. et al. The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health. Int. J. Mol. Sci. 2016; 17: 1733.
  2. Zaric B.L., Obradovic M., Bajic V. et al. Homocysteine and Hyperho-mocysteinaemia. Curr. Med. Chem. 2019; 26: 2948-61.
  3. Lu L., Yi H., Chen C. et al. Nucleolar stress: is there a reverse version? J. Cancer 2018; 9: 3723-7.
  4. Matos-Perdomo E., Machin F. TORC1, stress and the nucleolus. Aging (Albany NY) 2018; 10: 857-8.
  5. Nemeth A., Grummt I. Dynamic regulation of nucleolar architecture. Curr. Opin. Cell Biol. 2018; 52: 105-11.
  6. Russo A., Russo G. Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress. Int. J. Mol. Sci. 2017; 18: 140.
  7. Ploton D., Menager M., Lechki Ch. et al. Silver staining of nucleolus organizer regions (NORs). Application to the study of nucleolar structure and value in pathology. Ann. Pathol. 1988; 8: 248-52.
  8. Trere D. AgNOR staining and quantification. Micron 2000; 31(2): 127-31.
  9. Mentch S.J., Mehrmohamadi M., Huang L. et al. Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. Cell Metab. 2015; 22: 861-73.
  10. Klein Geltink R.I., Pearce E.L. The importance of methionine metabolism. Elife 2019; 8: e47221.
  11. Медведев Д.В., Звягина В.И., Фомина М.А. Способ моделирования тяжелой формы гипергомоцистеинемии у крыс. Российский медико-биологический вестник им. акад. И.П. Павлова 2014; 22(4): 42-6.
  12. Тукмачева К.А., Сметанина М.В., Чучкова Н.Н. Сравнительная оценка действия таутомеров калия оротата на активность воспалительного процесса у крыс с гипергомоцистеинемией. В: Баковецкая О.В., ред. Биология в высшей школе: актуальные вопросы науки, образования и междисциплинарной интеграции. Материалы Всероссийской научной конференции с международным участием; 2019 апрель 11-12; Рязань, Россия. Рязань: ОТСиОП; 2019. с. 96-8.
  13. Stead L.M., Brosnan M.E., Brosnan J.T. Characterization of homocysteine metabolism in the rat liver. Biochem. J. 2000; 350(Pt 3): 685-92.
  14. Pacana T., Cazanave S., Verdianelli A. et al. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease. PLoS One 2015; 10(8): e0136822.
  15. Howell W.M., Black D.A. Controlled silver-staining of nucleolus organizer regions with a protective colloidal developer: a 1-step method. Experientia 1980; 36: 1014-5.
  16. Elangovan T., Mani N., Malathi N. Argyrophilic nucleolar organizer regions in inflammatory, premalignant, and malignant oral lesions: a quantitative and qualitative assessment. Indian Journal of Dental Research 2008; 19(2): 141-6.
  17. Hossain M.I., Hassan M.Q., Bhattacharjee P. et al. Role of Multiparameter Analysis of AgNORs in FNA Smears of Thyroid Swellings in Differentiating Benign and Malignant Lesions. Patholog. Res. Int. 2012; 2012: 908106.
  18. Новогродская Я.И., Кравчук Р.И., Островская О.Б. и др. Морфологические изменения в печени крыс при гипергомоцистеинемии. Гепатология и гастроэнтерология 2019; 3(1): 93-8.
  19. Wang M.J., Chen F., Lau J.T.Y. et al. Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis. 2017; 8(5): e2805.
  20. Martin N.C., McCullough C.T., Bush P.G. et al. Functional analysis of mouse hepatocytes differing in DNA content: volume, receptor expression, and effect of IFNgamma. J. Cell. Physiol. 2002; 191(2): 138-44.
  21. Matsumoto T., Wakefield L., Tarlow B.D. et al. In Vivo Lineage Tracing of Polyploid Hepatocytes Reveals Extensive Proliferation during Liver Regeneration. Cell Stem Cell 2020; 26(1): 34-47.e3.
  22. Anatskaya O.V., Vinogradov A.E. Somatic polyploidy promotes cell function under stress and energy depletion evidence from tissue-specific mammal transcriptome. Funct. Integr. Genomics 2010; 10(4): 433-46.
  23. Derenzini M. The AgNORs. Micron 2000; 31: 117-20.
  24. Коржевский Д.Э., Гиляров А.В. Основы гистологической техники. СПб.: СпецЛит; 2010.
  25. Фролова О.Е. Морфофункциональная характеристика моноцитов. Значение исследования нуклеолярного аппарата. Клинико-лабораторная диагностика 1998; 10: 3-8.
  26. Madalena C.R., Diez J.L., Gorab E. Chromatin structure of ribosomal RNA genes in dipterans and its relationship to the location of nucleolar organizers. PLoS One 2012; 7: e44006.
  27. McStay B. Nucleolar organizer regions: genomic “dark matter” requiring illumination. Genes Dev. 2016; 30: 1598-610.
  28. Turan Sonmez F., Eroz R. The role of argyrophilic nucleolar organizing region-associated proteins in clinical exacerbation of chronic obstructive pulmonary disease. J. Int. Med. Res. 2018; 46: 4995-5003.
  29. Gunduz M., Okan M.A., Sengil A.Z. et al. The relationship of argyrophilic proteins of the nuclear-organized regions and atopic dermatitis in children. Exp. Dermatol. 2019; 28: 1309-12.
  30. Tyagi K.K., Chandra L., Kumar M. et al. AgNOR as an effective diagnostic tool for determining the proliferative nature of different types of odontogenic cysts. J. Family Med. Prim. Care 2020; 9: 125-30.
  31. Nisari M., Eroz R., Nisari M. et al. Investigation of argyrophilic nucleolar organizing region. Bratisl. Lek. Listy 2016; 117: 345-50.
  32. Jonsson W.O., Margolies N.S., Anthony T.G. Dietary Sulfur Amino Acid Restriction and the Integrated Stress Response: Mechanistic Insights. Nutrients 2019; 11: 1349.
  33. Yang K., Yang J., Yi J. Nucleolar Stress: hallmarks, sensing mechanism and diseases. Cell Stress 2018; 2: 125-40.
  34. Ji C., Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J. Gastroenterol. 2004; 10: 1699-708.
  35. Majumder A., Singh M., George A.K. et al. Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER stress condition. Can. J. Physiol. Pharmacol. 2019; 97: 441-56.
  36. Malhi H., Kaufman R.J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 2011; 54: 795-809.
  37. Mentch S.J., Mehrmohamadi M., Huang L. et al. Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. Cell Metab. 2015; 22: 861-73.

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