Chemotranscriptome analysis of synergism between D-chiroinositol and myoinositol in the context of postgenomic pharmacology

Torshin I.Yu., Gromova O.A., Tetruashvili N.K.

1) Institute of Pharmacoinformatics, Federal Research Center «Informatics and Management», Russian Academy of Sciences, Moscow, Russia; 2) Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia
Background: The effect of myoinositol (MI) and D-chiroinositol (DCI) on gene transcription is of great importance for assessing the molecular mechanisms of synergism between these micronutrients. Such micronutrients are necessary for the prevention of insulin resistance, manifestations of polycystic ovary syndrome, congenital malformations and fetal macrosomia, especially in pregnant women with insulin resistance, dyslipidemia, and overweight.
Materials and methods: The paper presents the results of a chemotranscriptome analysis of the effects
of myoinositol (MI) and D-chiroinositol (DCI). The dose-dependent effects of MI and DCI on the transcription of 12716 annotated human genes in human umbilical vein endothelial cells (HUVEC line, stimulation of cells with MI/DCI at 6 different concentrations for 24 h) were evaluated.
Results: MI was found to cause significant transcription changes (more than 50% per 10 µmol on average) of 6516 genes: the expression of 4085 genes increased, and the expression of 2431 genes decreased. DCI is an important MI synergist in six functional groups of genes: (1) fat metabolism, (2) carbohydrate metabolism, (3) thyroid function, (4) morphogenesis, cell differentiation and survival, (5) neuroprotection and neurotrophicity, (6) structure and function of blood vessels. MI and DCI changed the expression of genes involved in the human body’s response to 49 drugs.
Conclusion: It was possible to establish an individual pattern of DCI and MI action and to identify the molecular mechanisms of synergism between these two forms of inositol at the level of the human transcriptome. The results of the study suggest a higher efficiency of the combined administration of MI and DCI for the correction of disorders of carbohydrate and fat metabolism in pregnant women and for the prevention of abnormal fetal morphogenesis.

Keywords

D-chiroinositol
myoinositol
chemotranscriptomics
machine learning
Dikirogen

References

  1. Громова О.А., Торшин И.Ю., Тетруашвили Н.К. Роли мио-инозитола в поддержании репродуктивного здоровья женщины. Повышение эффективности технологий экстракорпорального оплодотворения. РМЖ. Мать и дитя. 2018; 1: 88-95. [Gromova O.A., Torshin I.Yu., Tetruashvili N.K. The role of myo-inositol in maintaining women's reproductive health. Improving the efficiency of in vitro fertilization technologies. Russian Medical Journal. Mother and Child. 2018; 1: 88-95. (in Russian)]. https://dx.doi.org/10.32364/2618-8430-2018-1-1-88-95.
  2. Rapiejko P.J., Northup J.K., Evans T., Brown J.E., Malbon C.C. G-proteinsof fat-cells. Role in hormonal regulation of intracellular inositol 1,4,5-trisphosphate. Biochem. J. 1986; 240(1): 35-40. https://dx.doi.org/10.1042/bj2400035.
  3. Salihu H.M., Dongarwar D., King L.M., Yusuf K.K., Ibrahimi S., Salinas-Miranda A.A. Phenotypes of fetal macrosomia and risk of stillbirth among term deliveries over the previous four decades. Birth. 2020; 47(2): 202-10.https://dx.doi.org/10.1111/birt.12479.
  4. Ляличкина Н.А., Макарова Т.В., Салямова Л.Ш. Макросомия плода. Aкушерские и перинатальные исходы. Современные проблемы науки и образования. 2016; 3; 71. (Электронный научный журнал). Доступно по: http://www.science-education.ru/ru/article/view?id=24572[Lyalichkina N.A., Makarova T.V., Salyamova L.Sh. Macrosomia of the fetus. obstetric and perinatal outcomes. Modern problems of science and education. 2016; 3 (electronic scientific journal).Available at:http://www.science-education.ru/ru/article/view?id=24572 (in Russian)].
  5. Громова О.А., Торшин И.Ю., Уварова Е.В., Тапильская Н.И., Калачева А.Г. Систематический анализ биологических ролей и фармакологических свойств D-хироинозитола. Гинекология. 2020; 22(3): 21-8. [Gromova O.A., Torshin I.Yu., Uvarova E.V., Tapilskaya N.I., Kalacheva A.G. Systematic analysis of the biological roles and pharmacological properties of D-chiroinositol. Gynecology. 2020; 22(3): 21-8. (in Russian)]. https://dx.doi.org/10.26442/20795696.2020.3.200210.
  6. Торшин И.Ю., Майорова Л.А., Уварова Е.В., Тапильская Н.И., Громова О.А.Хемореактомный анализ стереоизомеров инозитола: различные профили фармакологического действия мио-инозитола и D-хиро-инозитола при нарушениях женской репродуктивной системы. Вопросы гинекологии, акушерства и перинатологии. 2020; 19(5): 57-69. [Torshin I.Yu.,Mayorova L.A., Uvarova E.V., Tapilskaya N.I., Gromova O.A. Chemoreactome analysis of stereoisomers of inositol: different profiles of the pharmacological action of myo-inositol and D-chiro-inositol in disorders of the female reproductive system. Issues of gynecology, obstetrics and perinatology. 2020; 19(5): 57-69. (in Russian)]. https://dx.doi.org/10.20953/1726-1678-2020-5-57-69.
  7. Torshin I.Yu. Sensing the change: from molecular genetics to personalized medicine. Bioinformatics in the post-genomic era: the role of biophysics. New York: Nova Biomedical Books, cop. 2009.
  8. Torshin I.Y., Rudakov K.V. On the application of the combinatorial theory of solvability to the analysis of chemographs: part 2. local completeness of invariants of chemographs in view of the combinatorial theory of solvability. Pattern Recognition and Image Analysis. 2014; 24(2): 196-208.
  9. Торшин И.Ю., Громова О.А., Стаховская Л.В., Семенов В.А., Щукин И.А. Хемотранскриптомный анализ указывает на нейротрофические и нейромодулирующие эффекты молекулы цитиколина. Неврология, нейропсихиатрия, психосоматика. 2020; 12(4): 91-9. [Torshin I.Yu., Gromova O.A., Stakhovskaya L.V., Semenov V.A., Shchukin I.A. Chemotranscriptome analysis indicates the neurotrophic and neuromodulator effects of a citicoline molecule. Neurology, Neuropsychiatry, Psychosomatics. 2020; 12(4): 91-9. (in Russian)]. https://dx.doi.org/10.14412/2074-2711-2020-4-91-99.
  10. Торшин И.Ю., Громова О.А., Сардарян И.С., Федотова Л.Э. Сравнительный хемореактомный анализ мексидола. Журнал неврологии и психиатрии им. C.C. Корсакова. 2017; 117(1-2): 75-84. [Torshin I.Y., Gromova O.A., Sardaryan I.S., Fedotova L.E. Sravnitel'nyĭ khemoreaktomnyĭ analiz meksidola [A comparative chemoreactome analysis of mexidol]. Journal of Neurology and Psychiatry named after S.S. Korsakov. 2017; 117(1-2): 75-83. (in Russian)]. https://dx.doi.org/10.17116/jnevro20171171275-84.
  11. Marduel M., Ouguerram K., Serre V., Bonnefont-Rousselot D., Varret M. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum. Mutat. 2013; 34(1): 83-7. https://dx.doi.org/10.1002/humu.22215.
  12. Westerterp M., Berbee J.F., Rensen P.C. Apolipoprotein C-I binds free fatty acids and reduces their intracellular esterification. J. Lipid Res. 2007; 48(6): 1353-61. https://dx.doi.org/10.1194/jlr.M700024-JLR200.
  13. Nichols W.C., Dwulet F.E., Liepnieks J., Benson M.D. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem. Biophys. Res. Commun. 1988; 156(2): 762-8. https://dx.doi.org/10.1016/s0006-291x(88)80909-4.
  14. Тапильская Н.И., Сажина И.Н., Андреева М.Д., Сорокина О.В. Эффективность применения комбинации миоинозитола и D-хироинозитола в соотношении 5:1 с марганцем и фолиевой кислотой у пациенток репродуктивного возраста с нерегулярным менструальным циклом и ожирением. Гинекология. 2022; 24(2): 101-7. [Tapilskaya N.I., Sazhina I.N., Andreeva M.D., Sorokina O.V. The effectiveness of the combination of myoinositol and D-chiroinositol in a 5:1 ratio with manganese and folic acid in patients of reproductive age with irregular menstrual cycles and obesity. Gynecology. 2022; 24(2): 101-7. (in Russian)].
  15. Обоскалова Т.А., Воронцова А.В., Звычайный М.А., Гущина К.Г., Майтесян М.М. Результаты применения комбинации миоинозитола и D-хироинозитола в соотношении 5:1 у женщин с синдромом поликистозных яичников. Гинекология. 2020; 22(6): 84-9. [Oboskalova T.A., Vorontsova A.V., Zvychainyi M.A., Gushchina K.G., Maitesian M.M. Results of treatment with myo-Inositol and D-chiroinositol combination in ratio 5:1 in women with polycystic ovary syndrome. Gynecology. 2020; 22(6): 84-9.(in Russian)]. https://dx.doi.org/10.26442/20795696.2020.6.200548.
  16. Bonnet S., Archer S.L., Michelakis E.D. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11(1): 37-51. https://dx.doi.org/10.1016/j.ccr.2006.10.020.
  17. Deyev I.E., Sohet F., Vassilenko K.P., Petrenko A.G. Insulin receptor-related receptor as an extracellular alkali sensor. Cell Metab. 2011; 13(6): 679-89. https://dx.doi.org/10.1016/j.cmet.2011.03.022.
  18. Edens W.A., Sharling L., Cheng G., Lambeth J.D. Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox. J. Cell Biol. 2001; 154(4): 879-91. https://dx.doi.org/10.1083/jcb.200103132.
  19. Cha J.Y., Maddileti S., Mitin N., Harden T.K., Der C.J. Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform. J. Biol. Chem. 2009; 284(10): 6227-40. https://dx.doi.org/10.1074/jbc.M803998200.
  20. Citores L., Bai L., Sorensen V., Olsnes S. Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus. J. Cell. Physiol. 2007; 212(1): 148-56. https://dx.doi.org/10.1002/jcp.21014.
  21. Plotnikov A.N., Hubbard S.R., Schlessinger J., Mohammadi M. Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell. 2000; 101(4): 413-24. https://dx.doi.org/10.1016/s0092-8674(00)80851-x.
  22. Tolbert W.D., Daugherty-Holtrop J., Gherardi E., Vande Woude G., Xu H.E. Structural basis for agonism and antagonism of hepatocyte growth factor. Proc. Natl. Acad. Sci. USA. 2010; 107(30): 13264-9. https://dx.doi.org/10.1073/pnas.1005183107.
  23. Elabd C., Cousin W., Upadhyayula P., Chen R.Y., Chooljian M.S., Li J. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 2014; 5: 4082.https://dx.doi.org/10.1038/ncomms5082.
  24. Yachie A., Niida Y., Wada T., Igarashi N., Kaneda H., Toma T. et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 1999; 103(1): 129-35. https://dx.doi.org/10.1172/JCI4165.
  25. Калачева А.Г., Торшин И.Ю., Стельмашук Е.В., Генрихс Е.Е., Александрова О.П., Хаспеков Л.Г., Громова О.А. Нейропротекторное действие миоинозитола на клеточной модели глутаматного стресса как основа для профилактики нарушений внутриутробного развития головного мозга. Фармакокинетика и фармакодинамика. 2018; 3: 9-20. [Kalacheva A.G., Torshin I.Yu., Stelmashuk E.V., Genrikhs E.E., Aleksandrova O.P., Khaspekov L.G., Gromova O.A. Neuroprotective effect of myoinositol on the cellular model of glutamate stress as a basis for the prevention of intrauterine brain development disorders. Pharmacokinetics and Pharmacodynamics. 2018; 3: 9-20. (in Russian)]. https://dx.doi.org/10.24411/2587-7836-2018-10018.
  26. Zuberi S.M., Eunson L.H., Hanna M.G. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain. 1999; 122(Pt 5): 817-25.https://dx.doi.org/10.1093/brain/122.5.817.
  27. McKnight G.L., Karlsen A.E., Kowalyk S., Mathewes S.L., Sheppard P.O., O'Hara P.J., Taborsky G.J. Jr. Sequence of human galanin and its inhibition of glucose-stimulated insulin secretion from RIN cells. Diabetes. 1992; 41(1): 82-7. https://dx.doi.org/10.2337/diab.41.1.82.
  28. Mi S., Lee X., Shao Z., Thill G., Ji B., Relton J. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 2004; 7(3): 221-8. https://dx.doi.org/10.1038/nn1188.
  29. Shimizu S., Matsuzaki S., Hattori T., Kumamoto N., Miyoshi K., Katayama T., Tohyama M. DISC1-kendrin interaction is involved in centrosomal microtubule network formation. Biochem. Biophys. Res. Commun. 2008; 377(4): 1051-6. https://dx.doi.org/10.1016/j.bbrc.2008.10.100.
  30. Rossignol P., Ho-Tin-Noe B., Vranckx R., Bouton M.C., Meilhac O.,Lijnen H.R. et al. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J. Biol. Chem. 2004; 279(11): 10346-56.https://dx.doi.org/10.1074/jbc.M310964200.
  31. Delvaeye M., Noris M., De Vriese A., Conway E.M. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2009; 361(4): 345-57. https://dx.doi.org/10.1056/NEJMoa0810739.
  32. Merryweather-Clarke A.T., Cadet E., Bomford A., Robson K.J. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum. Mol. Genet. 2003; 12(17): 2241-7. https://dx.doi.org/10.1093/hmg/ddg225.
  33. Ghavami S., Eshragi M., Ande S.R., Chazin W.J., Klonisch T., Halayko A.J. et al. S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res. 2010; 20(3): 314-31. https://dx.doi.org/10.1038/cr.2009.129.
  34. Gordon C.T., Petit F., Kroisel P.M., Jakobsen L., Amiel J. Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears. Am. J. Hum. Genet. 2013; 93(6): 1118-25.https://dx.doi.org/10.1016/j.ajhg.2013.10.023.

Received 07.08.2022

Accepted 11.09.2022

About the Authors

Ivan Yu. Torshin, PhD in Applied Mathematics, Institute of Pharmacoinformatics, Senior Researcher at the Department of Intellectual Systems, Federal Research Center “Computer Science and Control” of Russian Academy of Sciences, https://orcid.org/0000-0002-2659-7998, 119333, Russia, Moscow, Vavilova str., 42.
Olga A. Gromova, Dr. Med. Sci., Professor, Science Нead of the Institute of Pharmacoinformatics, Leading Researcher at the Department of Intellectual Systems,
Federal Research Center “Computer Science and Control” of Russian Academy of Sciences, unesco.gromova@gmail.com, https://orcid.org/0000-0002-7663-710X,
119333, Russia, Moscow, Vavilova str., 42.
Nana K. Tetruashvili, Dr. Med. Sci., Head of the 2nd Obstetrics Department of Pathology of Pregnancy, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia,
n_tetruashvili@oparina4.ru, 117997, Russia, Moscow, Ac. Oparina str., 4.
Corresponding author: Olga A. Gromova, unesco.gromova@gmail.com

Authors’ contributions: Torshin I.Yu. – collecting and processing the material, writing the text; Gromova O.A. – developing the concept of the study, writing the text; Tetruashvili N.K. – editing the text.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The research was performed under the grant of the Russian Science Foundation (Project No. 20-12-00175).
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Torshin I.Yu., Gromova O.A., Tetruashvili N.K. Chemotranscriptome analysis
of synergism between D-chiroinositol and myoinositol in the context of postgenomic pharmacology.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 9: 135-145 (in Russian)
https://dx.doi.org/10.18565/aig.2022.9.135-145

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.