CYTOKINE REGULATION OF REGENERATIVE PROCESSES IN PANCREATIC GLAND IN ALLOXAN-INDUCED DIABETIC RATS, AND IT CORRECTION BY 1,3,4-THIADIAZINE COMPOSITION AND LIPOIC ACID
https://doi.org/10.15789/1563-0625-2018-1-35-44
Abstract
A comprehensive comparative evaluation of the ability of L-17 compound (2-morpholino-5- phenyl-1,3,4-thiadiazine) and antioxidant lipoic acid (LA) to correct blood cytokine levels, metabolic disorders and morphological alterations in pancreas in alloxan-induced diabetes was performed for the first time, using an experimental in vivo model. All the tested compounds have been found to correct hyperglycemia and decreased accumulation of glycated blood proteins. The tested L-17 compound belongs to the 1,3,4-thiadiazine series and is able to correct metabolic disorders occurring in alloxan-induced diabetes comparable to activity of LA antioxidant. However, L-17 reduces the cytokine levels to the values of intact animals, that preventing development of systemic inflammatory response which causes damage of target organs in diabetes mellitus.
About the Authors
I. G. DanilovaRussian Federation
PhD, MD (Biology), Assistant Professor, Head, Laboratory of Morphology and Biochemistry, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences; Head, Department of Medical Biochemistry and Biophysics, Institute of Natural Sciences, B.N. Yeltsin Ural Federal University, Ekaterinburg
V. V. Emelianov
Russian Federation
PhD (Medicine), Assistant Professor, Department of Immunochemistry, Institute of Chemical Engineering; Assistant Professor, Department of Medical Biochemistry and Biophysics, Institute of Natural Science and Mathematics, B.N. Yeltsin Ural Federal University, Ekaterinburg
I. F. Gette
Russian Federation
PhD (Biology), Senior Research Associate, Laboratory of Morphology and Biochemistry, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences; Senior Research Associate, Department of Immunochemistry, Institute of Chemical Engineering, B.N. Yeltsin Ural Federal University, Ekaterinburg
S. Yu. Medvedeva
Russian Federation
PhD (Medicine), Leading Research Associate, Laboratory of Morphology and Biochemistry, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences; Assistant Professor, Department of Medical Biochemistry and Biophysics, Institute of Natural Sciences, B.N. Yeltsin Ural Federal University, Ekaterinburg
T. S. Bulavintseva
Russian Federation
Junior Research Associate, Associate, Laboratory of Morphology and Biochemistry, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences; Junior Research Associate, Department of Immunochemistry, Institute of Chemical Engineering, B.N. Yeltsin Ural Federal University, Ekaterinburg
M. V. Chereshneva
Russian Federation
PhD, MD (Medicine), Main Research Associate, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences, Ekaterinburg
L. P. Sidorova
Russian Federation
PhD (Chemistry), Assistant Professor, Department of Organic and Biomolecular Chemistry, Institute of Chemical Engineering, B.N. Yeltsin Ural Federal University, Ekaterinburg
V. A. Chereshnev
Russian Federation
PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Director, Institute of Immunology and Physiology, Ural Branch, Russian Academy of Sciences; Head, Department of Immunochemistry, Institute of Chemical Engineering, B.N. Yeltsin Ural Federal University, Ekaterinburg
K. V. Sokolova
Russian Federation
Postgraduate Student, Department of Medical Biochemistry and Biophysics, Institute of Natural Sciences and Mathematics, B.N. Yeltsin Ural Federal University, Ekaterinburg
References
1. Балаболкин М.И., Клебанова Е.М., Креминская В.М. Лечение сахарного диабета и его осложнений: Руководство для врачей. М.: Медицина, 2005. 512 с. [Balabolkin M.I., Klebanova E.M., Kreminskaya V.М. Treatment of diabetes and its complications: Manual for Physicians]. Мoscow: Medicine, 2005. 512 p.
2. Беспалова И.Д., Рязанцева Н.В., Калюжин В.В., Афанасьева Д.С., Мурашев Б.Ю., Осихов И.А. Системное воспаление в патогенезе метаболического синдрома и ассоциированных с ним заболеваний // Сибирский медицинский журнал, 2013. № 2. С. 5-9. [Bespalova I.D., Ryazantseva N.V., Kalyuzhin V.V., Afanasyeva D.S., Myrashev B.Yu., Osikhov I.A. Systemic inflammation in pathogenesis of metabolic syndrome and associated diseases. Sibirskiy meditsinskiy zhurnal = Syberian Medical Journal, 2013, no. 2, pp. 5-9. (In Russ.)]
3. Бухтиярова И.П., Дроговоз С.М., Щекина Е.Г., Ищенко А.М. Влияние ралейкина на липидный обмен в условиях модельного диабета // Вестник фармации, 2014. Т. 65, № 3. С. 89-94. [Buhtiyarova I.P., Drogovoz S.M., Shchokina K.G., Ishchenko A.M.. The influence of raleukin on lipid metabolism in the model of diabetes. Vestnik farmatsii = Bulletin of Pharmacy, 2014, Vol. 65, pp. 89-94. (In Russ.)]
4. Волчегорский И.А., Мирошниченко И.Ю., Рассохина Л.М., Файзуллин Р.М. Влияние реамберина и α-липоевой кислоты на устойчивость к острой церебральной ишемии при экспериментальном сахарном диабете // Журнал неврологии и психиатрии имени С.С. Корсакова, 2016. Т. 116, № 6. С. 53-59. [Volchegorsky I.A., Miroshnichenko I.Yu., Rassokhina L.M., Faizullin R.М. Influence of reamberin and α-lipoic acid on resistance to acute cerebral ischemia in experimental diabetes mellitus. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = Journal of Neurology and Psychiatry named aſter S.S. Korsakov, 2016, Vol. 116, no. 6, pp. 53-59. (In Russ.)]
5. Геннадиник А.Г., Нелаева А.А. Роль инсулиноподобного фактора роста-I в метаболизме, регуляции клеточного обновления и процессах старения // Ожирение и метаболизм, 2010. № 2. С. 10-15. [Gennadinik A.G., Nelaeva A.A. The role of insulin-like growth factor-I in metabolism, regulation of cellular renewal and aging processes. Ozhirenie i metabolism = Obesity and Metabolism, 2010, no. 2, pp. 10-15. (In Russ.)]
6. Данилова И.Г., Гетте И.Ф. Способ моделирования аллоксанового диабета. Патент на изобретение №2534411; 27.11.2014. Бюл. № 33. [Danilova I.G., Gette I.F. Bulavintseva T.S. The method of modeling alloxan diabetes. Patent for invention No. 2534411; 27.11.2014. Bulletin No. 33].
7. Дедов И.И., Фадеев В.В. Введение в диабетологию: Руководство для врачей. М.: Берег, 1998. 200 с. [Dedov I.I., Fadeev V.V. Introduction to Diabetology: Manual for Physicians)]. Moscow: Bereg, 1998. 200 p.
8. Емельянов В.В., Леонтьев Д.В., Ищенко А.В., Булавинцева Т.С., Саватеева Е.А., Данилова И.Г. Атомно-силовая микроскопия эритроцитов и метаболические нарушения при экспериментальном сахарном диабете и его коррекции липоевой кислотой // Биофизика, 2016. Т. 61, № 5. С. 922-926. [Emelianov V.V., Leontiev D.V., Ishchenko A.V., Bulavintseva T.S., Savateeva E.A., Danilova I.G. Atomic force microscopy of erythrocytes and metabolic disturbances in experimental diabetes mellitus and its correction by lipoic acid. Biofizika = Biophysics, 2016, Vol. 61, no. 5, pp. 922-926. (In Russ.)]
9. Емельянов В.В., Саватеева Е.А., Мусальникова А.В., Сидорова Л.П., Перова Н.М., Новикова А.П., Булавинцева Т.С., Гетте И.Ф., Данилова И.Г., Максимова Н.Е., Мочульская Н.Н., Черешнев В.А. Перспективы поиска новых противодиабетических средств среди серосодержащих гетероциклических соединений // Аллергология и иммунология, 2013. Т. 14, № 2. С. 141-142. [Emelianov V.V., Savateeva E.A., Musalnikova A.V., Sidorova L.P., Perova N.M., Novikova A.P., Bulavintseva T.S., Gette I.F., Danilova I.G., Maksimova N.E., Mochulskaya N.N., Chereshnev V.A. Prospects for the search for new antidiabetics among sulfur-containing heterocyclic compounds. Allergologiya i immunologiya = Allergology and Immunology, 2013. Vol. 14, no. 2, pp 141-142. (In Russ.)]
10. Емельянов В.В., Саватеева Е.А., Сидорова Л.П., Цейтлер Т.А., Булавинцева Т.С., Гетте И.Ф., Данилова И.Г., Максимова Н.Е., Мочульская Н.Н., Чупахин О.Н., Черешнев В.А. Коррекция метаболических нарушений при аллоксановом сахарном диабете производными 1,3,4-тиадиазина // Российский иммунологический журнал, 2015. Т. 9 (18), № 2 (1). С. 487-489. [Emelianov V.V., Savateeva E.A., Sidorova L.P., Tseitler T.A., Bulavintseva T.S., Gette I.F., Danilova I.G., Maksimova N.E., Mochulskaya N.N., Chupakhin O.N., Chereshnev V.A. Correction of metabolic disorders in alloxan diabetes mellitus with 1,3,4-thiadiazine derivatives. Rossiyskiy immunologicheskiy zhurnal = Russian Immunological Journal, 2015, Vol. 9 (18), no. 2 (1), pp. 487-489. (In Russ.)]
11. Емельянов В.В., Саватеева Е.А., Сидорова Л.П., Цейтлер Т.А., Гетте И.Ф., Булавинцева Т.С., Смирных С.Е., Максимова Н.Е., Мочульская Н.Н., Чупахин О.Н., Черешнев В.А. 2-морфолино-5-фенил-6Н-1,3,4-тиадиазин корригирует метаболические нарушения при формировании аллоксанового сахарного диабета у крыс // Бюллетень экспериментальной биологии и медицины, 2016. Т. 162, № 7. С. 42-45. [Emelianov V.V., Savateeva E.A., Sidorova L.P., Tseitler T.A., Gette I.F., Bulavintseva T.S., Smirnykh S.E., Maksimova N.E., Mochulskaya N.N., Chupakhin O.N., Chereshnev V.A. 2-Morpholino-5phenyl-6H-1,3,4-thiadiazine corrects metabolic disorders during the development of alloxan diabetes mellitus in rats. Byulleten` eksperimental`noy biologii i meditsiny = Bulletin of Experimental Biology and Medicine, 2016, Vol. 162, no. 7, pp. 42-45. (In Russ.)]
12. Емельянов В.В., Сидорова Л.П., Саватеева Е.А., Булавинцева Т.С., Гетте И.Ф., Максимова Н.Е., Мочульская Н.Н., Черешнев В.А., Чупахин О.Н. Применение соединений класса 1,3,4-тиадиазина в качестве средства коррекции экспериментального аллоксанового сахарного диабета. Патент RU № 2597764 от 10.07.2016. Приоритет от 16.12.2014. [Emelianov V.V., Sidorova L.P., Savateeva E.A., Bulavintseva T.S., Gette I.F., Maksimova N.E., Mochulskaya N.N., Chereshnev V.A., Chupakhin O.N. The use of compounds of the 1,3,4-thiadiazine class as a means of correcting experimental alloxan diabetes. Patent RU No. 2597764 dated July 10, 2016. Priority from 16.12.2014].
13. Зайчик А.Ш., Чурилов Л.П. Патофизиология. Т. 2. Основы патохимии. СПб.: Элби-СПб., 2001. 687 с. [Zaichik A.Sh., Churilov L.P. Pathophysiology. Vol. 2. Fundamentals of pathochemistry]. St. Petersburg: Elbi-SPb., 2001. 687 p.
14. Насонов Е.Л., Елисеев М.С. Роль интерлейкина 1 в развитии заболеваний человека // Научно-практическая ревматология, 2016. Т. 54, № 1. С. 60-67. [Nasonov E.L., Eliseev M.S. Role of interleukin 1 in the development of human diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice, 2016, Vol. 54, no. 1, pp. 60-77. (In Russ.)]
15. Сидорова Л.П., Цейтлер Т.А., Емельянов В.В., Саватеева Е.А., Максимова Н.Е., Мочульская Н.Н., Черешнев В.А., Чупахин О.Н. 2-Тиоморфолин-5-арил-6H-1,3,4-тиадиазин гидробромиды и их способность ингибировать неферментативное гликозилирование белков // Химико-фармацевтический журнал, 2017. № 51. С. 11-14. [Sidorova L.P., Zeitler T.A., Emelianov V.V., Savateeva E.A., Maksimova N.E., Mochulskaya N.N., Chereshnev V.A., Chupakhin O.N. 2-Thiomorpholin-5-aryl-6H-1,3,4-thiadiazine hydrobromides and their ability to inhibit non-enzymatic glycosylation of proteins. Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal, 2017, no. 51, pp. 11-14. (In Russ.)]
16. Сарапульцев П.А., Чупахин О.Н., Сарапульцев А.П., Ранцев М.А., Медведева С.Ю., Сидорова Л.П., Данилова И.Г. Влияние соединения из группы замещенных 5R1, 6R2-1,3,4-тиадиазин-2-аминов на течение системного воспаления // Цитокины и воспаление, 2013. Т. 12, № 3. С. 40-44. [Sarapultsev P.A., Chupakhin O.N., Sarapultsev A.P., Rantsev M.A., Medvedeva S.Yu., Sidorova L.P., Danilova I.G. The effects of the compound of the group of substituted 5R1, 6R2-1,3,4-thiadiazine-2-amines on the course of systemic inflammation. Tsitokiny i vospalenie = Cytokines and Inflammation, 2013, Vol. 12, no. 3, pp. 40-44. (In Russ.)]
17. Фрейдлин И.С. Иммунная система и ее дефекты: Руководство для врачей. СПб.: НТФ «Полисан», 1998. 113 с. [Freidlin I.S. The immune system and its defects: Manual for Physicians]. St. Petersburg: NTF Polisan, 1998. 113 p.
18. Bianchi E., Ripandelli G., Taurone S., Feher J., Plateroti R., Kovacs I., Magliulo G., Orlando M.P., Micera A., Battaglione E., Artico M. Age and diabetes related changes of the retinal capillaries: An ultrastructural and immunohistochemical study. Int. J. Immunopathol. Pharmacol., 2016, Vol. 29, no. 1, pp. 40-53.
19. Butkowski E.G., Jelinek H.F. Hyperglycaemia, oxidative stress and inflammatory markers. Redox Rep., 2016, pp. 1-8.
20. Chen T., Gao J., Xiang P., Chen Y., Ji J., Xie P., Wu H., Xiao W., Wei Y., Wang S., Lan .L, Ji H., Yan T. Protective effect of platycodin D on liver injury in alloxan-induced diabetic mice via regulation of Treg/Th17 balance. Int. Immunopharmacol., 2015, Vol. 26, no. 2, pp. 338-348.
21. Corbett J.A., Kwon G., Turk J., McDaniel M.L. IL-1 beta induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. Biochemistry, 1993, Vol. 32, no. 50, pp. 13767-13770.
22. Cutando A., Montero J., Gómez-de Diego R., Ferrera M.J., Lopez-Valverde A.. Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with type 1 or type 2 diabetes and periodontal disease. J. Clin. Exp. Dent., 2015, Vol. 7, no. 5, pp. 628-633.
23. Dennis M.D., Kimball S.R., Fort P.E., Jefferson L.S. Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. J. Biol. Chem., 2015, Vol. 290, no. 6, pp. 3865-3874.
24. Donath M.Y., Størling J., Maedler K., Mandrup-Poulsen T. Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J. Mol. Med. (Berl.), 2003, Vol. 81, no. 8, pp. 455-470.
25. Heier M., Margeirsdottir H.D., Brunborg C., Hanssen K.F., Dahl-Jørgensen K., Seljeflot I. Inflammation in childhood type 1 diabetes; influence of glycemic control. Atherosclerosis, 2015, Vol. 238, no. 1, pp. 33-37.
26. Kuehl M.N., Rodriguez H., Burkhardt B.R., Alman A.C. Tumor necrosis factor-α, matrix-metalloproteinases 8 and 9 Levels in the saliva are associated with increased hemoglobin A1c in type 1 diabetes subjects. PLoS ONE, 2015, Vol. 10, no. 4, e0125320. doi: 10.1371/journal.pone.0125320.
27. Kumar G.L., Rudbeck L. Education guide. Immunohistochemical (IHC) staining methods. 2009. Dako North America, Carpinteria, California. 160 p.
28. Lagathu C., Yvan-Charvet L., Bastard J.P., Maachi M., Quignard-Boulangé A., Capeau J., Caron M. Longterm treatment with interleukin-1β induces insulin resistance in murine and human adipocytes. Diabetologia, 2006, no. 49, pp. 2162-2173.
29. Larsen C.M., Faulenbach M., Vaag A., Vølund A., Ehses J.A., Seifert B., Mandrup-Poulsen T., Donath M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med., 2007, Vol. 356, no. 15, pp. 1517-1526.
30. Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia, 2008, no. 51, pp. 216-226.
31. Like A.A., Rossini A.A. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science, 1976, no. 193, pp. 415-417.
32. Malaisse W. Alloxan toxicity to the pancreatic B-cell. Biochem. Pharmacol., 1982, no. 31, pp. 3527-3534.
33. Mollazadeh H., Cicero A.F.G., Blesso C.N., Pirro M., Majeed M., Sahebkar A. Immune modulation by curcumin: The role of interleukin-10. Crit. Rev. Food Sci. Nutr., 2017, pp. 1-13.
34. Moura F.A., de Andrade K.Q., dos Santos J.C., Goulart M.O. Lipoic acid: its antioxidant and anti-inflammatory role and clinical applications. Curr. Top. Med. Chem., 2015, Vol. 15, no. 5, pp. 458-483.
35. Nicola N.A. Guidebook to cytokines and their receptors. Oxford; New York: Oxford University Press, 1994. 176 p.
36. Sarapultsev A.P., Chupakhin O.N., Sarapultsev P.A., Rantsev M.A., Medvedeva S.U., Sidorova L.P., Danilova I.G. Effect of a new class of compounds of the group of substituted 5R1, 6H2-1,3,4-thiadiazine-2-amines on the inflammatory and cytokine response in experimental myocardial infarction. Current Vascular Pharmacology, 2015, no. 13, pp. 43-53.
37. Sidorova L.P., Tseitler T.A., Perova N.M., Emelianov V.V., Savateeva E.A., Maksimova N.E., Mochulskaya N.N., Chereshnev V.A., Chupakhin O.N. Synthesis of new 1,3,4-thiadiazines capable of inhibiting nonenzymatic glycosylation of proteins. Pharmaceutical Chemistry Journal, 2015, Vol. 49, no. 8, pp. 501-550.
38. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol. Res., 2001, no. 50, pp. 536-546.
39. Sun M., Yang J., Wang J., Hao T., Jiang D., Bao G., Liu G. TNF-α is upregulated in T2DM patients with fracture and promotes the apoptosis of osteoblast cells in vitro in the presence of high glucose. Cytokine, 2016, no. 80, pp. 35-42.
40. Tangvarasittichai S., Pongthaisong S., Tangvarasittichai O. Tumor necrosis factor-Α, interleukin-6, C-reactive protein levels and insulin resistance associated with type 2 diabetes in abdominal obesity women. Indian J. Clin. Biochem., 2016, Vol. 31, no. 1, pp. 68-74.
41. Wagner D. Type 1 Diabetes – pathogenesis, genetics and immunotherapy. Publisher: InTech, Chapters published, 2011. 670 p.
42. Willcox A., Richardson S.J., Bone A.J., Foulis A.K., Morgan N.G. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol., 2009, no. 155, pp. 173-181.
43. Withers D.J., Burks D.J., Towery H.H., Altamuro S.L., Flint C.L., White M.F. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulinsignalling. Nat. Genet., 1999, Vol. 23, no. 1, pp. 32-40.
44. Xiao X., Gaffar I., Guo P., Wiersch J., Fischbach S., Peirish L., Song Z., El-Gohary Y., Prasadan K., Shiota C., Gittes G.K. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proceedings of the National Academy of Sciences of USA, 2014, Vol. 111, no. 13, pp. 1211-1220.
45. Zhu T., Meng Q., Ji J., Lou X., Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neurosci. Lett., 2015, no. 585, pp. 28-32.
Review
For citations:
Danilova I.G., Emelianov V.V., Gette I.F., Medvedeva S.Yu., Bulavintseva T.S., Chereshneva M.V., Sidorova L.P., Chereshnev V.A., Sokolova K.V. CYTOKINE REGULATION OF REGENERATIVE PROCESSES IN PANCREATIC GLAND IN ALLOXAN-INDUCED DIABETIC RATS, AND IT CORRECTION BY 1,3,4-THIADIAZINE COMPOSITION AND LIPOIC ACID. Medical Immunology (Russia). 2018;20(1):35-44. (In Russ.) https://doi.org/10.15789/1563-0625-2018-1-35-44