Menu

A+ A A-

Download article

DOI: https://doi.org/10.22263/2312-4156.2017.5.49

Chekalina N.I., Manusha Y.I.
The expediency substantiation of the resveratrol and quercetin polyphenols use in ischemic heart disease combined with autoimmune thyroiditis. Part II
Ukrainian Medical Stomatological Academy, Poltava, Ukraine

Vestnik VGMU. 2017;16(5):49-61.

Abstract.
The review presents the results of modern experimental and clinical studies that substantiate the anti-inflammatory properties of polyphenols - stilbene resveratrol and flavonoid quercitrol. The data of studying the influence of resveratrol and quercetin in the conditions of cardiac and endocrine pathology are stated. The main points of their application, expediency, efficiency and prospects of these agents using in atherosclerosis, coronary heart disease (CHD) and autoimmune thyroiditis as well as in comorbidity conditions are formulated.
Key words: ischemic heart disease, atherosclerosis, autoimmune thyroiditis, chronic systemic inflammation, resveratrol, quercetin.

References

1. Dinarello CA. Proinflammatory cytokines. Chest. 2000 Aug;118(2):503-8.
2. Brunetti ND, Correale M, Pellegrino PL, Munno I, Cuculo A, De Gennaro L, et al. Early inflammatory cytokine response: A direct comparison between spontaneous coronary plaque destabilization vs angioplasty induced. Atherosclerosis. 2014 Oct;236(2):456-60. doi: http://dx.doi.org/10.1016/j.atherosclerosis.2014.07.037
3. Ganesh BB, Bhattacharya P, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res. 2011 Oct;31(10):721-31. doi: http://dx.doi.org/10.1089/jir.2011.0049
4. Calabriso N, Scoditti E, Massaro M, Pellegrino M, Storelli C, Ingrosso I, et al. Multiple anti-inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts: differential role of hydroxycinnamic acids, flavonols and stilbenes on endothelial inflammatory gene expression. Eur J Nutr. 2016 Mar;55(2):477-489. doi: http://dx.doi.org/10.1007/s00394-015-0865-6
5. Zalesskiy VN, Velikaya NV, Omel'chuk ST. Antiinflammatory delivery in prophylaxis and treatment noninfectious (including tumoral) diseases of the person. Molecular protective mechanisms of bioactive components of a nutrition: monografiia. Vinnitsa, Ukraine: Nova Kniga; 2014. 736 р. (In Russ.)
6. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000 Jun;164(12):6509-19.
7. Singh NP, Singh UP, Hegde VL, Guan H, Hofseth L, Nagarkatti M, et al. Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB. Mol Nutr Food Res. 2011 Aug;55(8):1207-18. doi: http://dx.doi.org/10.1002/mnfr.201000576
8. Kaydashev IP. NF-kB alarm system as basis of development of systemic inflammation, insulin resistance, lipotoksichnost, diabetes mellitus 2 type and atherosclerosis. Mezhdunar Endokrinol Zhurn. 2011;(3):35-45. (In Russ.)
9. Rasіn OM, Kaydashev ІP, Rasіn MS. Molecular mechanisms of antiinflammatory action of a glitazonama and statines: PPAR-gamma role [Elektronnii resurs]. Mezhdunar Endokrinol Zhurn. 2007;(6). Rezhim dostupu: http://www.mif-ua.com/archive/article_print/3778. Data dostupu: 12.10.2017. (In Ukr.)
10. Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010 Mar;59(3):554-63. doi: http://dx.doi.org/10.2337/db09-0482
11. Kaydashev IP. The system of sirtuin and a possibility of adjustment of its state in clinical practice (the review of literature). Zhurn Nats Akad Med Nauk Ukraїni. 2012;18(4):418-29. (In Rus.)
12. Said RS, El-Demerdash E, Nada AS, Kamal MM. Resveratrol inhibits inflammatory signaling implicated in ionizing radiation-induced premature ovarian failure through antagonistic crosstalk between silencing information regulator 1 (SIRT1) and poly(ADP-ribose) polymerase 1 (PARP-1). Biochem Pharmacol. 2016 Mar;103:140-50. doi: http://dx.doi.org/10.1016/j.bcp.2016.01.019
13. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006 Jun;5(6):493-506. doi: http://dx.doi.org/10.1038/nrd2060
14. Gasparrini M, Giampieri F, Alvarez Suarez J M, Mazzoni L, Y Forbes Hernandez T, Quiles JL, et al. AMPK as a new attractive therapeutic target for disease prevention: the role of dietary compounds. Curr Drug Targets. 2016;17(8):865-89.
15. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012 May;15(5):675-90. doi: http://dx.doi.org/10.1016/j.cmet.2012.04.003
16. Guo S, Yao Q, Ke Z, Chen H, Wu J, Liu C. Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. Mol Cell Endocrinol. 2015 Sep;412:85-94. doi: http://dx.doi.org/10.1016/j.mce.2015.05.034
17. Bi XL, Yang JY, Dong YX, Wang JM, Cui YH, Ikeshima T, et al. Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysacchride-activatewd microglia. Int Immunopharmacol. 2005 Jan;5(1):185-93. doi: http://dx.doi.org/10.1016/j.intimp.2004.08.008
18. Park HJ, Jeong SK, Kim SR, Bae SK, Kim WS, Jin SD, et al. Resveratrol inhibits Porphyromonas gingivalis lipopolysaccharide-induced endothelial adhesion molecule expression by suppressing NF-κappaB activation. Arch Pharm Res. 2009 Apr;32(4):583-91. doi: http://dx.doi.org/10.1007/s12272-009-1415-7
19. Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L774-83. doi: http://dx.doi.org/10.1152/ajplung.00110.2004
20. Agarwal B, Campen MJ, Channell MM, Wherry SJ, Varamini B, Davis JG, et al. Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int J Cardiol. 2013 Jun;166(1):246-8. doi: http://dx.doi.org/10.1016/j.ijcard.2012.09.027
21. Issuree PD, Pushparaj PN, Pervaiz S, Melendez AJ. Resveratrol attenuates C5a-induced inflammatory responses in vitro and in vivo by inhibiting phospholipase D and sphingosine kinase activities. FASEB J. 2009 Aug;23(8):2412-24. doi: http://dx.doi.org/10.1096/fj.09-130542
22. Sharma HS, Das DK. Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm. 1997;6(3):175-83. doi: http://dx.doi.org/10.1080/09629359791668
23. Bradamante S, Barenghi L, Piccinini F, Bertelli AA, De Jonge R, Beemster P, et al. Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol. 2003 Mar;465(1-2):115-23.
24. Cruz MN, Luksha L, Logman H, Poston L, Agewall S, Kublickiene K. Acute responses phytoestrogens in small arteries from men with coronary heart disease. Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1969-75. doi: http://dx.doi.org/10.1152/ajpheart.01065.2005  
25. Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, et al. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1876-81. doi: http://dx.doi.org/10.1152/ajpheart.00375.2009
26. Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NfkappaB. Free Radic Res. 2006 Oct;40(10):1066-75. doi: http://dx.doi.org/10.1080/10715760600833085
27. Chow SE, Hshu YC, Wang JS, Chen JK. Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages. J Appl Physiol (1985). 2007 Apr;102(4):1520-7. doi: http://dx.doi.org/10.1152/japplphysiol.00881.2006
28. Raj P, Zieroth S, Netticadan T. An overview of the efficacy of resveratrol in the management of ischemic heart disease. Ann N Y Acad Sci. 2015 Aug;1348(1):55-67. doi: http://dx.doi.org/10.1111/nyas.12828
29. Hattori R, Otani H, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of NO. Am J Physiol Heart Circ Physiol. 2002 Jun:282(6):H1988-95. doi: http://dx.doi.org/10.1152/ajpheart.01012.2001
30. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoids synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 1995 Mar;235(2):207-19.
31. Moreno JJ. Resveratrol modulates arachidonic acid release, prostaglandin synthesis and 3T6 fibroblast growth. J Pharmacol Exp Ther. 2000 Jul;294(1):333-8.
32. Olas B, Wachowicz B. Resveratrol: a phenolic antioxidant with effects on blood platelet functions. Platelets. 2005 Aug;16(5):251-60. doi: http://dx.doi.org/10.1080/09537100400020591
33. Olson ER, Naugle JE, Zhang X, Bomser JA, Meszaros JG. Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1131-8. doi: http://dx.doi.org/10.1152/ajpheart.00763.2004
34. Cheng TH, Liu JC, Lin H, Shih NL, Chen YL, Huang MT, et al. Inhibitory effects of resveratrol on angiotensin II-induced cardiomyocyte hypertrophy. Naunyn Schmiedebergs Arch Pharmacol. 2004 Feb;369(2):239-44. doi: http://dx.doi.org/10.1007/s00210-003-0849-6
35. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec;127(6):1109-22. doi: http://dx.doi.org/10.1016/j.cell.2006.11.013
36. Das S, Mitrovsky G, Vasanthi HR, Das DK4. Antiaging properties of a Grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev. 2014;2014:345105. doi: http://dx.doi.org/10.1155/2014/345105
37. Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010 Mar;285(11):8340-51. doi: http://dx.doi.org/10.1074/jbc.M109.088682
38. Gurusamy N, Ray D, Lekli I, Das DK. Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. J Cell Mol Med. 2010 Sep;14(9):2235-9. doi: http://dx.doi.org/10.1111/j.1582-4934.2010.01140.x
39. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H18-24. doi: http://dx.doi.org/10.1152/ajpheart.00260.2010
40. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, et al. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H363-72. doi: http://dx.doi.org/10.1152/ajpheart.01134.2010
41. Yue Z, Xie J, Yu AS, Stock J, Du J, Yue L. Role of TRP channels in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2015 Feb;308(3):H157-82. doi: http://dx.doi.org/10.1152/ajpheart.00457.2014
42. Yu L, Wang S, Kogure Y, Yamamoto S, Noguchi K, Dai Y. Modulation of TRP channels by resveratrol and other stilbenoids. Mol Pain. 2013 Feb;9:3. doi: http://dx.doi.org/10.1186/1744-8069-9-3
43. Tomé-Carneiro J, Visioli F. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine. 2016 Oct ;23(11):1145-74. doi: http://dx.doi.org/10.1016/j.phymed.2015.10.018
44. Kawabata K, Mukai R, Ishisaka A. Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability. Food Funct. 2015 May;6(5):1399-417. doi: http://dx.doi.org/10.1039/c4fo01178c
45. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, inflammation and immunity. Nutrients. 2016 Mar;8(3):167. doi: http://dx.doi.org/10.3390/nu8030167
46. Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007;2007:45673. doi: http://dx.doi.org/10.1155/2007/45673
47. Ruiz PA, Braune A, Hölzlwimmer G, Quintanilla-Fend L, Haller D. Quercetin inhibits TNF-induced NF-κB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr. 2007 May;137(5):1208-15.
48. Kobuchi H, Roy S, Sen CK, Nguyen HG, Packer L. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol. 1999 Sep;277(3 Pt 1):C403-11.
49. Pfeuffer M, Auinger A, Bley U, Kraus-Stojanowic I, Laue C, Winkler P, et al. Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms. Nutr Metab Cardiovasc Dis. 2013 May;23(5):403-9. doi: http://dx.doi.org/10.1016/j.numecd.2011.08.010
50. Hung CH, Chan SH, Chu PM, Tsai KL. Quercetin is a potent anti-atherosclerotic compound by activation of SIRT1 signaling under oxLDL stimulation. Mol Nutr Food Res. 2015 Oct;59(10):1905-17. doi: http://dx.doi.org/10.1002/mnfr.201500144
51. Lee J, Choi JW, Sohng JK, Pandey RP, Park YI. The immunostimulating activity of quercetin 3-O-xyloside in murine macrophages via activation of the ASK1/MAPK/NF-κB signaling pathway. Int Immunopharmacol. 2016 Feb;31:88-97. doi: http://dx.doi.org/10.1016/j.intimp.2015.12.008
52. Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin to decrease blood pressure: Review of efficacy. Adv Nutr. 2012 Jan;3(1):39-46. doi: http://dx.doi.org/10.3945/an.111.001271
53. Balasuriya N, Rupasinghe HP. Antihypertensive properties of flavonoid-rich apple peel extract. Food Chem. 2012 Dec;135(4):2320-5. doi: http://dx.doi.org/10.1016/j.foodchem.2012.07.023
54. Hügel HM, Jackson N, May B, Zhang AL, Xue CC. Polyphenol protection and treatment of hypertension. Phytomedicine. 2016 Feb;23(2):220-31. doi: http://dx.doi.org/10.1016/j.phymed.2015.12.012
55. Monteiro MM, França-Silva MS, Alves NF, Porpino SK, Braga VA. Quercetin improves baroreflex sensitivity in spontaneously hypertensive rats. Molecules. 2012 Nov;17(11):12997-3008. doi: http://dx.doi.org/10.3390/molecules171112997
56. Perez-Vizcaino F, Duarte J, Jimenez R, Santos-Buelga C, Osuna A. Antihypertensive effects of the flavonoid quercetin. Pharmacol Rep. 2009 Jan-Feb;61(1):67-75.
57. Egert S, Bosy-Westphal A, Seiberl J, Kürbitz C, Settler U, Plachta-Danielzik S, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr. 2009 Oct;102(7):1065-74. doi: http://dx.doi.org/10.1017/S0007114509359127
58. Lu Y, Wang RH, Guo BB, Jia YP. Quercetin inhibits angiotensin II induced apoptosis via mitochondrial pathway in human umbilical vein endothelial cells. Eur Rev Med Pharmacol Sci. 2016 Apr;20(8):1609-16.
59. Chirumbolo S. Role of quercetin in vascular physiology. Can J Physiol Pharmacol. 2012 Dec;90(12):1652-7. doi: http://dx.doi.org/10.1139/y2012-137. DOI: 10.1139/y2012-137
60. Zhao L, Wu J, Wang Y, Yang J, Wei J, Gao W, et al. Cholesterol metabolism is modulated by quercetin in rats. J Agric Food Chem. 2011 Feb;59(4):1104-8. doi: http://dx.doi.org/10.1021/jf1035367
61. de Pascual-Teresa S, Moreno DA, García-Viguera C. Flavanols and anthocyanins in cardiovascular health: a review of current evidence. Int J Mol Sci. 2010 Apr;11(4):1679-703. doi: http://dx.doi.org/10.3390/ijms11041679
62. Mosawy S, Jackson DE, Woodman OL, Linden MD. Treatment with quercetin and 3′,4′-dihydroxyflavonol inhibits platelet function and reduces thrombus formation in vivo. J Thromb Thrombolysis. 2013 Jul;36(1):50-7. doi: http://dx.doi.org/10.1007/s11239-012-0827-2
63. Mozzicafreddo M, Cuccioloni M, Bonfili L, Eleuteri AM, Fioretti E, Angeletti M. Antiplasmin activity of natural occurring polyphenols. Biochim Biophys Acta. 2008 Jul-Aug;1784(7-8):995-1001. doi: http://dx.doi.org/10.1016/j.bbapap.2008.03.016
64. Jin HB, Yang YB, Song YL, Zhang YC, Li YR. Protective roles of quercetin in acute myocardial ischemia and reperfusion injury in rats. Mol Biol Rep. 2012 Dec;39(12):11005-9. doi: http://dx.doi.org/10.1007/s11033-012-2002-4
65. Quarles EK, Dai DF, Tocchi A, Basisty N, Gitari L, Rabinovitch PS. Quality control systems in cardiac aging. Ageing Res Rev. 2015 Sep;23(Pt A):101-15. doi: http://dx.doi.org/10.1016/j.arr.2015.02.003
66. Sheng R, Gu ZL, Xie ML. Epigallocatechin gallate, the major component of polyphenols in green tea, inhibits telomere attrition mediated cardiomyocyte apoptosis in cardiac hypertrophy. Int J Cardiol. 2013 Jan;162(3):199-209. doi: http://dx.doi.org/10.1016/j.ijcard.2011.07.083
67. Duntas L. H. Resveratrol and its impact on aging and thyroid function. J Endocrinol Invest. 2011 Nov;34(10):788-92. doi: http://dx.doi.org/10.3275/7926
68. Giuliani C, Di Santo S, Hysi A, Iezzi M, Bucci I, Napolitano G. Anti-thyroid effect of resveratrol. In: Endocrine Society's 98th Annual Meeting and Expo; 2016 1-4 Apr; Boston. Boston; 2016.
69. Ge JF, Xu YY, Li N, Zhang Y, Qiu GL, Chu CH, et al. Resveratrol improved the spatial learning and memory in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization. Endocr J. 2015;62(10):927-38. doi: http://dx.doi.org/10.1507/endocrj.EJ15-0253
70. Ge JF, Xu YY, Qin G, Cheng JQ, Chen FH. Resveratrol ameliorates the anxiety- and depression-like behavior of subclinical hypothyroidism rat: possible involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin pathway. Front Endocrinol (Lausanne). 2016 May;7:44. doi: http://dx.doi.org/10.3389/fendo.2016.00044
71. Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G. Effects of resveratrol on human immune cell function. Life Sci. 2001 Nov;70(1):81-96.
72. Laupheimer MW, Perry M, Benton S, Malliaras P, Maffulli N. Resveratrol exerts no effect on inflammatory response and delayed onset muscle soreness after a marathon in male athletes: A randomised, double-blind, placebo-controlled pilot feasibility study. Transl Med UniSa. 2014 Apr;10:38-42.
73. Cheserek MJ, Wu G, Li L, Karangwa E, Shi Y, Le G. Cardioprotective effects of lipoic acid, quercetin and resveratrol on oxidative stress related to thyroid hormone alterations in long-term obesity. J Nutr Biochem. 2016 Jul;33:36-44. doi: http://dx.doi.org/10.1016/j.jnutbio.2016.02.008
74. de Souza Dos Santos MC, Gonçalves CF, Vaisman M, Ferreira AC, de Carvalho DP. Impact of flavonoids on thyroid function. Food Chem Toxicol. 2011 Oct;49(10):2495-502. doi: http://dx.doi.org/10.1016/j.fct.2011.06.074
75. Giuliani C, Bucci I, Di Santo S, Rossi C, Grassadonia A, Piantelli M, et al. The flavonoid quercetin inhibits thyroid-restricted genes expression and thyroid function. Food Chem Toxicol. 2014 Apr;66:23-9. doi: http://dx.doi.org/10.1016/j.fct.2014.01.016
76. van der Heide D, Kastelijn J, Schröder-van der Elst JP. Flavonoids and thyroid diseas. Biofactors. 2003;19(3-4):113-9.

Information about authors:
Chekalina N.I. – Candidate of Medical Sciences, associate professor of the Chair of Propedeutics of Internal Medicine with Patients Care, General Practice (Family Medicine), Ukrainian Medical Stomatological Academy;
Manusha Y.I. – postgraduate of the Chair of Internal Medicine with Patients Care, General Practice (Family Medicine), Ukrainian Medical Stomatological Academy.

Correspondence address: Ukraine, 36000, Poltava, 23 Shevchenko str., Ukrainian Medical Stomatological Academy, Chair of Propedeutics of Internal Medicine with Patients Care, General Practice (Family Medicine). E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Natalya I. Chekalina.

Поиск по сайту