Effects of Metformin and Preparations With Pleiotropic Effects on Testicular Biochemical Indices of Rats With Juvenile-Onset Metabolic Syndrome
DOI:
https://doi.org/10.20535/ibb.2023.7.2.285863Keywords:
metabolic syndrome, metformin, vitamins' complex, liposomal preparation, testes, juvenile ageAbstract
Background. Metabolic syndrome (MS) is a complex of disorders characterized by abdominal obesity, insulin resistance and glucose tolerance, arterial hypertension, and all types of metabolic disorders. Taking into account the wide range of symptoms accompanying MS, the use of preparations with pleiotropic effects on metabolic processes in the body could be promising for its treatment.
Objective. The aim of this study is comparative estimation of metformin or its combination with vitamins' complex or liposomal preparation treatment effects on DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes in testes of rats with MS induced in juvenile age.
Methods. MS model was induced by full replacement of drinking water with 10% fructose solution in Wistar male rats of 21–23 days age (50–70 g). DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes investigations were carried out after 60 days of MS modeling and metformin or its combination with vitamins' complex or liposomal preparation treatment.
Results. In experiments with pubertal rats with MS and metformin or its combination vitamins' complex or liposomal preparation treatment, we established partially corrective effects of these medications for DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes changes caused by MS development.
Conclusions. A comparative analysis of the studied preparations' effects under MS simulation in the juvenile age showed that none of these drugs was able to completely normalize the disorders in studied indicators caused by MS. However, both combinations of metformin with vitamins' complex or liposomal preparation were still more effective in these negative changes' correction then metformin itself. Metformin with vitamins' complex caused a more pronounced influence on the processes of DNA fragmentation, the levels of adenyl nucleotides, and the energy charge of rat testicular cells, while the corrective effect of metformin with liposomal preparation was more noticeable with respect to the content of chromatin components.
References
Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017 Jun 22;11(8):215-25. DOI: 10.1177/1753944717711379
Kasturi SS, Tannir J, Brannigan RE. The Metabolic Syndrome and Male Infertility. J Androl. 2008 Jan 9;29(3):251-9. DOI: 10.2164/jandrol.107.003731
Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. New Eng J Med. 2002 Feb 7;346(6):393-403. DOI: 10.1056/nejmoa012512
Shegem NS, Alsheek Nasir AM, Batieha AM, El-Shanti H, Ajlouni KM. Effects of short term metformin administration on androgens in diabetic men. Saudi Med J. 2004 Jan;25(1):75-8.
Ozata M, Oktenli C, Bingol N, Ozdemir IC. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obesity Res. 2001 Nov;9(11):662-7. DOI: 10.1038/oby.2001.90
Posokhova K, Stechyshyn I, Krynytska I, Marushchak M, Birchenko I, et al. Comparative study of the effect of various forms of quercetin on experimental diabetes. Roman J Diabetes Nutr Metab Dis. 2018 Dec 1;25(4):383-8. DOI: 10.2478/rjdnmd-2018-0046
Liu D, Hu H, Lin Z, Chen D, Zhu Y, Hou S, et al. Quercetin deformable liposome: Preparation and efficacy against ultraviolet B induced skin damages in vitro and in vivo. J Photochem Photobiol B Biol. 2013 Oct;127:8-17. DOI: 10.1016/j.jphotobiol.2013.07.014
Rivera F, Costa G, Abin A, Urbanavicius J, Arruti C, Casanova G, et al. Reduction of ischemic brain damage and increase of glutathione by a liposomal preparation of quercetin in permanent focal ischemia in rats. Neurotox Res. 2008 Jun;13(2):105-14. DOI: 10.1007/bf03033562
Rezaei-Sadabady R, Eidi A, Zarghami N, Barzegar A. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif Cells Nanomed Biotechnol. 2014 Jun 24;44(1):128-34. DOI: 10.3109/21691401.2014.926456
Asmolov OK, Rybak TA. Lipophlavon influence on functional activity of the bronchial epithelium cells in patients suffering from chonic obstruction lung disease of the III degree of severety with a long term of smoking. Adv Biol Med. 2009;2:83-6.
Shayakhmetova GM, Bondarenko LB, Voronina AK, Kovalenko VM. Comparative investigation of methionine and novel formulation Metovitan protective effects in Wistar rats with testicular and epididymal toxicity induced by anti-tuberculosis drugs co-administration. Food Chem Toxicol. 2017 Jan; 99:222-30. DOI: 10.1016/j.fct.2016.12.001
Kovalenko VN, Tkachenko AE, Shayakhmetova AM, Matvienko AV. Impact of metformin on testis morpho-functional characteristics in male rats induced by metabolic syndrome developed at the juvenile age. Pharmacol Drug Toxicol. 2018;2(58):32-40.
Bettaieb A, Vazquez Prieto MA, Rodriguez Lanzi C, Miatello RM, Haj FG, Fraga CG, et al. (-)-Epicatechin mitigates high-fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress. Free Radic Biol Med. 2014 Jul;72:247-56. DOI: 10.1016/j.freeradbiomed.2014.04.011
Guidance for industry. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy Volunteers. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); 2005 Jul. 30 p.
Mannervik B, Jemth P. The glutathione pathway. Measurement of glutathione transferases. In: Costa LG, Hodgson E, Lawrence DA, Ozolins TR, Reed DJ, Greenlee WF, editors. Current protocols in toxicology. New York: John Wiley & Sons Inc; 2005. 2758 p.
Bondarenko LB, Karatzuba TA, Shayakhmetova GM, Voronina AK, Matvienko AV, Strelkov IV, et al. Specificity of metabolic syndrome model reproduction at pubertal and adult male rats. Roman J Diabetes Nutr Metab Dis. 2015 Sep 1;22(3):251-60. DOI: 10.1515/rjdnmd-2015-0031
Smirnova NV. Fractionation of rat liver histone proteins. In: Modern methods in biochemistry. Moscow: Medicine; 1977:349-52.
Velikov VA. Molecular biology. Practical guide. Saratov: Publishing house "Saratov source"; 2013. p. 15-34.
Figueira MA, Ribeiro JA. Separation of adenosine and its derivatives by thin-layer chromatography on silica gel. J Chromatogr A. 1985 Jan;325:317-22. DOI: 10.1016/s0021-9673(00)96036-9
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265-75. DOI: 10.1016/s0021-9258(19)52451-6
Erol A. Systemic DNA damage response and metabolic syndrome as a premalignant state. Curr Mol Med. 2010 Apr 1;10(3):321-34. DOI: 10.2174/156652410791065282
Chianese R, Pierantoni R. Mitochondrial reactive oxygen species (ROS) production alters sperm quality. Antioxidants. 2021 Jan 11;10(1):92. DOI: 10.3390/antiox10010092
Ray SD, Kamendulis LM, Gurule MW, Yorkin RD, Corcoran GB. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 1993 Mar;7(3):453-63. DOI: 10.1096/fasebj.7.5.8462787
Cioce M, Pulito C, Strano S, Blandino G, Fazio VM. Metformin: metabolic rewiring faces tumor heterogeneity. Cells. 2020 Nov 9;9(11):2439. DOI: 10.3390/cells9112439
Wang Y, Zhang W, Lv Q, Zhang J, Zhu D. The critical role of quercetin in autophagy and apoptosis in HeLa cells. Tumor Biol. 2015 Aug 11;37(1):925-9. DOI: 10.1007/s13277-015-3890-4
Purwoko RY, Rosliana I, Sobariah S, Hermana N, Permatasari S, Wulandari D, et al. Apoptosis of adipose-derived stem cells induced by liposomal soybean phosphatidylcholine extract. Avicenna J Med Biotechnol, 2018 Jul-Sep;10(3):126-133.
Hsu C-L, Yen G-C. Phenolic compounds: Evidence for inhibitory effects against obesity and their underlying molecular signaling mechanisms. Mol Nutr Food Res. 2008 Jan;52(1):53-61. DOI: 10.1002/mnfr.200700393
Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev. 2010 Jun 25;68(7):418-28. DOI: 10.1111/j.1753-4887.2010.00301.x
Kuo PC, Liu HF, Chao JI. Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. J Biol Chem. 2004 Dec;279(53):55875-85. DOI: 10.1074/jbc.m407985200
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B. A model for p53-induced apoptosis. Nature. 1997 Sep;389(6648):300-5. DOI: 10.1038/38525
Yoon KA, Nakamura Y, Arakawa H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Human Gen. 2004 Feb 25;49(3):134-40. DOI: 10.1007/s10038-003-0122-3
Hussain SP, Amstad P, He P, Robles A, Lupold S, Kaneko I, et al. p53-Induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 2004 Apr 1;64(7):2350-6. DOI: 10.1158/0008-5472.can-2287-2
O'Connor JC, Wallace DM, O'Brien CJ, Cotter TG. A novel antioxidant function for the tumor-suppressor gene p53 in the retinal ganglion cell. Invest Ophthalmo Vis Sci. 2008 May 16;49(10):4237-44. DOI: 10.1167/iovs.08-1963
Ozaki T, Nakagawara A. p73, a sophisticated p53 family member in the cancer world. Cancer Science. 2005 Nov;96(11):729-37. DOI: 10.1111/j.1349-7006.2005.00116.x
Lee DH, Szczepanski M, Lee YJ. Role of Bax in quercetin-induced apoptosis in human prostate cancer cells. Biochem Pharmacol. 2008 Jun;75(12):2345-55. DOI: 10.1016/j.bcp.2008.03.013
Truong-Tran AQ, Ho LH, Chai F, Zalewski PD. Cellular zinc fluxes and the regulation of apoptosis/gene-directed cell death. J Nutrition. 2000 May;130(5):1459S-1466S. DOI: 10.1093/jn/130.5.1459s
Xiao Z, Locasale JW. Epigenomic links from metabolism – methionine and chromatin architecture. Curr Opin Chem Biol. 2021 Aug;63:11-8. DOI: 10.1016/j.cbpa.2021.01.011
Gosangi M, Ravula V, Rapaka H, Patri SV. α-Tocopherol-anchored gemini lipids with delocalizable cationic head groups: the effect of spacer length on DNA compaction and transfection properties. Org Biomol Chem. 2021;19(20):4565-76. DOI: 10.1039/d1ob00475a
Singh DK, Ahn B, Bohr VA. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology. 2008 Dec 15;10(3):235-52. DOI: 10.1007/s10522-008-9205-z
Håkansson A, Zhivotovsky B, Orrenius S, Sabharwal H, Svanborg C. Apoptosis induced by a human milk protein. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8064-8. DOI: 10.1073/pnas.92.17.8064
Jia YF, Feng Q, Ge ZY, Guo Y, Zhou F, Zhang KS, et al. Obesity impairs male fertility through long-term effects on spermatogenesis. BMC Urol. 2018 May 16;18(1). DOI: 10.1186/s12894-018-0360-5
Rato L, Alves MG, Dias TR, Lopes G, Cavaco JE, Socorro S, et al. High-energy diets may induce a pre-diabetic state altering testicular glycolytic metabolic profile and male reproductive parameters. Andrology. 2013 Mar 14;1(3):495-504. DOI: 10.1111/j.2047-2927.2013.00071.x
Gansukh E, Nile A, Kim DH, Oh JW, Nile SH. New insights into antiviral and cytotoxic potential of quercetin and its derivatives – A biochemical perspective. Food Chem. 2021 Jan;334:127508. DOI: 10.1016/j.foodchem.2020.127508
Song X, Wang Y, Gao L. Mechanism of antioxidant properties of quercetin and quercetin-DNA complex. J Mol Model. 2020 May 12;26(6). DOI: 10.1007/s00894-020-04356-x
Lin ES, Luo RH, Huang CY. A complexed crystal structure of a single-stranded DNA-binding protein with quercetin and the structural basis of flavonol inhibition specificity. Int J Mol Sci. 2022 Jan 6;23(2):588. DOI: 10.3390/ijms23020588
Arroyo MN, Green JA, Cnop M, Igoillo-Esteve M. tRNA biology in the pathogenesis of diabetes: Role of genetic and environmental factors. Int J Mol Sci. 2021 Jan 6;22(2):496. DOI: 10.3390/ijms22020496
Bai X, Yao L, Ma X, Xu X. Small molecules as SIRT modulators. Mini Rev Med Chem. 2018 Jul 9;18(13):1151-7. DOI: 10.2174/1389557516666160620095103
Ebert T, Tran N, Schurgers L, Stenvinkel P, Shiels PG. Ageing – Oxidative stress, PTMs and disease. Mol Aspects Med. 2022 Aug;86:101099. DOI: 10.1016/j.mam.2022.101099
Yang M, Dart C, Kamishima T, Quayle JM. Hypoxia and metabolic inhibitors alter the intracellular ATP:ADP ratio and membrane potential in human coronary artery smooth muscle cells. PeerJ. 2020 Nov 10;8:e10344. DOI: 10.7717/peerj.10344
Kutryb-Zajac B, Mierzejewska P, Slominska EM, Smolenski RT. Therapeutic perspectives of adenosine deaminase inhibition in cardiovascular diseases. Molecules. 2020 Oct 12;25(20):4652. DOI: 10.3390/molecules25204652
Shpakov AO. Improvement effect of metformin on female and male reproduction in endocrine pathologies and its mechanisms. Pharmaceuticals. 2021 Jan 8;14(1):42. DOI: 10.3390/ph14010042
Slovacek RE, Hind G. Correlation between photosynthesis and the transthylakoid proton gradient. Biochim Biophys Acta. 1981 Apr;635(2):393-404. DOI: 10.1016/0005-2728(81)90037-2
Peterson CT, Rodionov DA, Osterman AL, Peterson SN. B vitamins and their role in immune regulation and cancer. Nutrients. 2020 Nov 4;12(11):3380. DOI: 10.3390/nu12113380
Roth HP, Kirchgeßner M. Effect of zinc deficiency on 3',5'-cyclic-AMP content and parameters of energy metabolism in the rat. Z Ernahrungswiss. 1983 Jun;22(2):116-23. DOI: 10.1007/bf02026208
Moosavi SMS, Ashtiyani SC, Hosseinkhani S, Shirazi M. Comparison of the effects of l-carnitine and α-tocopherol on acute ureteral obstruction-induced renal oxidative imbalance and altered energy metabolism in rats. Urol Res. 2009 Nov 26;38(3):187-94. DOI: 10.1007/s00240-009-0238-9
Cruz AM, Beall C. Extracellular ATP increases glucose metabolism in skeletal muscle cells in a P2 receptor dependent manner but does not contribute to palmitate-induced insulin resistance. Front Physiol. 2020 Sep 25;11. DOI: 10.3389/fphys.2020.567378
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 The Author(s)
This work is licensed under a Creative Commons Attribution 4.0 International License.
The ownership of copyright remains with the Authors.
Authors may use their own material in other publications provided that the Journal is acknowledged as the original place of publication and National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” as the Publisher.
Authors are reminded that it is their responsibility to comply with copyright laws. It is essential to ensure that no part of the text or illustrations have appeared or are due to appear in other publications, without prior permission from the copyright holder.
IBB articles are published under Creative Commons licence:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under CC BY 4.0 that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
