Login Register Cart 0
Generic placeholder image

Current Drug Therapy

Editor-in-Chief

ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synergy Effects of Metformin and Berberine on Glyoxal-induced Carbonyl Stress in Isolated Rat Liver Mitochondria

Author(s): Mohsen Rezaei, Heibatullah Kalantari, Saeed Mehrzadi and Mehdi Goudarzi*

Volume 15, Issue 5, 2020

Page: [493 - 502] Pages: 10

DOI: 10.2174/1574885515666200214122055

Price: $65

Abstract

Objective: Carbonyl stress, resulting from toxic effects of alpha-dicarbonyls such as glyoxal (GO), plays an important role in mitochondrial dysfunction and subsequent development of diabetic complications. This study evaluated the ability of metformin (MET), berberine (BBR), and their combination to prevent GO-induced carbonyl stress in isolated rat liver mitochondria.

Methods: Mitochondria (0.5 mg protein/mL) were isolated from the Wistar rat liver and incubated with various concentrations of GO (1, 2.5, 5, 7.5, and 10 mM) for 30 minutes and IC50 for GO was calculated. The suspensions of mitochondria were incubated with various concentrations of MET (2.5, 5, 10, and 20 mM) or BBR (2.5, 5, 10, and 20 μM) for 30 min and then GO in a dose of IC50 at 37 ºC for 30 min. Mitochondrial complex II activity, mitochondrial membrane potential (MMP), MDA level, reactive oxygen species (ROS) formation, reduced glutathione (GSH) content, and protein carbonylation were assessed. The combination index and isobologram of MET and BBR on GO toxicity were calculated.

Results: IC50 of GO was assigned approximately 3 mM. GO disrupted the electron transfer chain and significantly increased mitochondrial ROS formation, protein carbonylation, and MDA level. GO decreased mitochondrial viability, MMP, and GSH content. Pre-treatment with MET and BBR could potentially reverse GO-induced deleterious effects in a concentration-dependent manner. Results of the drug combination indicated that CI for Fa 0.5 (Effect 50 %) was 0.83.

Conclusion: These results suggest that BBR in combination with MET has a moderate synergistic effect on GO-induced carbonyl stress in isolated rat liver mitochondria.

Keywords: Glyoxal, carbonyl stress, metformin, berberine, isobologram, mitochondria.

« Previous Next »
Graphical Abstract

[1]
Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128: 40-50.
[http://dx.doi.org/10.1016/j.diabres.2017.03.024] [PMID: 28437734]
[2]
Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab 2016; 20(4): 546-51.
[http://dx.doi.org/10.4103/2230-8210.183480] [PMID: 27366724]
[3]
Kawahito S, Kitahata H, Oshita S. Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol 2009; 15(33): 4137-42.
[http://dx.doi.org/10.3748/wjg.15.4137] [PMID: 19725147]
[4]
Yang K. Formation and metabolism of sugar metabolites, glyoxal and methylglyoxal, and their molecular cytotoxic mechanisms in isolated rat hepatocytes 2011.
[5]
Brings S, Fleming T, Freichel M, Muckenthaler MU, Herzig S, Nawroth PP. Dicarbonyls and advanced glycation end-products in the development of diabetic complications and targets for intervention. Int J Mol Sci 2017; 18(5): 984.
[http://dx.doi.org/10.3390/ijms18050984] [PMID: 28475116]
[6]
Goudarzi M, Kalantari H, Rezaei M. Glyoxal toxicity in isolated rat liver mitochondria. Hum Exp Toxicol 2018; 37(5): 532-9.
[http://dx.doi.org/10.1177/0960327117715900] [PMID: 28639457]
[7]
Green K, Brand MD, Murphy MP. Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 2004; 53(Suppl. 1): S110-8.
[http://dx.doi.org/10.2337/diabetes.53.2007.S110] [PMID: 14749275]
[8]
Leichter SB, Thomas S. Combination medications in diabetes care: an opportunity that merits more attention. Clin Diabetes 2003; 21(4): 175-8.
[http://dx.doi.org/10.2337/diaclin.21.4.175]
[9]
Falotico R, Kopia G, Landau G, et al. Drug combinations and delivery devices for the prevention and treatment of vascular disease Google Patents 2001.
[10]
Bonnefont-Rousselot D, Raji B, Walrand S, et al. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 2003; 52(5): 586-9.
[http://dx.doi.org/10.1053/meta.2003.50093] [PMID: 12759888]
[11]
Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux JL. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism 2005; 54(6): 829-34.
[http://dx.doi.org/10.1016/j.metabol.2005.01.029] [PMID: 15931622]
[12]
Mehta R, Wong L, O’Brien PJ. Cytoprotective mechanisms of carbonyl scavenging drugs in isolated rat hepatocytes. Chem Biol Interact 2009; 178(1-3): 317-23.
[http://dx.doi.org/10.1016/j.cbi.2008.10.026] [PMID: 19010314]
[13]
Hwang SW, Lee YM, Aldini G, Yeum KJ. Targeting reactive carbonyl species with natural sequestering agents. Molecules 2016; 21(3): 280.
[http://dx.doi.org/10.3390/molecules21030280] [PMID: 26927058]
[14]
Zhou Y, Cao S, Wang Y, et al. Berberine metabolites could induce low density lipoprotein receptor up-regulation to exert lipid-lowering effects in human hepatoma cells. Fitoterapia 2014; 92: 230-7.
[http://dx.doi.org/10.1016/j.fitote.2013.11.010] [PMID: 24321576]
[15]
Pirillo A, Catapano AL. Berberine, a plant alkaloid with lipid- and glucose-lowering properties: From in vitro evidence to clinical studies. Atherosclerosis 2015; 243(2): 449-61.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.09.032] [PMID: 26520899]
[16]
Li Z, Geng YN, Jiang JD, Kong WJ. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med 2014; 2014289264
[17]
Pang B, Zhao LH, Zhou Q, et al. Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015; 2015905749
[18]
Qiu Y-Y, Tang L-Q, Wei W. Berberine exerts renoprotective effects by regulating the AGEs-RAGE signaling pathway in mesangial cells during diabetic nephropathy. Mol Cell Endocrinol 2017; 443: 89-105.
[http://dx.doi.org/10.1016/j.mce.2017.01.009] [PMID: 28087385]
[19]
Hao M, Li SY, Sun CK, et al. Amelioration effects of berberine on diabetic microendothelial injury model by the combination of high glucose and advanced glycation end products in vitro. Eur J Pharmacol 2011; 654(3): 320-5.
[http://dx.doi.org/10.1016/j.ejphar.2010.12.030] [PMID: 21236251]
[20]
Heidari M, Badri R, Rezaei M, et al. Mitochondrial protection against arsenic toxicity by a novel gamma tocopherol analogue in rat. Bull Env Pharmacol Life Sci 2015; 4: 43-55.
[21]
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72(1-2): 248-54.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[22]
Zhao Y, Ye L, Liu H, et al. Vanadium compounds induced mitochondria Permeability Transition Pore (PTP) opening related to oxidative stress. J Inorg Biochem 2010; 104(4): 371-8.
[http://dx.doi.org/10.1016/j.jinorgbio.2009.11.007] [PMID: 20015552]
[23]
Zhang F, Xu Z, Gao J, Xu B, Deng Y. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain. Environ Toxicol Pharmacol 2008; 26(2): 232-6.
[http://dx.doi.org/10.1016/j.etap.2008.04.003] [PMID: 21783917]
[24]
Shaki F, Pourahmad J. Mitochondrial toxicity of depleted uranium: protection by Beta-glucan. Iran J Pharm Res 2013; 12(1): 131-40.
[PMID: 24250581]
[25]
Baracca A, Sgarbi G, Solaini G, Lenaz G. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta 2003; 1606(1-3): 137-46.
[http://dx.doi.org/10.1016/S0005-2728(03)00110-5] [PMID: 14507434]
[26]
Sadegh C, Schreck RP. The spectroscopic determination of aqueous sulfite using Ellman’s reagent. MURJ 2003; 8: 39-43.
[27]
Banach MS, Dong Q, O’Brien PJ. Hepatocyte cytotoxicity induced by hydroperoxide (oxidative stress model) or glyoxal (carbonylation model): prevention by bioactive nut extracts or catechins. Chem Biol Interact 2009; 178(1-3): 324-31.
[http://dx.doi.org/10.1016/j.cbi.2008.10.003] [PMID: 18983988]
[28]
Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 2003; 329(1-2): 23-38.
[http://dx.doi.org/10.1016/S0009-8981(03)00003-2] [PMID: 12589963]
[29]
Han Y, Randell E, Vasdev S, et al. Plasma methylglyoxal and glyoxal are elevated and related to early membrane alteration in young, complication-free patients with Type 1 diabetes. Mol Cell Biochem 2007; 305(1-2): 123-31.
[http://dx.doi.org/10.1007/s11010-007-9535-1] [PMID: 17594057]
[30]
Yu W, Sheng M, Xu R, et al. Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med 2013; 11(1): 24.
[http://dx.doi.org/10.1186/1479-5876-11-24] [PMID: 23360542]
[31]
Gomes AP, Duarte FV, Nunes P, et al. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta 2012; 1822(2): 185-95.
[http://dx.doi.org/10.1016/j.bbadis.2011.10.008] [PMID: 22027215]
[32]
Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci 2012; 91(11-12): 409-14.
[http://dx.doi.org/10.1016/j.lfs.2012.08.017] [PMID: 22925597]
[33]
Mo C, Wang L, Zhang J, et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal 2014; 20(4): 574-88.
[34]
Yin J, Ye J, Jia W. Effects and mechanisms of berberine in diabetes treatment. Acta Pharm Sin B 2012; 2(4): 327-34.
[http://dx.doi.org/10.1016/j.apsb.2012.06.003]
[35]
Sarna LK, Wu N, Hwang SY, Siow YL. OK. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can J Physiol Pharmacol 2010; 88(3): 369-78.
[http://dx.doi.org/10.1139/Y09-136] [PMID: 20393601]
[36]
Gray SP, Di Marco E, Okabe J, et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 2013; 127(18): 1888-902.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.132159] [PMID: 23564668]
[37]
Jiang F, Lim HK, Morris MJ, et al. Systemic upregulation of NADPH oxidase in diet-induced obesity in rats. Redox Rep 2011; 16(6): 223-9.
[http://dx.doi.org/10.1179/174329211X13049558293713] [PMID: 22195989]
[38]
García-Ruiz I, Solís-Muñoz P, Fernández-Moreira D, Grau M, Muñoz-Yagüe T, Solís-Herruzo JA. NADPH oxidase is implicated in the pathogenesis of oxidative phosphorylation dysfunction in mice fed a high-fat diet. Sci Rep 2016; 6: 23664.
[http://dx.doi.org/10.1038/srep23664] [PMID: 27173483]
[39]
Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001; 280(5): E685-94.
[http://dx.doi.org/10.1152/ajpendo.2001.280.5.E685] [PMID: 11287350]
[40]
Garg G, Singh S, Singh AK, Rizvi SI. Metformin alleviates altered erythrocyte redox status during aging in rats. Rejuvenation Res 2017; 20(1): 15-24.
[http://dx.doi.org/10.1089/rej.2016.1826] [PMID: 27185159]
[41]
Garg G, Singh S, Singh AK, Rizvi SI. Antiaging effect of metformin on brain in naturally aged and accelerated senescence model of rat. Rejuvenation Res 2017; 20(3): 173-82.
[http://dx.doi.org/10.1089/rej.2016.1883] [PMID: 27897089]
[42]
Bułdak Ł, Łabuzek K, Bułdak RJ, et al. Metformin affects macrophages’ phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep 2014; 66(3): 418-29.
[http://dx.doi.org/10.1016/j.pharep.2013.11.008] [PMID: 24905518]
[43]
Hosseini M-J, Shaki F, Ghazi-Khansari M, Pourahmad J. Toxicity of arsenic (III) on isolated liver mitochondria: a new mechanistic approach. Iranian J Pharmaceutical Res Iran J Pharm Res 2013; 12(Suppl.): 121-38.
[PMID: 24250680]
[44]
Hosseinzadeh A, Jafari D, Kamarul T, Bagheri A, Sharifi AM. Evaluating the protective effects and mechanisms of diallyl disulfide on interlukin-1β-Induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes. J Cell Biochem 2017; 118(7): 1879-88.
[http://dx.doi.org/10.1002/jcb.25907] [PMID: 28169456]
[45]
Dröse S. Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning. Biochim Biophys Acta 2013; 1827(5): 578-87.
[http://dx.doi.org/10.1016/j.bbabio.2013.01.004] [PMID: 23333272]
[46]
Wojtovich AP, Smith CO, Haynes CM, Nehrke KW, Brookes PS. Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel. Biochim Biophys Acta 2013; 1827(5): 598-611.
[http://dx.doi.org/10.1016/j.bbabio.2012.12.007] [PMID: 23291191]
[47]
Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett 2000; 466(2-3): 323-6.
[http://dx.doi.org/10.1016/S0014-5793(00)01082-6] [PMID: 10682852]
[48]
Liao H-Y, Kao CM, Yao CL, Chiu PW, Yao CC, Chen SC. 2, 4, 6-trinitrotoluene induces apoptosis via ROS-regulated mitochondrial dysfunction and endoplasmic reticulum stress in HepG2 and Hep3B cells. Sci Rep 2017; 7(1): 8148.
[http://dx.doi.org/10.1038/s41598-017-08308-z] [PMID: 28811603]
[49]
Khodayar MJ, Javadipour M, Keshtzar E, Rezaei M. Role of berberine against arsenic induced oxidative damage in isolated rat liver mitochondria. J Environ Biol 2016; 37(2): 285-90.
[PMID: 27097449]
[50]
Adil M, Kandhare AD, Dalvi G, et al. Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Ren Fail 2016; 38(6): 996-1006.
[http://dx.doi.org/10.3109/0886022X.2016.1165120] [PMID: 27056079]
[51]
Wang Y, Liu J, Ma A, Chen Y. Cardioprotective effect of berberine against myocardial ischemia/reperfusion injury via attenuating mitochondrial dysfunction and apoptosis. Int J Clin Exp Med 2015; 8(8): 14513-9.
[PMID: 26550442]
[52]
Morales AI, Detaille D, Prieto M, et al. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int 2010; 77(10): 861-9.
[http://dx.doi.org/10.1038/ki.2010.11] [PMID: 20164825]
[53]
Barreto-Torres G, Parodi-Rullán R, Javadov S. The role of PPARα in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats. Int J Mol Sci 2012; 13(6): 7694-709.
[http://dx.doi.org/10.3390/ijms13067694] [PMID: 22837722]

Rights & Permissions Print Cite
Article Metrics
15
© 2024 Bentham Science Publishers | Privacy Policy