Organ-Specific Effects of Selenium Glutathione Peroxidases in Response to Medicinal Plant Extracts

AMERICAN JOURNAL OF RESEARCH IN MEDICAL SCIENCES, 2018 VOL 1, NO. 1: 1–8 eJManager 10.5455/ajrms.281449

ORIGINAL ARTICLE Open Access Organ-specific effects of selenium glutathione peroxidases in response to medicinal plant extracts

Janka Vašková1, Gabriela Mojžišová2, Ladislav Vaško1, Michal Stanko1, Janka Poráčová3 1 Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Tr. SNP 1, 040 66 Košice, 2 Slovak Republic, Department of Experimental Medicine, Faculty of Medicine, Pavol Jozef Šafárik University, Tr. SNP 1, 040 66 Košice, 3 Slovak Republic, Department of Biology, Faculty of Humanities and Natural Sciences, Presov University in Presov, Ul. 17 Novembra 1, 080 01 Presov, Slovak Republic

ABSTRACT ARTICLE HISTORY Background: Various plant extracts are used in the prevention and treatment of various Received 3 August 2017 disease states, with their beneficial effects mainly attributed to their antioxidant prop- Accepted 30 October 2017 erties. Published Materials and Methods: Knowledge of their localisation, the importance of selenium KEYWORDS glutathione peroxidases, and the methodological options for their determination, led us to choose to investigate the affects of oregano, stevia, ginseng and agrimonia extracts on agrimony; ginseng; glutathione peroxidase; oregano; plasma, heart and kidney mitochondria under in vitro conditions. stevia Results: The lowest activity of selenium isoforms was observed in the heart mitochondria. In the kidney mitochondria, it was approximately 100-fold higher and the highest was observed in plasma. The same was detected for total glutathione peroxidases in the heart, although those in kidney mitochondria were higher than in plasma. Oregano caused a generally significant increase in selenium isoform activity and a decrease in total glutathione peroxidase activity in the heart, while both decreased in the kidney. Stevia significantly increased the activity of selenium isoforms in the heart at a concentration of 125 μg.ml−1, with while either having no effect, or a slightly opposite effect on total peroxidase activities. The same effect was observed at lower concentrations in the kidney. Conversely, stevia caused a significant reduction in selenium peroxidase activity in the plasma. Ginseng caused a statistically significant increase in selenium isoform activity in the heart but reduced its activity in the kidney and plasma, even in total glutathione peroxidases. Mutually comparable effects were observed with agrimony. Conclusion: In terms of total glutathione peroxidases, the extracts can be assumed to have significant antioxidant effects. When considering the physiological functions of selenium isoforms, it is possible to predict the ability of oregano and stevia to significantly affect redox signalling pathways, especially in heart mitochondria, and to a lesser extent in the kidney.

Introduction peroxide reactions, they must be detected by Physiologically generated reactive oxygen spe- means of proteins with very reactive thiol groups cies (ROS) are predominantly peroxides. Despite their being mediators of physiological processes, and then to the effector [1,2], such as glutathione at certain concentrations and in certain media, peroxidaseor selenium (GPx).to transport GPx maysignals function to the traffickers, as a sen- sor as oxidized GPx can also transfer oxidation

Contactthey can Janka exhibit Vašková harmful [email protected] effects. To be Department specific of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Tr. SNP 1, 040 66 Košice, Slovak Republic.

© EJManager. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, noncommercial use, distribution and reproduction in any medium, provided the work is properly cited. Janka Vašková, Gabriela Mojžišová, Ladislav Vaško, Michal Stanko, Janka Poráčová equivalents to the target proteins with selec- plasma and the mitochondria of the heart and enzymes utilize equivalents of GSH to reduce and organ-specific effects of plant extracts in the tivity for specific protein interactions. GPx selenium glutathione peroxidases in contrast to totalkidney, glutathione and also peroxidase the very specific activities. responses of action.peroxides Regulation [3]. Five of of the eight concentration known isoforms of hy- aredroperoxide selenium-dependent mediators is with implicated specific in sites many of Materials and Methods physiological and pathophysiological processes In the experiment, biological material was ob- [4-7]. An adequate concentration of hydroper- tained from Sprague-Dawley male rats from the oxide signalling is deduced from frequent dys- - regulation of the expression of selenium GPx in cess approved by State Veterinary and Food cancer cells [8]. The role of selenium-contain- control group, with the first stage of the pro ing GPx is obvious but in addition to these are the not inconsiderable cysteine-containing GPx Administration of the Slovak Republic no. Ro-- 2575/14-221. Animals were aged 6 weeks, GPx. Theweighing animals’ 250 organs grams. were After harvested sacrificing for the heart an (GPx-likeThe essential proteins) oils or of non-selenium-dependent aromatic and medicinal imals, blood was taken for plasma extraction. plants have different biological activity mediat- Fernández-Vizzara et al. [17]. The protein con- ed in particular by their antioxidant properties tentand kidneywas determined mitochondria by biuretisolation complex according under to - - lates. even[9,10]. in It such is clear small from amounts. observations Eleutherococcus in folk medi sen- alkalineFor the conditions analysis, ethanol by bicinchoninic root extract acid of Siberian in iso ticosuscine and scientific studies that their effects differ,- Ginseng (Eleutherococcus senticosus (Rupr. & Maxim.)), aqueous extract of stevia leaves (Stevia an adaptogen (Rupr. [11].& Maxim.), Stevia rebaudianaknown as ginseng, (Bert.), isna a rebaudiana (Bert.)), dry extract of agrimony tops planttive to native north-eastern to tropical Asia and is primarilysubtropical known regions as (Agrimonia eupatoria (L.)) and oregano essen- of South and Central America. Leaves of stevia tial oils (Origanum vulgare (L.)) were purchased due to steviol glycosides. They have been used The extracts were incubated with plasma and inare these several countries times for sweeter centuries than as refined a sweetener sugar from Calendula ojsc (Stará Ľubovňa, Slovakia). and also in medicine [12]. Oregano vulgare (L.) for 1 hour. is an aromatic plant used in many countries in mitochondriaGPx activities−1 at final(EC concentrations1.11.1.9) were of measured 125, 62.5 a 31.25 μg.ml for the prevention of respiratory disease, dys- - pepsia,seasoning dysmenorrhea, dishes [13]. Itrheumatoid is used in folk arthritis medicine and nalin plasma,concentrations heart andof reagents kidney in mitochondria the test mixture by problems of the urinary system [14]. Agrimonia wasmeans as follows:of a kit (Sigma-Aldrich, 0.25 mM NADPH Germany). reagent, 2.1 The mM fi eupatoria reduced glutathione, 0.5 U/ml glutathione re- - (L.), is used in folk medicine for the (t-Bu-OOH) for selenium containing GPx or 300 tract,treatment and liver of inflammatory disease [15]. diseases such as hae ductase, and 300 μM terc-butyl-hydroperoxide- morrhagicIt was showed colitis, that inflammation ginseng, stevia of and the oregano urinary ties determination. Absorbance was measured at demonstrate a various activity in counteracting μM cumene hydroperoxide for total GPx acitivi reactive oxygen and nitrogen compounds [16]. Beam UV/Vis spectrophotometer (Spectronic The removal of peroxides involved in signalling Camspec340 nm using Ltd, Leeds,the kinetic UK). program of M501 Single pathways through antioxidant molecules may Results were expressed as milligrams of protein per millilitre of homogenate (mg prot.ml ). of antioxidant enzymes, dependent on the con- −1 centrationbe specific ofand, redox-active as is clear substances from the very or the nature site was determined by Student’s t-test. Differences of action, and may lead to different conclusions. betweenStatistical the significance effects of extracts of the effectswas found of extractsby one- The aim of this paper is to highlight the different

way ANOVA followed by Tukey post-hoc test. 2 Am J Res Med Sci • 2018 • Vol 2 • Issue 1 Diversity of glutathione peroxidase efficiency

Table 1. The effects of extracts on total GPx and selenium glutathione peroxidases (Se-GPx) in heart mitochondria.

Concentration Total GPx Se-GPx group/extract Post-hoc analysis (μg.ml−1) (nkat/mg prot) (nkat/mg prot) control 2.929 ± 0.186 0.072 ± 0.068a,b ap = 0.0323 125 oregano 1.738 ± 0.071 0.969 ± 0.009c bp = 0.0177 stevia 2.544 ± 0.557 0.288 ± 0.088a,c cp > 0.0000 ginseng 3.688 ± 0.601 0.313 ± 0.124b,c agrimony 2.575 ± 0.088 0.238 ± 0.071c control 2.929 ± 0.186 0.072 ± 0.068 a,b,cp = 0.0010 62.5 oregano 1.175 ± 0.159 0.706 ± 0.080a,b,c dp = 0.0064 stevia 3.075 ± 0.495 0.019 ± 0.009a,d ginseng 2.875 ± 0.742 0.050 ± 0.018b agrimony 1.694 ± 0.256 0.163 ± 0.053c,d control 2.929 ± 0.186 0.072 ± 0.068 ap > 0.0000 31.25 oregano 1.406 ± 0.380 0.731 ± 0.009 bp = 0.0001 stevia 1.975 ± 0.177 0.031 ± 0.009 cp = 0.0020 ginseng 2.556 ± 0.256 0.244 ± 0.027 agrimony 2.300 ± 0.495 0.088 ± 0.035

Results - The effect of oregano on Se-GPx activity in heart of ginseng and agrimony significantly reduced com- chondria with stevia increased their activity at a Se-GPx activity but incubation of kidney mito parison to controls without addition of any com- . Total GPx consis- tently showed statistically lower−1 activity relative mitochondriapound (p < 0.001) was using significantly all three higherconcentrations in concentration of 62.5 μg.ml - to the control in the case of all four extracts and ities were observed at stevia and ginseng con- at all concentrations (Figure 2). Post-hoc analy- (Figure 1A). Similarly, significantly higher activ sis of the differences between activities revealed differences in the effect of extracts at higher Se-GPx activities were observed−1 after incubation centrationswith the lowest of 125concentration μg.ml . Remarkably of ginseng. The higher op- concentrations on total glutathione peroxidase, especially in the case of agrimony and stevia. activity, was observed after oregano essential oil ) showed a −1 incubationposite effect ( p- a< significant0.001 and reduction p < 0.01), in also total using GPx divergence mainly from the effect of ginseng. Lower concentrations (62.5 μg.ml all three concentrations (Figure 2A). In contrast to Se-GPx, incubation with stevia extract led to - Significant differences between effects on Se-GPx p < served among all the extracts and at all concen- activities in the mitochondria of kidney were ob 0.01) at the lowest concentration, compared to trations (Table 2B). a significant decrease in total GPx activities ( total GPx activities of the heart mitochondria the effect of stevia, ginseng and agrimony, but the Se-GPx activities were significantly reduced by (thep control. Agrimony also significantly reduced effect of oregano was not observed when com- - pared to control in plasma (Figure 1C). No sig- cant < differences 0.05). One-way in the ANOVA induction followed of activities by Tukey of post-hocthe individual analysis extracts revealed only for statistically Se-GPx (Table signifi 1). alteration of total GPx activity or between the ef- fectsnificant of the differences extracts themselves have been (Figure observed 2C). in the when comparing the extract of ginseng, oregano andIn particular, stevia. significant differences were found Discussion The effects of extracts on glutathione peroxi- Peroxidases are represented numerically in living organisms, whether plant or animal. From the time - of their discovery in the 19th century, they have centrationsdase in the kidney (Figure mitochondria 1B). Higher differed.concentrations Se-GPx gained an important position in biotechnology and activities were significantly decreased by all con www.ajrms.com 3 Janka Vašková, Gabriela Mojžišová, Ladislav Vaško, Michal Stanko, Janka Poráčová

Table 2.

Concentration Total GPx Se-GPx The effects of extractsgroup/extract on total GPx and selenium glutathionePost-hoc analysis peroxidases (Se-GPx) in kidneyPost-hoc mitochondria. analysis (μg.ml−1) (nkat/mg prot) (nkat/mg prot) control 5.175 ± 0.083a ap = 0.0083 0.748 ± 0.223a,b,c ap = 0.0029 125 oregano 1.163 ± 0.088b bp = 0.0069 0.194 ± 0.027a,d bp = 0.0279 stevia 1,031 ± 0.044c,d cp = 0.0261 0.956 ± 0.186d,e,f cp = 0.0008 ginseng 1.394 ± 0.221c dp = 0.0010 0.356 ± 0.027b,e dp = 0.0002 agrimony 0.619 ± 0.097a,b,d 0.088 ± 0.018c,f ep = 0.0016 fp = 0.0001 control 5.175 ± 0.083a ap = 0.0010 0.748 ± 0.223a,b,c ap = 0.0029 62.5 oregano 0.600 ± 0.053 bp = 0.0064 0.013 ± 0.001a,d,e bp = 0.0279 stevia 1,444 ± 0.203b cp = 0.0016 1.519 ± 0.062d,f cp = 0.0008 ginseng 1.863 ± 0.106a,b,c 0.050 ± 0.018b,f dp = 0.0002 agrimony 0.356 ± 0.009c 0.400 ± 0.071c,e ep = 0.0016 fp = 0.0001 control 5.175 ± 0.083 0.748 ± 0.223a,b ap = 0.0017 31.25 oregano 1.163 ± 0.194 0.081 ± 0.044a,c,d bp = 0.0035 stevia 1,106 ± 0.239 1.144 ± 0.115b,e cp = 0.0025 ginseng 1.619 ± 0.345 0.713 ± 0.106c dp = 0.0157 agrimony 1.369 ± 0.080 0.563 ± 0.177d,e ep = 0.0053 related research areas [18]. However, it stresses the biological material in vitro; namely plasma, heart importance of peroxidases mainly due to their wide distribution among living organisms and participa- detect the activities of Se-GPx in the liver mitochon- tion in physiological processes. In terms of resolved driaand kidneydue to methodologicalmitochondria. We differences, could not notably proceed the to issues, it is an important function of the endoge- use of H2O2 nous antioxidants. observed the lowest activity Se-GPx in the heart Glutathione peroxidases constitute only a very mitochondria instead (Figure of tert-butyl 1A). Kidney hydroperoxide. mitochondria We - Se-GPx activities have been about 100-fold higher ciency of some GPx isozymes is dependent on the and the highest were observed in plasma (Figure presencesmall group of theof peroxidases trace element, [19]. Se. The The catalytic distribution effi of these selenoproteins between tissues and within lowest in the mitochondria of the heart, but higher 1B). The specific activities of total GPx were again impact on the physiological functions of individu- Differences in activities showed that Se-GPx activi- alspecific compartments subcellular within compartments cells and relevancehas a significant to the tiesin kidney represented mitochondria a minor than portion in plasma (less in (Figureheart than 2). development of the diseases. Selenoenzyme GPx1 - is present in the cytosol and mitochondria. GPx4, sponsible for a substantial part of the observed GPx with a unique function in its ability to reduce phos- activities.kidney) in This mitochondria, is in line with but the in place the plasma of production are re pholipid hydroperoxides, is responsible for most and action of selenoenzymes. However, the object of the observed antioxidant effects in studies. The of most in vitro studies are the liver mitochondria, distribution of these selenoenzymes affects the or treatment methods containing H2O2 (cumene hy- level of ROS, the relative usage of glycolysis in a droperoxide) as a substrate. Therefore comparison ratio to oxidative phosphorylation as well as the of Se-GPx and total GPx activities in plasma, heart level of redox-sensitive transcription factors (NF- - Treatment of disease states based on the imbal- anceand kidney of ROS mitochondria production and could degradation not be performed. through althoughκB), and theit is resulting synthesised number in the of proximal important tubules cellu drugs is economically disadvantageous for the lar processes [20]. GPx3 is specific to the plasma, end-user. It is therefore easier to investigate and the location and importance of selenium glutathi- use plant material for that purpose, which are oneof the peroxidases kidney [21]. as The well acquired as methodological knowledge about pos- more easily accessible. Various plant compounds sibilities has led us to the selection of the studied form components of a balanced diet and the

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Figure 1. Comparison of changes in the activities of sele- Figure 2. Comparison of changes in the activities of total nium glutathione peroxidases affected by selected plant glutathione peroxidases affected by selected plant ex- extracts in comparison to the activities of selenium gluta- tracts in comparison to the activities of total glutathione thione peroxidases without effect in heart mitochondria peroxidases without effect in heart mitochondria (A), - p p p < 0.001. p p p < 0.001. (A), kidney mitochondria (B), and plasma (C). Statistical kidney mitochondria (B), and plasma (C). Statistical sig significance at * < 0.05, ** < 0.01, *** nificance at * < 0.5, ** < 0.01, *** in Se-GPx activities was observed in heart mito- amount of ethnobotanical studies provide infor- chondria, especially at the highest concentrations - of stevia and ginseng (Figure 1A, 2A). The inten- sity of the effects of extracts of oregano, sage and mation about their healing effects. These benefi cial effects are achieved thanks to the essential to heart mitochondria (Table 1). It was shown [22].active In antioxidants, light of these such considerations, as flavonoids, we flavones,assessed thatginseng reduced on the GPx1 Se-GPx activity was insignificantly humans may different be an theisoflavones, effect of lignans,the extracts catechins, from Oreganoand isocatechins vulgare, Stevia rebaudiana, Eleutherococcus senticosus shown that, in patients with coronary heart dis- and Agrimonia eupatoria on selenium and total ease,important lower cardiacGPx1 is riskassociated factor, withsince an it increased has been glutathione peroxidase activities and thus affect- ing production/decomposition of peroxides and effects of peroxides in cardiac tissue include in- resulted physiological processes. The activities tracellularrisk of cardiovascular acidosis, electrochemical events [23]. dysfunction, Detrimental alteration in cardiac action potential, and con- heart mitochondria for all oregano concentra- tractile force inhibition [18,24]. Ardanaz et al. [4] tionsof selenium tested, butGPx the were total significantly GPx activity increased constituted in evidence of cardiac left ventricular hypertrophy using a GPx1-knockout mouse model, provided awww.ajrms.com significant decline. A less significant increase 5 Janka Vašková, Gabriela Mojžišová, Ladislav Vaško, Michal Stanko, Janka Poráčová and dysfunction in GPx1–/– mice in the absence of via 5-lipoxygenase deactivation by decreasing a change in vascular medial hypertrophy. Changes hydroperoxide levels [29]. None of the extracts were not associated with increases in collagen deposition and were independent of blood pres- mitochondria in terms of the ability to induce an sure levels. Several studies also pointed out that increaseused showed in Se-GPx a hint ofactivity, protective except effects for stevia on kidney at a an increase in GPx1 activity preserved cardiac . Total glutathi- cells during ischaemia and reperfusion [25]. Our −1 - - eredfinal concentrationsuggesting rather of 62.5 the μg.ml opposite, reductive um-dependent enzymes in heart mitochondria one peroxidase activities were significantly low inresults response showed to oregano a significant and increasea less-pronounced in seleni oregano was also found to generally cause a de- increase affected by highest concentrations of creasestress. Anin GPx interesting activities finding in the is liver that mitochondria an extract of - and clearly showed cytotoxic effects at concen- tective effect even when considering decreased [16]. activitiesstevia and of ginseng. total GPx Results in heart indicate mitochondria specific prothat −1 - trationsare the mainof 125 location and 62.5 for μg.ml the synthesis of selenium-containingProximal convoluted GPx3 tubulebefore cellsits secretion of the kidney into tection against H2O2. collectivelyThe addition reflect of oregano satisfactory caused antioxidant an overall pro decrease in selenium and glutathione peroxidases number of other cell types have been proposed - toplasma produce and GPx3 extracellular based on fluids the presence [21]. However, of mRNA a ), inwhich kidney caused mitochondria. a reduction With either the inexception the activity of ste−1 of [30]. Commenting on our results, there were no via extracts (at a concentration of 62.5 μg.ml or immunological identification of the protein was found among all the extracts for Se-GPx and response to oregano. That being said, ginseng, Se-GPx or the total GPx. A difference in efficiency) for to- steviasignificant and agrimony effects on expressed selenium almost or total the GPx same in tal GPx (Table 2). The functional importance−1 of decreasing effects on selenium in plasma or none two concentrations (125 and 62.5 μg.ml on the total GPx (Figure 1, 2). Several studies - suggest that the reduced activity of GPx selenium itySe-GPx and glomerular in the kidney injury. increased especially after - confirmingA functional the roleassociation of prostanoids between in GPx1glomerular activ vascular disease or for septic patient outcome [31,32].levels are Oregano predictive alone of increasedfailed to cause risk fora decrease cardio in plasma Se-GPx activities. All other extracts de- alterinjury glomerular was first suggestedhaemodynamics by studies and showingurinary creased Se-GPx in plasma while maintaining total proteinthat nonsteroidal excretion in anti-inflammatory various proteinuric drugs states can GPx activities. [26]. Under physiological conditions, prostaglan- dins and thromboxanes are abundantly produced Conclusion - tracts affect activities of selenium and total gluta- pressurein kidney, regulation especially [27]. PGE2. However, They in significantly free radi- thioneThe results peroxidases of our differently, work suggest depending that plant on the ex cal-catalysedcontribute to peroxidation renal fluid metabolism of arachidonic and bloodacid, organ and the concentrations used. For selenium-dependent isoforms, it is particularly evident are also produced. Hydroperoxy derivatives of in the heart mitochondria, and to a lesser extent arachidonicthe prostaglandin-like acid were found compounds to be comparable isoprostanes in their ability to serve as substrates for the peroxi- can generally be characterized as operating in the dase activities of GPx [28]. samein the directionkidney. The on effectselenium of ginseng and total and glutathione agrimony Thus can be seen a very important role, par- peroxidases. Effects on Se-GPx are different in - mitochondrial bodies, and are also different to pendent GPx1 protection against nephropathy plasma. In terms of the overall trend of total GPx, byticularly removal as confirmed of hydroperoxides, by studies, of8-isoprostane, selenium-de the extracts can be understood to have exhibited 4-hydroxynonenal [5]. In turn, the function of - GPx-4 is the regulation of hydroperoxide me- es of selenium glutathione peroxidase activities andsignificant their physiological antioxidant effects. functions, In terms some of extracts chang tabolism6 and control of leukotriene metabolism Am J Res Med Sci • 2018 • Vol 2 • Issue 1 Diversity of glutathione peroxidase efficiency can be understood to have shown an organ-spe- [11] - - cosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an Davydov M, Krikorian AD. Eleutherococcus senti cific ability to influence redox signalling path 72:345–93. [12] adaptogen: a close look. J Ethnopharmacol. 2000; effectsways. Specifically,of oregano on oregano the heart and mitochondria ginseng in and the medicines used in the traditional Chinese med- plasma,heart and they stevia have in clearly the kidney. shown Considering interesting and the icalLi WL, system Zheng for HC, therapy Bukuru of J, Dediabetes Kimpe mellitus. N. 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