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In Vitro Pro-Glycative Effects of Resveratrol and Caffeic Acid

In Vitro Pro-Glycative Effects of Resveratrol and Caffeic Acid Eur. Pharm. J. 2019, 66(2), 11-17. ISSN 1338-6786 (online) and ISSN 2453-6725 (print version), DOI: 10.2478/afpuc-2019-0004 EUROPEAN PHARMACEUTICAL JOURNAL In Vitro Pro-Glycative Eec ff ts of Resveratrol and Caffeic Acid Original research article/Review Kurin E. , Mučaji P., Nagy M. Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic Received 8 February, 2019, accepted 20 March, 2019 Abstract Resveratrol and caffeic acid belong to plant polyphenols and are known for their antioxidant effects. The aim of our research was to study their impact on Maillard reaction. This one occurs when the reducing saccharides react with amino groups of biomolecules including proteins, alter their protein conformation and transform to the variety of advanced glycation end products (AGEs). AGEs exhibit browning and generate fluorescence. There exist expectations that this oxidative protein glycosylation could be prevented by antioxidants. In this study, we incubated bovine serum albumin (BSA) with glucose for 7 days at 37°C and measured characteristic fluorescence and UV absorbance of the formed AGEs. Surprisingly, resveratrol and caffeic acid enhanced transformation of BSA to glycation products, which was confirmed either when cupric Cu(II) or ferric Fe(III) ions in nanomolar concentration were added to the system as pro-oxidant agent. Keywords Protein glycation – BSA – AGEs – caffeic acid – resveratrol INTRODUCTION Polyphenols belong to a large and heterogeneous group of (ROS). ROS are continuously produced during normal phytochemicals. They are present in food such as tea, coffee, physiological events; there should be a balance between wine, cereal grains, vegetables and fruits. The structural the generation and inactivation of ROS by the functional diversity of polyphenols extends from simple monophenolic antioxidant system in an organism. ROS are overproduced substances (e.g., p-hydroxycinnamic acid) to large polymeric under pathological conditions and the result is an oxidative macromolecules like proanthocyanidins and ellagitannins stress, which leads to different oxidative modifications (Hanhineva, 2010). Recently, polyphenolic compounds have of cellular membranes or intracellular molecules (Gülçin, shown their biological activities linking to human health 2006). However, the same polyphenols can act as pro- benefits, such as antioxidant, cardioprotective, anticancer, oxidant under certain experimental conditions, for example, antiinflammatory, antiaging and antimicrobial properties depending on the concentration, or source of free radicals (Xia et al., 2010, Pascual-Teresa et al., 2010, Kurin et al. (Alarcón De La Lastra & Villegas, 2007) and particularly in 2012a). Resveratrol possesses some of these effects. There the presence of transition metal ions such as iron or copper is growing evidence that resveratrol can prevent or delay (Bhat et al., 2007). Resveratrol can act as a pro-oxidant of the onset of cancer, heart disease, ischemic and chemically DNA through reduction of ADP-Fe(III) (Miura et al., 2000) and induced injuries, diabetes, pathological inflammation and also by switching to pro-oxidant in the presence of Cu(II) by viral infection (Baur & Sinclair, 2006, Kurin et al, 2013). Caffeic the ROS generation (Alarcón De La Lastra & Villegas, 2007, acid has been studied due to its antibacterial, antifungal, Hadi et al., 2010). Similar effects were observed for caffeic antiviral and antiproliferative properties (Matus, 2010). Both, acid as well (Bhat et al., 2007, Fan et al., 2009). Caffeic acid resveratrol and caffeic acid are known as antioxidant agents accelerated LDL oxidation rate in the propagation phase, (Wang et al., 1999, Kurin et al. 2012b). which means that it exerts pro-oxidant activities in free Well-known antioxidant effect of both molecules is radical chain reactions such as lipid peroxidation ( Yamanaka connected with the protection from reactive oxygen species et al., 1997). * E-mail: elena.kurin@uniba.sk © European Pharmaceutical Journal OR 11 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Oxidation of polyphenols produces O , H O and a complex UV absorbance measurement 2 2 2 mixture of semiquinones and quinones, which are potentially cytotoxic (Halliwell, 2008). Formation of pro-oxidant molecules Browning of the samples of different concentration were has been observed in model systems during the early phases recorded by their absorbance in 96-well Greiner UV-Star of Maillard browning (López-Galilea et al., 2006). Highly microplates (Greiner-Bio One GmbH, Germany) with Tecan reactive radicals are formed in the early stages of the Maillard Infinite M200 microplate reader (Tecan AG, Austria) at 420 reaction just prior to the Amadori rearrangement and their nm according to Morales & Jiménez-Pérez (2001). All the disappearance is accompanied by a gradual development measurements were done in quadruplicate. of browning (Nicoli, 1999). Reducing saccharides react with amino groups of biomolecules including proteins, lipids, Statistical analysis and nucleic acids during Maillard reaction to form Schiff bases. These ones in turn undergo a transformation to the All the data were expressed as mean ± SD. Differences between variety of AGEs (Fatima, 2008). Increasing protein glycation the groups were examined for statistical significance using and the gradual build-up of AGEs in body tissues caused by the Student’s t-test. A p-value less than 0.05 was considered hyperglycaemia play an important role in the pathogenesis as significant. of diabetic complications (Ahmed, 2005). In this study, we RESULTS AND DISCUSSION incubated bovine serum albumin (BSA) with glucose and measured characteristic fluorescence and UV/VIS absorbance of the created AGEs. Effects of resveratrol and caffeic acid It is now well recognized that the reaction of reducing were examined in this system with or without the presence of saccharides with proteins can cause marked alterations in cupric or ferric ions as known pro-oxidant agents. protein conformation. Several investigators have shown that reaction of saccharides and dialdehydes with protein can also MATERIAL AND METHODS lead to the formation of structures showing strong emission between 400 and 500 nm, when excited at a wavelength of Incubation of BSA with glucose 370 nm (Fatima et al., 2008, Plaza et al. 2010). This method is different from the fluorescence spectroscopy of BSA excited The reaction was carried out under the conditions as reported at 295 nm and emission collected between 260 and 400 nm, by Morimitsu et al. (1995) with some modifications. The where intrinsic fluorescence of albumin are observed (Dufour reaction mixture was made of 250 mg D-(+)-glucose (ACS & Dangles, 2005). reagent, Sigma-Aldrich, China) and 25 mg bovine serum Fig. 1 shows the fluorescence spectra of BSA solutions in the albumin (pH 7, ≥ 98%, Sigma-Aldrich, USA) in 2.5 ml sodium absence and presence of glucose in PBS at pH 7.2 and 370 nm phosphate buffer (PBS, 67 mM, pH 7.2) containing Na HPO excitation wavelength. We observed only a small increase in 2 4 × 12 H O and NaH PO × 2 H O (p.a., Centralchem, Slovakia). the BSA fluorescence intensity in the presence of glucose as 2 2 4 2 Mixture was incubated at 37°C for 7 days with or without compared to the untreated sample. the tested compound, diluted with distilled water in 2.5 ml. However, after 7 days of incubation with glucose, fluorescence Samples (100 µM): caffeic acid (CA, ≥ 98%, Sigma-Aldrich, intensity was measured at 370 nm excitation and 440 nm USA) and resveratrol (Re, ≥ 99%, Sigma-Aldrich, USA) were emission wavelengths. A significant increase of relative used with aminoguanidin (AG, ≥ 98%, Sigma-Aldrich, USA) fluorescence (BSA fluorescence = 7 399.75 ± 850.43 vs. BSA as a positive control. Cupric ions (CuSO × 5 H O, Lachema, fluorescence treated with glucose = 19 055.00 ± 1 135.85, p < 4 2 Czech Republic) or ferric ions (FeSO × 7 H O, Lachema, Czech 0.001) was observed. This can be caused by new fluorophore 4 2 Republic) (3.906 nM) were added to another tested group and formation (Fatima et al., 2008). Protein glycation initiated by were incubated in the same way. a nucleophilic addition reaction between a free amino group of a protein and a carbonyl group of a reducing saccharide Fluorescence measurement forms a reversible Schiff base. This reaction can occur over a period of hours, and once formed, the labile Schiff base The formation of fluorescent AGEs was assessed by rearranges to a more stable ketoamine or Amadori product. It characteristic fluorescence of the glycated BSA and was needs a period of days to be formed and then it is practically measured at 370 nm excitation wavelength and 440 nm irreversible. Glycated proteins can undergo further reactions emission one according Wu et al. (2009) using Tecan Infinite giving rise to AGEs. AGEs exhibit browning and generate M200 (Tecan AG, Austria) microplate reader and 96-well Nunc fluorescence. PP black (0.5 ml, round bottom) microplates. The value (%) of There exist expectations that whereas the protein glycation inhibition by different concentrations of the tested glycosylation is an oxidative reaction, antioxidants should be polyphenols was calculated as follows: [1 - (fluorescence of able to prevent this reaction. Study of Asgary describes an the test group/fluorescence of the control group)] ´ 100. All inhibition of haemoglobin glycation by quercetin, rutin and measurements were done in quadruplicate. kaempferol (Asgary et al., 1999). Urios measured inhibition 12 13 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 1. Fluorescence spectra of BSA solutions in the absence (—) and presence (‧‧‧‧‧) of glucose in PBS pH 7.2, without incubation, λ = 370 nm, λ = 440 nm. EXC EM Figure 2. Glycation inhibition (%) of 100 µM samples (AG – aminoguanidin, CA – caffeic acid, Re – resveratrol) after 7 days incubation with BSA and glucose at 37 °C, λ = 370 nm, λ = 440 nm. EXC EM effects of some monomeric and oligomeric flavonoids on described that Cu(II)-induced pro-oxidant activity of pentosidine formation in collagen incubated with glucose phenolics proceeds via intra- and inter-molecular electron (Urios et al., 2007). Morimitsu tested methanol extracts of 34 transfer reactions accompanying ROS formation, and types of spices for the inhibitory activity of the AGEs formation, a copper complexation followed by an oxidation of and even though most of these were inhibiting, some of them resveratrol analogues (e.g., 3,4-dihydroxystilbene) ended accelerated the formation of AGEs (i.e., mustard, tarragon, up with quinone production (Apak et al., 2007). As shown cinnamon, cardamom, cumin, coriander, celery) (Morimitsu in the Fig. 3, the combination of polyphenols with metals et al., 1995). leads to the concentration dependent formation of BSA Fig. 2 shows the results of 7 days of incubation of BSA with glycated/transformed products. Only the combination of glucose in the presence of resveratrol, caffeic acid and ferric ions with resveratrol results in a slight inhibition of aminoguanidine, respectively. Aminoguanidine, which acts the glycation. The increase in proglycative (= pro-oxidative) as a nucleophilic scavenger by blocking the first step in the activity of phenolics in the presence of Fe(III) or Cu(II) is glycation (Lunceford & Gugliucci, 2005), was used as a positive primarily associated with their ability to reduce metal ions. control. Surprisingly, resveratrol and caffeic acid enhanced Subsequently, Fe(III) and Cu(II) can be re-oxidized in Fenton- the transformation of BSA to glycation-like products in type reactions leading to the production of hydroxyl radical concentration dependent manner. and other ROS. The antioxidant/pro-oxidant activities of Many polyphenols (flavonoids, caffeic acid) possess the phenolics are determined by many factors: the concentration ability to reduce transition metal ions, and consequently, and nature of transition metal ion(s) and the concentration to act as pro-oxidants (Simić et al., 2007). It was also and pH of phenolics (Apak et al., 2007). 12 13 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 3. Glycation inhibition (%) of polyphenols at 100 µM (CA – caffeic acid, Re – resveratrol) with metal catalyst Cu(II) or Fe(III) (3.906 nM) after 7 days incubation with BSA and glucose at 37 °C, λ = 370 nm, λ = 440 nm. EXC EM The Maillard reaction produces a variety of intermediate in browning. Thus, we can postulate that the presence of products and the final brown pigments (Lertittikul et al., brown pigments are the Maillard reaction products in the 2007). Intensity of brown colour is often used as an indicator reaction mixtures. of the extent of the reaction. It symbolizes an advanced stage Results of fluorescence and absorbance measurements of the Maillard reaction (Plaza et al., 2010). Because of the indicated that the Maillard reaction had progressed to variety and the complexity of Maillard reaction products, it advanced stages in the amino acid–glucose reaction. is usually admitted to classify them into early (or precursors), However, coloured and fluorescent compounds need not advanced and final products. Following this classification, the be identical and fluorogens may be precursors of brown intensity of non-enzymatic browning was generally based on pigments showing a shorter induction period (Morales & the changes in absorbance at 294–297 nm, 320–350 nm and Jiménez-Pérez, 2001). 420–450 nm, respectively. In our work, using fluorescence measurement of AGEs, we Cu(II) or Fe(III) ions were used as a catalyst for pro-oxidant observed that resveratrol and caffeic acid incubated with action of the polyphenols in the presence of protein and glucose and BSA accelerated formation of AGEs after 7 days glucose. As Fig. 4 shows, we observed an absorbance increase at 37°C. The nanomolar presence of Cu(II) confirmed the pro- of samples of BSA + glucose and resveratrol (100 μM) or glycative effects of resveratrol and caffeic acid. Presence of caffeic acid (100 μM) when incubated with ferric ions. Only Fe(III) with caffeic acid increased the formation of AGEs, but caffeic acid with cupric ions did not show any impressive there was observed slight inhibition of the glycation with changes in the in vitro glycation model. An increased resveratrol. The observed pro-glycative effects of polyphenols absorbance in the 340–360 nm regions should correspond can be based on the pro-oxidant activity of these. Resveratrol to the formation of heterocyclic derivatives and intermediate undergoes oxidation in the presence of Cu(II). The oxidative water-soluble compounds (reductones, amino-reductones or product of resveratrol is a dimer, which might be formed pre-melanoidins). Conversely, absorbance values at 420 nm by dimerization of resveratrol phenoxyl radical as a result of should correspond to the formation of brown pigments or the reductive activation of molecular oxygen (Alarcón De La melanoidins (Billaud et al., 2004). Lastra & Villegas, 2007). Caffeic acid could dissociate to form The absorbance increase at 420 nm is used as an indicator for a phenoxide, which chelates Cu(II) ions as bidentate ligand the browning development in the final stage of the browning and undergoes intramolecular electron transfer to form an reaction. As Fig. 5 and Fig. 6 show, we observed an absorbance o-hydroxyphenoxyl radical (semiquinone radical). The radical increase in the reaction mixture of BSA depending on the intermediate was also proven by the formation of the caffeic concentration of polyphenols and the presence of metals acid dimer (furofuran bislacton) in the presence of Cu(II) ions after 7 days of incubation. Fluorescent compounds – AGEs – (Fan et al., 2009). Pro-oxidant action of plant polyphenols may are also possible precursors of brown pigments. The higher be an important mechanism of their anti-cancer or apoptosis- concentration of saccharide used, the higher the increase in inducing properties (Hadi et al., 2010), and therefore, browning was found (Billaud et al., 2005). We observed, at a our results can be useful for the next research of their stable concentration of glucose and varying concentration of exact mechanism of action. However, in multicomponent polyphenols, a higher content of resveratrol or caffeic acid in mixtures, the risk of the pro-oxidative and pro-glycative the presence of pro-oxidant metal ions led to a higher increase effect is present, when phenolics are combined with even 14 15 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 4. Absorbance of polyphenols (CA – caffeic acid, 100 μM, Re – resveratrol, 100 μM) with metal catalyst Cu(II) or Fe(III), always 3.906 nM, after 7 days incubation with BSA and glucose at 37 °C. Figure 5. Absorbance of resveratrol (100 µM ) at 420 nm with metal catalyst Cu(II) or Fe(III), always 3.906 nM, without or after 7 days incubation with BSA and glucose at 37 °C. *p < 0.05 (error bars = mean ± SD). Figure 6. Absorbance of caffeic acid (100 µM ) at 420 nm with metal catalyst Cu(II) or Fe(III), always 3.906 nM, without or after 7 days incubation with BSA and glucose at 37 °C. *p < 0.05 (error bars = mean ± SD). 14 15 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. nanomolar concentration of transition metal ions. This should the formation of AGEs. We confirmed this by fluorescence be considered when multimineral food supplements with measurements of AGEs, which act as a fluorophore, and natural substances are made. by specific absorbance increase following the browning development. Whereas glycation can negatively alter protein CONCLUSION activity, folding or degradation, it is important to research the conditions, which leads to the pathological formation of In conclusion, resveratrol and caffeic acid are well known AGEs. antioxidants. However, in certain conditions, they can act as ACKNOWLEDGMENTS pro-oxidants and trigger pro-glycative action in the presence of glucose and amino acid. We found out that resveratrol and caffeic acid alone, as well as in the nanomolar presence of This work was supported by the Slovak Ministry of Education Cu(II) or Fe(III) ions, when incubated with glucose and BSA grant number VEGA 1/029/16, VEGA 1/0359/18 and ITMS after 7 days, can initiate Maillard reaction and accelerate 26240120023 project. 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Biological activities of polyphenols from grapes. Int J Mol Sci. 2010;11: 622–646. [35] Yamanaka N, Oda O, Nagao S. Prooxidant activity of caffeic acid, dietary non-flavonoid phenolic acid, on Cu2+-induced low density lipoprotein oxidation. FEBS Lett. 1997;405:186–190. 16 17 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

In Vitro Pro-Glycative Effects of Resveratrol and Caffeic Acid

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Eur. Pharm. J. 2019, 66(2), 11-17. ISSN 1338-6786 (online) and ISSN 2453-6725 (print version), DOI: 10.2478/afpuc-2019-0004 EUROPEAN PHARMACEUTICAL JOURNAL In Vitro Pro-Glycative Eec ff ts of Resveratrol and Caffeic Acid Original research article/Review Kurin E. , Mučaji P., Nagy M. Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovak Republic Received 8 February, 2019, accepted 20 March, 2019 Abstract Resveratrol and caffeic acid belong to plant polyphenols and are known for their antioxidant effects. The aim of our research was to study their impact on Maillard reaction. This one occurs when the reducing saccharides react with amino groups of biomolecules including proteins, alter their protein conformation and transform to the variety of advanced glycation end products (AGEs). AGEs exhibit browning and generate fluorescence. There exist expectations that this oxidative protein glycosylation could be prevented by antioxidants. In this study, we incubated bovine serum albumin (BSA) with glucose for 7 days at 37°C and measured characteristic fluorescence and UV absorbance of the formed AGEs. Surprisingly, resveratrol and caffeic acid enhanced transformation of BSA to glycation products, which was confirmed either when cupric Cu(II) or ferric Fe(III) ions in nanomolar concentration were added to the system as pro-oxidant agent. Keywords Protein glycation – BSA – AGEs – caffeic acid – resveratrol INTRODUCTION Polyphenols belong to a large and heterogeneous group of (ROS). ROS are continuously produced during normal phytochemicals. They are present in food such as tea, coffee, physiological events; there should be a balance between wine, cereal grains, vegetables and fruits. The structural the generation and inactivation of ROS by the functional diversity of polyphenols extends from simple monophenolic antioxidant system in an organism. ROS are overproduced substances (e.g., p-hydroxycinnamic acid) to large polymeric under pathological conditions and the result is an oxidative macromolecules like proanthocyanidins and ellagitannins stress, which leads to different oxidative modifications (Hanhineva, 2010). Recently, polyphenolic compounds have of cellular membranes or intracellular molecules (Gülçin, shown their biological activities linking to human health 2006). However, the same polyphenols can act as pro- benefits, such as antioxidant, cardioprotective, anticancer, oxidant under certain experimental conditions, for example, antiinflammatory, antiaging and antimicrobial properties depending on the concentration, or source of free radicals (Xia et al., 2010, Pascual-Teresa et al., 2010, Kurin et al. (Alarcón De La Lastra & Villegas, 2007) and particularly in 2012a). Resveratrol possesses some of these effects. There the presence of transition metal ions such as iron or copper is growing evidence that resveratrol can prevent or delay (Bhat et al., 2007). Resveratrol can act as a pro-oxidant of the onset of cancer, heart disease, ischemic and chemically DNA through reduction of ADP-Fe(III) (Miura et al., 2000) and induced injuries, diabetes, pathological inflammation and also by switching to pro-oxidant in the presence of Cu(II) by viral infection (Baur & Sinclair, 2006, Kurin et al, 2013). Caffeic the ROS generation (Alarcón De La Lastra & Villegas, 2007, acid has been studied due to its antibacterial, antifungal, Hadi et al., 2010). Similar effects were observed for caffeic antiviral and antiproliferative properties (Matus, 2010). Both, acid as well (Bhat et al., 2007, Fan et al., 2009). Caffeic acid resveratrol and caffeic acid are known as antioxidant agents accelerated LDL oxidation rate in the propagation phase, (Wang et al., 1999, Kurin et al. 2012b). which means that it exerts pro-oxidant activities in free Well-known antioxidant effect of both molecules is radical chain reactions such as lipid peroxidation ( Yamanaka connected with the protection from reactive oxygen species et al., 1997). * E-mail: elena.kurin@uniba.sk © European Pharmaceutical Journal OR 11 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Oxidation of polyphenols produces O , H O and a complex UV absorbance measurement 2 2 2 mixture of semiquinones and quinones, which are potentially cytotoxic (Halliwell, 2008). Formation of pro-oxidant molecules Browning of the samples of different concentration were has been observed in model systems during the early phases recorded by their absorbance in 96-well Greiner UV-Star of Maillard browning (López-Galilea et al., 2006). Highly microplates (Greiner-Bio One GmbH, Germany) with Tecan reactive radicals are formed in the early stages of the Maillard Infinite M200 microplate reader (Tecan AG, Austria) at 420 reaction just prior to the Amadori rearrangement and their nm according to Morales & Jiménez-Pérez (2001). All the disappearance is accompanied by a gradual development measurements were done in quadruplicate. of browning (Nicoli, 1999). Reducing saccharides react with amino groups of biomolecules including proteins, lipids, Statistical analysis and nucleic acids during Maillard reaction to form Schiff bases. These ones in turn undergo a transformation to the All the data were expressed as mean ± SD. Differences between variety of AGEs (Fatima, 2008). Increasing protein glycation the groups were examined for statistical significance using and the gradual build-up of AGEs in body tissues caused by the Student’s t-test. A p-value less than 0.05 was considered hyperglycaemia play an important role in the pathogenesis as significant. of diabetic complications (Ahmed, 2005). In this study, we RESULTS AND DISCUSSION incubated bovine serum albumin (BSA) with glucose and measured characteristic fluorescence and UV/VIS absorbance of the created AGEs. Effects of resveratrol and caffeic acid It is now well recognized that the reaction of reducing were examined in this system with or without the presence of saccharides with proteins can cause marked alterations in cupric or ferric ions as known pro-oxidant agents. protein conformation. Several investigators have shown that reaction of saccharides and dialdehydes with protein can also MATERIAL AND METHODS lead to the formation of structures showing strong emission between 400 and 500 nm, when excited at a wavelength of Incubation of BSA with glucose 370 nm (Fatima et al., 2008, Plaza et al. 2010). This method is different from the fluorescence spectroscopy of BSA excited The reaction was carried out under the conditions as reported at 295 nm and emission collected between 260 and 400 nm, by Morimitsu et al. (1995) with some modifications. The where intrinsic fluorescence of albumin are observed (Dufour reaction mixture was made of 250 mg D-(+)-glucose (ACS & Dangles, 2005). reagent, Sigma-Aldrich, China) and 25 mg bovine serum Fig. 1 shows the fluorescence spectra of BSA solutions in the albumin (pH 7, ≥ 98%, Sigma-Aldrich, USA) in 2.5 ml sodium absence and presence of glucose in PBS at pH 7.2 and 370 nm phosphate buffer (PBS, 67 mM, pH 7.2) containing Na HPO excitation wavelength. We observed only a small increase in 2 4 × 12 H O and NaH PO × 2 H O (p.a., Centralchem, Slovakia). the BSA fluorescence intensity in the presence of glucose as 2 2 4 2 Mixture was incubated at 37°C for 7 days with or without compared to the untreated sample. the tested compound, diluted with distilled water in 2.5 ml. However, after 7 days of incubation with glucose, fluorescence Samples (100 µM): caffeic acid (CA, ≥ 98%, Sigma-Aldrich, intensity was measured at 370 nm excitation and 440 nm USA) and resveratrol (Re, ≥ 99%, Sigma-Aldrich, USA) were emission wavelengths. A significant increase of relative used with aminoguanidin (AG, ≥ 98%, Sigma-Aldrich, USA) fluorescence (BSA fluorescence = 7 399.75 ± 850.43 vs. BSA as a positive control. Cupric ions (CuSO × 5 H O, Lachema, fluorescence treated with glucose = 19 055.00 ± 1 135.85, p < 4 2 Czech Republic) or ferric ions (FeSO × 7 H O, Lachema, Czech 0.001) was observed. This can be caused by new fluorophore 4 2 Republic) (3.906 nM) were added to another tested group and formation (Fatima et al., 2008). Protein glycation initiated by were incubated in the same way. a nucleophilic addition reaction between a free amino group of a protein and a carbonyl group of a reducing saccharide Fluorescence measurement forms a reversible Schiff base. This reaction can occur over a period of hours, and once formed, the labile Schiff base The formation of fluorescent AGEs was assessed by rearranges to a more stable ketoamine or Amadori product. It characteristic fluorescence of the glycated BSA and was needs a period of days to be formed and then it is practically measured at 370 nm excitation wavelength and 440 nm irreversible. Glycated proteins can undergo further reactions emission one according Wu et al. (2009) using Tecan Infinite giving rise to AGEs. AGEs exhibit browning and generate M200 (Tecan AG, Austria) microplate reader and 96-well Nunc fluorescence. PP black (0.5 ml, round bottom) microplates. The value (%) of There exist expectations that whereas the protein glycation inhibition by different concentrations of the tested glycosylation is an oxidative reaction, antioxidants should be polyphenols was calculated as follows: [1 - (fluorescence of able to prevent this reaction. Study of Asgary describes an the test group/fluorescence of the control group)] ´ 100. All inhibition of haemoglobin glycation by quercetin, rutin and measurements were done in quadruplicate. kaempferol (Asgary et al., 1999). Urios measured inhibition 12 13 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 1. Fluorescence spectra of BSA solutions in the absence (—) and presence (‧‧‧‧‧) of glucose in PBS pH 7.2, without incubation, λ = 370 nm, λ = 440 nm. EXC EM Figure 2. Glycation inhibition (%) of 100 µM samples (AG – aminoguanidin, CA – caffeic acid, Re – resveratrol) after 7 days incubation with BSA and glucose at 37 °C, λ = 370 nm, λ = 440 nm. EXC EM effects of some monomeric and oligomeric flavonoids on described that Cu(II)-induced pro-oxidant activity of pentosidine formation in collagen incubated with glucose phenolics proceeds via intra- and inter-molecular electron (Urios et al., 2007). Morimitsu tested methanol extracts of 34 transfer reactions accompanying ROS formation, and types of spices for the inhibitory activity of the AGEs formation, a copper complexation followed by an oxidation of and even though most of these were inhibiting, some of them resveratrol analogues (e.g., 3,4-dihydroxystilbene) ended accelerated the formation of AGEs (i.e., mustard, tarragon, up with quinone production (Apak et al., 2007). As shown cinnamon, cardamom, cumin, coriander, celery) (Morimitsu in the Fig. 3, the combination of polyphenols with metals et al., 1995). leads to the concentration dependent formation of BSA Fig. 2 shows the results of 7 days of incubation of BSA with glycated/transformed products. Only the combination of glucose in the presence of resveratrol, caffeic acid and ferric ions with resveratrol results in a slight inhibition of aminoguanidine, respectively. Aminoguanidine, which acts the glycation. The increase in proglycative (= pro-oxidative) as a nucleophilic scavenger by blocking the first step in the activity of phenolics in the presence of Fe(III) or Cu(II) is glycation (Lunceford & Gugliucci, 2005), was used as a positive primarily associated with their ability to reduce metal ions. control. Surprisingly, resveratrol and caffeic acid enhanced Subsequently, Fe(III) and Cu(II) can be re-oxidized in Fenton- the transformation of BSA to glycation-like products in type reactions leading to the production of hydroxyl radical concentration dependent manner. and other ROS. The antioxidant/pro-oxidant activities of Many polyphenols (flavonoids, caffeic acid) possess the phenolics are determined by many factors: the concentration ability to reduce transition metal ions, and consequently, and nature of transition metal ion(s) and the concentration to act as pro-oxidants (Simić et al., 2007). It was also and pH of phenolics (Apak et al., 2007). 12 13 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 3. Glycation inhibition (%) of polyphenols at 100 µM (CA – caffeic acid, Re – resveratrol) with metal catalyst Cu(II) or Fe(III) (3.906 nM) after 7 days incubation with BSA and glucose at 37 °C, λ = 370 nm, λ = 440 nm. EXC EM The Maillard reaction produces a variety of intermediate in browning. Thus, we can postulate that the presence of products and the final brown pigments (Lertittikul et al., brown pigments are the Maillard reaction products in the 2007). Intensity of brown colour is often used as an indicator reaction mixtures. of the extent of the reaction. It symbolizes an advanced stage Results of fluorescence and absorbance measurements of the Maillard reaction (Plaza et al., 2010). Because of the indicated that the Maillard reaction had progressed to variety and the complexity of Maillard reaction products, it advanced stages in the amino acid–glucose reaction. is usually admitted to classify them into early (or precursors), However, coloured and fluorescent compounds need not advanced and final products. Following this classification, the be identical and fluorogens may be precursors of brown intensity of non-enzymatic browning was generally based on pigments showing a shorter induction period (Morales & the changes in absorbance at 294–297 nm, 320–350 nm and Jiménez-Pérez, 2001). 420–450 nm, respectively. In our work, using fluorescence measurement of AGEs, we Cu(II) or Fe(III) ions were used as a catalyst for pro-oxidant observed that resveratrol and caffeic acid incubated with action of the polyphenols in the presence of protein and glucose and BSA accelerated formation of AGEs after 7 days glucose. As Fig. 4 shows, we observed an absorbance increase at 37°C. The nanomolar presence of Cu(II) confirmed the pro- of samples of BSA + glucose and resveratrol (100 μM) or glycative effects of resveratrol and caffeic acid. Presence of caffeic acid (100 μM) when incubated with ferric ions. Only Fe(III) with caffeic acid increased the formation of AGEs, but caffeic acid with cupric ions did not show any impressive there was observed slight inhibition of the glycation with changes in the in vitro glycation model. An increased resveratrol. The observed pro-glycative effects of polyphenols absorbance in the 340–360 nm regions should correspond can be based on the pro-oxidant activity of these. Resveratrol to the formation of heterocyclic derivatives and intermediate undergoes oxidation in the presence of Cu(II). The oxidative water-soluble compounds (reductones, amino-reductones or product of resveratrol is a dimer, which might be formed pre-melanoidins). Conversely, absorbance values at 420 nm by dimerization of resveratrol phenoxyl radical as a result of should correspond to the formation of brown pigments or the reductive activation of molecular oxygen (Alarcón De La melanoidins (Billaud et al., 2004). Lastra & Villegas, 2007). Caffeic acid could dissociate to form The absorbance increase at 420 nm is used as an indicator for a phenoxide, which chelates Cu(II) ions as bidentate ligand the browning development in the final stage of the browning and undergoes intramolecular electron transfer to form an reaction. As Fig. 5 and Fig. 6 show, we observed an absorbance o-hydroxyphenoxyl radical (semiquinone radical). The radical increase in the reaction mixture of BSA depending on the intermediate was also proven by the formation of the caffeic concentration of polyphenols and the presence of metals acid dimer (furofuran bislacton) in the presence of Cu(II) ions after 7 days of incubation. Fluorescent compounds – AGEs – (Fan et al., 2009). Pro-oxidant action of plant polyphenols may are also possible precursors of brown pigments. The higher be an important mechanism of their anti-cancer or apoptosis- concentration of saccharide used, the higher the increase in inducing properties (Hadi et al., 2010), and therefore, browning was found (Billaud et al., 2005). We observed, at a our results can be useful for the next research of their stable concentration of glucose and varying concentration of exact mechanism of action. However, in multicomponent polyphenols, a higher content of resveratrol or caffeic acid in mixtures, the risk of the pro-oxidative and pro-glycative the presence of pro-oxidant metal ions led to a higher increase effect is present, when phenolics are combined with even 14 15 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. Figure 4. Absorbance of polyphenols (CA – caffeic acid, 100 μM, Re – resveratrol, 100 μM) with metal catalyst Cu(II) or Fe(III), always 3.906 nM, after 7 days incubation with BSA and glucose at 37 °C. Figure 5. Absorbance of resveratrol (100 µM ) at 420 nm with metal catalyst Cu(II) or Fe(III), always 3.906 nM, without or after 7 days incubation with BSA and glucose at 37 °C. *p < 0.05 (error bars = mean ± SD). Figure 6. Absorbance of caffeic acid (100 µM ) at 420 nm with metal catalyst Cu(II) or Fe(III), always 3.906 nM, without or after 7 days incubation with BSA and glucose at 37 °C. *p < 0.05 (error bars = mean ± SD). 14 15 Eur. Pharm. J. 2019, 66(2), 11-17 In Vitro Pro-Glycative Eects of R ff esveratrol and Caeic Acid ff Kurin E., Mučaji P., Nagy M. nanomolar concentration of transition metal ions. This should the formation of AGEs. We confirmed this by fluorescence be considered when multimineral food supplements with measurements of AGEs, which act as a fluorophore, and natural substances are made. by specific absorbance increase following the browning development. Whereas glycation can negatively alter protein CONCLUSION activity, folding or degradation, it is important to research the conditions, which leads to the pathological formation of In conclusion, resveratrol and caffeic acid are well known AGEs. antioxidants. However, in certain conditions, they can act as ACKNOWLEDGMENTS pro-oxidants and trigger pro-glycative action in the presence of glucose and amino acid. We found out that resveratrol and caffeic acid alone, as well as in the nanomolar presence of This work was supported by the Slovak Ministry of Education Cu(II) or Fe(III) ions, when incubated with glucose and BSA grant number VEGA 1/029/16, VEGA 1/0359/18 and ITMS after 7 days, can initiate Maillard reaction and accelerate 26240120023 project. 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Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Nov 1, 2019

Keywords: Protein glycation; BSA; AGEs; caffeic acid; resveratrol

References