Natural polyphenols convert proteins into histone-binding ligands

Abstract

Antioxidants are sensitive to oxidation and are immediately converted into their oxidized forms that can react with proteins. We have recently found that proteins incubated with oxidized vitamin C (dehydroascorbate) gain a new function as a histone-binding ligand. This finding led us to predict that antioxidants, through conversion to their oxidized forms, may generally have similar functions. In the present study, we identified several natural polyphenols as a source of histone ligands and characterized the mechanism for the interaction of protein-bound polyphenols with histone. Through screening of 25 plant-derived polyphenols by assessing their ability to convert bovine serum albumin into histone ligands, we identified seven polyphenols, including (-)-epigallocatechin-3-O-gallate (EGCG). Additionally, we found that the histone tail domain, which is a highly charged and conformationally flexible region, is involved in the interaction with the polyphenol-modified proteins. Further mechanistic studies showed the involvement of a complex heterogeneous group of the polyphenol-derived compounds bound to proteins as histone-binding elements. We also determined that the interaction of polyphenol-modified proteins with histones formed aggregates and exerted a protective effect against histone-mediated cytotoxicity toward endothelial cells. These findings demonstrated that histones are one of the major targets of polyphenol-modified proteins and provide important insights into the chemoprotective functions of dietary polyphenols. Antioxidants are sensitive to oxidation and are immediately converted into their oxidized forms that can react with proteins. We have recently found that proteins incubated with oxidized vitamin C (dehydroascorbate) gain a new function as a histone-binding ligand. This finding led us to predict that antioxidants, through conversion to their oxidized forms, may generally have similar functions. In the present study, we identified several natural polyphenols as a source of histone ligands and characterized the mechanism for the interaction of protein-bound polyphenols with histone. Through screening of 25 plant-derived polyphenols by assessing their ability to convert bovine serum albumin into histone ligands, we identified seven polyphenols, including (-)-epigallocatechin-3-O-gallate (EGCG). Additionally, we found that the histone tail domain, which is a highly charged and conformationally flexible region, is involved in the interaction with the polyphenol-modified proteins. Further mechanistic studies showed the involvement of a complex heterogeneous group of the polyphenol-derived compounds bound to proteins as histone-binding elements. We also determined that the interaction of polyphenol-modified proteins with histones formed aggregates and exerted a protective effect against histone-mediated cytotoxicity toward endothelial cells. These findings demonstrated that histones are one of the major targets of polyphenol-modified proteins and provide important insights into the chemoprotective functions of dietary polyphenols. Dietary polyphenols link extracellular histones and nonhistone proteinsJournal of Biological ChemistryVol. 298Issue 12PreviewNumerous studies have demonstrated antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardio-protective activities of dietary polyphenols, but due to diverse structures and subclasses of polyphenols, little is known about their mechanisms of action. The study by Yamaguchi et al. published in JBC provides mechanistic insights into how dietary polyphenols confer histone-binding ability on certain proteins and motivates the research community to further explore health benefits of polyphenols. Full-Text PDF Open Access Polyphenols, the most diverse group of phytochemicals, have attracted a great deal of attention as potential chemopreventive agents for chronic diseases, such as heart disease, cancer, diabetes, stroke, and arteriosclerosis. Polyphenols are generally considered antioxidants. However, because they are susceptible to oxidation, they are easily converted into their oxidized form. Interestingly, some polyphenols, when oxidized, acquire a new function of reactivity with proteins (Fig. 1). For example, green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) is converted to its oxidized form, which covalently binds to lysine residues to form Schiff base intermediates, followed by the lysine deamination product, α-aminoadipic-5-semialdehyde (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar). The existence of a unique 6-membered ring 2-piperidinol product as an equilibrium form of α-aminoadipic-5-semialdehyde has recently been established (2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Piceatannol, a naturally occurring hydroxylation analog of the red wine polyphenol resveratrol, mediates protein polymerization through the formation of a lysine-derived crosslink, dehydrolysinonorleucine (3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google Scholar). Some of the oxidized polyphenols have also been shown to form covalent adducts with proteins via Michael addition (4Ishii T. Mori T. Tanaka T. Mizuno D. Yamaji R. Kumazawa S. et al.Covalent modification of proteins by green tea polyphenol (–)-epigallocatechin-3-gallate through autoxidation.Free Radic. Biol. Med. 2008; 45: 1384-1394Crossref PubMed Scopus (209) Google Scholar, 5Gerszon J. Serafin E. Buczkowski A. Michlewska S. Bielnicki J.A. Rodacka A. Functional consequences of piceatannol binding to glyceraldehyde-3-phosphate dehydrogenase.PLoS One. 2018; 13: e0190656Crossref PubMed Scopus (11) Google Scholar, 6Ku M.C. Fang C.M. Cheng J.T. Liang H.C. Wang T.F. Wu C.H. et al.Site-specific covalent modifications of human insulin by catechol estrogens: reactivity and induced structural and functional changes.Sci. Rep. 2016; 6: 28804Crossref PubMed Scopus (18) Google Scholar). Intriguingly, polyphenol-modified proteins have been shown to acquire new functions, including oxidation-specific epitope activity against natural antibodies (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar, 2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google Scholar). Based on has been that of the of polyphenols may due in to modification of proteins by the polyphenols. are the major protein of and as which and a in are also on the of such as and and as to the T. R. Identification of histone as a 45: PubMed Scopus Google Scholar, R. T. as a important on PubMed Scopus Google Scholar). In they are present in the extracellular from and cells. These extracellular histones as of extracellular and to by Y. et extracellular PubMed Scopus Google Scholar). the the extracellular histones are known to involved in the of due to and chronic J. R. M. F. et histones are major of in Med. PubMed Scopus Google Scholar, K. M. M. Y. A. K. et extracellular formation by is a of Med. 2018; PubMed Scopus Google Scholar, K. et histone chronic by PubMed Scopus Google Scholar). In extracellular histone has been shown to of and of K. et histone chronic by PubMed Scopus Google Scholar). study found that proteins with oxidized vitamin C function as histone ligands M. Yamaguchi K. Kitazawa R. Lim S.-Y. Y. J. et functions as a for 13: PubMed Scopus (5) Google Scholar). In proteins the binding of to the histone and the of to the of The of histones as for the proteins in addition to the of proteins as that they may also involved in the via binding to The findings led to an that by conversion to the oxidized form may generally have similar functions. This study the research into the of functions and that polyphenols can also a source of histone-binding provides about the mechanism of interaction polyphenol-modified proteins and the binding of polyphenol-modified proteins to we albumins serum and human serum and as proteins in incubated with polyphenols structures in in and the binding potential to histone by a binding The screening of 25 polyphenols by assessing their ability to convert to ligands identified seven polyphenols, including and (Fig. We the binding of the proteins toward major of histone proteins and in The binding that the bound to the histones for (Fig. These that some of the polyphenols in dietary and convert serum proteins into the histone-binding The that the proteins bound to histone proteins of their (Fig. that structural of the histones to the interaction with the proteins. can into the with a and the tail with a highly charged and conformationally flexible also the a binding in the we protein (Fig. in binding that the tail of histone but the a binding of the polyphenol-modified proteins (Fig. The binding activity of the by that lysine residues in the tail involved in the binding to the proteins. In the proteins showed the ability to to the and the but (Fig. These that the proteins to the of the histones but to the of the charged gain into we with (Fig. and their interaction with the proteins. The showed that the proteins binding for the charged such as and (Fig. Interestingly, a binding for the such as which have a of charged but In the proteins to (Fig. which are charged but the These that the charged but also the are important in the binding of the proteins to histone is known to react with lysine residues to form such as (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar). gain structural insights into the oxidized form of the lysine residues that to the interaction with we a lysine (Fig. to the histone-binding activity of the polyphenol-modified lysine shown in the 25 plant-derived polyphenols, several polyphenols showed the ability to convert the lysine analog into histone Based on study on the of the oxidized the of a unique ring 2-piperidinol with a product (Fig. (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar, 2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google we a of and its histone-binding shown in the oxidized showed a histone-binding the which is in equilibrium the and intermediates, may involved in the interaction of the polyphenol-modified proteins with the on the of the product as a histone that the binding of the oxidized product to histone due to the formation of Schiff base the aldehyde and histone lysine incubated with the oxidized by with and the proteins by of the with a for that the oxidized lysine analog form with the histone (Fig. However, the of and with (Fig. We also to as a form of a lysine-derived crosslink, in the of the and histone However, the in the (Fig. These that may involved in the binding to histones through the Schiff base studies have shown that polyphenols form covalent adducts with proteins (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar, T. Mori T. Tanaka T. Mizuno D. Yamaji R. Kumazawa S. et al.Covalent modification of proteins by green tea polyphenol (–)-epigallocatechin-3-gallate through autoxidation.Free Radic. Biol. Med. 2008; 45: 1384-1394Crossref PubMed Scopus (209) Google Scholar, 5Gerszon J. Serafin E. Buczkowski A. Michlewska S. Bielnicki J.A. Rodacka A. Functional consequences of piceatannol binding to glyceraldehyde-3-phosphate dehydrogenase.PLoS One. 2018; 13: e0190656Crossref PubMed Scopus (11) Google Scholar, 6Ku M.C. Fang C.M. Cheng J.T. Liang H.C. Wang T.F. Wu C.H. et al.Site-specific covalent modifications of human insulin by catechol estrogens: reactivity and induced structural and functional changes.Sci. Rep. 2016; 6: 28804Crossref PubMed Scopus (18) Google Scholar). we that polyphenols bound to proteins also to the histone we in the of shown in the of from about to about the addition of of The of in the from to to with the of and (Fig. This of is similar to the and of polyphenols in Y. T. Wang Y. R. et (EGCG) the activities of Chem. 2016; PubMed Scopus Google Scholar). is to can that polyphenols with may covalently to proteins and to the of the a of of compounds (Fig. showed that an into the protein by (Fig. the of into the protein with the of the histone-binding activity of the (Fig. These that protein-bound may involved in the binding of the proteins with histone. gain into the protein-bound polyphenols the histone-binding we characterized the modification of and their histone-binding shown in with and immediately several of Further in the of a with the of to the histone-binding The also with to a heterogeneous the histone-binding potential (Fig. These that a group of complex heterogeneous compounds formed by the of with may involved in the interaction with histone. the is known to and in an to form heterogeneous S. The and of tea PubMed Scopus Google Scholar). In of an similar to the and that binding to with histone. we several polyphenols with (Fig. as for the binding of the polyphenol-modified proteins to histone. shown in a followed by and showed a the and polyphenols The effect of polyphenols on the histone-binding activity of polyphenol-modified proteins to with their polyphenols several the protein-bound polyphenols may with in the histone tail through a interaction (Fig. have been shown to form aggregates with serum and and of histones and for PubMed Scopus Google Scholar, of and by histone Full Text PDF PubMed Scopus Google Scholar, K. M. R. R. K. T. et effect of the against histone-mediated endothelial cytotoxicity in PubMed Scopus Google Scholar). we histones form aggregates with protein-bound polyphenols. the histones incubated with into and by and by shown in several polyphenols demonstrated the ability to convert into that form aggregates with The screening of polyphenols identified polyphenols, including and (Fig. as of the are the as identified as of histone ligands (Fig. and formed aggregates with polyphenol-modified proteins (Fig. the mechanisms of we the of the formation of the incubated with and the and by The aggregates the proteins of to for and piceatannol (Fig. In when the of the polyphenol-modified proteins the histones from the similar has been shown to in the complex formation complex formation T. K. complex for of protein J. Biol. 2017; PubMed Scopus (26) Google Scholar). the of histone and polyphenol-modified proteins may by (Fig. histones and cytotoxicity due to charged residues in the tail K. et histone chronic by PubMed Scopus Google Scholar). histone cytotoxicity in of through agents for the histones histone to the polyphenol-modified proteins also to the histone we that they the histone cytotoxicity through binding to the showed a cytotoxicity to the endothelial which by polyphenol-modified proteins in a (Fig. the proteins but also polyphenol-modified proteins the histone-binding ability the histone cytotoxicity (Fig. The protein-bound polyphenols showed a effect on the cytotoxicity induced by and (Fig. the cytotoxicity of the of and of the tail the (Fig. These findings that the polyphenol-modified proteins can cytotoxicity through binding to the histone tail Antioxidants are sensitive to oxidation and are converted to an oxidized form an of is that oxidized react with such as proteins. In proteins with gain a new such as vitamin C and polyphenols, convert proteins into innate epitopes that can by natural antibodies (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar, 2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google Scholar, M. Shibata T. Y. S. et of antibodies against involvement of potential of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The proteins have been shown to to histone on the M. Yamaguchi K. Kitazawa R. Lim S.-Y. Y. J. et functions as a for 13: PubMed Scopus (5) Google Scholar). These findings led to the that may a similar activity through conversion to their oxidized study showed that several polyphenols convert proteins to histone Further mechanistic studies showed the involvement of a complex heterogeneous group of compounds bound to proteins as histone-binding elements. In we characterized the formation of aggregates from a interaction the polyphenol-modified proteins and histones and the protective effect of polyphenol-modified proteins on the endothelial cytotoxicity of histone. These findings established that histones are one of the major targets of polyphenol-modified proteins and provide important insights into the chemopreventive functions of dietary polyphenols. In the present study, we 25 polyphenols for the conversion of to histone ligands and identified several polyphenols, including and (Fig. The showed that compounds with such as and histone-binding activity with is the for polyphenols have been to to with structures of tea and tea by Chem. PubMed Scopus Google Scholar). has been that may react with of lysine residues (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar). the some compounds with catechol such as and also an catechol compounds the for activities polyphenols we predict that may due to how they can converted to Based on the that the proteins are bound to histone proteins of their that the structural of histones to the interaction with the proteins. In the and tail we identified the tail of histone as a binding for the polyphenol-modified proteins (Fig. This the conformationally flexible binding studies that binds to several of charged In the that the proteins showed the ability to to the with the that the of charged may important for the interaction of the proteins with the of the that an important in histone proteins the are involved in a of including binding and protein by as The and function in PubMed Scopus Google Scholar). findings that polyphenol-modified proteins may a of functions by binding to histones but also to polyphenols lysine to an equilibrium product of an aldehyde and 2-piperidinol (2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). showed a histone-binding activity (Fig. that the oxidation of lysine may involved in the interaction of the polyphenol-modified proteins with the The aldehyde with the 2-piperidinol product also to react with an group of an lysine in histones to form a lysine-derived via a Schiff base (3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google Scholar). However, the in the incubated with the histones (Fig. the of the Schiff base in the interaction the aldehyde and histone lysine residues is The 2-piperidinol with the aldehyde product may with the However, the mechanism of the involvement of the lysine residues in the interaction of the proteins with the histones modification of proteins is also known to with which is to by the interaction of polyphenols with proteins. et al. E. J. for by PubMed Scopus Google a for by as are formed which to form as is is an of the protein as binds to the The in as is because of the of to and Based on we the involvement of the protein-bound polyphenols in the binding to histone. showed a of into the which with the of the histone-binding activity of the protein (Fig. In we characterized the modification of the lysine and and found that a group of complex heterogeneous compounds to the interaction with histone. These are known to formed by a mechanism similar to the of S. Wang Y. of 2018; PubMed Scopus Google Scholar). several polyphenols with showed on the binding of the proteins to the histones (Fig. the to the interaction with histone may the polyphenol formed on the The covalent binding of polyphenols to proteins also the of a into proteins. The of the proteins to with such as lysine and through S. Wang J.A. et is by a and of 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). can that the covalent binding of polyphenols a to the to with in This study that histone and polyphenol-modified proteins form aggregates (Fig. The of formation demonstrated the of histone by of and the complex by the of histone by may as the interaction histone and is due to of the proteins and in the formation of of an of the histone and due to a in the of protein of proteins by certain polyphenols may as This is by the that in the of the proteins (1Hatasa Y. Chikazawa M. Furuhashi M. Nakashima F. Shibata T. Kondo T. et al.Oxidative deamination of serum albumins by (-)-epigallocatechin-3-o-gallate: a potential mechanism for the formation of innate antigens by antioxidants.PLoS One. 2016; 11: e0153002Crossref PubMed Scopus (26) Google Scholar). et al. J. J. J. A. et study of in Med. PubMed Scopus Google have shown that a of to in in a of in with in study is in However, in and binding of to serum proteins when incubated with for In binding of proteins to histones also These that the of polyphenols may to proteins and histone binding in histones from have been in such as E. D. The of extracellular histone in 2017; PubMed Scopus Google Scholar). with the of the through their charged tail the to K. et histone chronic by PubMed Scopus Google Scholar). We found that endothelial from extracellular histone-mediated cytotoxicity in (Fig. mechanism the of histone cytotoxicity to due to the interaction of with the tail of the study polyphenol-modified proteins as potential of extracellular histone-mediated the of the polyphenol-modified proteins the chemopreventive functions of polyphenols for chronic In histone from and However, histone a of charged and with histone have been shown to the cytotoxicity and the of the K. et histone chronic by PubMed Scopus Google Scholar). which can with the histone tail as as histone may also to chronic In study identified polyphenol-modified proteins as a potential histone ligand. studies have shown the involvement of complex heterogeneous of polyphenol-derived compounds bound to proteins as histone-binding elements. The interaction of polyphenol-modified proteins with histones has been shown to form aggregates and provide a protective effect against the histone-mediated cytotoxicity of endothelial cells. The of study that of the of polyphenols may in to the formation of protein-bound polyphenols and their interaction with However, the the polyphenol modification of proteins and the of protein-bound polyphenols has been studies to the formation of protein-bound polyphenols in and the of unique to human health and proteins by human serum albumin and with a in 25 for the against The polyphenol-modified proteins by proteins proteins with polyphenols in for the and with The protein by a to studies of with the of PubMed Scopus Google Scholar). The polyphenol-modified of with polyphenols in for The oxidized to a (2Yamaguchi K. Itakura M. Kitazawa R. Lim S.-Y. Nagata K. Shibata T. et al.Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products.J. Biol. Chem. 2021; 297: 101035Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). The the human histones and and the the human histone by of The and of the histones to Y. M. S. T. K. et and of human PubMed Scopus Google Scholar, S. M. M. J. et by and in histone Rep. PubMed Scopus Google Scholar, T. K. K. S. A. et and function of human histone 2016; PubMed Scopus Google Scholar). the with the and on a the into the and in and The by of for The for The histones and in the in the The in and by and the the histones with and the for The into and with and The histones with the that the of The against and For of the the and into the E. with and in the in of and incubated the to when the induced by the addition of to a of a the and the with an The incubated for with followed by for The the in incubated for on and for The with to a of to with and with The the and against from the histones histones and The with in and for with and of the compounds to the a in incubated for For the binding the compounds and for the The binding of the compounds to histones by the For the incubated with polyphenols for on of the to of and of in S. A. PubMed Scopus Google Scholar). of a of to of on of to the and for on the against incubated with oxidized for the with for The protein the a incubated with a one and incubated with for This followed by the addition of the The by incubated with oxidized for the with for The protein with for The to an the The of on an the of of with as and in the as the The as source The to the product from the We the to a (3Furuhashi M. Hatasa Y. Kawamura S. Shibata T. Akagawa M. Uchida K. Identification of polyphenol-specific innate epitopes that originated from a resveratrol analogue.Biochemistry. 2017; 56: 4701-4712Crossref PubMed Scopus (8) Google Scholar). We the proteins by a interaction and to with a (4Ishii T. Mori T. Tanaka T. Mizuno D. Yamaji R. Kumazawa S. et al.Covalent modification of proteins by green tea polyphenol (–)-epigallocatechin-3-gallate through autoxidation.Free Radic. Biol. Med. 2008; 45: 1384-1394Crossref PubMed Scopus (209) Google Scholar, A. covalently and Med. 11: PubMed Scopus Google Scholar). of protein with of in of The incubated with The with of of and of The proteins from the by with of The protein of the and a in the The of a The of with for For the the of by on a the of of with as to and The by into from to and in and to a binding of the by to an a with the The of on the of of with as and The in the as the The as source The of with for For the the of by on a the of of with as to 25 and The by to the of and characterized by and to to to and and by to the of the of the of The of and by the from The in a with from to and to and from the tail and to for which the by for and The by the with histones and incubated with in for The for and the and as the and The proteins in by and with the of the polyphenol-modified on the cytotoxicity in human endothelial the the the on a and for The incubated with histone polyphenol-modified The incubated for and the to the are This the The that they have of with the of We for This by and by K. 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