You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Chelating Ability of Plant Polyphenols
Edit
This entry is adapted from the peer-reviewed paper 10.3390/antiox12030630

Many studies have widely examined the effects of dietary polyphenols on human health. Polyphenols are well known for their antioxidant properties and for their chelating abilities, by which they can be potentially employed in cases of pathological conditions, such as iron overload. The iron-binding abilities of dietary polyphenols can be important in inflammatory/immunomodulatory responses, especially involving macrophages and dendritic cells, and they also might contribute to reshape the gut microbiota into a healthy profile. As the axes “polyphenol–iron metabolism–inflammatory responses” and “polyphenol–iron availability–gut microbiota” have not been very well explored so far, there is the need for further investigation to exploit such a potential to prevent or counteract pathological conditions.

polyphenols iron metabolism inflammation

1. Introduction

According to their chemical structure, polyphenols can be divided into the following different sub-groups: phenolic acids (including hydroxycinnamic and hydroxybenzoic acids, commonly present in coffee, tea, cocoa, oats, rice, wheat, and some fruits); flavonoids, which include different subclasses, such as flavones (reported in vegetables and fruits, e.g., citrus fruits), flavanones (citrus fruits), isoflavones (soya-derived products), flavonols (mostly present in vegetables, such as onions, tomatoes, cauliflower, and broccoli), flavanols (wine, tea, and cocoa), and anthocyanins (berries, grapes, and red wine); stilbenoids (grapes, berries, peanuts, and wine); tannins (grapes and wine); and lignans (seeds and grains) [1][2][3][4].
Polyphenol-enriched diets exert several beneficial roles in human health, thus supporting the prevention of many non-communicable diseases that are associated with oxidative stress and inflammation [5][6][7]. Specifically, these bioactive compounds from foods are able to modulate human health at multiple levels, as follows: acting as scavengers of reactive oxygen species (ROS) [8]; imprinting an anti-inflammatory profile to the innate immune cells; downmodulating inflammatory cytokines and chemokine secretion; inhibiting the correct immunological synapse formation and, consequently, the initiation of antigen-specific adaptive immunity [9][10]; modulating some important cellular pathways that are linked to tumorigenesis, such as cellular proliferation [11]; and regulating gut microbiota [12].
One of the possible mechanisms that could connect all of these biological activities is the iron-chelating ability of polyphenols, which can influence iron homeostasis in the human body. In fact, iron is a pivotal microelement for living organisms. Indeed, upon the onset of an infection, one of the primary host responses is related to iron sequestration and accumulation into phagocytes. Vice versa, tissue repair is characterized by the immune cells’ depletion of the cytoplasmic iron content.
Iron chelation can negatively impact iron deficiency conditions, thus resulting in a higher risk of anemia, which impacts the immune system, also inducing metabolic and neurological impairments [13][14]. On the other hand, iron overload and accumulation can lead to other pathological conditions, such as hemochromatosis, metabolism dysfunction, and other complicated symptoms [15]. Excessive iron availability represents a risk factor for cancer development, as a consequence of the increased level of reactive iron, which promotes ROS and DNA damage and mutations. Therefore, the chelating activity of polyphenols can play a positive role in iron-overload conditions by helping to reverse the damages that are caused by iron accumulation and, consequently, can act as a nutritional tool for chronic inflammatory syndrome prevention. Moreover, many polyphenols can favor the selection of beneficial bacteria that can transform them into molecules with increased anti-inflammatory activity [16].

2. Anti/Pro-Oxidant Activities of Polyphenols

Polyphenols are antioxidant compounds that are well known for their radical scavenging activity. By this mechanism, polyphenols behave as reducing agents towards ROS and reactive nitrogen species (RNS), such as OH•, O2•−, and NO•, thus preventing the oxidative stress and DNA damage that are caused by these species. The hydroxyl radical can be generated by different pathways, including the decomposition of peroxynitrous acid [17] or the reduction of peroxides, whereas the production of H2O2, O2•−, and NO• is mostly derived by cellular respiration or cell signaling mechanisms [18]. Polyphenols are able to act as antioxidant compounds by donating an electron or hydrogen atom, thus neutralizing the free radicals. They also act as radical scavengers and chain breakers in lipid peroxidation chain reactions, with the consequent formation of more stable and less reactive species and block of chain reactions before the cell viability can be seriously affected [3][19][20]. Furthermore, polyphenols can induce the expression of antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, which act on hydroxyperoxides, hydrogen peroxide, and superoxide anions, and inhibit the expression of pro-oxidant enzymes, such as cyclooxygenases and lipoxygenases [3][21].
Besides their antioxidant abilities, polyphenols have also been shown to behave as pro-oxidant compounds [21][22][23]. In different cases, the pro-oxidant activity has been related to the structural characteristics of polyphenols, e.g., the flavonol quercetin showed a pronounced pro-oxidative activity, while the flavanones hesperetin and naringenin have displayed milder effects [24]. Some flavonoids containing multiple hydroxyl groups, especially in the B-ring, have been shown to increase the production of hydroxyl radicals [25]. Baicalein, containing a pyrogallol structure in the A-ring, has also been reported to promote hydrogen peroxide production [25][26]. In addition, the pro-oxidant effect can be caused by the autoxidation or enzymatic oxidation (for example, by peroxidases) to which polyphenols can be subjected, causing the production of highly reactive phenoxyl radicals, such as flavonoid quinones. These compounds can be stabilized in vivo by conjugation with nucleophiles, such as GSH, cysteine, or nucleic acids [27].
The pro-oxidant activity of polyphenols could also be associated with their ability to reduce Fe3+ (or other transition metal ions) and the prevention of their binding to other chelating ligands, such as EDTA. In fact, the pro-oxidant properties of polyphenols have been experimentally observed in the presence of metal chelators, such as EDTA, and the oxidized form of the metal ion Fe3+ [22][28][29][30][31]. Increased levels of OH• have been observed following the reduction in Fe3+ complexed with EDTA in the presence of myricetin, quercetin, or catechin [28]. Some phenolics (quercetin, phloretin, phloridzin, phloroglucinol, gallic acid, ferulic acid, and 3,4-dihydroxyphenylacetic acid) have been found to enhance OH• generation under the Fe2+-EDTA-H2O2 system [21]. However, an important consideration that should be taken into account is that the intracellular environment is prevalently reducing, due to the presence of reductant agents such as NADH, glutathione, ascorbic acid, etc., [32][33][34]. Therefore, most of the metal ions that are not bound to proteins would be mainly in their reduced forms in vivo [35]. Polyphenols can display both antioxidant and pro-oxidant activities in very similar conditions, even though their pro-oxidant activity may increase in the presence of very strong chelators (such as EDTA, or medications with chelating abilities, e.g., bleomycin) or high concentrations of H2O2 [21][35]. Furthermore, the pro-oxidative potential of polyphenols can also differ within the same class, dependent on their concentration (low levels of polyphenols may have antioxidant activity, whereas higher concentrations may display pro-oxidant effects), pH conditions, or stereochemistry, which might partly explain the controversy among their antioxidant and pro-oxidant effects [23].

3. Iron-Chelating Abilities of Polyphenols

Besides their radical scavenging activities, another mechanism by which polyphenols can exert their antioxidant activity involves iron binding. Iron, and transition metals in general, can be involved in the generation of oxygen free radicals, the reduction of peroxides, or reactions with superoxide anions [36][37][38], and, subsequently, oxidative stress. Polyphenols have been shown to have iron-binding abilities, which are mainly related to the presence of catechol and galloyl groups. Some studies have shown that the 6,7-dihydroxy structure, B-ring catechol, the galloyl groups, the 2,3-double bond, and the 3- and 5-hydroxylic groups in co-presence with the 4-keto group are associated with chelation properties, and therefore are eligible as iron-binding sites [35][39][40][41][42] (Figure 1). For example, baicalein and baicalin, containing 6,7-dihydroxy groups, have strong iron-binding activities [43]. Flavonoids, such as quercetin and rutin, with 3- and 5-hydroxy-4-keto groups, or flavones and flavonols with 2,3-double bonds in general, are also important metal chelators [44][45]. Ellagic acid, with its four hydroxyl groups, shows metal-transition-chelating abilities, with the possibility to participate in antioxidant redox reactions, resulting in an efficient free radical scavenger [46][47]. Interestingly, when it is incubated with iron–EDTA or iron–citrate complexes, ellagic acid is able to remove iron from those ligands by forming an iron–ellagic acid complex, which reduces the levels of iron ions in the solution that catalyze free radical formation, and therefore showing an antioxidant mechanism that is different from “classical” OH• radical scavenging [31]. In the case of curcumin, the β-diketone group has been suggested to be responsible for iron chelation, even though it does not affect or block iron cellular uptake [48][49]. In in vivo systems, curcumin’s iron-chelating abilities show the ability to affect the systemic iron metabolism (e.g., a decline in serum iron and transferrin saturation, decreased iron levels in the spleen and bone marrow, IRPs activation, repressed ferritin levels, and hepcidin hepatic synthesis), thus suggesting possible effects in patients with both a marginal and a high iron status [50][51]. Furthermore, the iron-chelating abilities of curcumin have also been suggested to contribute to anticancer activities through the formation of redox-active iron complexes and iron depletion in cancer cells [49][50][51].
Antioxidants 12 00630 g002a
Antioxidants 12 00630 g002b
Figure 1. Representative classes of polyphenols and examples of compounds belonging to each group, showing different iron-chelating abilities. Polyphenol general structure is formed by two aromatic rings, indicated as A and B, linked together by three carbon atoms forming an oxygenated heterocycle, the C ring. The 6,7-dihydroxy structure, B-ring catechol, galloyl groups, 2,3-double bond, 3- and 5-hydroxylic groups, β-diketone group, and carboxylic groups associated with iron-binding properties are highlighted in red.
In the case of isoflavones, the 5-hydroxy-4-keto group has been suggested to chelate ferric and ferrous ions, even though the affinity towards these ions was lower than those of the other iron-chelating flavonoids [52]. In particular, genistein and biochanin A, but not daidzein, show chelating abilities of Fe3+, indicating that isoflavones bind the metals at the 4-keto and the 5-OH sites [53].
Lakey-Beitia and co-workers [54] propose the following three groups of polyphenols based on the binding sites: a group with one metal binding site, to which belong the curcuminoids, some stilbenoids, isoflavones, and flavanones; the group with two binding sites that includes some flavones and some anthocyanins; and the group with three metal binding sites that includes flavonols, flavanols, some anthocyanins, and tannins.
In general, the polyphenolic compounds with catechol moieties on the B-ring are more potent inhibitors of the Fenton reaction than those without catechol groups [55]. In addition, the presence of a large number of catechol/galloyl groups (as in the case of tannic acid) contributes to enhanced iron chelation. Perron and co-workers [56] have shown that compounds with galloyl groups have a higher antioxidant activity compared to those with only catechol groups. Phenolic acids bearing catechol or galloyl groups (caffeic acid, gallic acid, protocatechuic acid, and chlorogenic acid) have shown more intriguing iron-binding properties compared to the other polyphenols lacking these groups (ferulic acid, syringic acid, and vanillic acid) [39]. For these, the carboxylate group has been proposed as the most eligible group for iron complexation [57]. In addition, the structures with galloyl moiety, as in the case of gallic acid within the group of hydroxybenzoic acids, scored better than those of the catechol type (as in the case of protocatechuic acid), which could be attributed to the number and position of the hydroxyl groups. It is worthy of notice that gallic acid alone exhibits a reduced iron-chelating capacity, which is probably because of the third hydroxyl group in position three. Indeed, this third OH group can stabilize the flavonoid ring structure and has radical scavenging abilities [58][59], but reduces the iron-chelation ability [39]. Similarly, the presence of methoxy groups (as in the case of vanillic acid, syringic acid, and ferulic acid) increases the radical scavenging activities but hinders the chelation abilities of polyphenols [39][60].

4. Polyphenols’ Bioavailability

The bioavailability of dietary nutrients and compounds usually designates the quantity or fraction of the ingested dose that is absorbed from the gastrointestinal tract [61]. In the case of polyphenols, the bioavailability is strongly influenced by their physical properties (e.g., molecular mass, polarity, and hydrophobic moieties) and the presence of proteins, lipids, and fibers in the ingested food matrixes [62]. For instance, poor anthocyanin bioavailability can be improved by their binding to dietary fibers, which are able to protect them from degradation due to the pH of the intestinal environment and allow them to reach the large intestine and remain there for a longer time [62]. Once they are ingested, polyphenols reach the intestine, where they are first deconjugated by enzymes such as lactase phlorizin hydrolase (LPH, located on the enterocytes membrane) or β-glucosidase (CBG, cytosolic), in order to facilitate the absorption by the epithelial cells. Following this first process of absorption, the polyphenols are transported through the portal vein to the liver, where they undergo phase I metabolism, which implies hydrolysis and oxidation reactions, and phase II metabolism, prevalently including glucuronidation, methylation, and sulfonation reactions [63][64]. Such metabolites can have markedly changed iron-chelating and anti/pro-oxidant properties [65][66]. They can be detected in systemic circulation; however, such modifications (in particular, sulfation and glucuronidation) also facilitate their efflux into the intestinal lumen. Once they are released into the intestinal lumen, the polyphenols are then subjected to microbial biotransformation, which can produce smaller and structurally simpler compounds [67][68]. Several studies report the presence of phase II metabolites (glucuronides or sulfated forms) in plasma samples after the ingestion of polyphenols, or foods that are enriched in polyphenols, indicating that the intestines and the liver are the main sites of polyphenol metabolism [69], whereas polyphenolic aglycones are not commonly found there [70][71]. Table 1 reports some examples from published studies describing the bioavailability and the excretion paths of representative classes of polyphenols. The maximal plasma concentration (Cmax) and the time to reach it (tmax) strongly depend on the diverse classes of compounds, the type and amount of the food source, the studied species, and the interindividual variability [72][73]. In some cases, such as for quercetin, the type of bound sugar moiety can also influence the efficiency of the intestinal absorption and, therefore, the polyphenol bioavailability [69].
The main route of elimination of polyphenols is urinary excretion, even though biliary excretion should be considered for some compounds, such as quercetin or curcumin [73][74][75][76].
Polyphenols’ intestinal absorption is mainly mediated by epithelial glucose or monocarboxylates transporters (MCTs) [77]. Quercetin glucosides can be directly transported via SGLT1 (sodium-dependent glucose transporter 1) or hydrolyzed to quercetin before their absorption by passive diffusion in the small intestine [69]. Rutin is metabolized by intestinal bacteria into phenolic compounds prior to being absorbed via MCT, or through the paracellular pathway. The uptake transporters OATPs (organic anion transport polypeptides) and OATs (organic anion transporter) contributes to the uptake of quercetin and its metabolites into the liver and the kidneys [69]. A hesperetin derivative, MTBH (8-methylene-tert-butylamine-3’,5,7-trihydroxy-4’-methoxyflavanone), has been shown to be mainly absorbed by the transcellular passive diffusion mechanism and to use MCT carriers to enter the cells [78]. Trans-resveratrol has been reported to use a passive transport to cross the apical membrane of the intestinal cells, whereas the transport of its trans-piceid derivative is likely to be active, involving SGLT1 [79]. On the other hand, the main transporters that are implicated in polyphenol efflux are MRP2 (multi-drug resistance protein 2), BCPR (breast cancer resistance protein), and P-gp (P-glycoprotein transporters) [77]. MPR2 and BCPR mediate the excretion of quercetin and its metabolites through bile and urine, eliminating them from the body [69]. MRP2 has been also shown to be involved in stilbene efflux [79]. P-gp and BCPR are used for MTBH efflux transport [78]. However, Teng and co-workers (2012) [77] reported different affinities for SLGT1, MRP2, and P-gp transporters among the different classes of polyphenols, indicating that their influx or efflux may be dependent on their chemical structures.
Table 1. Examples of studies reporting polyphenols’ bioavailability in humans.
Table
Polyphenol Compound—Food Source Dosage Cmax 1 of the Main Compounds in Plasma (tmax 2) Main Compounds Excreted in Urine (Time) Reference
Quercetin-4’-O-glucoside 100 mg 2.12 µg·mL−1 of quercetin-4’-O-glucoside (0.70 h) NA 3 [80]
Quercetin-3-O-rutinoside 200 mg 0.32 µg·mL−1 of quercetin-3-O-rutinoside (6.98 h) NA [80]
Fried onions (containing 275 µmol flavonols, principally quercetin-4’-glucoside and quercetin-3,4’-diglucoside) 270 g 665 nM of quercetin-3’-sulfate (0.75 h)
351 nM of quercetin-3-glucuronide (0.60 h)
63 nM of quercetin diglucuronide (0.80 h)		 274 nM quercetin diglucuronide (8–24 h) [81]
Fresh blackcurrant (containing 897 mg total anthocyanins) 100 g Anthocyanins
not detected		 339 µg total anthocyanins (48 h)
17.3 mg hippuric acid (0–24 h)		 [70]
Elderberry concentrate (containing 1.9 g anthocyanins and equivalent to 235 mL fresh juice) 11 g NA 15.8 µg cyanidin-3-glucoside (1 h)
29.8 µg cyanidin-3-sambubioside (2 h)		 [82]
Homogenized raspberries (containing 292 µmol anthocyanins, 6.3 µmol ellagic acids, 251 µmol ellagitannins, and 2.5 µmol phenolic acids) 300 g 180 nmol·L−1 of 3’,4’-dihydroxyphenylaceticacid (6 h)
78 nmol·L−1 of 4’-Hydroxyhippuricacid (1 h)
47 nmol·L−1 of ferulic acid-4′-sulfate (1.5 h)
18 nmol·L−1 of ferulic acid-4′-O-glucuronide (1.5 h)
14 nmol of isoferulic acid-3’-O-glucuronide (1.5 h)		 19.9 nmol cyanidin-3-O-glucoside (0–48 h)
6.4 nmol 4-Hydroxybenzoic acid (0–48 h)
6.5 nmol ferulic acid-4-sulfate (0–48 h)
16.1 nmol 4-hydroxyhippuricacid (0–48 h)
239 nmol hippuric acid (0–48 h)		 [83]
Evelor 500 mg tablets (containing trans-resveratrol) 500 g 71.18 mg·mL−1 of trans-resveratrol (1.339 h)
1516.014 mg·mL−1 of sulfated resveratrol
4083.900 mg·mL−1 of glucuronated resveratrol		 NA [84]
Coffee beverage, containing various doses of chlorogenic acid:
412 µmol (A)
635 µmol (B)
795 µmol (C)		 200 mL 808 µmol of total chlorogenic acid derivatives
(0.5–6 h) (A)
1242 µmol of total chlorogenic acid derivatives
(0.5–6 h) (B)
1164 µmol of total chlorogenic acid derivatives
(0.5–6 h) (C)		 100.7 µmol of total chlorogenic acid derivatives (0–24 h) (A)
160.0 µmol of total chlorogenic acid derivatives (0–24 h) (B)
125.2 µmol of total chlorogenic acid derivatives (0–24 h) (C)		 [85]
Curcuminoids as native powder, micronized powder, or liquid micelles (containing
410 mg curcumin, 80 mg demethoxycurcumin, and 10 mg bis-demethoxycurcumin)		 500 mg 7.1 nmol curcumin (7.5 h) (native powder)
41.6 nmol curcumin (8.8 h) (micronized powder)
3228 nmol curcumin (1.1 h) (liquid micelles)		 5.1 nmol 4 curcumin (0–24 h) (native powder)
70.6 nmol 4 curcumin (0–24 h) (micronized powder)
753 nmol 4 curcumin (0–24 h) (liquid micelles)		 [86]

1 Cmax: maximal plasma concentration. 2 tmax: time to reach Cmax. 3 NA: not available. 4 data expressed as nmol·g−1 creatinine.

References

  1. Scarano, A.; Chieppa, M.; Santino, A. Looking at flavonoid biodiversity in horticultural crops: A colored mine with nutritional benefits. Plants 2018, 7, 98.
  2. Scarano, A.; Chieppa, M.; Santino, A. Plant polyphenols-biofortified foods as a novel tool for the prevention of human gut diseases. Antioxidants 2020, 9, 1225.
  3. Tsao, R. Chemistry and biochemistry of dietary polyphenols. Nutrients 2010, 2, 1231–1246.
  4. Laddomada, B.; Blanco, A.; Mita, G.; D’Amico, L.; Singh, R.P.; Ammar, K.; Crossa, J.; Guzmán, C. Drought and Heat Stress Impacts on Phenolic Acids Accumulation in Durum Wheat Cultivars. Foods 2021, 10, 2142.
  5. Speer, H.; D’Cunha, N.M.; Botek, M.; McKune, A.J.; Sergi, D.; Georgousopoulou, E.; Mellor, D.D.; Naumovski, N. The effects of dietary polyphenols on circulating cardiovascular disease biomarkers and iron status: A systematic review. Nutr. Metab. Insight 2019, 12, 1–12.
  6. Koch, W. Dietary Polyphenols-Important Non-Nutrients in the Prevention of Chronic Noncommunicable Diseases. A Systematic Review. Nutrients 2019, 11, 1039.
  7. De Santis, S.; Clodoveo, M.L.; Cariello, M.; D’Amato, G.; Franchini, C.; Faienza, M.F.; Corbo, F. Polyphenols and obesity prevention: Critical insights on molecular regulation, bioavailability and dose in preclinical and clinical settings. Crit. Rev. Food Sci. Nutr. 2021, 61, 1804–1826.
  8. Rudrapal, M.; Khairnar, S.J.; Khan, J.; Dukhyil, A.B.; Ansari, M.A.; Alomary, M.N.; Alshabrmi, F.M.; Palai, S.; Deb, P.K.; Devi, R. Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects, Antioxidant Potentials and Mechanism(s) of Action. Front. Pharmacol. 2022, 13, 806470.
  9. Delvecchio, F.R.; Vadrucci, E.; Cavalcanti, E.; De Santis, S.; Kunde, D.; Vacca, M.; Myers, J.; Allen, F.; Bianco, G.; Huang, A.Y.; et al. Polyphenol administration impairs T-cell proliferation by imprinting a distinct dendritic cell maturational profile. Eur. J. Immunol. 2015, 45, 2638–2649.
  10. Shakoor, H.; Feehan, J.; Apostolopoulos, V.; Platat, C.; Al Daheri, A.S.; Ali, H.I.; Ismail, L.C.; Bosevski, M.; Stojanovska, L. Immunomodulatory Effects of Dietary Polyphenols. Nutrients 2021, 13, 728.
  11. Patra, S.; Pradha, B.; Nayak, R.; Behera, C.; Das, S.; Patra, S.K.; Efferth, T.; Jena, M.; Bhutia, S.K. Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action. Phytomedicine 2021, 90, 153554.
  12. Wan, M.L.Y.; Co, V.A.; El-Nezami, H. Dietary polyphenol impact on gut health and microbiota. Crit. Rev. Food Sci. Nutr. 2021, 61, 690–711.
  13. Hare, D.; Ayton, S.; Bush, A.; Lei, P. A delicate balance: Iron metabolism and diseases of the brain. Front. Aging Neurosci. 2013, 5, 34.
  14. Fan, F.S. Iron deficiency anemia due to excessive green tea drinking. Clin. Case Rep. 2016, 4, 1053–1056.
  15. Mobarra, N.; Shanaki, M.; Ehteram, H.; Nasiri, H.; Sahmani, M.; Saeidi, M.; Goudarzi, M.; Pourkarim, H.; Azad, M. A review on iron chelators in treatment of iron overload syndromes. Int. J. Hematol. Oncol. Stem Cell Res. 2016, 10, 239–247.
  16. Aravind, S.M.; Wichienchot, S.; Tsao, R.; Ramakrishnan, S.; Chakkaravarthi, S. Role of dietary polyphenols on gut microbiota, their metabolites and health benefits. Food Res. Int. 2021, 142, 110189.
  17. Beckman, J.S.; Beckman, T.W.; Chen, J.; Marshall, P.A.; Freeman, B.A. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA 1990, 87, 1620–1624.
  18. Thannickal, V.J.; Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 279, L1005–L1028.
  19. Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013, 2013, 162750.
  20. Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M.C.B.; Rahu, N. Oxidative stress and inflammation: What polyphenols can do for us? Oxid. Med. Cell Longev. 2016, 2016, 7432797.
  21. de Graft-Johnson, J.; Nowak, D. Effect of selected plant phenolics on Fe2+-EDTA-H2O2 system mediated deoxyribose oxidation: Molecular structure-derived relationships of anti- and pro-oxidant actions. Molecules 2017, 22, 59.
  22. Laughton, M.J.; Halliwell, B.; Evans, P.J.; Hoult, J.R. Antioxidant and pro-oxidant actions of the plant phenolics quercetin, gossypol and myricetin: Effects on lipid peroxidation, hydroxyl radical generation and bleomycin-dependent damage to DNA. Biochem. Pharmacol. 1989, 38, 2859–2865.
  23. Makácová, K.; Mladěnka, P.; Filipský, T.; Říha, M.; Jahodár, L.; Trejtnar, F.; Bovicelli, P.; Proietti Silvestri, I.; Hrdina, R.; Saso, L. Iron reduction potentiates hydroxyl radical formation only in flavonols. Food Chem. 2012, 135, 2584–2592.
  24. Yen, G.C.; Duh, P.D.; Tsai, H.L.; Huang, S.L. Pro-oxidative properties of flavonoids in human lymphocytes. Biosci. Biotechnol. Biochem. 2003, 67, 1215–1222.
  25. Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flvaonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002, 13, 572–584.
  26. Hodnick, W.F.; Kung, F.S.; Bohmont, C.W.; Pardini, R.S. Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids. A structure-activity study. Biochem. Pharmacol. 1986, 35, 2345–2357.
  27. Procházková, D.; Boušová, I.; Wilhemová, N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011, 82, 513–523.
  28. Puppo, A. Effect of flavonoids on hydroxyl radical formation by Fenton-type reactions; influence of the iron chelator. Phytochemistry 1992, 31, 85–88.
  29. Moran, J.F.; Klucas, R.V.; Grayer, R.J.; Abian, J.; Becana, M. Complexes of iron with phenolic compounds from soybean nodules and other legume tissues: Prooxidant and antioxidant properties. Free Radic. Biol. Med. 1997, 22, 861–870.
  30. Inoue, S.; Ito, K.; Yamamoto, K.; Kawanishi, S. Caffeic acid causes metal-dependent damage to cellular and isolated DNA through H2O2 formation. Carcinogenesis 1992, 13, 1497–1502.
  31. Dalvi, L.T.; Moreira, D.C.; Andrade Jr, R.; Ginani, J.; Alonso, A.; Hermes-Lima, M. Ellagic acid inhibits iron-mediated free radical formation. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2017, 173, 910–917.
  32. Bradshaw, P.C. Cytoplasmic and mitochondrial NADPH-coupled redox systems in the regulation of aging. Nutrients 2019, 11, 504.
  33. Marì, M.; de Gregorio, E.; de Dios, E.; Roca-Agujetas, V.; Cucarull, B.; Tutusaus, A.; Morales, A.; Colell, A. Mitochondrial glutathione: Recent insights and role in disease. Antioxidants 2020, 9, 909.
  34. Zhitkovich, A. Nuclear and cytoplasmic functions of vitamin C. Chem. Res. Toxicol. 2020, 33, 2515–2526.
  35. Perron, N.R.; Brumaghim, J.L. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell Biochem. Biophys. 2009, 53, 75–100.
  36. Romano, G.; Del Coco, L.; Milano, F.; Durante, M.; Palombieri, S.; Sestili, F.; Visioni, A.; Abderrazek, J.; Fanizzi, F.P.; Laddomada, B. Phytochemical Profiling and Untargeted Metabolite Fingerprinting of the MEDWHEALTH Wheat, Barley and Lentil Whole-Meal Flours. Foods 2022, 11, 4070.
  37. Kehrer, J.P. The Haber–Weiss reaction and mechanisms of toxicity. Toxicology 2000, 149, 43–50.
  38. Henle, E.S.; Han, Z.; Tang, N.; Rai, P.; Luo, Y.; Linn, S. Sequence-specific DNA cleavage by Fe2+-mediated Fenton reaction has possible biological implications. J. Biol. Chem. 1999, 274, 962–971.
  39. Andjelković, M.; Camp, J.V.; De Meulenaer, B.; Depaemelaere, G.; Socaciu, C.; Verloo, M.; Verhe, R. Iron-chelation properties of phenolic acids bearing catechol and galloyl groups. Food Chem. 2006, 98, 23–31.
  40. Braakhuis, A. Evidence on the health benefits of supplemental propolis. Nutrients 2019, 11, 2705.
  41. Wang, X.; Li, Y.; Han, L.; Li, J.; Liu, C.; Sun, C. Role of flavonoids in the treatment of iron overload. Front. Cell Dev. Biol. 2021, 9, 685364.
  42. Kasprzak, M.M.; Erxleben, A.; Ochocki, J. Properties and applications of flavonoid metal complexes. RSC Adv. 2015, 5, 45853–45877.
  43. Borges, A.; Abreu, A.; Dias, C.; Saavedra, M.; Borges, F.; Simões, M. New perspectives on the use of phytochemicals as an emergent strategy to control bacterial infections including biofilms. Molecules 2016, 21, 877.
  44. Khalili, M.; Ebrahimzadeh, M.; Kosaryan, M. In vivo iron-chelating activity and phenolic profiles of the Angel’s wings mushroom, Pleurotus porrigens (Higher Basidiomycetes). Int. J. Med. Mushrooms 2015, 17, 847–856.
  45. Fernandez, M.T.; Mira, M.L.; Florêncio, M.H.; Jennings, K.R. Iron and copper chelation by flavonoids: An electrospray mass spectrometry study. J. Inorg. Biochem. 2002, 92, 105–111.
  46. Galano, A.; Marquez, M.F.; Pérez-González, A. Ellagic acid: An unusually versatile protector against oxidative stress. Chem. Res. Toxicol. 2014, 27, 904–918.
  47. Alfei, S.; Marengo, B.; Zuccari, G. Oxidative stress, antioxidant capabilities and bioavailability: Ellagic acid or urolithins? Antioxidants 2020, 9, 707.
  48. Messner, D.J.; Sivam, G.; Kowdley, K.V. Curcumin reduces the toxic effects of iron loading in rat liver epithelial cells. Liver Int. 2009, 29, 63–72.
  49. Rainey, N.E.; Moustapha, A.; Saric, A.; Nicolas, G.; Sureau, F.; Petit, P.X. Iron chelation by curcumin suppresses both curcumin-induced autophagy and cell death together with iron overload neoplastic transformation. Cell Death Discov. 2019, 5, 150.
  50. Jiao, Y.; Wilkinson IV, J.; Pietsch, E.C.; Buss, J.L.; Wan, W.; Planalp, R.; Torti, F.M.; Torti, S.V. Iron chelation in the biological activity of curcumin. Free Radic. Biol. Med. 2006, 40, 1152–1160.
  51. Jiao, Y.; Wilkinson IV, J.; Di, X.; Wang, W.; Hatcher, H.; Kock, N.D.; D’Agostino Jr, R.; Knovich, M.A.; Torti, F.M.; Torti, S.V. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 2009, 113, 462–469.
  52. Karlíčková, J.; Macáková, K.; Říha, M.; Teixeira Pinheiro, L.M.; Filipský, T.; Horňasová, V.; Hrdina, R.; Mladěnka, P. Isoflavones reduce copper with minimal impact on iron in vitro. Oxid. Med. Cell Longev. 2015, 2015, 437381.
  53. Dowling, S.; Regan, F.; Hughes, H. The characterisation of structural and antioxidant properties of isoflavone metal chelates. J. Inorg. Biochem. 2010, 104, 1091–1098.
  54. Lakey-Beitia, J.; Burillo, A.M.; La Penna, G.; Hedge, M.L.; Rao, K.S. Polyphenols as potential metal chelation compounds against Alzeimer’s disease. J. Alzheimer’s Dis. 2021, 82, S335–S357.
  55. Cheng, I.F.; Breen, K. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the Fenton reaction of the iron-ATP complex. BioMetals 2000, 13, 77–83.
  56. Perron, N.R.; Hodges, J.N.; Jenkins, M.; Brumaghim, J.L. Predicting how polyphenol antioxidants prevent DNA damage by binding to iron. Inorg. Chem. 2008, 47, 6153–6161.
  57. Malacaria, L.; Corrente, G.A.; Beneduci, A.; Furia, E.; Marino, T.; Mazzone, G. A review on coordination properties of Al(III) and Fe(III) toward natural antioxidant molecules: Experimental and theoretical insights. Molecules 2021, 26, 2603.
  58. Pannala, A.S.; Chan, T.S.; O’Brien, P.J.; Rice-Evans, C.A. Flavonoid B-ring chemistry and antioxidant activity: Fast reaction kinetics. Biochem. Biophys. Res. Commun. 2001, 282, 1161–1168.
  59. Fiuza, S.M.; Van Besien, E.; Milhazes, N.; Borges, F.; Marques, M.P.M. Conformational analysis of a trihydroxylated derivative of cinnamic acid—A combined Raman spectroscopy and ab initio study. J. Mol. Struct. 2004, 693, 103–118.
  60. Mladěnka, P.; Macáková, K.; Filipský, T.; Zatloukalová, L.; Jahodář, L.; Bovicelli, P.; Silvestri, I.P.; Hrdina, R.; Saso, L. In vitro analysis of iron chelating activity of flavonoids. J. Inorg. Biochem. 2011, 105, 693–701.
  61. McGhie, T.K.; Walton, M.C. the bioavailability and absorption of anthocyanins: Towards a better understanding. Mol. Nutr. Food Res. 2007, 51, 702–713.
  62. Scarano, A.; Chieppa, M.; Santino, A. 2022. Microbiota as a metabolic organ processing dietary polyphenols. In Comprehensive Gut Microbiota; Glibetic, M., Ed.; Elsevier: Amsterdam, The Netherlands, 2022; Volume 1, pp. 20–26.
  63. Marín, L.; Miguélez, E.M.; Villar, C.J.; Lombó, F. Bioavailability of dietary polyphenols and gut microbiota metabolism: Antimicrobial properties. BioMed Res. Int. 2015, 2015, 95215.
  64. Hussain, M.B.; Hassan, S.; Waheed, M.; Javed, A.; Farooq, M.A.; Tahir, A. Bioavailability and metabolic pathway of phenolic compounds. In Plant Physiological Aspects of Phenolic Compounds; Soto-Hernández, M., García-Mateos, R., Palma-Tenango, M., Eds.; InTechOpen: London, UK, 2019.
  65. Lomozová, Z.; Catapano, M.C.; Hrubša, M.; Karlíčkova, J.; Macáková, K.; Kučera, R.; Mladěnka, P. Chelation of iron and copper by quercetin B-ring methyl metabolites, isorhamnetin and tamarixetin, and their effect on metal-based Fenton chemistry. J. Agric. Food Chem. 2021, 69, 5926–5937.
  66. Saito, A.; Sugisawa, A.; Umegaki, K.; Sunagawa, H. Protective effects of quercetin and its metabolites on H2O2-induced chromosomal damage to WIL2-NS cells. Biosci. Biotechnol. Biochem. 2004, 68, 271–276.
  67. Mosele, J.I.; Macià, A.; Motilva, M.J. Metabolic and microbial modulation of the large intestine ecosystem by non-absorbed diet phenolic compounds: A review. Molecules 2015, 20, 17429–17468.
  68. Catalkava, G.; Venema, K.; Lucini, L.; Rocchetti, G.; Delmas, D.; Daglia, M.; De Filippis, A.; Xiao, H.; Quiles, J.L.; Capanoglu, E. Interaction of dietary polyphenols and gut microbiota: Microbial metabolism of polyphenols, influence on the gut microbiota, and implications on host health. Food Front. 2020, 1, 109–133.
  69. Hai, Y.; Zhang, Y.; Liang, Y.; Ma, X.; Qi, X.; Xiao, J.; Xue, W.; Luo, Y.; Yue, T. Advance on the absorption, metabolism, and efficacy exertion of quercetin and its important derivatives. Food Front. 2020, 1, 420–434.
  70. Holland, W.; Brett, G.M.; Radreau, P.; Saha, S.; Teucher, B.; Bennet, R.; Kroon, P. Processing blackcurrants dramatically reduces the content and does not enhance urinary yield of anthocyanins in human subjects. Food Chem. 2008, 108, 869–878.
  71. Li, H.; Li, M.; Fu, J.; Ao, H.; Wang, W.; Wang, X. Enhancement of oral bioavailability of quercetin by metabolic inhibitory nanosuspensions compared to conventional nanosuspensions. Drug Deliv. 2021, 28, 1226–1236.
  72. Kasikci, M.B.; Bagdatlioglu, N. Bioavailability of quercetin. Curr. Res. Nutr. Food Sci. 2016, 4, 146–151.
  73. Crespy, V.; Morand, C.; Manach, C.; Besson, C.; Demigne, C.; Remesy, C. Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am. J. Physiol. 1999, 277, G120–G126.
  74. Matsukawa, N.; Matsumoto, M.; Hara, H. High biliary excretion levels of quercetin metabolites after administration of a quercetin glycoside in conscious bile duct cannulated rats. Biosci. Biotechnol. Biochem. 2009, 73, 1863–1865.
  75. Lee, J.H.; Oh, J.-H.; Lee, Y.-J. Biliary excretion of curcumin is mediated by multidrug resistance-associated protein 2. Biol. Pharm. Bull. 2012, 35, 777–780.
  76. Prasad, S.; Tyagi, A.K.; Aggarwal, B.B. Recent development in delivery, bioavailability, absorption and metabolism of curcumin: The golden pigment from golden spice. Cancer Res. Treat. 2014, 46, 2–18.
  77. Teng, Z.; Yuan, C.; Zhang, F.; Huan, M.; Cao, W.; Li, K.; Yang, J.; Cao, D.; Zhou, S.; Mei, Q. Intestinal absorption and first-pass metabolism of polyphenol compounds in rat and their transport dynamics in Caco-2 cells. PLoS ONE 2012, 7, e29647.
  78. Shen, C.; Chen, R.; Qian, Z.; Meng, X.; Hu, T.; Li, Y.; Chen, Z.; Huang, C.; Hu, C.; Li, J. Intestinal absorption mechanisms of MTBH, a novel hesperetin derivative, in Caco-2 cells, and potential involvement of monocarboxylate transporter 1 and multidrug resistance protein 2. Eur. J. Pharm. Sci. 2015, 78, 214–224.
  79. Henry, C.; Vitrac, X.; Decendit, A.; Ennamany, R.; Krisa, S.; Merillon, J.-M. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem. 2005, 53, 798–803.
  80. Graefe, E.U.; Witting, J.; Pharm, D.; Mueller, S.; Riethling, A.-K.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.; Derendorf, H. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin. Pharmacol. 2001, 41, 492–499.
  81. Mullen, W.; Edwards, C.A.; Crozier, A. Absorption, excretion and metabolite profiling of methyl-, glucuronyl-, glucosyl- and sulpho-conjugates of quercetin in human plasma and urine after ingestion of onions. Br. J. Nutr. 2006, 96, 107–116.
  82. Mülleder, U.; Murkovic, M.; Pfannhauser, W. Urinary excretion of cyanidin glycosides. J. Biochem. Biophys. Methods 2002, 53, 61–66.
  83. Ludwig, I.A.; Mena, P.; Calani, L.; Borges, G.; Pereira-Caro, G.; Bresciani, L.; Del Rio, D.; Lean, M.E.; Crozier, A. New insights into the bioavailability of red raspberry anthocyanins and ellagitannins. Free Radic. Biol. Med. 2015, 89, 758–769.
  84. Sergides, C.; Chirilă, M.; Silvestro, L.; Pitta, D.; Pittas, A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp. Ther. Med. 2016, 11, 164–170.
  85. Stalmach, A.; Williamson, G.; Crozier, A. Impact of dose on the bioavailability of coffee chlorogenic acids in humans. Food Funct. 2014, 5, 1727–1737.
  86. Schiborr, C.; Kocher, A.; Behnam, D.; Jandasek, J.; Toelstede, S.; Frank, J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol. Nutr. Food Res. 2014, 58, 516–527.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Aurelia Scarano
,
Barbara Laddomada
,
Federica Blando
,
Stefania De Santis
,
Giulio Verna
,
Marcello Chieppa
,
Angelo Santino
View Times: 1.1K
Revisions: 2 times (View History)
Update Date: 16 Mar 2023
Table of Contents
Academic Video Service
Feedback