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Natural antioxidants: Is the research going in the right direction?

The terms “Natural Antioxidants” are commonly used to indicate natural molecules present in fruits and vegetables able to exert some beneficial effects for human health, by maintaining a good well-being and preventing the most diffuse chronic diseases. Several studies have in fact shown that the consumption of foods rich in these substances is essential to ensure a good health and protect against many human pathologies, such as diabetes, metabolic syndrome, cardiovascular diseases and some types of cancer [1–7]. Thanks to several health promotion programs launched all over the world, such as “the 5 a day for Better Health Program” in USA or the “Mediterranean Pyramid” in Europe, also consumers have become increasingly aware of the importance of a correct and balanced diet for their health and they have started to consider foods as their medicine [8].

From a scientific point of view, the first definition of antioxidants dates back in the early 1980s, when Halliwell and Gutteridge proposed the broad explanation of an antioxidant as “any substance that, when present at concentrations compared with those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate” [9]. Afterwards, the antioxidants were defined by a more general perspective as “all those compounds that protect biological systems against the harmful effects of excessive generation of oxidants,” and this description is currently the most widely used [10]. This last definition is strictly correlated to the more modern concept of “bioactive compounds”: even if there is still not an unique explanation, we can define them as any type of molecules found in small amounts in plant foods that may promote a good health, even if they are not essential for life; they have been studied especially for the prevention of metabolic, cardiovascular and neurodegenerative diseases, as well as in some type of cancer [11–23].

Over the last 50 years, the scientific research in this field has dramatically increased, as demonstrated by the number of papers published each year on PubMed (Fig. 1) and the concept of antioxidants has evolved over the years.

Fig. 1

Number of papers present in PubMed, published from 1970 to 2020 and focused on antioxidants.

Number of papers present in PubMed, published from 1970 to 2020 and focused on antioxidants.

Despite this, can we say with total certainty that a very high consumption of foods rich in antioxidants keeps us healthy? In other words, are we healthier if we eat more and more antioxidants?

First of all, we should keep in mind that in the last decade many studies have been performed in cell cultures in order to discover mechanistic effects: if this is an excellent way “from the research point of view” to thoroughly investigate the molecular mechanisms involved in the biological effects exerted by antioxidants, “from a nutritional point of view” it is not so good. Indeed, in these cases, it is very difficult to translate the in vitro evidence into in vivo outcomes, considering that: (i) the bioavailability of dietary antioxidants is in general rather low and the metabolites that reach the target tissues are structurally and chemically different from the original ones, (ii) cell cultures with high levels of oxidative stress usually adapt and modify their properties or even mutate, as embryonic stem cells do, so it is hard to compare these cells with those in vivo, (iii) the doses that are used in cell cultures are scarcely reached in in vivo models, including humans, (iv) many antioxidants are not stable in cell culture media and can be decomposed into pro-oxidant molecules, and (v) the endocrine connections, the antibiotic presence and the lipid composition, as well as the rates of oxygen and nutrient supply, are very different between in vitro and in vivo models [8, 24, 25]. Besides this, some concerns exist also for in vivo studies, because animals usually used in laboratory are more sensitive to dietary intervention than humans and this can easily generate misleading data; in addition, the predictive power of these models in some pathological conditions, such as stroke, seems to be zero [26, 27]. Therefore, we should be very cautious when we use culture cells or animal models to predict and even claim the preventive and/or the therapeutic effects of some dietary antioxidants against the onset of the most common human diseases.

Another critical point is that studies that have demonstrated the inefficacy of dietary antioxidants consumption in preventing/treating human disease or in slowing the aging process are accumulating [28–30]. For example, β-carotene, vitamin A, vitamin C, vitamin E and selenium have shown no significant and beneficial effects on the prevention of mortality in adults [31], on the risk to develop diabetes [32], on the treatment of patients affects by different types of cancer [333–36], cardiovascular pathologies [36–39], and dementia, Alzheimer’s and Parkinson disease [40, 41]. Moreover, depending on cellular redox state and concentrations (generally very high), natural antioxidants seem to act as pro-oxidants, inducing oxidative stress and increasing toxicity, as reported for epigallocatechin-3-gallate [42], ascorbic acid [43] and β-carotene [44].

Last but not least, it should be taken into consideration that humans are able to produce several antioxidants, such as for example reduced glutathione, catalases and superoxide dismutase, and, if there is not a vitamin deficiency, this antioxidant endogenous system is maybe more essential than any other antioxidants that can be assumed from foods. In other words, instead of evaluating the effects of the consumption of mega-doses of antioxidants (that seem to be ineffective in many cases), scientists should focus their attention on how these bioactive compounds are able to stimulate and increase the human adaptative and protective systems, in the same way as mild toxins do. Not surprisingly, in the last years several studies have shown that, beside the simple antioxidant capacity, different types of antioxidants and bioactive compounds, including polyphenols, terpenoids and chalcones, are able to activate the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, the most important pathway that modulates the endogenous antioxidant and cytoprotective system [6, 45–48]. On one side the activation of this pathway contributes to prevent and treat many chronic diseases, on the other side its inactivation may represent a promising strategy against multi-drug resistance, enhancing the efficacy of treatment. Of note, the results of these studies reinforce once again the essentiality of consuming foods rich in bioactive compounds that act in a synergistic way to maintain a good health and prevent the most common non-communicable diseases, but certainly dampen the importance of assuming mega-doses.

In conclusion, are we sure that continuing to evaluate the mere effects of antioxidants is the right way to understand how to prevent and counteract the main common human diseases? The debate has only just begun.

Funding

The Authors have not received any financial support for this research.

Conflict of interest

The authors declare that there is no conflict of interest.

Acknowledgments

The authors have no acknowledgments.

References

[1] 

Giampieri F , Gasparrini M , Forbes-Hernandez TY , Mazzoni L , Capocasa F , Sabbadini S , et al. Overexpression of the anthocyanidin synthase gene in strawberry enhances antioxidant capacity and cytotoxic effects on human hepatic cancer cells. J Agric Food Chem. 2018;66(3):581–92.

[2] 

Forbes-Hernández TY , Afrin S , Cianciosi D , Manna PP , Zhang J , Gasparrini M , Reboredo-Rodriguez P . Strawberry extract attenuates oxidative stress in 3T3-L1 cells. J Berry Res. 2018;8:193–203.

[3] 

Neha K , Haider MR , Pathak A , Yar MS . Medicinal prospects of antioxidants: A review. Eur J Med Chem. 2019;178:687–704.

[4] 

Afrin S , Giampieri F , Gasparrini M , Forbes-Hernández TY , Cianciosi D , Reboredo-Rodriguez P , et al. The inhibitory effect of Manuka honey on human colon cancer HCT-116 and LoVo cell growth. Part Induction of oxidative stress, alteration of mitochondrial respiration and glycolysis, and suppression of metastatic ability. Food Funct. 2018;9(4):2158–70.

[5] 

Tena N , Martín J , Asuero AG . State of the art of anthocyanins: antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants. 2020;9(5):451.

[6] 

Alvarez-Suarez JM , Giampieri F , Cordero M , Gasparrini M , Forbes-Hernández TY , Mazzoni L , et al. Activation of AMPK/Nrf2 signalling by Manuka honey protects human dermal fibroblasts against oxidative damage by improving antioxidant response and mitochondrial function promoting wound healing. J Funct Foods. 2016;25:38–49.

[7] 

Banez MJ , Geluz MI , Chandra A , Hamdan T , Biswas OS , Bryan NS , Von Schwarz ER . A systemic review on the antioxidant and anti-inflammatory effects of resveratrol, curcumin, and dietary nitric oxide supplementation on human cardiovascular health. Nutr Res. 2020;78:11–26.

[8] 

Giampieri F , Alvarez-Suarez JM , Battino M . Strawberry and human health: effects beyond antioxidant activity. J Agric Food Chem. 2014;62(18):3867–76.

[9] 

Halliwell B , Gutteridge JMC . Free radicals in biology and medicine. Oxford Science Publication. 1989, Second edition.

[10] 

Krinsky NI . Mechanism of action of biological antioxidants. Proc Soc Exp Biol Med. 1992;200:248–54.

[11] 

Afrin S , Giampieri F , Gasparrini M , Forbes-Hernández TY , Cianciosi D , Reboredo-Rodriguez P , et al. The inhibitory effect of Manuka honey on human colon cancer HCT-116 and LoVo cell growth. Part the suppression of cell proliferation, promotion of apoptosis and arrest of the cell cycle. Food Funct. 2018;9(4):2145–57.

[12] 

Alasalvar C , Salvadó JS , Ros E . Bioactives and health benefits of nuts and dried fruits. Food Chem. 2020;314:126192.

[13] 

Forbes-Hernández TY , Giampieri F , Gasparrini M , Afrin S , Mazzoni L , Cordero MD , et al. Lipid accumulation in HepG2 cells is attenuated by strawberry extract through AMPK activation. Nutrients. 2017;9(6):621.

[14] 

Nediani C , Ruzzolini J , Romani A , Calorini L . Oleuropein, a bioactive compound from Olea europaea L. , as a potential preventive and therapeutic agent in non-communicable diseases. Antioxidants. 2019;8(12):578.

[15] 

Muceniece R , Klavins L , Kviesis J , Jekabsons K , Rembergs R , Saleniece K , et al. Antioxidative, hypoglycaemic and hepatoprotective properties of five Vaccinium spp. berry pomace extracts. J Berry Res. 2019;9:267–82.

[16] 

Alvarez-Suarez JM , Giampieri F , Brenciani A , Mazzoni L , Gasparrini M , González-Paramás AM , et al. Apis mellifera vs Melipona beecheii Cuban polifloral honeys: A comparison based on their physicochemical parameters, chemical composition and biological properties. LWT- Food Sci Technol. 2018;87:272–9.

[17] 

Pistollato F , Iglesias RC , Ruiz R , Aparicio S , Crespo J , Lopez LD , et al. Nutritional patterns associated with the maintenance of neurocognitive functions and the risk of dementia and Alzheimer’s disease: A focus on human studies. Pharmacol Res. 2018;131:32–43.

[18] 

Morand C , Tomás-Barberán FA . Contribution of plant food bioactives in promoting health effects of plant foods: why look at interindividual variability? Eur J Nutr (2019;58(Suppl 2):13–9.

[19] 

Mazzoni L , Perez-Lopez P , Giampieri F , Alvarez-Suarez JM , Gasparrini M , Forbes-Hernandez TY , et al. The genetic aspects of berries: from field to health. J Sci Food Agric. 2016;96(2):365–71.

[20] 

Çanadanović-Brunet J , Tumbas Šaponjac V , Stajçić S , Ćetković G , Çanadanović V , Ćebović T , Vulić J . Polyphenolic composition, antiradical and hepatoprotective activities of bilberry and blackberry pomace extracts. J Berry Res. 2019;9:349–62.

[21] 

Giampieri F , Alvarez-Suarez JM , Cordero MD , Gasparrini M , Forbes-Hernandez TY , Afrin S , et al. Strawberry consumption improves aging-associated impairments, mitochondrial biogenesis and functionality through the AMP-activated protein kinase signaling cascade. Food Chem. 2017;234:464–71.

[22] 

Sajadimajd S , Bahramsoltani R , Iranpanah A , Kumar Patra J , Das G , Gouda S , et al. Advances on Natural Polyphenols as Anticancer Agents for Skin Cancer. Pharmacol Res. 2020;151:104584.

[23] 

Cianciosi D , Simal-Gándara J , |Forbes-Hernández TY . The importance of berries in the human diet. Med J Nutr Metab. 2019;12:335–40.

[24] 

Halliwell B . Free radicals and antioxidants: updating a personal view. Nutr Rev. 2012;70(5):257–65.

[25] 

Berger RG , Lunkenbein S , Ströhle A , Hahn A . Antioxidants in food: mere myth or magic medicine? Crit Rev Food Sci Nutr (2012;52(2):162–71.

[26] 

Halliwell B . Free radicals and antioxidants –quo vadis? Trends Pharmacol Sci (2011;32:125–30.

[27] 

Halliwell B . Free Radicals in Biology and Medicine, 4th ed. Oxford, UK: Oxford University Press; 2007.

[28] 

Iannitti T , Palmieri B . Antioxidant therapy effectiveness: an up to date. Eur Rev Med Pharmacol Sci. 2009;13(4):245–78.

[29] 

Murphy MP . Antioxidants as therapies: can we improve on nature? Free Radic Biol Med (2014;66:20–3.

[30] 

Fusco D , Colloca G , Lo Monaco MR , Cesari M . Effects of antioxidant supplementation on the aging process. Clin Interv Aging. 2007;2(3):377–87.

[31] 

Bjelakovic G , Nikolova D , Gluud LL , Simonetti RG , Gluud C . Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;(3):CD007176.

[32] 

Stranges S , Marshall JR , Natarajan R , Donahue RP , Trevisan M , Combs GF , et al. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med. 2007;147:217–23.

[33] 

Kirsh VA , Hayes RB , Mayne ST , Chatterjee N , Subar AF , Dixon LB , et al. Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst. 2006;98:245–54.

[34] 

Bardia A , Tleyjeh IM , Cerhan JR , Sood AK , Limburg PJ , Erwin PJ , Montori VM . Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and metaanalysis. Mayo Clin Proc. 2008;83:23–34.

[35] 

Martínez ME , Jacobs ET , Baron JA , Marshall JR , Byers T . Dietary supplements and cancer prevention: balancing potential benefits against proven harms. J Natl Cancer Inst. 2012;104(10):732–9.

[36] 

Lee IM , Cook NR , Gaziano JM , Gordon D , Ridker PM , Manson JE , et al. Vitamin E in the primary prevention of cardiovascular disease and cancer. The women’s health study: a randomized controlled trial. JAMA. 2005;294:56–65.

[37] 

Sesso HD , Buring JE , Christen WG , Kurth T , Belanger C , et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008;300:2121–33.

[38] 

Hatzigeorgiou C , Taylor AJ , Feuerstein IM , Bautista L , O’malley PG . Antioxidant vitamin intake and subclinical coronary atherosclerosis. Prev Cardiol. 2006;9:75–81.

[39] 

Cook NR , Albert CM , Gaziano JM , Zaharris E , Macfadyen J , Danielson E , et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610–8.

[40] 

Gray SL , Anderson ML , Crane PK , Breitner JC , Mccormick W , Bowen JD , et al. Antioxidant vitamin supplement use and risk of dementia or Alzheimer’s disease in older adults. J Am Geriatr Soc. 2008;56:291–5.

[41] 

Weber CA , Ernst ME . Antioxidants, supplements, and Parkinson’s disease. Ann Pharmacother. 2006;40:935–8.

[42] 

Wang D , Wei Y , Wang T , Wan X , Yang CS , Reiter RJ , Zhang J . Melatonin attenuates (-)-epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice. J Pineal Res. 2015;59(4):497–507.

[43] 

Mendes-da-Silva RF , Lopes-de-Morais AA , Bandim-da-Silva ME , Cavalcanti Gde A , Rodrigues AR , Andrade-da-Costa BL , Guedes RC . Prooxidant versus antioxidant brain action of ascorbic acid in well-nourished and malnourished rats as a function of dose: a cortical spreading depression and malondialdehyde analysis. Neuropharmacology. 2014;86:155–60.

[44] 

Blumberg J , Block G . The alpha-tocopherol, beta-carotene cancer prevention study in finland. Nutr Rev. 1994;52(7):242–5.

[45] 

Kumar H , Kim IS , More SV , Kim BW , Choi DK . Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep. 2014;31(1):109–39.

[46] 

Gugliandolo A , Bramanti P , Mazzon E . Activation of Nrf2 by natural bioactive compounds: a promising approach for stroke? Int J Mol Sci. 2020;21(14):E4875.

[47] 

Ooi BK , Chan KG , Goh BH , Yap WH . The role of natural products in targeting cardiovascular diseases via Nrf2 pathway: novel molecular mechanisms and therapeutic approaches. Front Pharmacol. 2018;9:1308.

[48] 

Rusu ME , Gheldiu AM , Mocan A , Vlase L , Popa DS . Anti-aging potential of tree nuts with a focus on the phytochemical composition, molecular mechanisms and thermal stability of major bioactive compounds. Food Funct. 2018;9(5):2554–75.