There is an interest in the use of compounds able to prevent organism damages. Antioxidants are such compounds that can protect from cells damages caused by free radicals and may be used in the treatment and prevention on many diseases, such as cancer, cardiovascular disease, diabetes, brain stroke, skin diseases as well as they delay the aging process. There are many sources of antioxidants. They can be synthetic or natural and especially those derived from natural sources, demand special attention. Phenolic compounds are substances which mainly possess such activity, but also vitamins and minerals. There are a lot of antioxidants, but in that review, the chosen compounds with outstanding antioxidant activity, mainly used in pharmaceuticals and cosmetics were described. The review shows the activity of phenolic acids (ferulic acid and caffeic acid) and polyphenols (ellagic acid, curcumin, genistein, hydroxytyrosol, resveratrol) and vitamins (C and E).

Keywords: antioxidants, polyphenols, ellagic acid, ferulic acid, hydroxytyrosol, resveratrol, vitamins

Antioxidants are compounds having ability to scavenge free radicals and inhibit the oxidation of moieties. Free radicals are reactive molecules or atoms containing an unpaired electron and they tend to react with another molecules, to gain electron and stabilize themselves. The formation of free radicals is a risk for all tissues. Free radicals affect lipids, proteins, enzymes, nucleic acids, what leads to damage cells, faster process of aging and moreover cancer disease as a result of destruction of the genetic cell material. These free radicals are formed as a result of action of many factors such as UV radiation, high temperature, environmental pollution, nicotine or drugs.¹

Antioxidants can be synthetic or natural and especially those derived from natural sources, demand special attention. There are many phenolic compounds, vitamins and minerals having antioxidant properties. Plant extracts are often used due to the richness of antioxidant compounds. Antioxidants can be administered both orally and topically. They are commonly used in systemic therapy to protect people from the risk of cancer, cardiovascular disease, diabetes, brain stroke, cataract. Moreover, they decrease the effects of aging and protect also against extremely skin-aging. Free radicals lead to the most typical histological and clinical signs of skin photoaging. They affect damage the lipid components of sebum, oxidation of polyunsaturated fatty acids forming the composition of phospholipids in cell membranes as well as destruction of collagen and elastin fibers and hyaluronic acid in dermis. The results are premature wrinkling, pigmentary changes, lack of skin firmness and elasticity, excessive skin dryness as well as a weakness of the immune skin system and increase the risk of skin cancer.^2‒4

There is also growing interest for non-sunscreen photoprotective agents. Topical antioxidants are commonly used in combination with sunscreen to enhance their efficacy and offer greater protection to patients. Non-sunscreen materials such as antioxidants may further decrease UV-induced damages compared with sunscreen alone.⁵

That knowledge about action of free radicals induces to constantly searching for substances able to prevent from many diseases as well as cutaneous damages.

Ferulic acid

Phenolic acids have very good antioxidant potential. Ferulic acid, one of the hydroxycinnamic acids, naturally occurs in many plants. It is commonly found in tomatoes, blueberries, blackberries, strawberries, cereal grains (Figure 1).^6‒8

Figure 1 Ferulic acid.⁹

Ferulic acid may act as antioxidant by different mechanisms such as scavenging reactive oxygen species, metal chelation and inhibition lipid peroxidation.^9,10 Moreover, ferulic acid absorbs UV and inhibits inflammatory reactions induced by UV such as erythema, sunburn. Such action plays the role in delaying the skin aging and prevents cancer. Furthermore, ferulic acid stabilizes vitamin C, which makes it more effective.^11,12 These all properties make the ferulic acid be used as a health promoter.

Oxidative stress is one of the agent which induces the development of diabetic nephropathy. Experiments showed the antioxidant effect of ferulic acid by decreasing the formation of reactive oxygen species and anti-inflammatory mechanism in rats of type 2 diabetes. Morphological changes in kidneys rats were reduced by treatment with ferulic acid. Therefore ferulic acid may be protective agent in diabetic nephropathy.¹³

Protective role of ferulic acid on sepsis- induced oxidative damage in the lymphocytes, liver and kidney cells was presented. Protective role of ferulic acid on sepsis- induced oxidative damage in the lymphocytes, liver and kidney cells was presented. The results indicated that DNA damages in sepsis in a ferulic acid-treated group was lower.¹⁴

Nicotine plays a significant role in the development of lung cancer through the increasing free radical production. Ferulic acid exerts protective effect against nicotine toxicity and decreases the lipid peroxidation and DNA damages in nicotine-treated rats.^15,16 Furthermore, ferulic acid can be used as a potential treatment for cancer via its antiproliferative activity.¹⁷ Such actions might be useful in prevention of lung cancer. Ferulic acid shows also cardioprotective effect. The use of ferulic acid in the treatment of cardiovascular diseases resulted in decrease the blood pressure.^18,19

Derivatives of ferulic acid also demonstrate an antioxidant activity such as ester derivative of ferulic acid- isopentyl ferulate. Studies revealed that isopentyl ferulate is a good modification of ferulic acid, suggesting that can be used as a new antioxidant agent. Its antioxidant capacity was evaluated by in vitro methods. The radical scavenging ability was assessed by DPPH and ABTS tests. Moreover, an antioxidant capacity against the hydroxyl radical and nitric oxide were also evaluated as well as the inhibition of lipid peroxidation by TBARS method.²⁰

Caffeic acid

Another hydroxycinnamic acid possessing an antioxidant activity is caffeic acid, presents in fruits, wine, coffee and olive oil (Figure 2).^21,22

Figure 2 Caffeic acid.⁹

Caffeic acid exerts a very good radical scavenging effect, which was confirmed in different in vitro antioxidant assays.^9,21,23 The antioxidant properties of caffeic acid affect against many global diseases. Caffeic acid indicated the neuroprotective activity on cerebral ischemia-reperfusion injury in rats, which action was likely mediated through the inhibition of 5- lipoxygenase.²²

Moreover, the modification of caffeic acid by the addition of glucose could improve its biological properties. Studies demonstrated that enzymatic glucosylation of caffeic acid improved its antioxidant activity in a skin cells models.²⁴

Ellagic acid

Polyphenols have extraordinary antioxidant potential. Ellagic acid, one of the polyphenolic compounds, naturally occurs in various fruits and seeds, such as strawberries, raspberries, grapes, pomegranates. That potential antioxidant can be introduced by diet, pharmaceutical preparations or used as anti-aging agent to external application on the skin (Figure 3).²⁵

Figure 3 Ellagic acid.²⁶

Ellagic acid demonstrates a great radical scavenging activity. Its antioxidant properties were measured by using the in vitro methods such as DPPH, ABTS, FRAP, ORAC and lipid peroxidation assays. Results indicated that ellagic acid may be useful in prevention of many diseases which are induced by the formation of free radicals.^27,28

Liver injuries are often caused by oxidative stress and inflammation reaction. Ellagic acid exerted the protective effect against acute hepatic injury in mice. Results indicated that ellagic acid pretreatment prevent against lipopolysaccharide/D-galactosamine-induced liver injury, by increasing the antioxidative defense system and reducing inflammatory response.²⁹ Ellagic acid protected hepatocytes from damages in mice. That role of relied on prevention vitamin k3-induced reactive oxygen species production and therefore protects against liver cell death.³⁰

Problems with cardiovascular system are often the result of unhealthy lifestyle and the formation of reactive free radicals in organism. Unfortunately, synthetic drugs are commonly used for the treatment of prevention of such diseases. These drugs may certainly adverse side effects. Therefore there is looking for natural compounds showing the therapeutic action.³¹ Alternative therapies using naturally compounds to protect organism from damages such as heart diseases are becoming popular. The cardioprotective effect of ellagic acid against experimentally induced cardiac arrhythmias in rats was evaluated. Results indicated that oral pretreatment with ellagic acid was effective in cardioprotection and prevented from myocardial infarction. The function of ellagic acid was probably based on inhibition the lipid peroxidation and reduction the concentration of triglycerides and cholesterol in the plasma.^32,33 Studies performed on rabbits indicated that ellagic acid could prevent atherosclerosis via suppression of oxidative stress and cell apoptosis.³⁴

Nowadays cancer is frequently occurring disease and a novel strategy for the prevention and treatment are constantly needed. Ellagic acid is able to inhibit the growth of several cancer cells by inhibiting the proliferation. The results indicated the potential antioxidative and chemopreventive effect of ellagic acid. Ellagic acid exhibits potent anticancer activities towards breast, colorectal, ovarian, pancreatic, melanoma and lymphoma cells.^35‒39

Skin exposure to UV leads to skin damages such as sunburn, irritations and accelerates the aging process of the skin and induces skin cancer. There is growing interest in the use of natural components in photoprotection. Dietary or pharmacological intervention of ellagic acid delayed the skin aging process induced by UV radiation. Ellagic acid exerted the photoprotective effect on collagen breakdown in UVB-irradiated human skin cells and hairless mice. Ellagic acid prevented from collagen degradation by blocking matrix metalloproteinase production in UVB-exposed fibroblasts. Also topical administration of ellagic acid reduced production of pro-inflammatory cytokines in UVB-exposed hairless mice. That demonstrated that ellagic acid prevents collagen destruction and therefore shows anti-wrinkle activity. Moreover anti-inflammatory properties of ellagic acid lead to its use in prevention of skin photoaging and skin cancer.²⁶ Ellagic acid protected from dermal elastin degradation. Pretreatment with that polyphenol decreased proteolytic degradation of elastin and enhanced it synthesis in aged skin.⁴⁰

Curcumin

Curcumin is a polyphenol derived from turmeric (Curcuma longa), which is very often used as a food additive (Figure 4).⁴¹

Figure 4 Curcumin.⁴²

Curcumin showed anti-photoaging effect by inhibiting UVB-induced matrix metalloproteinases expression in human dermal fibroblasts, which are responsible for collagen degradation in skin. Moreover, curcumin suppressed the reactive oxygen species formation in fibroblast cells.^41,43

The treatment with curcumin indicated essential cardioprotective effects against cardiovascular diseases, which can be induced by high fat diet and obesity. In cardiac H9c2 cells the reactive oxygen species formation, fibrosis and hypertrophy of tissue, as well as apoptosis of cells were suppressed after oral administration of curcumin. The therapeutic effect of curcumin was associated with its capability to activate Nrf2 and inactivate NF-κB.⁴³

The therapeutic activity of curcumin may be hindered by its poor water solubility. Therefore, the complex of curcumin with sulfobutylether-β-cyclodextrin, glucosyl conjugates of curcumin and tetrahydrocurcumin resulted significantly better water solubility as well as showed antioxidant activity.^44,45 The novel monocarbonyl analogues of curcumin (MACs) limited myocardial ischemia reperfusion injury through activating Nrf2. First, these curcumin analogues increased its stability, second exerted an antioxidant activity. Studies on H9c6 cells showed the inhibition of oxidant stress parameters. Experiments in animal model indicated the reduction of infarct size and myocardial apoptosis after administration of curcumin.⁴²

Genistein

Genistein is a flavonoid known for modulating activity of estrogens but also characterizes antioxidant and photoprotective activity. Genistein occurs in many leguminous plants but especially in soybeans (Figure 5).^46-48

Figure 5 Genistein.⁴⁹

Genistein showed the inhibition of the processes inducted by UV such as photo-aging and photodamages. In human fibroblasts irradiated with UVB, genistein suppressed activity of senescence-associated beta-galactosidase (SA-β-gal), which is a biomarker of aging. Moreover, genistein reduced the activity of proteins p66Shc and FKHRL1, which are involved in the production of free radicals and consequently oxidative stress.⁴⁷

That flavonoid is effective in protecting cells against DNA oxidative damages. The activity was also confirmed by the reduction of DNA strand breaks in lymphocytes.⁵⁰ Genistein ameliorated degenerative changes in cardiac tissue and improved the function of the diabetic myocardium by its anti-inflammatory and antioxidant effects.⁵¹ Furthermore its neuroprotective effect in traumatic brain injury was demonstrated, which activity was confirmed by inhibition the disruption of blood-brain-barrier.⁵² Genistein improved also antioxidant status of kidney in nephrotic syndrome.⁵³

Hydroxytyrosol

Hydroxytyrosol is one of the major phenolic compounds that occurs in olive oil (Figure 6).^54,55

Figure 6 Hydroxytyrosol.⁵⁶

The main olive component- hydroxytyrosol is an efficient scavenger of several free radicals species such as hydroxyl radicals, superoxide radicals, peroxynitrite.^57,58 Hydroxytyrosol indicates anti-proliferative and apoptotic activities which lead to anti-cancer action.^59‒61 Studies on human breast cancer on MCF-7 cells models indicated that hydroxytyrosol reduced cell viability, cell proliferation and cell cycle, which led to cell death.⁵⁹ Anti-cancer effect of hydroxytyrosol on human colon adenocarcinoma cells was exerted through its ability to induce apoptosis by generating reactive oxygen species in colon cancer cells and anti-proliferative activity.^60,61

Hydroxytyrosol protects against UVB-induced DNA damages. Research on human skin keratinocyte cell line HaCaT, after exposed them to UVB and treated with hydroxytyrosol, demonstrated the reduction of DNA damages caused by UVB. Furthermore hydroxytyrosol reduced intracellular reactive oxygen species formation caused by UVB.⁶² Pre-treated human keratinocytes with hydroxytyrosol before UVB exposure also decreased their apoptosis, what is important in protection from skin damages.⁶³ Anti-apoptotic activity of hydroxytyrosol was shown in studies on human monocytic cell line and murine myoblasts cell model. Hydroxytyrosol was the protective agent against H₂O₂, one of the reactive oxygen species, which induced the apoptotic death in cell lines.⁶⁴

Oxidative stress is involved in the pathogenesis of various diseases. Hydroxytyrosol can reduce it. It exerted an antioxidant action by inhibiting the production of oxidation products in kidney cells, therefore protected them from damage and renal dysfunction.⁵⁶ The neuroprotective effect of hydroxytyrosol in mice brain and neuroblastoma cells was also associated with decreased of oxidative stress. That improved the neuron survival after hydroxytyrosol administered.⁶⁵ Furthermore, hydroxytyrosol exhibited the protective role against oxidative and morphological changes induced by mercury in human erythrocytes. Hydroxytyrosol treatment prevented from hemolysis and reactive oxygen species generation.⁶⁶

Hydroxytyrosol showed also protective effect in an animal model suffering on rheumatoid arthritis. Hydroxytyrosol supplementation decreased histological damages and improved articular function in treated animals.⁶⁷ Modifications of hydroxytyrosol may also increase its antioxidant activity. Inclusion a lipophilic chain in the hydroxytyrosol molecule may enhance that activity. Lipophilic hydroxytyrosyl esters showed greater radical scavenging capacity and the protection against protein and lipid oxidation.⁶⁸ Ester derivatives of hydroxytyrosol penetrate better through human epidermis so they constitute an effective antioxidant for potential topical administration.⁶⁹ The antioxidant effect of ester hydroxytyrosol laurate carried out on human monocytoid cell line and murine myoblasts cell model resulted in better antioxidant capacity against H₂O₂ than hydroxytyrosol.⁶⁴

Resveratrol

Resveratrol, a natural plant polyphenol, commonly occurs in dark grapes, red wine, grapefruits, having strong antioxidant activity as well as inhibits carcinogenesis (Figure 7).⁷⁰

Figure 7 Resveratrol.⁷¹

Resveratrol indicates the scavenging DPPH activity and is effective in inhibiting lipid oxidation.⁷² Moreover, the natural resveratrol dimers such as parthenocissin A, quadrangularin A and pallidol were observed to have better scavenging effects toward DPPH radical than resveratrol monomer.⁷¹ Pallidol is a naturally occuring resveratrol dimer from red wine and it demonstrated the strong quenching effects on singlet oxygen.⁷³ The findings showed the potential of resveratrol as a possible agent to reduce lung injury. Resveratrol protected from histopathological changes in the lung during endotoxemia by increasing the anti-oxidant biomarkers. Such activity decreased oxidative stress in endotoxemic lung.⁷⁴

Next promising effect of resveratrol is photoprotection. Resveratrol showed the chemopreventive effect against UVB-induced damages in hairless mouse skin. Topical pretreatment of resveratrol resulted in inhibition of UVB-induced adverse effects.⁷⁵ Pretreatment of resveratrol on UVB-treated HaCaT cells resulted in an increase in cell survival. The generation of reactive oxygen species was also attenuated. Therefore, resveratrol attenuated UVB-induced damages and indicated the photoprotective action.⁷⁶ The derivative of resveratrol- resveratrate, exerted also photoprotective effect on human skin. Resveratrate inhibited erythema on UV-irradiated skin and inhibited sunburn cell formation.⁷⁷

Furthermore, resveratrol exerts significant cardioprotective effect.⁷⁸ Studies in rats indicated that resveratrol reduced infarct size and improved ventricular function after myocardial infarction.^79,80 Resveratrol decreased myocardial damages by inducing the growth of new capillary vessels and their density, so that maintained the blood flow to the myocardium.⁸⁰ Besides, resveratrol attenuated ventricular arrhythmias and extended the survival of rats with myocardial infarction.⁸¹ Potential cardioprotective activity of resveratrol might be associated with protection cardiomyocytes from ischemia or hypoxia-induced their apoptosis.⁸² Resveratrol also protected against development of type 2 diabetic vascular disease.⁸³

Vitamin C

Vitamins possess also an antioxidant activity.^48,84,85

Vitamin C (L-ascorbic acid), mainly occurs in citrus, but also in wild rose, raspberries, strawberries, cranberries, blueberries. The main activity of vitamin C is to donate electrons and neutralize free radicals. Moreover vitamin C regenerates another antioxidant- vitamin E (Figure 8).^84‒87 Vitamin C indicates an antioxidant activity which was confirmed by antioxidants assays (TEAC, FRAP, HOCl).⁸⁸

Figure 8 Vitamin C.⁸⁴

Vitamin C alleviated the inflammation through reducing the levels of inflammatory and metabolic markers such as interleukins, triglyceride, which was demonstrated in hypertensive and diabetic obese adults.⁸⁹ Topical treatment with vitamin C in photoaged human skin, indicated the improvement of skin hydration, firmness and reduction of superficial wrinkles and skin roughness.⁹⁰ Vitamin C stimulated the synthesis of collagen and elastin, remodeling elastic fibres in sun-damaged skin as well as prevented erythema and inhibited sunburn cells formation caused by UV exposure.^87,90

Vitamin C supplementation in mice showed protective effect against cantharidin-induced liver injuries. Canthadrin is an anti-cancer medication which possesses hepatic toxicity. Also vitamin C demonstrated hepatoprotective activity against chemical liver damage induced by concanavalin A- a lectin. Toxicity within hepatocytes was reduced through inhibition of NF-κB signal pathway.^91,92

Vitamin E

Vitamin E is the form of tocopherols and tocotrienols. α-tocopherol is the most biologically active form of vitamin E (Figure 9).^84,85

Figure 9 α-tocopherol.⁸⁴

Vitamin E occurs in wheat, corn, nuts, lettuce, spinach, cabbage. It is one of the main factors that prevents body from free radicals, protects proteins against oxidation, therefore also elastic and collagen fibers in the skin. Due to these antioxidant properties, vitamin E protects the skin from aging.^{48,84,85,93,94}

Topical use of vitamin E provides photoprotection by both antioxidant and UV absorptive properties. The use of vitamin E formulation protected against irritations caused by UV and prevented skin damages.⁹⁵ Moreover, the combination of vitamin E with vitamin C is recommended due to enhance antioxidant activity. Vitamin C and E provided essential photoprotection for the skin. Taken together in topical formulations, protected from erythema-induced by UV exposure and decreased the number of sunburn cells. Moreover they reduced thymine dimer mutations known to be associated with skin cancer.¹¹

Vitamin E indicated chemoprotective effect in protecting liver tissue from damages caused by cyclophosphamide (CP), which is used in the treatment of cancer or autoimmune diseases. It has serious, life-threatening side effects and toxic effect on liver tissue. Therefore it may be administered with an antioxidant such as vitamin E, which much decreased changes of histological structure of cells apoptosis.⁹⁶

Furthermore, vitamin E improved the action of chemotherapeutic medications such as Paclitaxel (PTX) or Doxorubicin, which have antiproliferative activity in cancer cells. Anti-cancer activity of PTX against breast cancer was significantly improved with inclusion the vitamin E compare to free PTX. That may improve the chemotherapy of breast cancer by enhance the efficiency and decrease toxicity of PTX. Also, vitamin E loaded with Doxorubicin showed the enhancement of anticancer activity.^97,98

Antioxidants are compounds, which exhibit beneficial effect on human health by protection against ultraviolet radiation and free radicals. Human cells are permanently damaged by constant attacks from free radicals which may lead to photocarcinogenesis, immunosuppression and photoaging. That induces a lot of diseases as well as influence adverse on skin condition. Antioxidants prevent from such changes, therefore may be used in the treatment and delay the aging process.³

Phenolic compounds are substances possessing extraordinary antioxidant activity. The most important antioxidants having ability to neutralize free radicals and protect from ultraviolet radiation are polyphenols such as: ellagic acid, curcumin, genistein, hydroxytyrosol, resveratrol as well as phenolic acids: ferulic acid and caffeic acid. Moreover vitamin C and E also exhibit outstanding antioxidant activity. These components with specific activity, different mechanisms of action and possibility of application could be further utilized both in medicine and cosmetic and food industries.

None.

The authors declare that there is no conflict of interest.

1. Sarbak Z, Jachymska‒Sarbak B, Sarbak A. Chemia w kosmetyce i kosmetologii. MedPharm: Poland; 2013.
2. Andreassi M, Andreassi L. Antioxidants in dermocosmetology: from the laboratory to clinical application. J Cosmet Dermatol. 2003;2(3‒4):153‒160.
3. Ganceviciene R, Liakou AI, Theodoridis A, et al. Skin anti‒aging strategies. Dermatoendocrinol. 2012;4(3):308‒319.
4. Molski M. Chemia piękna. PWN, Poland: Warsaw; 2009.
5. Matsui MS, Hsia A, Miller JD, et al. Non‒Sunscreen Photoprotection: Antioxidants Add Value to a Sunscreen. J Investig Dermatol Symp Proc. 2009;14(1):56‒59.
6. Sellappan S, Akoh CC, Krewer G. Phenolic compounds and antioxidant capacity of Georgia‒grown blueberries and blackberries. J Agric Food Chem. 2002;50(8):2432‒2438.
7. Sri Balasubashini M, Rukkumani R, Menon VP. Protective effects of ferulic acid on hyperlipidemic diabetic rats. Acta Diabetol. 2003;40(3):118‒122.
8. Aaby K, Ekeberg D, Skrede G. Characterization of phenolic compounds in strawberry (Fragaria x ananassa) fruits by different HPLC detectors and contribution of individual compounds to total antioxidant capacity. J Agric Food Chem. 2007;55(11):4395‒4406.
9. Maurya DK, Devasagayam TP. Antioxidant and prooxidant nature of hydroxycinnamic acid derivatives ferulic and caffeic acids. Food Chem Toxicol. 2010;48(12):3369‒3373.
10. Shirou Itagaki, Toshimitsu Kurokawa, Chie Nakata, et al. In vitro and in vivoantioxidant properties of ferulic acid: a comparative study with other natural oxidation inhibitors. Food Chemistry. 2009;114(2):466–471.
11. Murray JC, Burch JA, Streilein RD, et al. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol. 2008;59(3):418‒425.
12. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol. 2005;52(6):937‒958.
13. Choi R, Kim BH, Naowaboot J, et al. Effects of ferulic acid on diabetic nephropathy in a rat model of type 2 diabetes. Exp Mol Med. 2011;43(12):676‒683.
14. Bacanli M, Aydin S, Taner G, et al. The protective role of ferulic acid on sepsis‒inducedoxidative damage in Wistar albino rats. Environ Toxicol Pharmacol. 2014;38(3):774‒782.
15. Sudheer AR, Muthukumaran S, Kalpana C, et al. Protective effect of ferulic acid on nicotine‒induced DNA damage and cellular changes in cultured rat peripheral blood lymphocytes: a comparison with N‒acetylcysteine. Toxicol In Vitro. 2007;21(4):576‒585.
16. Sudheer AR, Muthukumaran S, Devipriya N, et al. Influence of ferulic acid on nicotine‒induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N‒acetylcysteine. Toxicology. 2008;243(3):317‒329.
17. Janicke B, Hegardt C, Krogh M, et al. The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p‒coumaric acid on the cell cycle of Caco‒2 cells. Nutr Cancer. 2011;63(4):611‒622.
18. Ardiansyah, Ohsaki Y, Shirakawa H, et al. Novel effects of a single administration of ferulic acid on the regulation of blood pressure and the hepatic lipid metabolic profile in stroke‒prone spontaneously hypertensive rats. J Agric Food Chem. 2008;56(8):2825‒2830.
19. Alam MA, Sernia C, Brown L. Ferulic acid improves cardiovascular and kidney structure and function in hypertensive rats. J Cardiovasc Pharmacol. 2013;61(3):240‒249.
20. Machado KC, Oliveira GL, De Sousa ÉB, et al. Spectroscopic studies on the in vitro antioxidant capacity of isopentyl ferulate. Chem Biol Interact. 2015;225:47‒53.
21. Gülçin I. Antioxidant activity of caffeic acid (3,4‒dihydroxycinnamic acid). Toxicology. 2006;217(2‒3):213‒220.
22. Liang G, Shi B, Luo W, et al. The protective effect of caffeic acid on global cerebral ischemia‒reperfusion injury in rats. Behav Brain Funct. 2015;11:18.
23. Mori H, Iwahashi H. Antioxidant activity of caffeic acid through a novel mechanism under UVA irradiation. J Clin Biochem Nutr. 2009;45(1):49‒55.
24. Nadim M, Auriol D, Lamerant‒FayeL N, et al. Improvement of polyphenol properties upon glucosylation in a UV‒induced skin cell ageing model. Int J Cosmet Sci. 2014;36(6):579‒587.
25. Amakura Y, Okada M, Tsuji S, et al. Determination of ellagic acid in fresh and processed fruits by HPLC. Journal of the Food Hygienic Society of Japan. 2000;41(3):206–211.
26. Bae JY, Choi JS, Kang SW. Dietary compound ellagic acid alleviates skin winkle and inflammation induced by UV‒B irradiation. Exp Dermatol. 2010;19(8):e182‒e190.
27. Thitilertdecha N, Teerawutgulrag A, Kilburn JD, et al. Identification of Major Phenolic Compounds from Nephelium lappaceum L. and Their Antioxidant Activities. Molecules.2010;15(3):1453‒1465.
28. Hayes JE, Allen P, Brunton N, et al. Phenolic composition and in vitro antioxidant capacity of four commercial phytochemical products: Olive leaf extract (Olea europaea L.), lutein, sesamol and ellagic acid. Food Chemistry. 2011;126(3):948–955.
29. Gu L, Deng WS, Liu Y, et al. Ellagic acid protects Lipopolysaccharide/D‒galactosamine‒induced acute hepatic injury in mice. Int Immunopharmacol. 2014;22(2):341‒345.
30. Hwang JM, Cho JS, Kim TH, et al. Ellagic acid protects hepatocytes from damage by inhibiting mitochondria production of reactive oxygen species. Biomed Pharmacother. 2010;64(4):264‒270.
31. Alsheikh‒Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol. 2004;94(7):935‒938.
32. Kannan MM, Quine SD. Ellagic acid ameliorates isoproterenol induced oxidative stress: evidence from electrocardiological, biochemical and histological study. Eur J Pharmacol. 2011;659(1):45‒52.
33. Kannan MM, Quine SD. Ellagic acid inhibits cardiac arrhythmias, hypertrophy and hyperlipidaemia during myocardial infarction in rats. Metabolism. 2013;62(1):52‒61.
34. Yu YM, Chang WC, Wu CH, et al. Reduction of oxidative stress and apoptosis in hyperlipidemic rabbits by ellagic acid. J Nutr Biochem. 2005;16(11):675‒681.
35. Chung YC, Lu LC, Tsai MH, et al. The Inhibitory Effect of Ellagic Acid on Cell Growth of Ovarian Carcinoma Cells. Evid Based Complement Alternat Med. 2013;2013:306705.
36. Losso JN, Bansode RR, Trappey A, et al. In vitro anti‒proliferative activities of ellagic acid. J Nutr Biochem. 2004;15(11):672‒678.
37. Edderkaoui M, Odinokova I, Ohno I, et al. Ellagic acid induces apoptosis through inhibition of nuclear factor 𝜅B in pancreatic cancer cells. World J Gastroenterol. 2008;14(23):3672‒3680.
38. Kim S, Liu Y, Gaber MW, et al. Development of chitosan‒ellagic acid films as a local drug delivery system to induce apoptotic death of human melanoma cells. J Biomed Mater Res B Appl Biomater. 2009;90(1):145‒155.
39. Mishra S, Vinayak M. Anti‒carcinogenic action of ellagic acid mediated via modulation of oxidative stress regulated genes in Dalton lymphoma bearing mice. Leuk Lymphoma. 2011;52(11):2155‒2161.
40. Jimenez F, Mitts TF, Liu K, et al. Ellagic and Tannic Acids Protect Newly Synthesized Elastic Fibers from Premature Enzymatic Degradation in Dermal Fibroblast Cultures. J Invest Dermatol. 2006;126(6):1272‒1280.
41. Hwang BM, Noh EM, Kim JS, et al. Curcumin inhibits UVB‒induced matrix metalloproteinase‒1/3 expression by suppressing the MAPK‒p38/JNK pathways in human dermal fibroblasts. Exp Dermatol. 2013;22(5):371‒374.
42. Li W, Wu M, Tang L, et al. Novel curcumin analogue 14p protects against myocardial ischemia reperfusion injury through Nrf2‒activating anti‒oxidative activity. Toxicol Appl Pharmacol. 2015;282(2):175‒183.
43. Zeng C, Zhong P, Zhao Y, et al. Curcumin protects hearts from FFA‒induced injury by activating Nrf2 and inactivating NF‒κB both in vitro and in vivo. J Mol Cell Cardiol. 2015;79:1‒12.
44. Cutrignelli A, Lopedota A, Denora N, et al. A New Complex of Curcumin with Sulfobutylether‒_‒Cyclodextrin:Characterization Studies and In VitroEvaluation of Cytotoxic and Antioxidant Activity on HepG‒2 Cells. J Pharm Sci. 2014;103(12):3932‒3940.
45. Bhaskar Rao A, Prasad E, Deepthi SS, et al. Synthesis and Biological Evaluation of Glucosyl Curcuminoids. Arch Pharm (Weinheim). 2014;347(11):834‒839.
46. Adamczyk K, Jurzak M, Garncarczyk A, et al. Biological activity of genistein with cosmetic application. Pol J Cosmetol. 2014;17(2):114‒117.
47. Wang YN, Wu W, Chen HC, et al. Genistein protects against UVB‒ induced senescence‒like characteristics in human dermal fibroblasts by p66Shc down‒regulation. J Dermatol Sci. 2010;58(1):19‒27.
48. Alam M, Gladstone HB, Tung RC. Cosmetic Dermatology. Elsevier & Urban Partner, 2009.
49. Grynkiewicz G, Achmatowicz O, Pucko W. Bioaktywny izoflawon genisteina‒ perspektywy zastosowań medycznych. Postępy Fitoterapii. 2000;3:15‒20.
50. Foti P, Erba D, Riso P, et al. Comparison between daidzein and genistein antioxidant activity in primary and cancer lymphocytes. Arch Biochem Biophys. 2005;433(2):421‒427.
51. Gupta SK, Dongare S, Mathur R, et al. Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin‒induced diabetic cardiomyopathy in rats. Mol Cell Biochem. 2015;408(1‒2):63‒72.
52. Soltani Z, Khaksari M, Jafari E, et al. Is genistein neuroprotective in traumatic brain injury? Physiol Behav. 2015;152(Pt A):26‒31.
53. Javanbakht MH, Sadria R, Djalali M, et al. Soy protein and genistein improves renal antioxidant status in experimental nephrotic syndrome. Nefrologia. 2014;34(4):483‒490.
54. Amiot MJ, Fleuriet A, Macheix JJ. Importance and evolution of phenolic compounds in olive during growth and maturation. J. Agric. Food Chem. 1986;34(5):823–826.
55. Bonoli M, Bendini A, Cerretani L, et al. Qualitative and semiquantitative analysis of phenolic compounds in extra virgin olive oils as a function of the ripening degree of olive fruits by different analytical techniques. J Agric Food Chem. 2004;52(23):7026‒7032.
56. Loru D, Incani A, Deiana M, et al. Protective effect of hydroxytyrosol and tyrosol against oxidative stress in kidney cells. Toxicol Ind Health. 2009;25(4‒5):301‒310.
57. Rietjens SJ, Bast A, Haenen GR. New insights into controversies on the antioxidant potential of the olive oil antioxidant hydroxytyrosol. J Agric Food Chem. 2007;55(18):7609‒7614.
58. Umeno A, Takashima M, Murotomi K, et al. Radical‒scavenging Activity and Antioxidative Effects of Olive Leaf Components Oleuropein and Hydroxytyrosol in Comparison with Homovanillic Alcohol. J Oleo Sci. 2015;64(7):793‒800.
59. Han J, Talorete TP, Yamada P, et al. Anti‒proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF‒7 cells. Cytotechnology. 2009;59(1):45‒53.
60. Sun L, Luo C, Liu J. Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. 2014;5(8):1909‒1914.
61. Corona G, Deiana M, Incani A, et al. Hydroxytyrosol inhibits the proliferation of human colon adenocarcinoma cells through inhibition of ERK1/2 and cyclin D1. Mol Nutr Food Res. 2009;53(7):897‒903.
62. Guo W, An Y, Jiang L, et al. The Protective Effects of Hydroxytyrosol Against UVB‒induced DNA Damage in HaCaT cells. Phytother Res. 2010;24(3):352‒359.
63. Salucci S, Burattini S, Curzi D, et al. Antioxidants in the prevention of UVB‒induced keratynocyte apoptosis. J Photochem Photobiol B. 2014;141:1‒9.
64. Burattini S, Salucci S, Baldassarri V, et al. Anti‒apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Food Chem Toxicol. 2013;55:248‒256.
65. Zheng A, Li H, Xu J, et al. Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP‒activated protein kinase activation. Br J Nutr. 2015;113(11):1667‒1676.
66. Tagliafierro L, Officioso A, Sorbo S, et al. The protective role of olive oil hydroxytyrosol against oxidative alterations induced by mercury in human erythrocytes. Food Chem Toxicol. 2015;82:59‒63.
67. Silva S, Sepodes B, Rocha J, et al. Protective effects of hydroxytyrosol‒supplemented refined olive oil in animal modelsof acute inflammation and rheumatoid arthritis. J Nutr Biochem. 2015;26(4):360‒368.
68. Trujillo M, Mateos R, Collantes de Teran L, et al. Lipophilic Hydroxytyrosol Esters. Antioxidant Activity in Lipid Matrices and Biological Systems. J Agric Food Chem. 2006;54(11):3779‒3785.
69. Procopio A, Celia C, Nardi M, et al. Lipophilic Hydroxytyrosol Esters: Fatty Acid Conjugates for Potential Topical Administration. J Nat Prod. 2011;74(11):2377‒2381.
70. Ball S. Antyoksydanty w medycynie i zdrowiu człowieka. Wyd Medyk, Poland: Warszawa; 2001.
71. Li C, Xu X, Tao Z, et al. Resveratrol dimers, nutritional components in grape wine, are selective ROS scavengers and weak Nrf2 activators. Food Chem. 2015;173:218‒223.
72. Zhang Y, Shen Y, Yongchao Zhu, et al. Assessment of the correlations between reducing power, scavenging DPPH activity and anti‒lipid‒oxidation capability of phenolic antioxidants. LWT ‒ Food Science and Technology. 2015;63(1):569‒574.
73. He S, Jiang L, Wu B, et al. Pallidol, a resveratrol dimer from red wine, is a selective singlet oxygen quencher. Biochem Biophys Res Commun. 2009;379(2):283‒287.
74. Zhang HX, Duan GL, Wang CN, et al. 2014. Protective effect of resveratrol against endotoxemia‒induced lung injury involves the reduction of oxidative/nitrative stress. Pulm Pharmacol Ther. 2014;27(2):150‒155.
75. Aziz MH, Afaq F, Ahmad N. Prevention of Ultraviolet‒B Radiation Damage by Resveratrol in Mouse Skin Is Mediated via Modulation in Survivin. Photochem Photobiol. 2005;81(1):25‒31.
76. Park K, Lee JH. Protective effects of resveratrol on UVB‒irradiated HaCaT cells through attenuation of the caspase pathway. Oncol Rep. 2008;19(2):413‒417.
77. Wu Y, Jia LL, Zheng YN, et al. Resveratrate protects human skin from damage due to repetitive ultraviolet irradiation. J Eur Acad Dermatol Venereol. 2013;27(3):345‒350.
78. Lin JF, Wu S, Huang SS, et al. Resveratrol Protects Left Ventricle by Increasing Adenylate Kinase 1 and Isocitrate Dehydrogenase Activities in Rats with Myocardial Infarction. Chin J Physiol. 2011;54(6):406‒412.
79. Lin JF, Lin SM, Chih CL, et. al. Resveratrol reduces infarct size and improves ventricular function after myocardial ischemia in rats. Life Sci. 2008;83(9‒10):313‒317.
80. Fukuda S, Kaga S, Zhan L,et al. Resveratrol Ameliorates Myocardial Damage by Inducing Vascular Endothelial Growth Factor‒Angiogenesis and Tyrosine Kinase Receptor Flk‒1. Cell Biochem Biophys. 2006;44(1):43‒49.
81. Chen YR, Yi FF, Li XY, et al. Resveratrol Attenuates Ventricular Arrhythmias and Improves the Long‒Term Survival in Rats with Myocardial Infarction. Cardiovasc Drugs Ther. 2008;22(6):479‒485.
82. Chen CJ, Yu W, Fu YC, et al. Resveratrol protects cardiomyocytes from hypoxia‒induced apoptosis through the SIRT1–FoxO1 pathway. Biochem Biophys Res Commun. 2009;378(3):389‒393.
83. Xu Q, Hao X, Yang Q, et al. Resveratrol prevents hyperglycemia‒induced endothelial dysfunction via activation of adenosine monophosphate‒activated protein kinase. Biochem Biophys Res Commun. 2009;388(2):389‒394.
84. Molski M. Nowoczesna kosmetologia. Tom 2 PWN, Poland: Warsaw; 2014.
85. Sikorski Z. Chemia żywności. Tom 3. Wydawnictwo Naukowo‒Techniczne, Poland: Warszawa; 2007.
86. Wawer I. Suplementy dla Ciebie. Wektor, Poland: Warsaw; 2009.
87. Adamski Z, Kaszuba A. Dermatologia dla kosmetologów. Elsevier Urban & Partner, Poland: Wroclaw; 2010.
88. Ramful D, Tarnus E, Aruoma OI, et al. Polyphenol composition, vitamin C content and antioxidant capacity of Mauritian citrus fruit pulps. Food Research International. 2011;44(7):2088‒2099.
89. Ellulu MS, Rahmat A, Patimah I, et al. Effect of vitamin C on inflammation and metabolic markers in hypertensive and/or diabetic obese adults: a randomized controlled trial. Drug Des Devel Ther. 2015;1;9:3405‒3412.
90. Haftek M, Mac‒Mary S, Le Bitoux MA, et al. Clinical, biometric and structural evaluation of the long‒term effects of a topical treatment with ascorbic acid and madecassoside in photoaged human skin. Exp Dermatol. 2008;17(11):946‒952.
91. Wu W, Su M, Li T, et al. Cantharidin‒induced liver injuries in mice and the protective effect of vitamin C supplementation. Int Immunopharmacol. 2015;28(1):182‒187.
92. Liang T, Chen X, Su M, et al. Vitamin C exerts beneficial hepatoprotection against Concanavalin A‒induced immunological hepatic injury in mice through inhibition of NF‒kB signal pathway. Food Funct. 2014;5(9):2175‒2182.
93. Rutkowski M, Grzegorczyk K, Chojnacki J, et al. Antioxidative properties of vitamin E as a new approach to its applications in therapy. Pol Merk Lek. 2006;20:609‒614.
94. Abla MJ, Banga AK. Formulation of tocopherol nanocarriers and in vitro delivery into human skin. Int J Cosmet Sci. 2014;36(3):239‒246.
95. Pedrelli VF, Lauriola MM, Pigatto PD. Clinical evaluation of photoprotective effect by a topical antioxidants combination (tocopherols and tocotrienols). J Eur Acad Dermatol Venereol. 2012;26(11):1449‒1453.
96. Cuce G, Çetinkaya S, Koc T, et al. Chemoprotective effect of vitamin E in cyclophosphamide‒induced hepatotoxicity in rats. Chem Biol Interact. 2015;232:7‒11.
97. Pawar VK, Panchal SB, Singh Y, et al. Immunotherapeutic vitamin E nanoemulsion synergies the antiproliferative activity of paclitaxel in breast cancer cells via modulating Th1 and Th2 immune response. J Control Release. 2014;196:295‒306.
98. Danhier F, Kouhé TT, Duhem N, et al. Vitamin E‒based micelles enhance the anticancer activity of doxorubicin. Int J Pharm. 2014;476(1‒2):9‒15.