Lycopene Is Good for What?

Lycopene is mainly found in red fruits and vegetables. The lycopene content in ripe tomatoes is 0.03 mg/g to 0.14 mg/g. Lycopene is known as the “gold hidden in tomatoes”and its content is positively correlated with the maturity of the tomato [1]. Lycopene is currently the carotenoid with the strongest antioxidant capacity in nature. Its antioxidant activity is 100 times that of vitamin E and more than twice that of beta-carotene [2]. Continuous research into the biological functions of lycopene has shown that it is more biologically active than other carotenoids, with important biological functions such as antioxidant [3], lowering blood lipids [4], anti-cancer [5], and improving immunity [6].

1. Physicochemical properties of lycopene

Lycopene has the molecular formula C40H56, a relative molecular mass of 536.88, a melting point of 176 °C, and contains 11 conjugated bonds and 2 non-conjugated carbon-carbon double bonds in its molecule, as shown in Figure 1 [7]. The carbonyl group in the chemical structure of lycopene determines that it is insoluble in water, slightly soluble in strong polar solvents (methanol, ethanol), soluble in chloroform and benzene, soluble in lipids and non-polar solvents, and is a fat-soluble pigment [8]. Lycopene's solubility increases with temperature, and the higher the purity, the less soluble it is. Studies have found that cooking tomatoes can improve the utilization of lycopene in tomatoes and tomato products. 

The lycopene contained can be better absorbed by the human body, mainly because lycopene is prone to isomerization, from trans isomer to cis isomer [9]. In addition, lycopene is relatively unstable, easily oxidized and degraded, and prone to cis-trans isomerization. It is sensitive to light, oxygen, acids, heat, oxidants, and metal ions such as Fe3+ and Cu2+. After 12 hours of exposure to sunlight, lycopene is essentially lost[10]. Improper processing and storage can change the lycopene content or completely degrade lycopene, reducing the effect after consumption. To prevent lycopene from oxidizing and isomerizing, laboratories will add antioxidants and inert gases when storing it, and keep it in a brown reagent bottle in a cool place. Commercial processing usually uses microencapsulation technology, liposome technology, nano-dispersion technology, embedding technology, and emulsification technology, which can effectively improve the problem of poor stability and low bioavailability of lycopene due to its fat solubility. [11]

2 Biological functions of lycopene

2.1 Antioxidant function

Lycopene powder is currently the carotenoid with the strongest antioxidant capacity found in nature. Its polyunsaturated double bond structure allows it to quickly quench singlet oxygen and peroxide free radicals. One lycopene molecule can remove thousands of singlet oxygen molecules, thereby effectively inhibiting harmful oxidation reactions in the body [2]. Lycopene can remove excessive reactive oxygen species (ROS) in the body by regulating the activity of three antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). and can also effectively scavenge hydroxyl radicals through addition reactions [12].

Studies have confirmed that increasing lycopene intake can effectively inhibit the oxidation of lipids, DNA and proteins, increase the activity of liver and plasma antioxidant enzymes, and significantly reduce the content of malondialdehyde (MDA) in the serum [13-14]. Fan Yuanjing et al. [15] found that after 4 consecutive days (2 times/day) of oral administration of 30 mg/kg lycopene, the activities of SOD, GSH-Px and CAT in the serum of female mice were significantly increased, and the MDA content was reduced, indicating that the antioxidant effect of lycopene in vivo is related to the activation of the activity of the endogenous antioxidant enzyme system. Liu Chongbin et al. [16] found that lycopene can protect neurons and alleviate symptoms of Alzheimer's disease by increasing the enzymatic activities of SOD, GSH-Px and CAT in the serum of Parkinson's mice.

Zhao et al. [17] found that in a mouse experiment of cerebral ischemia/reperfusion, continuous feeding of 6 mg/kg lycopene for 2 weeks significantly reduced MDA levels, thereby alleviating oxidative damage caused by cerebral ischemia. Prakash et al. [18] showed that in a model of mitochonrial oxidative damage induced by colchicine in mice, lycopene supplementation significantly increased the activities of nicotinamide adenine dinucleotide dehydrogenase, succinate dehydrogenase and cytochrome c oxidase, thereby improving mitochondrial function. In addition, lycopene can improve mitochondrial function by increasing total antioxidant capacity and high-density lipoprotein (HDL) activity, and downregulating the expression of inflammatory factors in the plasma to relieve lipopolysaccharide (LPS)-induced oxidative stress [19]. 

In aquaculture, lycopene is often used as a feed additive to exert its coloring and antioxidant functions. Adding 400 mg/kg lycopene to the diet can significantly increase the levels of GSH-Px and SOD in the serum of Ross 308 broilers and reduce the content of MDA, thereby alleviating oxidative stress caused by circulatory heat stress [20]. Lycopene, as a coloring agent, can also increase the color and nutritional value of egg yolks. Adding 200 mg/kg lycopene to the diet for 21 days can improve the color of egg yolks. Due to the high bioavailability of the Z isomer of lycopene, it is effectively absorbed by laying hens and transferred to egg yolks, thereby increasing the concentration of lycopene in egg yolks and improving egg yolk color [21].

Lycopene can also be used as a feed additive to improve meat quality. It increases the redness of lamb meat and the levels of vitamin A and vitamin E, and delays the oxidation of meat proteins and lipids during storage [22]. Adding 200 mg/kg lycopene to the basic diet can effectively improve the tenderness of lamb during the ripening period [23]. Adding 200 mg/kg lycopene to the diet of 3-month-old male goats for 110 consecutive days can increase the activity of SOD, CAT and GSH-Px in the serum and thus improve animal growth performance [24]. Continuous feeding of a diet containing 5% tomato pomace (containing lycopene 708 mg/kg) for 14 days can increase the serum GSH-Px and SOD levels and reduce the MDA content of 42-day-old broilers, thereby enhancing the antioxidant capacity of broilers [25].

The strong antioxidant properties of lycopene have been shown to significantly improve animal growth performance, egg yolk nutrition and meat quality. The antioxidant effect of lycopene is mainly dependent on the nuclear factor erythroid-2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Lycopene can upregulate the expression of the electrophile response element (EPRE), ARE and Nrf2, thereby stimulating the production of phase II detoxification antioxidant enzymes and protecting cells from damage caused by reactive oxygen species and other electrophilic molecules [26].

Dai et al. [27] reported that in a mouse model of nephrotoxicity induced by colchicine, lycopene supplementation in the diet down-regulated the expression of nuclear factor kappa B (NF-κB) mRNA and up-regulated the expression of Nrf2 and heme oxygenase 1 (HO-1) mRNA. Lycopene can induce Nrf2 gene transcription and inhibit the expression of NF-κB and cas-pase-3 mRNA, thereby scavenging oxygen free radicals [28]. In addition, lycopene can alleviate oxidative stress-induced neuroinflammation and cognitive impairment by activating the Nrf2/NF-κB signaling pathway [29]. In BV2 microglial cells, lycopene can reduce LPS-induced neuroinflammation and oxidative stress by activating the Nrf2 signaling pathway [30]. Sahin et al. [20] found that adding 400 mg/kg lycopene to the diet can increase Nrf2 mRNA expression by inhibiting the mRNA expression of Kelch-like ECH-associated protein 1 (Keap1) in the muscle, thereby enhancing the activity of the antioxidant enzymes GSH-Px and SOD in the breast muscle of broilers. Lycopene can therefore exert its antioxidant function through Nrf2, protecting the body from oxidative damage and thereby improving the growth performance of animals.

2.2 Lipid-lowering function

Lycopene is a fat-soluble substance that regulates lipid metabolism by lowering blood lipids. Lycopene is mainly found in cell membranes and lipoproteins, and is concentrated in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) [31]. Jiang et al. [32] found that the level of lycopene in plasma was negatively correlated with the thickness and damage of the carotid artery and aortic blood vessel walls, and can effectively prevent the formation of atherosclerosis. LDL oxidation is a key factor in the development of atherosclerosis. Lycopene has strong antioxidant properties, so the hypolipidemic effect of lycopene is related to its ability to inhibit the oxidation of DNA and lipoproteins and prevent the formation of oxidized products of LDL cholesterol.

Lycopene has a regulatory effect on the lipid and lipoprotein metabolic disorders of atherosclerosis. In a study by Qin Wei et al. [33], a model of rabbits fed a high-fat diet and induced to atherosclerosis was treated with 50 mg/kg lycopene by gavage for 40 consecutive days. This significantly inhibited the expression of low-density lipoprotein receptor mRNA in the aorta and heart, reduced the level of triglycerides (TG) in the serum, and effectively alleviated atherosclerosis. Tang Xiangyu et al. [34] found that adding lycopene to a high-fat diet and giving 6% lycopene powder per kg of body weight per day can slow down the damage caused by lipid peroxidation in the rabbit aorta, while also reducing TG levels, protecting the rabbit's vascular endothelial function, and reducing the occurrence of atherosclerosis in high-fat rabbits. It has a good anti-atherosclerotic effect. Lycopene has a significant effect in regulating lipid metabolic disorders. In obese rats, after being given 10 mg/kg lycopene orally for 12 consecutive weeks, the serum total cholesterol (TC), TG and LDL in the liver tissue and atherosclerosis parameters were significantly reduced [35]. 

In a copper-induced oxidative model in broiler chickens, lycopene supplementation significantly reduced plasma TC and LDL levels and significantly slowed the oxidation rate of LDL. It is speculated that lycopene may exert an antioxidant effect by penetrating into LDL [36]. In a model of kidney damage in mice poisoned with trans fatty acids, an oral administration of 20 mg/kg lycopene significantly reduced the levels of TG, TC and LDL in the mice's serum and increased the level of HDL [37]. It can be seen that the mechanism by which lycopene reduces lipid metabolism disorders in liver tissue is by increasing the expression of high-density lipoprotein cholesterol, reducing the accumulation of TC, TG, and LDL in liver tissue, and thereby regulating lipid metabolism disorders in liver tissue. In addition, Zeng et al. [38] found that in a mouse model fed a high-fat diet, the addition of lycopene can reduce the content of TG, TC, and LDL in the liver and increase the content of HDL. The mechanism is that lycopene prevents insulin resistance and alleviates lipid metabolic disorders by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3) alleviates lipid metabolic disorders. Lycopene regulates lipid metabolism by increasing the expression of peroxisome proliferator-activated receptors alpha and gamma in the liver, and reduces cholesterol levels by inhibiting the rate-limiting enzyme for cholesterol synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and promoting the degradation of LDL [39].

2.3 Anti-cancer effects

Excessive ROS in the body can react randomly with lipids, proteins and nucleic acids in cells, causing oxidative stress and damage to DNA, mutations that activate oncogenes or inactivate tumor suppressor genes, and the development of chronic diseases and cancer [40]. Studies have confirmed that adding lycopene to the diet can reduce the risk of cancer and inhibit tumor growth. Antioxidants are the first line of defence against oxidative damage, converting oxidants into less active substances. Antioxidant intake can neutralise endogenous or exogenous ROS, reducing DNA damage and cancer risk [41].

Lycopene has two main anti-cancer effects: an oxidative mechanism and a non-oxidative mechanism. In the oxidative mechanism, lycopene, as the most effective antioxidant among common carotenoids, can inhibit singlet oxygen (1O2), and scavenge nitrogen dioxide radicals (NO2 ·), sulphur radicals (RS·) and sulfenyl radicals (RSO2 ·) [42]. During singlet oxygen quenching, energy is transferred from 1O2 to the lycopene molecule, which is converted to an energy-rich triplet state [43]. The trapping of other ROS, NO2 · or peroxynitrite leads to the oxidative decomposition of the lycopene molecule. Lycopene can therefore protect the body against oxidation of lipids, proteins and DNA [44]. In non-oxidative mechanisms, lycopene protects against oxidative damage to lipids, proteins and DNA by inhibiting the phosphorylation of regulatory proteins by carcinogens, such as the p53 and Rb anti-cancer genes, and stopping cell division in the resting cell phase of the cell cycle to the pre-DNA synthesis phase [45]. Bandeira et al. [46] proposed that the regulation of the cytochrome P4502E1 by lycopene-induced liver metabolic enzymes is a potential mechanism for protecting the liver from carcinogen-induced precancerous lesions in rats. Lycopene can effectively reduce insulin-growth factor-induced cell proliferation, and insulin-growth factor is an effective mitogen in various cancer cell lines [47].

Rowles et al. [48] found that consumption of tomatoes and tomato products or circulating levels of lycopene were negatively correlated with cancer risk, especially breast, colon, lung and prostate cancer. Lycopene is more effective than α-carotene and β-carotene in inhibiting cell growth in a variety of human cancer cell lines. Compared to carotenoids, lycopene can more effectively inhibit breast cancer cell proliferation and increase apoptosis. However, only lycopene can disrupt the formation of the cytoskeleton, selectively inhibit cells, thereby inhibiting cell cycle progression, and ultimately inhibit cell proliferation [49]. Langner et al. [50] found that lycopene-rich tomato juice (17 mg/L) has an inhibitory effect on a rat colon cancer model and reduced the number of bladder transitional cell carcinomas in male rats. Adding lycopene (50 mg/L) to drinking water also inhibited the development of lung cancer in male mice.

Lycopene has a therapeutic effect on leukoplakia, a precancerous lesion of the oral cavity and other mucous membranes. In a double-blind placebo-controlled study, 58 patients with oral leukoplakia were given 4 or 8 mg of lycopene orally per day or placebo capsules for 3 months. The results showed that both doses of lycopene were more effective than the placebo in reducing the symptoms of leukoplakia, and that the daily intake of 8 mg of lycopene was more effective than 4 mg [51]. Lycopene plays a potential role in the treatment of prostate cancer [52], and increasing the intake of tomato products and other foods containing lycopene can reduce the incidence of prostate cancer. There is growing evidence that eating one portion of tomatoes or tomato products every day can help prevent DNA damage. Since DNA damage is involved in the pathogenesis of prostate cancer, frequent consumption of tomatoes and their products can prevent prostate cancer [53]. Therefore, the anticancer effect of lycopene is related to its strong free radical quenching mechanism on the one hand, and on the other hand, it can stimulate lymphocytes to release cancer cell inhibitory factors. If it is widely used in humans, large-scale animal experiments are needed to verify it.

2.4 Improve immunity

Singlet oxygen and oxygen radicals are the culprits that attack the body's immune system. Lycopene has a very strong ability to scavenge free radicals and quench singlet oxygen, and therefore can be used to improve the body's immune function. Lycopene improves the body's immune function mainly through two pathways. One pathway is that lycopene promotes the proliferation of T and B lymphocytes and enhances the activity of natural killer cells (NK), thereby enhancing the body's immune response. Lycopene can protect phagocytes from oxidative damage, promote the proliferation of T and B lymphocytes, and significantly promote nonspecific cellular immunity [54]. Lycopene can also promote the transformation of T lymphocytes and enhance the killing function of NK cells. The mechanism is to protect the DNA of cells, prevent damage to DNA replication during proliferation, and promote cell-to-cell communication to enhance cell-to-cell interactions [55]. Another way is that lycopene inhibits inflammatory factors such as tumor necrosis factor-α (TNF-α) by promoting the secretion of interleukin (IL), preventing its activation of the NF-κB signaling pathway. Interleukins IL-2, IL-4, and IL-10 are all immune factors that promote the body's immune response by downregulating inflammatory mediators.

Du Hongju et al. [56] showed that lycopene can stimulate the proliferation of specific T cells and enhance cellular and humoral immune functions in mice. Similarly, Chen et al. [57] found that after mice were orally administered a dose of 0.25 g/kg·bw lycopene for 30 consecutive days, there was a significant increase in the ability of delayed-type hypersensitivity, the ability of macrophages to phagocytize chicken red blood cells, and the activity of NK cells. He Liang et al. [58] reported that lycopene can enhance the immune function of broilers by increasing their bactericidal activity. Jiang et al. [13] found that the immunity of laying hens was significantly enhanced after being fed 100 mg/kg lycopene for 120 days. Izquierdo et al. [59] found that when pregnant women consumed 25 g of tomato juice (containing 7 mg of lycopene and 0.3 mg of β-carotene) daily for 14 days, the concentration of lycopene in their lymphocytes and plasma increased significantly, and lymphocyte DNA damage decreased by about 50%.

Luo et al. [6] reported that in mice with a model of gastric cancer induced by methyl-N-nitrosoguanidine, after oral administration of lycopene, serum levels of IL-2, IL-4, IL-10 and TNF-α increased significantly, while IL-6 levels decreased significantly. There was also a dose-dependent increase in immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM). Lycopene can reduce the inflammatory response induced by LPS and the expression of IL-6, IL-1β and mRNA in RAW264.7 mouse macrophages after pretreatment. The mechanism is that lycopene exerts an anti-inflammatory effect by inhibiting the NF-κB and C-Jun amino-terminal kinase signaling pathways [60]. Sahin et al. [61] found that that feeding 200 and 400 mg/kg lycopene can alleviate the incidence of spontaneous ovarian cancer in laying hens. The mechanism is to enhance antioxidant and anti-inflammatory activities, inhibit NF-κB expression, and inhibit signal transduction protein and signal transduction and transcription activator protein expression by activating PIAS3 protein. Makon et al. [62] found that the addition of lycopene to the diet up-regulates the expression of IL-1α and IL-8 and increases the activity of the matrix metalloproteinase 9 gene in LPS-induced human colorectal adenocarcinoma cells (Caco-2) by regulating the adenosine cyclic phosphate-adenosine cyclic phosphate-dependent protein kinase A signaling pathway. Lycopene therefore protects the body from oxidative damage and improves immunity by regulating the secretion of T and B lymphocytes and interleukins.

3 Outlook

With the rapid development of food technology, the nutritional value and efficacy of lycopene are being continuously developed and utilized. For example, its antioxidant, anticancer, hypolipidemic, immunity-enhancing, and skin-protecting effects are widely used in health foods. Therefore, the development and use of lycopene products has become a hot topic of interest among researchers in this field. The above studies have found that lycopene has many benefits for the animal body. Although further research is needed on dosage, usage methods and metabolic mechanisms, lycopene as a raw material for health foods will be the main focus of future research.

References:

[1] Qi Lele, Gao Yan. Research progress and application of lycopene [J]. Modern Food, 2015, 12(24): 44-46

[2]  Torregrosa-Crespo J,  Montero Z, Fuentes J L, et al. Exploring the  valuable carotenoids for the large-scale production by marine mi- croorganisms[J]. Marine Drugs, 2018, 16(6): 203

[3] Chen Yao, Lu Lianhua, Lv Zhimin, et al. Research on the immune enhancing and antioxidant effects of lycopene [J]. Preventive Medicine Forum, 2018, 24(5): 393-396

[4] Dong Peng, Liu Chunlin. Research on the hypolipidemic effect of lycopene on rats with hyperlipidemia [J]. Shandong Chemical Industry, 2019, 48(3): 21,32

[5]  Gajowik A, Dobrzyńska M M. Lycopene-antioxidant with radiopro - tective and anticancer properties. A review[J]. Roczniki Państwowego Zakadu Higieny, 2014, 65(4): 263-271

[6]  Luo C, Wu X  G. Lycopene enhances antioxidant  enzyme activities and immunity function in N -methyl -N ′ - nitro -N -nitrosoguani- dine-enduced gastric cancer rats[J]. International Journal of Molecular Sciences, 2011, 12(5): 3340-3351

[7] Pan Xiaowei, Ye Jianzhi, Su Zipeng, et al. Research progress and application prospects of the biological functions of lycopene [J]. Modern Agricultural Science and Technology, 2018(1): 237-238,240

[8] Ma Yun, Jiang Rui, Wu Yan. Evaluation of the determination method of lycopene content in watermelon [J]. Ningxia Agricultural and Forestry Science and Technology, 2013, 54(10): 88-89

[9]  El-Raey M A, Ibrahim G E, Eldahshan O A. Lycopene and lutein; A review for their chemistry and medicinal uses[J]. Journal of Pharma - cognosy and Phytochemistry, 2013, 2(1): 245-254

[10]Gupta S K, Trivedi D, Srivastava S, et al. Lycopene attenuates oxida - tive stress induced experimental cataract development: an  in vitro and in vivo study[J]. Nutrition, 2003, 19(9): 794-799

[11]Baningning, Wang Yingming, Liu Rui, et al. Research progress in the preparation technology of lycopene [J]. Cereal, Oil and Food Science and Technology, 2018, 26(3): 45-49

[12]Pereira A C, Martel F. Oxidative stress in pregnancy and fertility pathologies[J]. Cell Biology and Toxicology, 2014, 30(5): 301-312

[13]Jiang H Q, Wang Z Z, Ma Y, et al. Effects of dietary lycopene sup - plementation on plasma lipid profile, lipid peroxidation and antioxidant defense system in feedlot Bamei lamb  [J]. Asian-Australasian Journal of Animal Sciences, 2015, 28(7): 958-965

[14]Tekeli I O, Ate§§ahinA, Sakin F, et al. Protective effects of conven- tional and colon-targeted lycopene and linalool on ulcerative colitis induced by acetic acid in rats  [J]. Inflammopharmacology, 2019, 27(2): 313-322

[15] Fan Yuanjing, Huang Lu. Research on the mechanism of lycopene absorption and in vivo antioxidant [J]. Food Science, 2007, 28(11): 545-548

[16] Liu Zhongbin, Wang Rui, Pan Huibin, et al. Effects of lycopene on oxidative stress damage and neurological behavior in mice with Parkinson's disease model [J]. Chinese Journal of Applied Physiology, 2013, 29(4): 380-384,390

[17]Zhao Y S, Xin Z, Li N N, et al. Nano-liposomes of lycopene reduces ischemic brain damage in rodents by regulating iron metabolism[J]. Free Radical Biology & Medicine, 2018, 124: 1-11

[18]Prakash A, Kumar A. Lycopene protects against memory impairment and mito-oxidative damage induced by colchicine in rats: an evi - dence of nitric oxide signaling[J]. European Journal of Pharmacolo - gy, 2013, 721(1/3): 373-381

[19]Alvi S S, Ansari I A, Ahmad M K, et al. Lycopene amends LPS in- duced oxidative stress and hypertriglyceridemia via modulating PC - SK-9 expression and Apo-CIII mediated lipoprotein lipase activity [J]. Biomedicine & Pharmacotherapy, 2017, 96: 1082-1093

[20]Sahin K, Orhan C, Tuzcu M, et al. Lycopene activates antioxidant enzymes and nuclear  transcription  factor  systems in heat-stressed broilers[J]. Poultry Science, 2016, 95(5): 1088-1095

[21]Honda M, Ishikawa H, Hayashi Y. Alterations in lycopene concen - tration and Z-isomer content in egg yolk of hens fed all-E-isomer- rich and Z-isomer-rich lycopene[J]. Animal Science Journal, 2019, 90(9): 1261-1269

[22]Xu C C, Qu Y H, Hopkins D L, et al. Dietary lycopene powder im -  proves  meat  oxidative  stability in Hu lambs[J]. Journal of the Sci - ence of Food and Agriculture, 2019, 99(3): 1145-1152

[23] Xu C, Xu S, Liu C, et al. Effect and kinetic analysis of different antioxidants added to the feed on the tenderness of lamb during the ripening period [J]. Meat Research, 2017, 31(10): 1-5

[24] Qu Yanghua, Luo Hailin, Liu Ce, et al. Effect of lycopene added to the feed on growth and development, slaughter performance and serum antioxidant indicators of sheep [J]. Journal of Animal Nutrition, 2017, 29(4): 1257-1264

[25]Hosseini-Vashan S J, Golian A, Yaghobfar A. Growth, immune, an - tioxidant, and bone responses of heat stress-exposed broilers fed diets  supplemented  with  tomato  pomace[J]. International Journal of Bio-meteorology, 2016, 60(8): 1183-1192

[26]Palozza P, Catalano A, Simone R, et al. Lycopene as a guardian of redox signalling[J]. Acta Biochimica Polonica, 2012, 59(1): 21-25

[27]Dai C S, Tang S S, Deng S J, et al. Lycopene attenuates colistin-in -  duced nephrotoxicity in mice via activation of the Nrf2/HO-1 path - way[J]. Antimicrobial Agents and Chemotherapy, 2015, 59(1): 579-  585

[28]Abass M A, Elkhateeb S A, Abd El-Baset S A, et al. Lycopene ame - liorates  atrazine-induced  oxidative  damage  in  adrenal  cortex  of male rats by activation of the Nrf2/HO-1 pathway[J]. Environmental Science and Pollution Research International, 2016, 23(15): 15262-  15274

[29]Zhao B, Ren B, Guo R, et al. Supplementation of lycopene attenuates oxidative stress induced neuroinflammation and cognitive im - pairment via  Nrf2/NF -κB  transcriptional  pathway   [J].  Food  and Chemical Toxicology, 2017, 109(1): 505-516

[30]Wang J, Li L X, Wang Z, et al. Supplementation of lycopene attenu - ates lipopolysaccharide-induced amyloidogenesis and cognitive im -  pairments via mediating neuroinflammation and oxidative stress [J].  The Journal of Nutritional Biochemistry, 2018, 56: 16-25

[31] Fu Zhetun, Yuan Jie, Huang Xiongwei, et al. Research overview and application prospects of lycopene [J]. Modern Research and Practice of Traditional Chinese Medicine, 2007, 21(1): 58-61

[32]Jiang H Q, Wang Z Z, Ma Y, et al. Effect of dietary lycopene supplementation on  growth performance,  meat  quality, fatty  acid  profile and  meat  lipid  oxidation  in lambs in summer conditions[J]. Small Ruminant Research, 2015, 131: 99-106

[33] Qin Wei, Qian Yan. Effect of lycopene on blood lipids and low-density lipoprotein receptor mRNA expression in atherosclerotic rabbits [J]. Chinese Journal of Hospital Pharmacy, 2010, 30(3): 191-194

[34] Tang Xiangyu, Sun Wenqing, Wang Lei, et al. Effects and mechanisms of lycopene on vascular lipid peroxidation damage in rabbits fed a high-fat diet [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(2): 158-163

[35] Liu Qiling, Zhou Ling, Xu Xinqing. The effect and mechanism of lycopene in preventing lipid metabolism disorders in rats fed a high-fat diet [J]. Journal of Xi'an Jiaotong University (Medical Sciences), 2008, 29(1): 70-73

[36]Lee K W, Choo W D, Kang C W, et al. Effect of lycopene on the copper-induced  oxidation  of  low-density lipoprotein in broiler chick ens[J]. Springerplus, 2016, 5: 389

[37] Ding X, Xie X, Liu J, et al. The protective effect of lycopene on kidney injury caused by trans fatty acids in mice [J]. Journal of Hunan Normal University (Medical Sciences), 2017, 14(5): 8-12

[38]Zeng Z H, He W, Jia Z, et al. Lycopene improves insulin sensitivity through inhibition of STAT3/Srebp -1c -Mediated lipid accumula- tion  and  inflammation in mice fed a high-fat diet[J]. Experimental

and Clinical Endocrinology & Diabetes, 2017, 125(9): 610-617

[39]Ford N A, Elsen A C, Erdman J W Jr. Genetic ablation of carotene oxygenases  and  consumption  of  lycopene  or  tomato  powder diets modulate carotenoid and lipid metabolism in mice[J]. Nutrition Re- search, 2013, 33(9): 733-742

[40]Yang Y, Zhu Y P, Xi X W. Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species   (Review)[J]. Oncology Let- ters, 2018, 16(3): 2771-2776

[41]Rao A V, Rao L G. Carotenoids and human health[J]. Pharmacologi - cal Research, 2007, 55(3): 207-216

[42]Kumcuoglu S, Yilmaz T, Tavman S. Ultrasound assisted extraction of lycopene  from  tomato processing wastes[J]. Journal of Food Science and Technology, 2014, 51(12): 4102-4107

[43]Wertz K, Siler U, Goralczyk R. Lycopene: modes of action to promote prostate  health[J].  Archives of Biochemistry and Biophysics, 2004, 430(1): 127-134

[44]Stahl  W, Sies  H. Antioxidant activity of  carotenoids[J]. Molecular Aspects of Medicine, 2004, 24(6): 345-351

[45]StojanovicJ, Giraldi L, Arzani D, et al. Adherence to Mediterranean diet  and  risk  of  gastric  cancer:  results of a case-control study in Italy[J]. European Journal of Cancer Prevention, 2017, 26(6): 491 - 496

[46]Bandeira A C B, da Silva R C, Rossoni J V Júnior, et al. Lycopene pretreatment improves hepatotoxicity induced by acetaminophen in C57BL/6  mice[J]. Bioorganic  &  Medicinal Chemistry, 2017, 25(3): 1057-1065

[47]Diener A, Rohrmann S. Associations of serum carotenoid concentra- tions and fruit  or  vegetable  consumption  with serum insulin-like growth factor   (IGF)-1 and IGF binding protein-3 concentrations in the  Third  National   Health   and   Nutrition   Examination   Survey (NHANES III)[J]. Journal of Nutritional Science, 2016, 5(13): 1-8

[48]Rowles J L 3rd, Ranard K M, Smith JW, et al. Increased dietary and circulating  lycopene  are  associated  with  reduced  prostate  cancer risk:  a  systematic review and meta-analysis[J]. Prostate Cancer and Prostatic Diseases, 2017, 20(4): 361-377

[49]Uppala P T, Dissmore T, Lau B H, et al. Selective inhibition of cell proliferation by lycopene in MCF -7 breast cancer cells in vitro: a proteomic analysis[J]. Phytotherapy Research, 2013, 27(4): 595-601

[50] Langner E,  Lemieszek  M  K,  Rzeski  W.  Lycopene,  sulforaphane,quercetin, and curcumin applied together show improved antiprolif- erative  potential  in  colon cancer cells in vitro[J]. Journal of Food Biochemistry, 2019, 43(4): 1-12

[51]Singh M, Krishanappa R, Bagewadi A, et al. Efficacy of oral ly- copene in the treatment of oral leukoplakia[J]. Oral Oncology, 2004,  40(6): 591-596

[52]Ilic D, Misso M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: asystematic review[J]. Maturitas, 2012, 72(4): 269-276

[53]Ellinger S, Ellinger J, Stehle P. Tomatoes, tomato products and lycopene in the prevention and treatment of prostate cancer: do we  have the evidence from intervention studies?[J]. Current Opinion in  Clinical Nutrition and Metabolic Care, 2006, 9(6): 722-727

[54] Chai Jingbo, Li Ping, Pei Zhiping. Research on the effect and mechanism of lycopene on the immune function of rats with ovarian cancer [J]. Journal of Practical Oncology, 2017, 31(1): 13-17

[55] Yuan Yun, Wei Dapeng, Liao Linchuan, et al. An in vitro study of the effect of lycopene on nonspecific immune function [J]. Food Science, 2003, 24(4): 133-136

[56] Du Hongju, Zheng Shan, Ma Ling, et al. The effect of lycopene on immune function in mice [J]. Toxicology Journal, 2014, 28(3): 211-214

[57] Chen Yao, Lv Zhimin, Sun Chuanyu, et al. Research on the immune function enhancement of lycopene [J]. Preventive Medicine Forum, 2017, 23(5): 390-392,395

[58] He Liang, He Junlin, Xu Qiankun, et al. Research progress on the application of lycopene in animal production [J]. China Feed, 2016(21): 9-11,17

[59]Izquierdo-Vega JA, Morales-González JA, SánchezGutiérrez M, et al. Evidence of some natural products with antigenotoxic effects. Part 1: fruits and polysaccharides[J]. Nutrients, 2017, 9(2): 102

[60]Zou J, Feng D, Ling W H, et al. Lycopene suppresses proinflammato- ry  response  in  lipopolysaccharide-stimulated macrophages by in-  hibiting ROS-induced trafficking of TLR4 to lipid raft-like domains[J].  The Journal  of Nutritional  Biochemistry, 2013, 24(6): 1117-1122

[61]Sahin K, Yenice E, Tuzcu M, et al. Lycopene protects against spon- taneous ovarian cancer formation in  laying  hens[J]. Journal of Can- cer Prevention, 2018, 23(1): 25-36

[62]Makon -Sébastien N, Francis F, Eric S, et al. Lycopene modulates THP1 and  Caco2  cells  inflammatory  state  through  transcriptional and nontranscriptional processes[J]. Mediators of Inflammation, 2014, 2014(2): 507272