The Foods That Contain Carotenoids

As a micronutrient, carotenoids are widely found in plants, algae, bacteria, and fungi. More than 600 types of carotenoids have been discovered so far, and they can be found in abundance in common fruits and vegetables, such as citrus and mango, which are rich in carotene; and vegetables such as pumpkin and chili, which are rich in lutein [1]. In addition, as fat-soluble pigments, carotenoids to a certain extent determine the coloring of organisms [2]. Among them, β-carotene and lycopene have significant antioxidant and immune-enhancing activities, so carotenoids have become the focus of research in this field.

Recent studies have found that zeaxanthin, among others, play important biological roles in diseases such as cancer and osteoporosis, which has attracted the attention of researchers in the field [3]. Epidemiological surveys have shown that carotenoids are closely related to diseases such as cancer, cardiovascular disease, osteoporosis, diabetes, cataracts and HIV infection [4]. This paper reviews the chemical structure, properties, and synthesis methods of carotenoids, and focuses on the biological activities of common carotenoids and their application in clinical disease treatment, providing a theoretical basis for further research on the application of carotenoids.

1 Structure, properties and classification of carotenoids

1. 1 Structure and properties of carotenoids

Carotenoids are a class of C40 terpenoid compounds and their derivatives that are mainly composed of eight isoprene units. All carotenoids contain a polyisoprene structure, and most of them have multiple double bond structures with bilateral symmetry, so they have strong reducing power and electron transfer ability [5]. They are unstable under conditions such as light, heat and strong acids, and are very prone to oxidative reactions, producing carotenoid cleavage products. Without the protection of antioxidants, the content of lycopene and β-carotene decreases by 16.71% and 28.71% respectively within 3 months [6].

In addition, the chromophores contain conjugated double bonds in the hydrocarbon chain, which can absorb light of a specific wavelength and exhibit a characteristic color. Some carotenoids have multiple isomers. For example, β-carotene contains more than 20 isomers, the most common of which are all-trans, 9-cis, 13-cis and 15-cis [7]. There are three common astaxanthin isomers: 3R, 3'R structure, 3R, 3'S cis structure and 3S, 3'S structure [8]. Most carotenoids are organic compounds containing polar groups such as hydroxyl, carbonyl and methoxy groups, so they have high solubility in polar organic solvents such as ketones, ethers and trichloromethane [9].

1.2 Classification of carotenoids

Carotenoids can be divided into vitamin A precursor compounds and non-vitamin A precursor compounds according to whether they can be broken down to form vitamin A. For example, common β-carotene, α-carotene and lycopene are vitamin A precursor substances [10]. On the other hand, carotenoids can be classified according to their functional groups as follows: (a) xanthophylls containing oxygen-containing functional groups, such as lutein, zeaxanthin, and astaxanthin; (b) carotenoids with a polyisoprenyl group at the center and a cyclic or acyclic structure at both ends, and without any functional groups, such as α-carotene, β-carotene and lycopene [11]. Lutein with an oxygen-containing functional group is more polar and is present on the surface of lipoproteins during transport and absorption, while non-polar carotenoids are often found in the hydrophobic core of lipoproteins [12].

SHIH et al. [13] showed that both β-carotene and zeaxanthin can reduce the concentration of conjugated dienes in the liver and thiobarbituric acid reactive substances (TBARS) in the blood, but the effect of zeaxanthin is more obvious, because the polar zeaxanthin can be transferred between lipoproteins more quickly than the non-polar β-carotene. Other compounds such as vitamin A, β-ionone and α-ionone are derivatives formed by the cleavage of carotenoids by the action of the enzyme double-bond-cleavage. In general, carotenoids are mostly fat-soluble and act on the hydrophobic regions of cells. Polar functional groups such as hydroxyl and ketone groups attached to the parent hydrocarbon chain can also change the polarity of carotenoids, thereby affecting their membrane localization and interactions with different molecules [14].

2 Absorption, synthesis and tolerance of carotenoids

2. 1 Absorption

As large organic molecules, carotenoids are absorbed in the body in a similar way to lipids, usually forming complexes with proteins and entering the liver via the lymphatic system [15]. Under the action of digestive enzymes, carotenoids are separated from proteins, pass through the duodenum, emulsified by bile to form chylomicrons, and taken up by the brush border of the small intestine. Some are absorbed under the action of enzymes, while the rest enter the lymph and blood, and are transported to the liver for storage and utilization by low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the body [16].

2. 2 Synthesis methods

The body cannot synthesize carotenoids itself, so it obtains them through external ingestion to meet its needs. Common methods of synthesizing carotenoids include chemical synthesis, plant extraction, microbial culture, and other methods [17]. Compared with chemical synthetics, natural carotenoids are complex and often have isomers. Many studies have shown that the isomers of natural carotenoids can interact with each other to exert more effective effects. For example, zeaxanthin is an isomer of lutein, and the two are commonly found in natural plants such as wolfberry and Physalis fruits. When lutein and zeaxanthin exist in a ratio of 1:2, they exhibit significant synergistic antioxidant activity [18].

Chemically synthesized carotenoids are mostly all-trans, which inhibits absorption due to competition, and by-products from the chemical production process increase the risk of diseases such as lung cancer and cardiovascular disease, increasing safety risks and therefore limiting their application. Plant sources of extraction are limited, the composition is complex, and the later processing steps such as extraction and purification are cumbersome, resulting in high production costs and inability to meet the requirements of mass production. Single-cell microorganisms grow rapidly, have relatively simple nutritional requirements, and are rich in carotenoids. Current research focuses on innovations in cultivation methods, harvesting, extraction, and purification methods, in the hope of finding safe, cost-effective production methods [19].

2. 3 The body's tolerance to carotenoids

Among the more than 600 carotenoids currently discovered, more than 50 have been found in the normal human diet. However, only more than 10 can be detected in the body. The body has a good tolerance to trans and cis-lycopene isomers. Although under certain conditions, individual carotenoids in high doses exhibit pro-oxidant activity, lycopene is currently known to have no adverse effects on human health. CLARK et al. [20] found that patients with recurrent prostate cancer (PCa) are relatively tolerant to lycopene, with an average plasma lycopene dose of 15–90 mg/d.

Clinical studies have shown that the body absorbs lycopene at different rates at different doses, and that 80% of study subjects absorb less than 6 mg of lycopene. Therefore, it is speculated that saturation may occur. This finding is of great significance for determining the dosage of lycopene for clinical cancer prevention [21]. BEN-DICH [22] research shows that daily intake of 15 to 50 mg of β-carotene does not cause adverse reactions in the body, and toxicological analysis shows that high doses of β-carotene are not mutagenic, carcinogenic, teratogenic, or toxic to embryos, and do not cause excessive vitamin A levels in the body. However, under conditions of oxidative stress, β-carotene can form many carotenoid breakdown products (CBPs). The main site of attack of CBPs is mitochondria, which can disrupt the body's oxidative balance by reducing the levels of protein sulfhydryl groups and glutathione and increasing the accumulation of malondialdehyde [23].

3 Biological activity of carotenoids

3.1 Antioxidant properties

The conjugated double bond structure of carotenoids determines their strong reducibility, which plays an electron transfer role in redox reactions, thereby enabling carotenoids to effectively remove reactive oxygen species and reactive nitrogen species produced by pathological processes or normal metabolism [24]. Lycopene can regulate redox-related kinases at the protein and nucleic acid levels, including protein kinases, protein tyrosine phosphatases (PTPs), and MAP kinases (MAPKs), thereby quenching O2 in the body and reducing (ROS) levels [25]. β-Carotene inhibits the expression of the heme oxygenase 1 gene in human skin fibroblasts (FEK4), consistent with the effect of antioxidants [26].

As a chain-breaking antioxidant, β-carotene, acting together with other carotenoids, can effectively scavenge free radicals, and its efficiency is much higher than the sum of the efficiencies of other carotenoids used alone. Similarly, STAHL et al. [27] reported that β-carotene, acting together with vitamin E or vitamin C, has a synergistic effect on the scavenging of reactive nitrogen and the inhibition of lipid peroxidation, far higher than the sum of the effects when used alone, which is consistent with the results of studies by CAPLLI et al. [28]. DI et al. [9] showed that β-carotene and lycopene can significantly reduce the production of ROS and the formation of nitrotyrosine (ONOO-), improve the bioavailability of NO, and maintain redox balance, thereby playing a preventive role in cardiovascular disease. In the treatment of certain diseases, carotenoids play a physiological role by maintaining redox balance.

SHIH et al. [13] found that β-carotene and zeaxanthin prevent lipid metabolism disorders such as cardiovascular disease and non-alcoholic fatty liver disease by promoting fat oxidation. Natural astaxanthin from Haematococcus pluvialis is more than 50 times more effective than synthetic astaxanthin at quenching O2−, and its ability to eliminate free radicals is also about 20 times stronger than synthetic astaxanthin [28]. MACEDO et al. [29] showed that astaxanthin (ASTA) can significantly reduce the damage caused by oxidation products of proteins and lipids by down-regulating the levels of superoxide anions and hydrogen peroxide. Astaxanthin compound additives can increase daily weight gain, reduce feed conversion ratio, improve muscle tenderness, Fu Xingzhou et al. [30] speculated that it was the antioxidant effect of astaxanthin that improved feed utilization and reduced the pH. YADAV et al. [31] confirmed that curcumin can effectively remove ROS (such as hydroxyl and superoxide anions), thereby improving endoplasmic reticulum stress (ERS) and mitochondrial dysfunction.

3. 2 Effect on the immune system

Many studies have shown that carotenoids can affect the immune response through different pathways, either at the protein or nucleic acid level, to enhance immunity. JYONOUCHI et al. [32] found that astaxanthin can increase the levels of immunoglobulins IgM, IgA and IgG in peripheral blood mononuclear cells, enhancing the body's immune system. PARK et al. [33] studied adult women and found that astaxanthin can reduce DNA damage, enhance natural killer cell cytotoxicity, increase the ratio of T/B cell subsets, promote lymphoid tissue proliferation, and enhance the immune response process. β-carotene or β-cryptoxanthin regulates macrophage-related immune responses by affecting redox levels and reducing the transcriptional levels of the immune-active molecules IL-1b, IL-6, and IL-12 p40 [34]. Unlike this, DI FILIPPOET al. [35] showed that lutein, like β-cryptoxanthin, can inhibit the production of NF-κBp50, and β-cryptoxanthin can inhibit the production of IFN-γ, IL-1α, IL-2, IL-4 and IL-10 cytokines. while lutein exhibits the opposite effect to β-cryptoxanthin on cytokine expression. XU et al. [36] showed that lutein, as a strong antioxidant, can significantly reduce the levels of IL-6 and monocyte chemotactic protein-1 (MCP-1) in the serum of patients with early atherosclerosis, and to a certain extent, inhibit the early formation of atherosclerosis.

The results of this laboratory study confirmed that β-carotene can alleviate the immunosuppressive effect caused by cyclophosphamide to a certain extent by increasing the content of cytokines and immunoglobulins and enhancing the humoral immune function of mice [37]. BAI et al. [38] showed that β-carotene inhibits the degradation of IκB and the subsequent nuclear translocation of the NF-κBp65 subunit, resulting in the suppression of the activity of the iNOS promoter, thus regulating the expression of inflammatory-related factors TNF- α, IL-1β, PGE2, and NO. Therefore, the molecular mechanism of the anti-inflammatory effect of β-carotene may be related to the inhibition of IκBα degradation and NF-κB activation. Similarly, curcumin also inhibits the activation of IκB kinase by Helicobacter pylori, thereby preventing the degradation of IκBα and blocking the binding of NFκB to DNA. Experiments have shown that 40 μmol/L curcumin can significantly inhibit Helicobacter pylori-induced NF-κB activation and IL-8 synthesis, thereby alleviating the damage of Helicobacter pylori to the gastrointestinal tract [39].

BAE et al. [40] reported that lycopene can inhibit the activation of NF-κB induced by LPS, reduce the expression of cell adhesion molecules (CAMs), and reduce vascular permeability, thereby alleviating inflammation in the blood vessels to a certain extent. LPS can activate the phosphorylation of JNK, p38, and ERK in the mitogen-activated protein kinase (MAPKs) pathway of RAW264.7 mouse macrophages, regulating the expression of pro-inflammatory factors. Some studies have found that lutein does not reduce LPS-induced inflammation. However, YANG et al. [41] applied an algae-derived carotenoid to LPS-induced macrophages. The results showed that the extract could significantly inhibit the activation of JNK and the expression of inflammatory factors iNOS and COX-2, indicating that algae carotenoid extracts have the potential to treat inflammation-related diseases.

3. 3 Anti-cancer

Current research has shown that carotenoids have outstanding performance in inhibiting tumors and preventing cancer, involving multiple mechanisms, including the scavenging of ROS, inhibition of cell cycle progression, and interference with intercellular junctions and signal transduction [42-43]. Beta-carotene can significantly inhibit the production of HL-60 leukemia cells. NIRANJANA et al. [44] reported that β-carotene can cause cell division to stop at the G1 phase, and the mode of action is concentration-dependent, which is consistent with the research results of UPADHYAYA et al. [45]. It has also been shown that 20 μmol/L β-carotene significantly reduces cell viability by inducing apoptosis. KUCUK et al. [46] found that lycopene has a significant inhibitory effect on prostate cancer, and inferred that it may inhibit the growth of prostate cancer cells by upregulating the gap junction protein Cx43, reducing IGF-1 levels or increasing the level of IGF-binding protein-3.

AMIN et al. [47] reported that saffron can significantly prevent the occurrence of liver cancer by inhibiting the proliferation of liver cancer cells and inducing apoptosis of liver cancer cells. The specific mechanism is to inhibit the inflammatory response by reducing the expression of TNF receptor 1 protein, down-regulating the level of inflammatory mediators; restoring the levels of superoxide dismutase, catalase and glutathione-S-transferase and reducing the activity of myeloperoxidase, maintaining the redox level, thereby preventing liver cancer. Meanwhile, crocin treats mild depression by increasing the levels of cAMP response element binding protein, brain-derived neurotrophic factor and vascular endothelial growth factor (VEGF) in the hippocampus [48], and can effectively treat traumatic brain injury by inhibiting apoptosis in early brain injury and enhancing angiogenesis in the subacute period [49]. effectively treat traumatic brain injury [49]. CHEW et al. [50] found that high doses of lutein have unique functions in enhancing immune function and anti-cancer effects. It not only inhibits the growth of disseminated breast cancer cells, but also enhances the proliferative effect of lymphocytes.

YASUI et al. [51] found that astaxanthin can significantly inhibit the expression of inflammatory cytokines, NF-κB, TNF-α and IL-1β, inhibit the proliferation of colon cancer cells, and induce apoptosis of colon adenocarcinoma cells, thereby relieving colon mucosal ulcers and preventing colon inflammation and inflammation-related colon cancer. ZHOU et al. [52] showed that a low concentration of the synthetic curcumin analogue, hydrazinyl benzoyl curcumin, can inhibit the proliferation of human lung adenocarcinoma A549 cells by inducing autophagy in a short period of time, and has the potential to prevent cancer.

4 Summary

Carotenoids are widely found in nature, and play an important role in maintaining normal animal growth and improving production performance, enhancing immunity, and preventing disease. Different carotenoids have different structures and functions, but the mechanisms of their absorption, transport and metabolism are not yet fully understood. Due to the complex internal environment and the unstable structure of carotenoids themselves, they usually function through their metabolites, and most carotenoids have synergistic effects with each other or with other substances. Despite the many studies on carotenoids, further research is needed in the treatment and prevention of cancer.

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