Recent Advancement in Therapeutic Activity of Carotenoids

Abstract

Carotenoids are a class of organic pigments that are widely distributed in nature and are responsible for the bright colours of many fruits and vegetables. Carotenoids are found in many plant-based foods such as carrots, sweet potatoes, spinach, kale, and tomatoes. Some of the most well-known carotenoids include beta-carotene, lutein, zeaxanthin, and lycopene. Lutein and zeaxanthin are concentrated in the eyes and have been shown to protect against age-related macular degeneration, a leading cause of blindness in the elderly. Lycopene is found in high concentrations in tomatoes and has been associated with a reduced risk of prostate cancer. Recent research has focused on the potential therapeutic applications of carotenoids for the treatment of various diseases. For example, astaxanthin, a carotenoid found in salmon and other seafood, has been shown to have anti-inflammatory and antioxidant properties and may be useful in the treatment of conditions such as arthritis and cardiovascular disease. Similarly, lycopene has been investigated for its potential to prevent or treat certain types of cancer, including prostate, lung, and breast cancer. In addition to their potential health benefits, carotenoids are also being studied for their role in the prevention of cognitive decline and ageing-related diseases. Ongoing research is exploring their potential therapeutic applications for the treatment of various conditions, including cancer, cardiovascular disease, and cognitive decline. On completion of the chapter you shall be able to explain: (1) the sources and classification of carotenoids, (2) the bioactive compounds used to in various treatments and (3) novel discoveries related to carotenoids.

1. Introduction

The vibrant colours found in fruits and vegetables are due to carotenoids, a type of pigment. Carotenoids are dietary tetraterpenoid (C40 containing eight isoprenoid residues) chemicals that play an important function in cell defence [1, 2].

These naturally occurring, lipid-soluble, highly unsaturated red, yellow, or orange pigments are found in plants, fungus, bacteria, and algae, and the quantity of carotenoids determines how intense the colour is. As naturally occurring elements of fruits and vegetables, these have been widely distributed. Carotenoids are responsible for the coloration of many flowers, birds, and marine animals [3]. Carotenoids’ therapeutic activities and actions are determined by their molecular structure, that defines their physical and chemical qualities.

It’s interesting to know that there are approximately 600 known carotenoids, and some experts think the actual number may be closer to 750. However, only 100 of these carotenoids are commonly found in the food we eat. The top five carotenoids, such as α-carotene, β-carotene, lycopene, β-cryptoxanthin, lutein, and zeaxanthin, make up a significant 95% of our diet. These carotenoids have been extensively researched over the years, as they play crucial roles in photobiology, photochemistry, and photomedicine [4].

Carotenoids are frequently referred to as provitamin A because this vitamin is a by-product of carotenoid metabolism. They are gaining popularity due to their supposed antioxidant effects. Decades of research on carotenoids have improved our understanding of their role as important players in the prevention of ageing-related diseases such as cancer, cardiovascular disease, cataracts, and age-related macular degeneration [5]. Carotenoids’ numerous health advantages have motivated their incorporation in foods and beverages as nutraceuticals and nutritional supplements.

Carotenoids research is progressing in three major areas:

• Carotenoids production from natural sources and downstream processing optimisation;

• the encapsulation for improved physical as well as chemical properties; and

• preclinical, clinical, and epidemiological evaluations of carotenoids health benefits. Carotenoids are crucial bioactive molecules that have a significant impact on human health.

They can be present in a broad range of foods made from plants and have been linked to a lower risk for long-term diseases. Global demand for carotenoids is expected to rise from a value of US$1.5 billion in 2014 to a total of US$1.8 billion in 2019. Carotenoids from natural sources are used to make some of the commercially available carotenoids. Synthetic carotenoids have some advantages over natural carotenoids. First, synthesised carotenoids are particularly constructed to minimise oxidation or isomerization, making them more stable. Synthetic carotenoids are created in colloidal suspension, emulsification, and dispersion colloids to make carotenoid application in food easier. They are commonly sold on the market as soluble in water and stable emulsions.

Despite these benefits, chemically produced carotenoids are known to have significant levels of toxicity, carcinogenicity, and teratogenicity. As a result, customers who care about their health have a lot of reservations about them. As a result, carotenoids derived from natural resources are highly sought after by today’s customers.

2. Chemistry of carotenoids

Carotenoids are a class of pigments found mostly in plants that are responsible for the vibrant yellow, orange, and red colours found in vegetables and fruits [6]. All have antioxidant action, and some are vitamin A precursors. Furthermore, carotenoids play a function in interaction between cells, immune system activation, and illness prevention, promoting human health [7].

Carotenoids are made up of eight repeating units of isoprene with cyclic or linear structures at both ends, resulting in numerous cis and trans isomers, with the latter type being more prevalent in nature [8].

3. Classification of carotenoids

Carotenoids are categorised based on their chemical structure or their usefulness.

1. Chemical structure: Carotenoids that are found as pure hydrocarbons are known as carotenes, including α-carotene, β-carotene, and lycopene. On the other hand, xanthophylls are carotenoids that have oxygen as a functional group in their structure, such as β-cryptoxanthin, lutein, and zeaxanthin. It’s worth noting that the presence of polar groups, like epoxy, hydroxyl, and keto, in the structure can have an impact on the polarity and biological activity of the compounds [4].

2. Functionality: carotenoids can also be classified as primary or secondary carotenoids.

Primary carotenoids are photosynthetic pigments that play an important role in photosynthesis. Carotenes with orange to red wavelengths are responsible for transporting light energy from chlorophyll-absorbed sunlight. They are also known to operate as plant antioxidants by collecting energy from singlet oxygen generated during photosynthesis [9]. Xanthophyll molecules, on the other hand, are plentiful in plant leaves but do not play a direct role in photosynthesis. Xanthophylls absorb a wavelength of sunlight that chlorophyll does not. Plants use them as secondary carotenoids or as supplementary pigments.

3.1 Xanthophylls

Xanthophylls are soluble in both polar (e.g., alcohols) and organic (e.g., ether and hexane) solvents.

Xanthophylls are made up of hydrogen, carbon, and one or more functional groups including oxygen. They are oxygenated carotenoid derivatives that generate alcohols, aldehydes, ketones, and acids. Fucoxanthin, lutein, and violaxanthin are examples of xanthophylls.

Xanthophylls are naturally present in the tissues of green plants, but they only appear as fatty acid esters in fruits and flowers.

They are, however, slightly soluble in oils at ambient temperature as well as non-polar organic solvents such as chloroform and acetone.

3.2 Carotenes

Carotenes are pure hydrocarbons. Plants and numerous microorganisms synthesise carotenoids in nature [10]. Animals can metabolise them in a specific way, but they cannot synthesise them. Carotenoids degrade slowly in storage, with losses varying depending on the matrix and storage circumstances [11].

Plant tissues, or plastids, such as chromoplasts (coloured plastids), amyloplasts (starch storage plastids), and elaioplasts (lipid storage plastids), are where carotenoids are stored. Carotenoids are found in the chromoplasts of fruits, flowers, and roots, whereas they are found in the amyloplasts and elaioplasts of grains and oilseeds, respectively.

Plants’ carotenoids are typically lipid-based and insoluble in water; they are found in the chloroplast cells. Due to their water insolubility, they do not leach away when the veggies are prepped and cooked. They also do not significantly alter colour with heat or pH, especially if the chloroplast cells are still largely intact.

Carotenoids are terpenoids that are synthesised from the fundamental C5-terpenoid precursor, isopentyl diphosphate. Geranyl-geranyl diphosphate is formed from this chemical [11]. Its dimerisation produces phytoene, which is then dehydrogenated stepwise via phytofluene, zeta-carotene, and neyrosporene to produce lycopene. The additional naturally occurring carotenoids are produced through further oxidation, dehydrogenation, and cyclization processes.

Technology has advanced to the point that it is now possible to synthesise carotenoids with well-controlled, reproducible hues, without quality variations, and in a volume that can be scheduled to suit the needs of the food industry [12].

4. Natural occurrence of carotenoids

Only 40 of the more than 700 known carotenoids are present in the diet of humans, with α-carotene, β-carotene, lycopene, β-cryptoxanthin, lutein, and zeaxanthin being the most prevalent ones (Table 1) [44].

Carotenoids	Biological source	Common name	Pharmacological activity	References
α-Carotene	Daucus carota	Carrot	Antioxidant, anti-carcinogenic, immune function enhancing, and lower risk of cardiovascular disease.	Mangels et al. [16]; Holden et al. [17]; Tanumihardjo [18]
	Citrus spp.	Orange
	Carica papaya	Papaya
	Musa acuminate	Banana
	Prunus armeniaca	Apricot
β-Carotene	Lactuca sativa	Lettuce	Lower occurrences of certain cancers (lung cancer), enhance the immune function, antioxidant and anti-inflammatory.	Harrison [19]; Wawrzyinak et al. [20]; Stahl and Sies [21]; Bendich [22]; Liebler and Mcclure [23]; Fiedor and Burda [24]; Böhm et al. [25]
	Citrus paradise	Grapefruit
	Prunus armeniaca	Apricot
	Brassica oleracea	Broccoli
	Daucus carota	Carrot
β-Cryptoxanthin	Capsicum annuum	Red pepper	Antioxidant, anti-obesity, anti-inflammatory, anti-osteoporosis and anticancer	Burri [26]; Burri et al. [27]; Coronel et al. [28]; Jiao et al. [29]
	Prunus armeniaca	Apricot
	Mangifera indica	Mango
	Curcubita spp.	Pumpkin
	Curcubita moschata	Pumpkin or Squash
Lutein	Spinacia oleracea	Spinach	Antioxidant, anti-inflammatory, autophagy, neuroprotective, photo protection, hepatoprotective, immunomodulation, anti-carcinogenic	Krinsky et al. [30]; Xu et al. [31]; Woodside et al. [32]; Eisenhauer et al. [33]; Cho et al. [34]
	Citrus spp.	Orange
	Zea mays	Corn
	Capsicum annuum	Red pepper
	Brassica oleracea	Broccoli
Lycopene	Solanum lycopersicum	Tomato	Enhance immunity, antioxidant, anti-proliferative, anticancer, anti-inflammatory, cognition enhancer, neuroprotective, hepatoprotective, bone protective, anti-obesity, anti-diabetic and against dermatologic disease	Di Masico et al. [35]; Luo and Wu [36]; Agarwal and Rao [37]; Liu et al. [38]; Neyestani et al. [39]; Story et al. [40]; Aydin et al. [41]; Wang et al. [42]; Wang et al. [43]; Böhm et al. [25]
	Carica papaya	Papaya
	Citrullus lanatus	Watermelon
	Prunus armeniaca	Apricot
	Daucus carota	Carrot
Zeaxanthin	Zea mays	Corn	Antioxidant, anti-inflammatory, neuroprotective, hepatoprotective, immunomodulation, anti-carcinogenic, and also to improve skin pliability	Krinsky et al. [30]; Xu et al. [31]; Woodside et al. [32]; Eisenhauer et al. [33]; Cho et al. [34]; Böhm et al. [25]
	Capsicum annuum	Red pepper
	Cucurbita moschata	Pumpkin
	Diospyros kaki	Persimmon
	Malphigia punicifolia	Acerola

Table 1.

Carotenoids with their sources and bioactivity/pharmacological activity [13, 14, 15].

In paprika and pepper, the xanthophylls violaxanthin (yellow), capsanthin, and capsorubin (orange to red) are usually present. Neoxanthin, which has a yellow tint, is a naturally occurring component found in vegetable leaves. Saffron’s yellow hue can be attributed to crocin [45].

Some carotenoids can only be found in algae or seafood. Due to its natural occurrence in krill and the microalga hematococcus pulvialis, which are eaten by small crustaceans like prawn and crawfish, fish like salmon and birds like flamingos, astaxanthin gives prawn, salmon and flamingo feathers their pink-red hue.

Based on the levels of carotenoid in the foods, Britton and Khachik [46] developed a ranking of vegetables and fruits. They divided foods into the following categories:

• Low (0–1 g/g),

• Moderate (1–5 g/g),

• High (5–20 g/g), and

• Very High (>20 g/g) levels.

Many factors influence the composition and number of carotenoids in food, including:

• Those inherent to the plant (variety, genotype, and ripening stage),

• Plant external factors (harvest season, growth circumstances, post-harvest treatment, handling, storage conditions, plant diseases, and climatic variables)

5. Dietary carotenoids in foods

The main dietary carotenoids include the hydrocarbons beta-carotene, alpha-carotene, and lycopene, as well as the xanthophylls, or oxygen-containing carotenoids, cryptoxanthin, lutein, and zeaxanthin [47].

5.1 Beta-carotene

The most extensively researched carotenoid is beta-carotene, which is also a prominent carotenoid in our diet as well as in our blood and tissues. It is a bright red-orange pigment found in many plants and fruits. Green leafy vegetables, as well as orange and yellow fruits and vegetables [48], such as carrots, sweet potatoes, mangoes, pumpkin, kale, spinach, apricots, pepper, cantaloupe, lettuce, and tomato paste, are high in beta-carotene. Because carotenes are fat soluble, eating them with fat improves absorption.

5.2 Lycopene

Lycopene is a brilliant red carotene pigment and phytochemical that plants and microorganisms produce; absorbs light during photosynthesis and protect them from photosensitization. Despite being a carotene chemically, lycopene has no vitamin A action [47].

Heating tomatoes in oil was observed to be related with an increase in lycopene absorption when compared to unprocessed tomato juice absorption, similar to the effect on beta-carotene bioavailability [49]. Furthermore, lycopene bioavailability was higher with a single dose of tomato paste than with an identical lycopene dose of fresh tomatoes.

5.3 Lutein and zeaxanthin

Dark green leafy foods like spinach and kale contain lutein, a significant carotenoid [50]. Lutein is chemically distinct from other carotenoids. One of the most frequent carotenoid alcohols discovered in nature is zeaxanthin. Lutein and zeaxanthin are similar in terms of food sources, human metabolism, and tissue storage. Although the levels are modest in eggs, recent research indicates that both zeaxanthin and lutein from this kind of food are highly accessible.

6. Therapeutic activity of carotenoids

SeeFigure 1 [53, 54].

Figure 1.

Carotenoids to prevent disease [24, 51, 52].

6.1 Anti-ageing activity

One of the main signs of ageing is considered to be the onset and development of atherosclerosis. One of the causes of atherosclerosis is the inflammation-induced generation of reactive oxygen species (ROS) by atherosclerotic plaque.

Age-related blood vessel damage and endothelial dysfunction are caused by the degree of ROS present, which promotes the development of atherosclerosis. Additionally, a decrease in nitric oxide (NO) in the vascular tissue contributes to atherosclerosis and the ageing process brought on by ROS. However, the bioavailability or concentration of NO is often high in normal vascular tissue. Through a number of processes, including the preservation of normal blood flow in organs via flow/shear stress-mediated vasodilation, NO produced in the endothelium inhibits atherosclerotic vascular ageing. One of the primary ways for preventing anti-vascular ageing is maintained vasodilation, which mediates blood flow in organs.

Carotenoids such as lutein, lycopene, and others prevent vascular ageing by anti-oxidant action, which increases the bioavailability of NO in the vascular system. Tomato extracts containing -carotene and lycopene consistently lower blood pressure while increasing NO levels in the plasma [55].

Many other studies have demonstrated lycopene’s actions as an inhibitor of inflammation and ROS, as well as in the amelioration of inflammatory-mediated atherosclerotic processes. Specifically, lutein and lycopene, as well as other carotenoids, impede this process by lowering the level of ROS in biological systems. The anti-oxidant activity of lutein was demonstrated in vascular smooth muscle cells.

6.2 Osteo-protective activity

Carotenoids like β-cryptoxanthin have the ability to regulate the health of bone and inhibit osteoporosis. β-Cryptoxanthin intake increases calcium content and alkaline phosphatase activity in cortical bone and metaphyseal tissues in vitro, leading to a stimulatory effect on bone resorption, which eventually minimises the risk of osteoporosis. The intake of reinforce juice which has higher β-cryptoxanthin than a usual juice, displayed a preventive action on loss of bone. Long term intake of juice containing β-cryptoxanthin results to activation of bone formation and preventive action on reabsorption of bone in humans, which is favourable among menopausal women.

6.3 Antioxidant activity

One of the most effective singlet oxygen scavengers in nature has been shown to be carotenoids, which have a quick quenching rate (1010 M1 s1). They can effectively neutralise ROS and other free radicals to provide oxidation protection for both photosynthetic and non-photosynthetic species. Many epidemiological and clinical research have been conducted to determine whether carotenoids have the ability to protect various ROS-mediated illnesses such as cancer, inflammation, retinal degeneration, and neurodegeneration [56].

Carotenoids have antioxidant properties, but they can also activate endogenous antioxidant enzymatic activity and reduce DNA damage to shield cells from the oxidative stress brought on by specific stimuli. Crocetin, a pharmacologically active metabolite of Crocus sativus L., shows cardioprotective benefits by enhancing superoxide dismutase (SOD) and glutathione peroxidase activity in ventricular hypertrophy. It has also been demonstrated that crocin, another Crocus sativus L. component, increases SOD activity to stop PC-12 cells from dying when they are denied glucose or serum.

Recent research has shown that marine carotenoids like astaxanthin and fucoxanthin exhibit antioxidant characteristics as well by energising the antioxidant network, which includes SOD and catalase [30]. In addition, beta-cryptoxanthin shields human cells from H₂O₂-induced harm by promoting DNA oxidation-related damage repair in addition to its antioxidant activities. At low doses, lycopene and -carotene also protect against DNA damage. However, at greater concentrations, the opposite effects have been observed in cells undergoing oxidative damage [14].

6.4 Effect of carotenoids on neurodegenerative disease

Neurodegenerative diseases are neuronal disorders characterised by increasing neuronal loss and protein aggregation [34]. The most common neurodegenerative disorders are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Although the causes of these neurodegenerative diseases differ, they share certain traits that may be intimately associated to disease start and progression through inducing neuronal cell death.

One common trait is oxidative stress caused by increased ROS production throughout disease progression. ROS are reactive compounds containing oxygen that can target and damage live cell macromolecules such as lipids, DNA, and proteins. Various cellular processes, such as mitochondrial insults and the production of redox metals that interact with oxygen, raise the amount of ROS in the neuronal cells of patients with neurodegenerative disorders, which leads to neuronal cell death [57].

In a case of Alzheimer’s disease, the most studied neurodegenerative disease, multiple studies have found reduced quantities of carotenoids including beta-carotene, lutein, and vitamin A in the blood plasma of Alzheimer’s patients. A recent case-control study found that the concentration of six key carotenoids in serum (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, and zeaxanthin) was considerably lower in individuals with Alzheimer’s disease [58].

Carotenoid consumption reduced the risk of Alzheimer’s disease and the rate of cognitive deterioration. Antioxidant supplementation, like astaxanthin and a vitamin complex containing alpha-tocopherol, ascorbic acid, and beta-carotene, lowered Aβ levels in red blood cells and ROS production in AD patients’ cells, respectively [59].

Carotenoids’ diverse modes of action are expected to occur concurrently in neurodegenerative disease states. Lycopene, for example, reduced A-induced mitochondrial dysfunction, inflammatory cytokine mediators, and caspase-3 activity all at the same time. A-induced damage was reduced in a cultured cell model by astaxanthin administration by many pathways, including downregulation of apoptotic factors, suppression of inflammatory cytokine mediating activity, and concomitant reduction of ROS.

6.5 Anticancer activity

A carotenoid can help prevent cancer through a variety of processes. A carotenoid, as a provitamin A, would influence cellular differentiation and proliferation. Furthermore, the antioxidant action may protect cellular DNA and other components from free radical damage Immunomodulatory effects may improve immune surveillance during carcinogenesis and improved cell-cell communication may limit the clonal proliferation of started cells.

Carotenoids are known to stop the cell cycle in the majority of cases, which is related with decreased expression of cyclin D1, cyclin D2, CDK4 and CDK6. As a result, it up regulates GADD45, which blocks cell entrance into S phase [60].

Furthermore, chemicals derived from saffron such as crocin and crocetin demonstrated anti-metastasis properties such as anti-migration, anti-invasive, and anti-non-adhesive effects when used together on the 4T1 cell line in breast cancer [55, 61]. Carotenoids such as beta-cryptoxanthin and lycopene have been discovered to block the NF-B signalling pathway, which is effective for lung and prostate cancer. Beta-carotene has been proven to have anti-angiogenic action, which means it helps to prevent the formation of new blood vessels, which is common in malignant tumours.

6.6 Cardiovascular diseases

Carotenoids have been shown to reduce oxidative stress, inflammation, dyslipidaemia, and thrombosis, which are all factors in the development of cardiovascular disease.

Carotenoids appear to restore the endothelial bioavailability of nitric oxide (NO) by purging superoxide anion (O₂), which is a direct cause of reactive oxygen species (ROS) formation [62]. By oxidising LDL and lowering HDL, some carotenoids, such as astaxanthin, lutein, and beta-cryptoxanthin, are proven to be more effective at avoiding cardiovascular disease. Myocardial damage and many other conditions can be treated with this [63].

6.7 Ophthalmic infections

Rhodopsin, a component of vitamin A, is essential for the efficient conversion of light energy from pictures into electrochemical impulses, which is a crucial function of the human eye [64]. Night blindness is a result of a vitamin A deficiency; it can be avoided by taking enough carotenoids, which will enhance vision. Only 10% of the carotenoids are categorised as provitamin A and later in vitamin A.

The oxygenated carotenoids lutein and zeaxanthin, which are essential for clear, detailed vision as well as for filtering the blue light from screens and removing free radicals from the retina, are found in the macular portion of the retina. They can also assist in preventing eye cataracts and macular degeneration associated with ageing.

6.8 Anti-hyperglycaemia

Uses of carotenoids by humans decreases the risk of type2 diabetes mellitus. Astaxanthin, a well-studied carotenoid, has better antioxidant characteristics than other carotenoids such as lutein, zeaxanthin, and beta-carotene, and it has been claimed to be useful in the prevention and control of diabetes [65]. The antioxidant properties of astaxanthin can help to maintain the morphology and function of beta cells.

The main cause of hyperglycaemia is lifestyle and eating choices. Hypertension causes oxidative stress, which complicates the body by linking it to obesity, diabetes, dyslipidaemia, and hyperhomocysteinemia. Here, fatty acid radicals and (ROS) play a crucial part in raising the body’s levels of GR, GPx, and other hormones that cause illnesses [66, 67]. Carotenoids restore regulatory signals to normal by scavenging fatty acid radicles and ROS [68].

6.9 Skin protection

The skin accumulates a lot of the carotenoids that are taken as part of a typical diet and uses them to defend itself from sunburn, ageing, and damage caused by UV rays [48]. Carotenoids, with their antioxidant and anti-inflammatory characteristics, as well as their capacity to regulate cell growth and division, can help protect the skin from photodamage and prevent skin disorders.

Several investigations showed that beta-carotene had a preventive effect against sunburn, or erythema, in clinical settings. The colourless carotenoids phytoene and phytofluene may also effectively shield the skin [69]. However, dietary carotenoids like lycopene or beta-carotene provide much lower levels of photoprotection than topical sunscreens do.

7. Conclusion

Carotenoids have emerged as fascinating natural compounds with significant potential for promoting public health and serving as therapeutic interventions. Their antioxidant, anti-inflammatory, immune-modulating, and photoprotective properties contribute to their diverse range of health benefits. Carotenoids have shown promise in preventing chronic diseases, supporting eye and skin health, and potentially serving as novel therapeutic agents.

However, further research is necessary to fully understand the mechanisms underlying the therapeutic activity of carotenoids, optimise their bioavailability, and establish evidence-based guidelines for their use. Rigorous clinical trials, nutrigenomic studies, and investigations into novel delivery systems are required to unlock the full potential of carotenoids for public health and therapeutic interventions [70].

Incorporating a varied and balanced diet rich in carotenoid-containing foods, along with considering the potential benefits of carotenoid supplementation under appropriate circumstances, may contribute to overall health and well-being. As scientific knowledge continues to expand, carotenoids hold promise as valuable components of preventive medicine and therapeutic strategies, offering opportunities for improving human health and reducing the burden of chronic diseases.