Abstract
Cactus has been used in traditional folk medicine because of its role in treating a number of diseases and conditions. Prickly pear fruit is an excellent source of secondary metabolites (i.e., betalains, flavonoids, and ascorbic acid) with health-promoting properties against many common human diseases, including diabetes, hypertension, hypercholesterolemia, rheumatic pain, gastric mucosa diseases and asthma. In addition, prickly pears are potential candidates for the development of low-cost functional foods because they grow with low water requirements in arid regions of the world. This review describes the main bioactive compounds found in this fruit and shows the in vitro and some clinical studies about the fruit of most important cactus (Opuntia ficus-indica) and its relationship with some chronic diseases. Even though a lot of effort have been done to study the relationship between this fruit and the human health, more studies on Opuntia ficus-indica could help better understand its pharmacological mechanism of action to provide clear scientific evidence to explain its traditional uses, and to identify its therapeutic potential in other diseases.
Introduction
In the last decades, several components from natural sources are getting a lot of attention due to their important role in improving overall well-being in the human health and their possible contribution in the prevention of some diseases, like diabetes, cancer, obesity and cardiovascular. In this matter, vegetables and fruits are have been recognized as valuable sources of bioactive compounds that must be consumed during a lifetime in a balanced diet [1]. In this context, Opuntia spp. are of current interest as foods or for developing nutraceuticals and functional ingredients because they possess bioactive compounds such as ascorbic acid, flavonoids, phenolic acids, betalains, carotenoids, and fiber [2].
Opuntia spp. is a genus member of the Cactaceae family and is a diverse and widely distributed in the American, Africa, central Mediterranean area (Sicilia, Murcia, Andalucía, Extremadura, Ceuta, Melilla, Navarra, Aragón as well as in the Balearic and Canary Islands), Asia and Australia [2, 3]. This plant and its fruit are known also as nopal, prickly pear, Indian fig opuntia, Barbary fig, spineless cactus and cactus pear [4]. There are several species, but the highly cultivated and domesticated is Opuntia ficus-indica (OFI) due to its nutritional, medicinal, pharmaceutical and economic impacts [5].
Opuntia spp. plant grows easily into large clonal colonies with low water requirements and in extreme soil and climatic conditions [6, 7]. The Mediterranean region, particularly in land areas, are currently suffering from severe drought during extensive summers, and global climate change is expected to deeply affect this area in the near future [8]. For that reason, Opuntia spp. cultivar can be a good alternative to get heathy food during hard times.
Betanin and indicaxanthin pigments are the main responsible compounds of Opuntia spp. color. Also, they have strong radical-scavenging and antioxidant activity. On the other hand, the most abundant flavonoids, isorhamnetin glycosides (IGs), possess high antioxidant activity; piscidic acid is the most abundant phenolic acid [2].
This review aims to summarize the main bioactive compounds that can be found in the fruit of the most common Opuntia spp., Opuntia ficus-indica, as well as the main in vitro and in vivo studies related with the benefits in the human health. The information to write this review was collected from papers published in PubMed, Scopus and Web of Science in the last 30 years.
Phytochemistry and bioactive compounds in prickly pear fruits
The diversity of bioactive molecules detected and quantified in Opuntia ficus-indica have contributed to consider it as a health promoting foods [4].
It has been reported by Cota-Sánchez [9] that prickly pear fruit contains approximately 85% water, 15% sugar, 0.3% ash, and less than 1% protein. The flesh fruit is a good source of minerals and several types of amino acids (asparagine, alanine, arginine and and). In addition, it is a good source of vitamins include vitamin C, E, K, beta-carotenes and betalains and flavonoids.
The main bioactive compounds that have been found and studied in this fruit are the pigments betalains (betacyanins and betaxanthing) and polyphenols (flavonoids). The amount found in some studies are shown in Table 1.
Betalains (Betaxanthing and Betacyanins) and polyplenols reported in pulp and peel extracts from Opuntia ficus-indica var
Betalains (Betaxanthing and Betacyanins) and polyplenols reported in pulp and peel extracts from Opuntia ficus-indica var
1Values are expressed as mg of indicaxanthin equivalents. 2Values are expressed as mg of betanin equivalents. 3Concentration expressed as mg equivalent of gallic acid.
Betalains are water-soluble, nitrogenous compounds that constitute the main pigments of plants belonging to the order Caryophyllales, where edible plants like beets, chards, or cactus pears are found [22]. They are found as secondary metabolites in many plants where they replace anthocyanins [23]. Betalains are classified into two groups that differ in the nature of the compounds condensed with betalamic acid. These groups are the violet betacyanin betanidin, or with amines or amino acids to produce yellow betaxanthins by Schiff condensation [24].
Gómez-Maqueo et al. [2], using high performance liquid chromatography, identified in the pulp indicaxanthin (Ind) as the main betaxanthina and betanin as the main betacyanin. Other betalains, such as portulacaxanthin, vulgaxanthin (I, II, III and IV), isobetanin, betanidin, and neobetanin, were also identified in lower amount. Furthermore, they found piscidic acid and hydroxybenzoic acid derivative, quercetin glycoside, quercetin glycoside, isorhamnetin glucoxyl-rhamnoside, isorhamnetin glucoxyl-rhamnosyl-pentoside, isorhamnetin hexosyl-hexosyl-pentoside, isorhamnetin glucoxyl-pentoside, rutin, kaempferol-glucosyl rhamnoside, isorhamnetin glucoxyl-rhamnoside and isorhamnetin.
A study carried out with several wild fruits collected in different sites of Portugal showed that the main constituents identified and presented in the extract are flavonoids (namely isorhamnetins and its derivatives such as isorhamnetin 3-O-rhamnose-rutinoside and isorhamnetin 3-O-rutinoside) and phenolic acids (such as ferulic, piscidic and eucomic acid) [25]. Additionally, Mata et al. [4] identified malic, quinic, citric and succinic acid, as well as aromatic acids as hydroxybenzoic, caffeic, piscidic, ferulic and eucomic acid in the orange-red Opuntia fruit. Furthermore, the flavonols identification showed as main compounds: isorhamnetin glucosyl-di-rhamnoside, isorhamnetin pentosylrutinoside, isorhamnetin pentosyl-glucoside, isorhamnetin rutinoside, isorhamnetin pentosyl-rhamnoside, isorhamnetin glucoside, isorhamnetin-3-O-rutinoside, isorhamnetin-3-O-glucoside, rutin, quercetin glucoside and quercetin. The presence of betanin, isobetanin, indicaxanthin, leucine- betaxanthin, phenylalanine- betaxanthin, tryptophan- betaxanthin was also obtained.
Fruits from three O. ficus-indica species, namely cultivars Meyers (pink), Gymno-Carpo (orange), and Nepgen (green) were picked from an experimental orchard in the Free State, South Africa to determinate the levels of the main antioxidants. The components were distributed as fellow: betalain contents in pink fruit (4.62±0.25 mg/kg), green (3.11±0.94 mg/kg) and orange (2.33±0.47 mg/kg). Related with ascorbic acid, orange fresh products had the highest ascorbic acid content (15.03 mg/100 g), then green (91.69±8.98 mg/100 g) and pink (52.52±5.75 mg/100 g). Carotenoids values were from 1.78±0.23μg/g in orange fruit to 0.92±0.16 (pink) and 0.62±0.19 (green). Phenolics from pink fruit had the highest value (17.74±0.91 mg/kg), orange (17.45±9.15 mg/kg) and green (16.72±7.48 mg/kg) [26].
García-Cayuela et al. [11] identified and quantified the main betalains and phenolic compounds, in different tissues (peel, pulp and whole fruit) from purple, red and yellow/orange Mexican and Spanish prickly pear cultivars. A total of 14 betalains were detected, where betanin and indicaxanthin were the most abundant. The purple cultivars (Mexican and Spanish one) showed the highest concentration of betacyanins (1,372 and 2176μg/g dry whole fruit, respectively), while the highest betaxanthin values were obtained in red and yellow Mexican cultivars (435 and 488μg/g dry whole fruit, respectively). 17 phenolics compounds were detected corresponding mostly to flavonoid (isorhamnetin, quercetin and kaempferol) glycosides and a phenolic acid, piscidic acid.
Four prickly pear varieties from the Canary Islands (Spain) have been characterized in terms of betalains and phenolic compounds. In this study, the authors identified 14 betalains (9 betaxanthins and 5 betacyanins). The major betacyanin in red fruit was betanin, in agreement with other studies, meanwhile the main betaxanthin was betaxanthins-proline (indicaxanthin) in orange prickly pears. Related with phenolic compounds, 17 were found, which included 3 phenolic acids (mainly, piscidic acid and 4-hydroxybenzoic acid) and 14 flavonoids. Regarding flavonoids, the most abundant were isorhamnetin glycosides [12].
Moreover, several Opuntia ficus indica juices obtained from wild fruits collected in different sites of Portugal showed that the main constituents identified and presented in the extract are flavonoids (namely isorhamnetins and its derivatives such as isorhamnetin 3-O-rhamnose-rutinoside and isorhamnetin 3-O-rutinoside) and phenolic acids (such as ferulic, piscidic and eucomic acid) [25].
The juice of whole fruits of Sicilian cultivars was investigated by Galati et al. [27]. The major flavonol quantified was Isorhamnetin-3-rutinoside, but also small amounts of isorhamnetin-3-glucoside, rutin, and kaempferol-3-rutinoside were detected.
Prickly pear peel is an agroindustrial by-product and is also good source of dietary fiber and bioactive compounds [28]. For this reason, some authors have studied this matrix. An investigation conducted by K. Milán-Noris et al. [29] showed that the prickly pear peel extract (PPPE) contained 65.65 + 1.5 mg/g total phytosterols. The major phytosterols were β-sitosterol (76.6%), campesterol (19.5%) and stigmasterol (3.9%). Additionally, PPPE had a total phenolic content of 6.05 + 0.11 mg garlic acid equivalent/g.
Changing lifestyles is a priority to decrease the incidence of chronic diseases. Strategies focusing on smoking and dietary habits have gain a lot of importance. In this matter, there is an increasing interest for natural bioactive compounds in the diet, present especially on fruits and vegetables [30–37]. Opuntia spp. can be a good alternative because many studies have highlighted the health effects on human being such like antioxidant capacity, anti-inflammatory, hepatoprotective, antitumor, antidiabetic, hypolipidemic, antimicrobial, and antiproliferative agents [38].
The main ways in which Opuntia spp. can interrelate and exert their biological effects are summarized in Fig. 1.
Main pathways that Opuntia spp. can positively enhance the human heathy.
Cancer is a devastating disease. Numerous studies have demonstrated the anti-inflammatory and cytotoxic effects of various parts of Opuntia, namely the prickly pears (fruits), with or without peels and seeds, the cladodes or stems, and even the roots, on cancerous cell lines [6]. The main studies related with the fruit properties are summarized in the next paragraphs.
Naselli et al. [39] investigated the effect of the aqueous extract from the Sicilia edible fruit (yellow cultivar), and its isolated indicaxanthin (Ind), on proliferation of human colon cancer Caco-2 cells. Treating these cells with the whole extract or the equivalent amounts of purified Ind caused a dose-dependent apoptosis of proliferating cells. The results showed that extracts caused growth arrest of adeno-carcinoma Caco-2 cells, and suggested involvement of Ind. Furthermore, the application of the extract and Ind resulted in a significant reactivation of the silenced mRNA expression, p16INK4a protein accumulation and the cell cycle arrest in the G2/M-phase. Notably, Ind caused a specific reversal of the hypermethylation of the onco-suppressor gene p16INK4a, accompanied by re-expression of mRNA and accumulation of 16 kD p16INK4a protein. Therefore, hyper-phosphorylated decreased in favor of the hypophosphorylated retinoblastoma, with unaltered level of the cycline-dependent kinase (CDK4).
In another study, betanin, isolated from the fruits, induced apoptosis in human chronic myeloid leukemia cell line (K562) in a dose and time dependent manner. Betanin action was mediated by the release of cytochrome C from mitochondria into the cytosol, and PARP cleavage [40].
Indicaxanthin, isolated from cactus pear fruits (yellow cultivar), effectively inhibited the proliferation of the highly metastatic and invasive A375 cells. In this in vitro study, the results showed a growth inhibition, apoptosis induction and cell invasiveness reduction. On the other hand, the oral administration of indicaxanthin to mice significantly reduced tumor development. The molecular mechanisms underlying the antiproliferative effect of indicaxanthin, can be related with the inhibition of NF-κB pathway as the main factor [41].
Combination of indicaxanthin, isolated from the fruit, with cisplatin showed synergistic cytotoxic effects against cervical cancer cells. This treatment had significant effects on phosphatidylserine externalization, cell morphological changes, cell cycle arrest, release of reactive oxygen species (ROS) production and GSH. In addition, Bax, cytochrome c, p53 and p21waf1 were over-expressed, while Bcl-2 was downregulated [42].
The clarified juice extracted from yellow fruit displayed antioxidant activity as well as a selective cytotoxic effect on a liver cancer cell line with no toxic effect on fibroblasts [18].
The administration of cactus pear fruits from the yellow Sicilian cultivar in healthy human adult diet resulted in the reduction of proinflammatory mediators TNF-α, interleukin (IL)-1β, interferon-γ (INF)-γ, IL-8, C-reactive protein and the erythrocyte sedimentation rate and the elevation in levels of anti-inflammatory marker IL-10 and dermal carotenoids [43].
The release of ROS and key inflammatory markers (IL-6, IL-8, and NO) was strongly inhibited by both isolated betalains and even higher in prickly pear extracts. These results point out the synergistic activity of bioactive compounds in prickly pears extracts on in vitro cell-free and cell-based assays [44].
Orange, red and yellow OFI fruit pulp and peel betalain extracts showed an anti-angiogenic activity by cell-free, cell-based, and in vivo assays. It is important to notice that the highest values were obtained with the orange samples [45].
Cell death in the U87-MG and HT-29 cell lines increased due to the application of pinkish fruit extract in a concentration-dependent manner [46].
Other biological activities of prickly pear fruit extracts
To our knowledge, the main focus on the pear fruit studies is related with its bioactive compounds profile and antioxidant capacity. Their properties are attributed mainly to their betalain and polyphenols composition, but not many studies have been done to support those properties. However, it is important to point out that Opuntia ficus-indica fruit is good source of bioactive compounds so the intake of this fruit can positively affect the body’s balance. The studies highlighted shows different properties of the fruit extracts and its isolated main compounds.
It is important to note that Betanin and indicaxanthin purified from fresh pulp were able to slightly inhibit the expression of the cell-adhesion molecule ICAM-1 at a micromolar concentration in a Human umbilical vein endothelial cells model. This means that extract from this fruit can act as modulators of adhesive molecule expression in endothelial cells [47].
Regarding gastrointestinal diseases, a study conducted by K. Milán-Noris et al. [29] showed that prickly pear peel extract significantly reduced the plasma total cholesterol in male hamsters fed with Hypercholesterolemic diet and phytosterols (HCPh). This evidence suggests that the prickly pear byproduct has potential to be used as ingredient or supplement to prevent cardiovascular diseases and lower cholesterol.
Not only polyphenols or pigments from prickly pear fruit have the beneficial effects in lipid profile, but also glycoprotein. For instance, Oh and Lim [48] isolated a prickly pear glycoprotein from the fruit and its intake had a positive effect in the hyperlipidemic system; specifically, it had the ability to lower plasma lipids (triglycerides, total cholesterol and low-density lipoprotein) and to increase antioxidative enzyme activities and blocking lipid peroxidation in mice.
Furthermore, Tesoriere et al. [49] conducted a clinical trial to investigate the effects of short-term supplementation with cactus pear fruit from yellow Sicilian fruit on total body oxidative status in healthy humans. In general, the results showed the consumption of cactus pear fruit positively affects the body’s redox balance, decreases oxidative damage of lipids, and improves antioxidant status.
Other study showed that the gastric mucosa of male Wistar rats treated with fruit juice was almost normal in appearance after ethanol-induced ulcer. Significant reduction in gastric hyperaemia and in both number and severity of the lesions was observed animals treated [27].
Other study where male Sprague Dawley rats were administered with dry powdered fruit suggested the reduction of hepatic damage cause by the exposure alcoholic oxidative stress [50].
It was reported by Gambino et al. [51] the effects of indicaxanthin, isolated from cactus pear fruits (yellow cultivar), on the neuron physiology. This betaxanthin was intragastric administrated in adult rats. After the treatment, indicaxanthin was accumulated in cortex, hippocampus, diencephalon, cerebellum and brainstem but not in striatopallidal complex. The local injection showed that the bioelectric activity of neurons belonging to different brain areas was modulated, mainly with dose-related responses; interestingly, a possible beneficial effect of indicaxanthin in reducing cell excitability was described.
Pre-treatment of olfactory ensheathing cells (OEC) with indicaxanthin isolated from yellow fruit pulp prevented the production of superoxide anion and ROS as well as the reduction of vimentin and glial fibrillary acid protein. The betaxanthin extract, mainly Ind, inhibited apoptotic pathway activation, increased nestin and cyclin D1 expression and stimulated renewal of stem cells through the reparative activity played by transglutaminase (TG2). Furthermore, the data suggest that native peptide of amyloid-beta (Aβ) (1-42) might modify TG2 conformation in OECs and indicaxanthin pre-administration might modulate TG2 conformation, stimulating neural regeneration in Alzheimer’s disease [52].
Pinkish fruits extract was able to ameliorate cisplatin-induced renal toxicity in mice. The potent antioxidant compounds might be responsible for the observed renoprotective effect [53]. The summarized of the in vitro and in vivo studies carried out to evaluate the biological activity of the peel and pulp or juice are showed in Table 2.
Main results related with the in vitro and in vivo studies using pulp, juice or peel from Opuntia ficus-indica var
Main results related with the in vitro and in vivo studies using pulp, juice or peel from Opuntia ficus-indica var
Finally, but not less important, the antioxidant properties of cactus pear fruit have been studied pliantly. This property is associated mainly to ascorbic acid, phenolics and a mixture of purple-red betacyanin and yellow-orange betaxanthin pigments. In general, the extracts from the pulp or juice and peel have showed a good radical scavenging activity using DPPH, ABTS, FRAP, TEAC and ORAC methods [54].
Even though more studies have to be conducted (in vitro, in vivo and clinical) to get more information about the Opuntia ficus-indica fruit benefit effects in the human health, the fact is that this fruit is a good source of bioactive compounds against chronic diseases and other pathologies. In particular, the purple and yellow-orange varieties could be an interesting source of colored bioactive compounds which not only have coloring potential, but are also an excellent source of dietary antioxidant components. Also, it is important to get more insight related with the different mechanisms of action of their bioactive molecules.
Conflicts of interest
The authors declare no conflict of interest.
Funding
This research received no external funding.