Chrysophyllum cainito: A Tropical Fruit with Multiple Health Benefits

Chrysophyllum cainito is a tropical fruit tree with multiple benefits to human health. C. cainito possesses strong antioxidant properties either in vitro or in vivo. Extracts from the leaves, stem bark, fruits, peel, pulp, or seed of C. cainito are promising candidates in traditional medicine for curing diabetes and fighting against bacterial, fungal, and viral infections. C. cainito leaf extract alone or in a complex formula exhibits anti-inflammatory responses by reducing hypersensitivity, acts as inflammatory markers, and has antinociceptive effects. The leaf extract also increases wound healing speed and assists in regulating fat uptake. In addition, the C. cainito fruit shows anticancer activity against osteosarcoma. In conclusion, the aerial parts of C. cainito have strong beneficial biological effects on human health.


Introduction
Chrysophyllum cainito L. (C. cainito) is a tropical tree belonging to the family Sapotaceae. C. cainito is grown as an ornamental or orchard tree, which produces fruit. ere are different names for C. cainito depending on where it is present such as star apple, cainito, and caimito [1]. e seed of C. cainito is in the center which has the appearance of an asterisk when cut transversely, giving the fruit its common English name "star apple." is tree species is commonly found in Mexico, Argentina, Peru [2], the Pacific side of Guatemala [1], and Vietnam, India, China, Malaysia, and other countries where the altitude is low to medium [3].
Medicinal plants have been used in traditional healthcare systems for years, and C. cainito is not an exception. Traditional practicians and patients have used the tree and its fruit as folk medicine. Traditional medicinal plants play vital roles not only in disease prevention but also in treatments [4]. e biological activity of C. cainito has been researched heavily lately, which can be seen by the overall health benefits and properties of C. cainito being studied which includes but is not limited to antioxidants [5,6], antidiabetic [7,8], anti-inflammatory [9], anticancer [10], and antihypertensive properties [11]. is review is to summarize the valuable information of C. cainito where medicinal benefits have been proven.

Nutritional Facts.
e flesh of C. cainito is very sweet mainly due to the high levels of glucose, which is presented in Table 1 along with further nutritional information. e seeds contain 1.2% of the bitter, cyanogenic glycoside, lucumin, and a number of active compounds. As shown in Table 1, the star apple fruit consists of approximately 78.4-85.7% water. Each 100 g of fruit has 0.72-2.33 g of protein present, 14.65 g of carbohydrates, and between 8.45 and 10.39 g of total sugars. Moreover, the fruit also contains several minerals, vitamins, and amino acids [1,2].
Other researchers have found that the leaves of C. cainito contain gallic acid, galloyl myrecetrin, rutin, quercetrin, myrecetrin, myricetin, quercetin and two triterpenoids β-amyrin and lupeol [19], ursolic acid, β-sitosterol, lupeol, and gallic acid [20]. e aerial parts of star apples are rich in phenolic content [7] and total flavonoid content [21], and some of the active compounds have been identified. ose components show promise to have strong antioxidant activity and other biological actions. Table 2 summarizes the phytochemical compound estimated from C. cainito.
3.5. Antioxidant Capacity of C. cainito. Plants are known as an antioxidant reservoir due to rich phytochemical compounds, particularly phenolics [5], flavonoids [26], and alkaloids [27]. An antioxidant agent possesses preventive effects on oxidation processes, ameliorating cellular damage, which is the initial step in the development of cancer and many other diseases [28]. Recently, there has been increasing evidence that C. cainito has high antioxidant activity [21][22][23]29].
A semipurified water : methanol extract of C. cainito fruit showed strong antioxidant activity toward 2,2diphenyl-1-picrylhydrazyl (DPPH) free radical with IC 50 = 7.9 ± 0.3 μg/ml. e strong free radical scavenging activity of the pure compound from semipurified fraction was obtained by H 2 O : methanol (MeOH) extraction, and the isolated cyanidin-3-O-b-glucopyranoside, an anthocyanin antioxidant, was evaluated [17]. Using a DPPH assay, Luo et al. [6] demonstrated that the ethyl acetate soluble fraction from fresh edible fruit of C. cainito had high free radical scavenging activity with IC 50 = 22 μg/ml. Luo et al. [6] concluded that quercetin showed highest antioxidant potential. Similarly, Kubola et al. [18] demonstrated the antioxidant activity of C. cainito fruits (both green and ripe) with FRAP (ferric reducing antioxidant power), DPPH, and AEAC (ascorbic acid equivalent antioxidant capacity) assays, where high levels of activity may be due to the vitamin C, phenolic compounds, and flavonoid compounds present.
Other parts of the star apple, the peel, and pulp of the fruit provide promising effects for free radical scavenging via DPPH, FRAP, NO, and TBARS examinations [23]. Leaf extract from 4 types of C. cainito with ethanol or acetone at different concentrations revealed their scavenging activity against DPPH. Ningsih et al. [21] concluded that 70% ethanol extract of leaf possessed the highest antioxidant property. e crude extract of C. cainito stem bark was evaluated for its antioxidant capacity through ABTS, DPPH, and FRAP assays [7]. e leaf extract significantly reduced the level of malondialdehyde in rat liver and kidney homogenates. Rats that received this extract also showed improved levels of internal antioxidant enzyme glutathione, superoxide dismutase activity, and metallothionein in the liver and kidney homogenates, in comparison to a nontreated gamma radiation-induced oxidative stress rat [20].   C. cainitopossesses strong antioxidant capacities which are demonstrated in vitro and in vivo. e background of these actions was reliant on the rich antioxidant phenolic content and total flavonoid content. erefore, C. cainito is a promising natural agent for the prevention and treatment of diseases related to an imbalance of antioxidant homeostasis such as diabetes, atherosclerosis, hypertension, ischaemic diseases, Alzheimer's disease, Parkinsonism, cancer, and inflammation.
3.6. Antidiabetic Properties of C. cainito. C. cainito is a tropical fruit tree having many benefits in lessening the symptoms of diseases, including diabetes. Diabetes mellitus is one of the most common metabolic disorders worldwide. To achieve good glycemic control in diabetes, the advice is to combine changes in lifestyle and pharmacological treatment [30]. In addition to synthetic drugs, medical plants are effective and often more affordable while giving less adverse effects [31,32].
C. cainito has been used as a remedy for diabetic patients traditionally for years [14,33]; however, the evidence of its benefits has only been investigated recently.
e Dida people, in the area of Divo in Côte-d'Ivoire, Ivory Coast, Africa, create a drink from the stem bark of C. cainito which is believed to lessen the effects of diabetes and push it into remission [33]. An infusion of the leaves has been used as an antidiabetic agent [1]. To demonstrate the antidiabetic activity of C. cainito extract, an experiment with alloxan-induced diabetic rabbits was performed. e diabetic rabbits had a decrease in blood glucose after drinking C. cainito 20 g/l in 6 weeks from 5 g/ l to 1.4 g/l (500 mg/dL to 140 mg/dL). From this study, it was concluded that C. cainito leaves have a glucose-lowering effect at doses >10 g/l and appear to be toxic at 30 g/l. e hypoglycemic effect mainly occurs through active constituents such as alkaloids, sterols, or triterpenes [34]. In 2016, Hegde et al. [8] studied the antidiabetic effects of C. cainito using both model alloxan and streptozotocin-induced diabetic rats. e hydroalcoholic solution (water : alcohol; 1 :1) was used as a solvent for hot percolation extraction. e extract at doses 200 mg/kg and 400 mg/kg body weight of rats induced blood glycemic reduction significantly in comparison with untreated diabetic control. e concentration of triglyceride, cholesterol levels, and low-density lipoprotein declined, whereas an increase was found in highdensity lipoprotein in the treated diabetic rats when compared with diabetic control. Additionally, the extract was found to help protect the islet cells in the pancreas [8].
e ethyl acetate leaf extract of C. cainito in Indonesia significantly decreased blood sugar levels by days 7, 10, and  (25,50, and 75 mg/kg) showed a decrease in blood sugar levels when compared to the negative control, but still below a metformin control comparison, of which the rats that received 75 mg/kg extract exhibited the most effective result [24]. e mechanisms underlying the antidiabetic property of C. cainito were uncovered by the study of Doan et al. [7], where the aqueous crude extract of the stem bark was used to investigate its effect on diabetes. ey reported that a single dose of the extract (500 mg/kg) significantly decreased fasting blood glucose level of alloxan-diabetic mice from 387.17 ± 29.84 mg/dl to 125.67 ± 62.09 mg/dl after 6 hours from treatment. e extract could reduce the area under the curve of blood glucose in an oral glucose tolerance test applied on normal mice. To reduce glucose levels, the extract might stimulate the absorption of glucose in muscle tissue over glucose uptake in the intestinal membrane. e in vitro study revealed the strong inhibition power of C. cainito extract on α-glucosidase, a key enzyme in the digestion process of long-chain carbohydrates to an absorbable sugar form. Although the action mechanism of C. cainito on diabetic control has not been fully explored, the antidiabetic property of C. cainito was confirmed and the topic of this plant has been attracting global scientists.

Antimicrobial and Antiviral Activity of C. cainito.
e pulp and seed of C. cainito were analyzed for their antimicrobial activity using agar well diffusion methods [15]. e seed and pulp exhibited varying levels of antibacterial and antifungal activities against some clinical isolates such as Staphylococcus aureus, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Candida albicans, Aspergillus, and Penicillium ascomycetous fungi. e extract was more sensitive to Staphylococcus, Pseudomonas, and Salmonella at concentrations of 250 mg/ml, 250 mg/ml, and 31.25 mg/ml, respectively, where the zones of inhibition ranged from 1 mm to 10 mm [15]. e green synthesis of silver nano/ micro particles of leaf extract from star apple combined with leaf extract from mango inhibited the growth of Staphylococcus aureus [35], and interestingly, the peels of C. cainito exhibited significant antiviral activity. Antiviral activity was demonstrated through HIV-1 RT inhibition using a nonradioactive immuno/colorimetric assay. Extracts from the peels of C. cainito showed HIV-1 reverse transcriptase inhibition values of 72.55 ± 2.26% [36]. It can therefore be concluded that C. cainito can be considered as a potential source of antibacterial, antifungal, and anti-HIV-1 virus substance.

Antihypertensive Activity of C. cainito.
e blood pressure lowering ability of C. cainito pulp was first discovered by Mao et al. [11]. Firstly, the extracts and fractions from C. cainito pulp showed inhibition of the angiotensin-Iconverting enzyme (ACE) potential, known as a key part of the renin-angiotensin system that regulates blood pressure [37]. ACE inhibition activity was found to be maximized in ethyl acetate fractions of alcoholic extract, compared to all other fractions. Secondly, an ex vivo study using isolated tissue of aorta showed a prominent relaxation effect occurred when treated with the extract or fraction containing the concentration of phenolics equal to 50 μg/ml and 10 μg/ml gallic acid equivalents (GAE) which were comparable with standard control captopril 0.5 and 0.25 μg/ml. en, finally, an ethyl acetate fraction of alcoholic extract was found to reduce the elevated arterial pressure of a salt-induced hypertensive rat significantly compared to that of a nonhypertensive rat.

Anti-Inflammatory Effect of C. cainito.
e antihypersensitivity and anti-inflammatory effects of crude methanolic extract (CME), fractions, and two isolated triterpenes (Lup-20(29)-en-3β-O-hexanoate and 3β-Lup-20(29)-en-3-yl acetate) obtained from the leaves of C. cainito on carrageenan-induced hypersensitivity and paw oedema mice were determined [9]. According to the report, hexane fraction (Hx) showed slight, significant inhibition of mechanical hypersensitivity induced by carrageenan, whereas the ethyl acetate fraction showed no effect. CME slightly inhibited paw oedema compared with the control group (p < 0.0001). Both the CME and the Hx significantly reduced the myeloperoxidase activity. e chloroform fraction was found to reduce the level of IL-1β in the paw tissue with TNF-α releasing still intact. e two isolated triterpenes presented inhibition activity on carrageenan-induced hypersensitivity in mice.
In support of this, the methanol extract from C. cainito leaf proved the inhibition activity on the phagocytosis and significantly decreased IL-6, TNF-α, NO, and H 2 O 2 released by the macrophage. Also, this study confirmed that the extract had a low cytotoxicity effect against the normal Vero cells [25].
Déciga-Campos et al. [38] stated that the ethanol extract of C. cainito leaf in combination with the extract of Pouteria campechiana (Kunth) Baehni, Citrus limonum, and Annona muricata Linn with a ratio of 1 : 1: 1 : 1 demonstrated that each plant displayed antinociceptive potential through formalin and capsaicin tests. Additionally, the formula revealed antihyperalgesic effects in alloxan hyperglycemic rats.

Activities of C. cainito in Bone Diseases.
Osteosarcoma is one of the most common primary malignant bone cancers and is a disease mainly diagnosed in adolescents and young adults and small percentage of cases have occurred in older adults [39]. e polyphenolic fraction of C. cainito pulp with a concentration of 50 μg GAE/ml and higher has shown an increase in reactive oxygen species (ROS) concentration significantly in U-2 osteosarcoma cells compared to the nontreatment control group. e fraction produced ROS statistically equivalent to ROS production stimulated by 100 μM H 2 O 2 . Extracts with 25 to 200 GAE μg/mL showed major linear relations with U-2 osteosarcoma (ATCC HTB-96 ™ ) cell death, where the value of half-maximal effective concentration (EC 50 ) was 133 GAE μg/ml. e supposed mechanism of cell death was oxidative stress, Evidence-Based Complementary and Alternative Medicine leading the cells to enter apoptosis and ultimately to cell death thereafter [10].
However, the extract from C. cainito leaf modulated the elevation of the vertebral trabecular bone density in an osteoporosis mice model. is report indicated that the 70% ethanol extract of C. cainito leaf showed the highest activity with the dose of 400 mg/kg body weight of mice/day. is result was obtained due to active phytoestrogen content in 70% ethanol extract of C. cainito leaves [40].

Wound Healing Activity of C. cainito.
e application of an ethanolic extract of C. cainito leaves on excision, soft tissue, and wounds significantly shortens the recovery time of the wound compared to control drugs (Jatyadi Taila and Betadine) [41]. An ethanolic extract of C. cainito leaves was prepared as an ointment with three different doses 2.5%, 5%, and 20%. e test ointment (0.5 g each) was used and applied on excision wound sites of rats. e highest dose of the extract (20%) showed the fastest rate of wound healing and complete recovery on the 10th day after wound, whereas the control group showed complete wound recovery on the 12th day after wound. e parameters of hydroxyproline, hexosamine, and proteins are the biomarkers of the rate of wound healing and collagen turnover [42], which were found to be substantially increased in the granulation tissue of treated rats when compared with the untreated control.
3.12. Antilipase Activities of C. cainito. Obesity leads to an increase in risk for the development of chronic conditions including cardiovascular diseases [43], diabetes [44], hypertension [45] cancer [46], and many others [47]. One of the approaches to control body weight is to inhibit the absorption of fat, and in this case, C. cainito is an interesting candidate because its extract can interfere with the activity of lipase [48]. e methanol extract of C. cainito leaves could inhibit 74.91% activity of lipase. However, the hexane partition from the methanol extract showed a higher inhibition effect up to 92.11%. It was concluded that the nonpolar pancreatic lipase inhibitory agents dissolve in the hexane solution most efficiently.

Discussion
e normal level of reactive oxygen species (ROS) in the human body plays a crucial role in physiological and pathophysiological activities such as regulating protein phosphorylation, ion channel, transcription factors, and many biosynthetic processes. In contrast, ROS and free radicals can damage cellular structures, including carbohydrate, nucleic acid, protein structure, and lipids [49]. ROS accumulate daily from both intracellular metabolism and exogenous factors such as stress, ionizing radiation, or toxic. Although there is the antioxidant defense system in the body, excess production of ROS can lead to the development of many chronic diseases such as cancer, diabetes and degenerative diseases (neurodegenerative, aging), or digestive diseases [50]. Many studies suggest that antioxidant agents can ameliorate oxidative damage, which helps to prevent disease progression and improve treatment strategies [51].
ose activities have been found richly in medicinal plants [52][53][54]. C. cainito extracts possessed strong antioxidant potential in vitro [7,21,22] and in vivo [20]. Hence, using C. cainito may promote oxidative status in cells and tissues. It is a promising candidate for healing various diseases, in particular, oxidative stress-related diseases.
As described above, multiple pharmacological activities of C. cainito have been discovered, including antimicrobial, antiviral, antihypertensive, anti-inflammatory, antilipase activity, wound healing, antibone cancer, and antidiabetic actions. By recognizing multiple biological functions, C. cainito has become more interesting to scientists. e effect of C. cainito on blood glucose concentration has caught the consideration of scientists most [7,8,24,34].
It is known that diabetes mellitus is a chronic disease characterized by long-term hyperglycemia. e characteristic is derived from insufficient insulin hormone or from the utilization of insulin improperly. Diabetes mellitus has been affected by approximately 415 million people worldwide in 2015, and the number of cases has been estimated to increase to 642 million in 2040 [55]. Most medications for type 2 diabetes are synthetic drugs orally taken, but the frequent insulin injection is essential for type 1 diabetes to survive. Diabetes medications, however, have exhibited many adverse effects such as the sodium-glucose transport protein 2 inhibitor, thiazolidinediones, or sulfonylureas [56][57][58][59]. erefore, antidiabetic agents from natural plants are of interest since natural products are sources of novel drug leads and relatively none or less toxic [60,61]. C. cainito could significantly decrease blood glucose levels in experimental mice [7], rats [24], and rabbits [34]. Beyond glucose regulation, the extract also improved lipid profiles and contributed to pancreatic β-cells regeneration [8]. Several mechanisms of the blood glucose lowering effect of C. cainito were revealed in vitro and in vivo, for instance, protecting β-cells, stimulating glucose consumption from muscle, inhibiting α-glucosidase activity, or basing on its antioxidant power. Unfortunately, the active chemicals in C. cainito crude extract have not been explored yet. erefore, active ingredients within the extract need to be further investigated.
Besides antioxidant and antidiabetic potentials, C. cainito also has strong antibacterial, antiviral, and antifungal activities [15]. Its extract could inhibit the growth of common clinical isolated bacterial strains like S. aureus, E. coli, or C. albicans. However, the action mechanisms remain undiscovered. ese antimicrobial actions may play a part in the treatment of infectious diseases or used as an alternative antimicrobial agent. Moreover, the antimicrobial capacity of the extract enhances its antidiabetic effect in diabetic patients with infection. Infectious diseases were difficult to fight and relatively more serious in diabetes mellitus due to immune system dysfunction [62].

Conclusions
Although C. cainito is planted worldwide mainly for fruits which contain many nutrients such as proteins, carbohydrates, vitamins, phenolics, and amino acids. Its extract has been used as traditional medicine for a long time, and recently several biological functions of this extract have been explored and demonstrated. Many pharmacological activities of C. cainito found such as antioxidant, antidiabetic, anti-inflammation, anticancer, antihypertensive, promoting wound healing, and vertebral trabecular bone cell division. Among them, C. cainito exhibits prominently capabilities in antioxidant, antimicrobiological, and antidiabetic activities. Recent evidences support the use of C. cainito for traditional users. Nonetheless, the mechanisms underlying all activities and pure and active compounds as well as more applications of this plant are expected to be further studied.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.