Nutritional and medicinal properties of Star fruit (Averrhoa carambola): A review

Abstract Star fruit (Averrhoa carambola), a popular fruit in many parts of the world, is considered to have many beneficial nutritional and medicinal effects. However, harmful nephrotoxic and neurotoxic effects have also been described. In this review, we have discussed the reported beneficial effects of star fruit, explored the potential mechanisms for such beneficial effects, and outline factors that may affect the safe level of consumption. The beneficial effects include the following: antioxidant (mediated via L‐ascorbic acid, epicatechin, and gallic acid), hypoglycemic (mediated via high fiber levels and 2‐dodecyl‐6‐methoxycyclohexa‐2,5‐diene‐1,4‐dione), hypotensive (mediated via apigenin), hypocholesterolemic (mediated via micronized fiber), anti‐inflammatory, anti‐infective, antitumor effects, and immune‐boosting effects. The presence of chronic kidney disease, gastroenteropathies, chronic pancreatitis, dehydration, consumption on an empty stomach, and higher concentration of oxalate in fruit/juice consumed predisposes to toxicity. The level of ingestion at which the beneficial effects transition to nephrotoxicity and neurotoxicity is still to be accurately ascertained. Furthermore, the relationship between the amount of star fruit ingested and the severity of toxicity is not certain and warrants further study.


| INTRODUC TI ON
Star fruit (Averrhoa carambola) is a commonly consumed fruit in both tropical and other countries. It is cultivated in many parts of the world (extensively in the South-East Asian Region) to harvest its fruit (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). It has several nutritional and medicinal uses. Star fruit is considered a rich source of natural antioxidants and minerals (Carolino et al., 2005;Moresco et al., 2012). The star fruit may be eaten raw or be used in the preparation of juices, salads, or pickles. It is considered as a herb in several countries (Patel et al., 2015;Wang et al., 2016).
As it helps with removing rust, it may be used for cleaning utensils. On the other hand, there are case reports and case series in the literature describing nephrotoxicity and neurotoxicity related to star fruit ingestion (Yasawardene et al., 2020). In this review, we have summarized the main nutritional benefits of star fruit and outlined the observed effects on different physiological processes. The beneficial pharmacological properties of star fruit and factors influencing a potential safe limit of consumption have been discussed.

| Nutritional and day-to-day use
There are two known varieties of Averrhoa: Averrhoa carambola and Averrhoa bilimbi (Ferrara, 2018). A. carambola, which is known as star fruit, is widely consumed in Asia. These are eaten as fresh fruit or cooked with other delicacies. They may be cooked and transformed into jams and stored in sterilized jars for long periods (Ferrara, 2018).
Alcoholic beverages may be obtained by fermentation with the addition of yeasts such as Saccharomyces cerevisiae which release alcohol and carbon dioxide. Some communities also eat flowers and leaves of star fruit either fresh or in the cooked form (Ferrara, 2018). Star fruit contains approximately 60% of cellulose, 27% of hemicelluloses, and 13% of pectin (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). The acidity and composition of nutrients vary with the advance in maturity.
According to Narain et al. (2001), the pH of the fruits become less acidic as the fruits' ripening occurs (Narain, 2001). Furthermore, the calcium content was more at ripe stage. Factors such as titratable acidity, tannin contents, and reducing sugars varied considerably at different stages of maturity. Star fruits are a good source of vitamins and minerals. Star fruits are rich in natural antioxidants such as vitamin C, β-carotene, and gallic acid (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). Furthermore, it is a good source of magnesium, iron, zinc, manganese, potassium, and phosphorous (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). Furthermore, it contains high amounts of fibers and low calories which may aid in controlling blood sugar (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). The second species Averrhoa bilimbi is native to Cuba. The fruit is small, green, and sour, and not suitable for consumption. However, it has been used as a treatment for bee sting, a stain for various dyes, antirust agent for the treatment of metals, and also as a stain remover for clothes (Ferrara, 2018). Furthermore, it is utilized as a base for various perfumes and colognes (Ferrara, 2018 Full-text arƟcles excluded, with reasons (n = 3: review arƟcles) Studies included in qualitaƟve synthesis (n = 27; Human -2,  of saponins, flavonoids, alkaloids, tannins, and pyrogallic steroids (Khoo et al., 2010(Khoo et al., , 2016Muthu et al., 2016). Other phytochemicals such as phenols, anthocyanin and anthocyanidin, chalcones and aurones, leucoanthocyanidins, catechins, and triterpenoids were also extracted from various parts of star fruit (Silva et al., 2020).

| Medicinal properties
Star fruits are considered to have a number of beneficial health effects. These include antioxidant, hypoglycemic, hypotensive, hypocholesterolemic, anti-inflammatory, anti-infective, antitumor, and immune-boosting effects ( Figure 2). Star fruits are commonly used in Ayurvedic and Traditional Chinese Medicine (TCM), and some of the clinical conditions they are used for include the following: fever, cough, diarrhea, chronic headache, inflammatory skin disorders (eczema), and fungal skin infections (Patel et al., 2015;Wang et al., 2016). The ripened fruit is also used in some countries to treat bleeding hemorrhoids.

| Hypoglycemic and antidiabetic effects
Each star fruit has a high amount of fiber, and this contributes to the beneficial effects on glucose homeostasis. The insoluble fibers inhibit the activity of α-amylase and delays the release of glucose from starch (Chau et al., 2004). Potent hypoglycemic activity has been demonstrated in vitro. In 2007, a study performed on male Wister rats found a decrease in blood sugar level when they were fed with hydroalcoholic extract of leaves of Averrhoa carambola. (HELAC) (Ferreira et al., 2008). In 2016, an in vitro study on cultured pancreatic beta-cells found the compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1, 4-dione (DMDD) extracted from star fruit to attenuate inflammation and cell F I G U R E 2 Schematic diagram of potential beneficial effects of Averrhoa carambola (DMDD:2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione; MEACL: methanolic extract of Averrhoa carambola leaf; 7α-HDE B: 7α-hydroxy-dihydro-epideoxyarteannuin B; 3α-HDE B: 3-α-hydroxy-dihydro-epideoxyarteannuin B, TNF-α: tumor necrosis factor alpha, NO: nitric oxide; IL: interleukin) apoptosis. Furthermore, the same compound increased glucosestimulated insulin secretion (Xie et al., 2016). Using DMDD, Zheng et al. showed this compound to be effective in reducing blood sugar levels in diabetes-induced mouse models (Zheng et al., 2013). In 2019, a study on diabetic mice found DMDD treatment to attenuate diabetic nephropathy. There was a decline in blood glucose, serum creatinine, and blood urea nitrogen levels and an increase in the quantity and density of podocytes (Lu et al., 2019). In another study from 2020, the administration of benzoquinone isolated from the roots of Averrhoa carambola to male Kunming mice with induced diabetes found a reduction in the blood glucose levels when compared with a control group . Zhang et al. showed that the beneficial effects of Averrhoa carambola extracts in mice with induced diabetes were probably due to inhibition of the TLR4/TGF-β signaling pathway by active compounds like DMDD .
So far, the evidence lies in experimental animal studies and one in vitro study (Table 1), and thus, clinical studies are needed to assess the clinical relevant antidiabetic effects in humans.

| Hypocholesterolemic effects
The intake of star fruit increases the removal of cholesterol and bile acids from the body. For instance, in hypercholesterolemic hamsters, the consumption of the water-insoluble fraction of a star fruit increased the excretion of fecal total lipids, cholesterol, and bile acids (Chau et al., 2004). There was also a reduction in in feces (Wu et al., 2009). Another study found the methanolic extract of Averrhoa carambola leaf (MEACL) reduces the levels of serum lipids in rats fed high-fat diets (Aladaileh et al., 2019).
In addition, MEACL decreased the body mass index, atherogenic index, hepatic cholesterol, and triglycerides and increased fecal cholesterol and bile acids (Aladaileh et al., 2019). Most evidence on lipid-lowering effects is extrapolated from animal studies (mouse models) and has so far been demonstrated in only one human study (Table 1). In 2016, Leelarungrayub studied the effect of star fruit consumption on lipid status among elderly Thai individuals. The study subjects were asked to drink 100g of fresh star fruit juice twice daily for 4 weeks. At the end of the study period, the HDL-C level was higher (p = .03) and LDL-C level was significantly lower (p = .02) when compared to measurements at baseline. There were no significant differences in levels of triglyceride (p = .65) and cholesterol (p = .71) (Leelarungrayub, Yankai, et al., 2016).

| Antioxidant activity
Star fruit has high antioxidant activity and is able to efficiently scavenge reactive oxygen species (ROS) and other free radicals.
The fruit has high levels of flavonoids, proanthocyanidins, vitamin C, β-carotene saponins, alkaloids, tannins, and gallic acid. It is able to inhibit the activity of cytochrome P450 3A (Hidaka et al., 2006).
Several studies have analyzed its antioxidant capacity from a biochemical perspective. In 2004, Shui and Leong detected polyphenolic antioxidants in star fruit using liquid chromatography and mass spectrometry. The main antioxidant action was attributed to phenolic compounds such as L-ascorbic acid, epicatechin, and gallic acid in gallotannin form (Shui & Leong, 2004). In another study done by the same team, the star fruit residue (following juice extraction) was found to account for around 70% of the total antioxidant activity (Shui & Leong, 2006). In a study investigating the antioxidant actions of common Mauritian exotic fruits, A. carambola was found to be an important source of phenolic antioxidants, and to exhibit potent health benefits in humans (Luximon-Ramma et al., 2003). Among fruits tested from a Aizawl market of Mizoram in India, A. carambola was found to have moderate antioxidant activity (Ali et al., 2011).
Chemical constituent analysis of A. carambola leaves found the antioxidant activity of the extract to be significantly correlated with its phenolic content . Most of the findings so far are from in vitro studies, and only one human study (with a small sample size) has been done ( Table 2). This human study assessed the effects of star fruit consumption on 27 elderly individuals. The consumption of 100g star fruit juice twice daily for 4 weeks resulted in significant improvement in antioxidant status (Leelarungrayub, Yankai, et al., 2016). There were increased total antioxidant capacity, reduced malondialdehyde and protein hydroperoxide levels (p < .05), and significantly increased vitamin A and C levels.  (Cabrini et al., 2011). The evidence base among humans is limited and so far only one study has described the effects in humans (Table 2). In 2016, the levels of proinflammatory factors were assessed in community-dwelling elderly subjects, following the consumption of star fruit juice for 4 weeks.

| Cardiovascular effects
The C-glycoside flavone, apigenin (also called carambola flavone), is a secondary metabolite of Averrhoa carambola leaves (Araho et al., 2005). Apigenin relaxes rat thoracic aorta primarily by suppressing calcium influx through both voltage-and receptor-operated calcium channels (Ko et al., 1991). An aqueous extract of Averrhoa carambola leaves promoted a reduction in guinea pig atrial contractility and automaticity (Vasconcelos et al., 2005). This was secondary to blockade of an L-type Ca 2+ channel. Furthermore, it caused electrophysiological changes in the normal guinea pig heart (Vasconcelos et al., 2006).  (Table 3).

| Immune-boosting effects
Several claims have been made in the lay literature regarding possible immune function boosting effects of star fruit. At the present moment, more robust and well-designed studies need to be carried out to explore this aspect further.

| When do the beneficial pharmacological effects turn into toxic effects?
Many reports of toxicity have been described following consumption of star fruit, mainly in relation to nephrotoxicity and

Author (Year) Country Type of study Metabolic effect
In vitro studies Xie et al. (2016) China In vitro study (pancreatic beta cell line)

TA B L E 1 (Continued)
neurotoxicity. Several mechanisms of star fruit toxicity have been postulated; however, most evidence is based on animal studies.
There has been much debate on the beneficial dose of star fruit and the dose at which it may become toxic (Yasawardene et al., 2020).
Several clinical reports on star fruit toxicity suggest that the toxic dose is likely to vary depending on multiple factors such as comorbidities (chronic kidney disease, gastroenteropathies, chronic pancreatitis), levels of hydration at time of ingestion, consumption on an empty stomach, the type of star fruit consumed (sour as compared to sweet variety), and concentration of oxalate in the star fruit extract (Yasawardene et al., 2020). Caramboxin and oxalate are key structural compounds that cause toxicity. A detailed review on star fruit toxicity has described the pathophysiological mechanisms of caramboxin and oxalate in causing neurotoxicity and nephrotoxicity (Yasawardene et al., 2020). Oxalate concentrations differ between freshly prepared and commercially available juices with the pickling and diluting processes used in commercial juice production contributing to reduced oxalate concentrations when compared to freshly prepared star fruit extract (Yasawardene et al., 2020).
Furthermore, the toxic dose of star fruit in humans has not been defined. There is a wide variation in the actual amount of star fruit consumed in relation to reported toxicity. For example, from half to as many as 50 fruits at a time have been reported to cause toxic effects (Stumpf et al., 2020). In relation to volume, it ranged from 25 to 3,000 ml of undiluted start fruit juice. However, several patients have consumed the juice mixed with herbal drugs (Chen et al., 2001).
Toxicity has been described in association with single consumption and long-term ingestion. For example, consumption of 5-6 star fruits every month for 2-3 years (Abeysekera et al., 2015) and consumption of one star fruit per day for an year (Wijayaratne et al., 2018) have been reported to cause toxicity. Moreover, studies have also found that ingestion of even small amounts of star fruit on an empty stomach can lead to toxic effects (Ananna et al., 2016;Barman et al., 2016).
As magnesium and calcium ions bind to oxalate in the gastrointestinal tract, their absence when on an empty stomach may lead to increased absorption of oxalate and subsequent toxicity (Azim & Salam, 2016;Chen et al., 2001). Some studies showed no association with the amount of consumed star fruit and severity of intoxication or mortality (Auxiliadora-Martins et al., 2010;Neto et al., 2003).
Therefore, associations between the above factors and toxicity in humans need further evaluation as the toxic dose of star fruit seems multifactorial. A genetic predisposition for toxicity may also be considered in future studies. Further studies are needed to characterize the mechanisms of absorption, metabolism, and excretion of toxic molecules in star fruit (such as caramboxin and oxalate) in both healthy humans and subjects with preexisting renal impairment. Therefore, the question on the beneficial dose of star fruit and the dose at which it may become toxic remains unanswered.
It is important to note that majority of the studies describing beneficial effects of star fruit are based on experimental animal studies and in vitro animal studies. However, several claims have been made in the lay literature regarding the potential benefits of start fruit among humans. Based on the available evidence (as described in this review), there is a scarcity of human studies, and therefore, the potential benefits in humans should be interpreted with caution.
Furthermore, studies on pharmacokinetics and bioavailability of star fruit are limited. Further studies in humans are required to examine the clinical relevance of these potential benefits, the dose required to reach clinically significant effects and also to assess the potential toxicity at such doses. Furthermore, until further studies are available, routine consumption of star fruit in view of achieving the above potential benefits should not be advised.

| CON CLUS IONS
Star fruit extracts have demonstrated several potential beneficial medicinal properties including antioxidant, hypoglycemic, hypocholesterolemic, anti-inflammatory, cardiovascular, antitumor, and immune-boosting effects both in vitro and in vivo studies. However, majority of these findings are extrapolated from in vitro or animal studies. On the other hand, star fruit ingestion has also been shown

Methods Results
Active compound identified Possible mechanism of the effect DMDD dissolved in dimethyl sulfoxide (DMSO) -10 mmol/l introduced to the cell culture Cell viability and glucose-stimulated insulin secretion increased in DMDDtreated cells DMDD DMDD inhibited generation of inflammatory cytokines IL−6, TNFα, and MCP−1 Cleaved-caspase−3, caspase−8, and caspase−9 downregulated (responsible for apoptosis) to cause nephrotoxicity and neurotoxicity. At the present time, the level of ingestion at which the beneficial effects become toxic has not yet been precisely defined. The presence of chronic kidney disease, gastroenteropathies, chronic pancreatitis, dehydration, consumption on an empty stomach, and higher concentration of oxalate in the fruit/juice consumed predisposes to toxicity. Therefore, considering the lack of human studies and the reported toxicity profile, further studies in humans are necessary, specifically related to pharmacokinetics and bioavailability.

ACK N OWLED G M ENTS
None declared.

E TH I C A L A PPROVA L
Not applicable.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Active compound identified
Possible mechanism of the effect The ethanolic extract at doses of 800 and 1,200 mg/kg per oral was given to rats with induced ulcers Anti-ulcer activity in the acidified-ethanolinduced ulcer model in rats. However, the extract did not show any activity in the indomethacin and acute-stress ulcerogenic models. Thus, the study concluded ethanolic extract of A. carambola as having low anti-ulcer activity NA NA Evaluate the prophylactic role of the fruit of Averrhoa carambola on diethylnitrosamineinduced liver cancer in Swiss albino mice. Administration of extract was made orally at a dose of 25mg/kg body weight/day for 5 consecutive days prior to induction of the cancer A. carambola extract administration resulted in a considerable reduction in tumor incidence, tumor yield, and tumor burden NA NA Two compounds isolated from the bark of Averrhoa carambola were subjected to antimicrobial screening at 400 μg/disk Inhibited the growth of E. coli with zone of inhibition 15 mm. In the case of fungi, mild inhibitory activity was exhibited p-anisaldehyde and β-sitosterol NA Two compounds (7α-hydroxy-dihydroepideoxyarteannuin B, and 3-α-hydroxydihydro-epideoxyarteannuin B) extracted from culture cells of A. carambola were examined for the antitumor activity on K562 and HeLa cell lines Demonstrate that 7-hydroxyl product exhibited stronger antitumor activity than the 3-hydroxyl product against the K562 and HeLa cell lines 7α-hydroxy-dihydroepideoxyarteannuin B, and 3-α-hydroxydihydroepideoxyarteannuin B

Active compound identified
Possible mechanism of the effect Measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria after introduction of A. carambola leaf extraction.
Extract abolished the contractile force in a concentration-dependent manner and reduced the inotropic response to CaCl 2 NA Effect of extract on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.
Aqueous extract of Averrhoa carambola L. leaves was used to assess electrophysiological effects The extract induced many kinds of atrioventricular blocks (1st, 2nd, and 3rd degrees); increased the QT interval; increased the QRS complex duration; depressed the cardiac rate NA NA Aqueous leaf extract of Averrhoa carambola used on guinea pig left atrium in order to evaluate the inotropic effect In the atrium, the aqueous extract (1,500 μg/ ml) shifted to the right the concentrationeffect curve of the positive inotropic effect produced by L-type calcium channel agonist