Passiflora edulis: An Insight Into Current Researches on Phytochemistry and Pharmacology

Passiflora edulis, also known as passion fruit, is widely distributed in tropical and subtropical areas of the world and becomes popular because of balanced nutrition and health benefits. Currently, more than 110 phytochemical constituents have been found and identified from the different plant parts of P. edulis in which flavonoids and triterpenoids held the biggest share. Various extracts, fruit juice and isolated compounds showed a wide range of health effects and biological activities such as antioxidant, anti-hypertensive, anti-tumor, antidiabetic, hypolipidemic activities, and so forth. Daily consumption of passion fruit at common doses is non-toxic and safe. P. edulis has great potential development and the vast future application for this economically important crop worldwide, and it is in great demand as a fresh product or a formula for food, health care products or medicines. This mini-review aims to provide systematically reorganized information on physiochemical features, nutritional benefits, biological activities, toxicity, and potential applications of leaves, stems, fruits, and peels of P. edulis.


INTRODUCTION
The genus Passiflora, comprising about 500 species, is the largest in family Passifloraceae. Among which, the Passiflora edulis are stands out because of its economic and medicinal importance. (Dhawan et al., 2004). It is widely planted in tropical and subtropical regions in several parts of the world, especially in South America, Caribbean, south Florida, South Africa, and Asia (Zhang et al., 2013;Yuan et al., 2017;Hu et al., 2018). There are seven varieties provided in The Plant List including P. edulis Sims, P. edulis f. edulis, P. edulis f. flavicarpa O. Deg., P. edulis var. kerii (Spreng.) Mast., P. edulis var. pomifera (M. Roem.) Mast., P. edulis var. pomifera (M. Roem.) Mast., P. edulis var. rubricaulis (Jacq.) Mast., and P. edulis var. verrucifera (Lindl.) Mast (The Plant List, 2013). Among them, the yellow-fruited P. edulis f. flavicarpa O. Deg. and the purple-fruited type, P. edulis Sims are the two main and common varieties with considerable economic importance (Zucolotto et al., 2009;Cazarin et al., 2016). The yellow passion fruit is 6-12 cm long and 4-7 cm in diameter. The peel is bright yellow, hard, and thick. The seeds are brown. The pulp is acidic and has a strong aromatic flavor. The purple passion fruit is relatively small in size (4-9 cm long and 3.5-7 cm in diameter). Its peel is purple and seed is black (Narain et al., 2010). Their relevant pictures are listed in Figure 1.
In recent years, with the considerable work done on P. edulis development, there has been an increasing interest to utilize passion fruit for human consumption due to the eating quality of its fruits, juiciness, attractive nutritional values, essential health benefits, and the people's choice (Cazarin et al., 2016;Lima et al., 2016;Pereira et al., 2019). Passion fruit, also well known as "the king of fruits", "maracuja", "love fruit", and "fruitlover", is frequently eaten freshly or squeezed for juice. Meanwhile, a range of products made with passion fruit has been developed including cake, ice cream, jam, jelly, yoghurt, compound beverage, tea, wine, vinegar, soup-stock, condiment sauce, and so on. Passion fruit is also used as traditional folk medicines and cosmetic moisturizing agent in many countries (Xu et al., 2016). In China, the purple passion fruit has been adapted for the cultivation in the warm climate of Jiangsu, Fujian, Taiwan, Hunan, Guangdong, Hainan, Guangxi, Guizhou, Yunnan, and so forth. The purple passion fruit consumption occurs mainly in the form of fresh fruit and fruit juice. According to ZhongHuaBenCao (Simplified Chinese: 中华本草) records, it is sweet, sour in flavour, and highly aromatic, and acts on the heart and large intestine meridians. ZhongHuaBenCao recommends its dosage between 10 and 15 g when taken orally as decoct soup for treatment of cough, hoarseness, constipation, dysmenorrhea, arthralgia, dysentery, insomnia, and so forth. In Brazil, the yellow passion fruit is most commonly used for the preparation of soft drinks and as a remedy in folk medicine, like juices nectars, tinctures or tablets. Today, other parts of P. edulis have also been developed and utilized in many countries. The leaves of P. edulis with highly appreciated and pleasant taste are widely used as sedatives or tranquilizers in the United States and European countries. The flowers are large and beautiful, and can be used as garden ornamental plants. The peels, characterized by high levels of polyphenols, fibers and trace elements, have been widely used for making wine or tea, cooking dishes, extracting pectin and medicinal ingredients, and processing feed. The seeds are edible, and high in protein and oil (mainly composed of linoleic acid, oleic acid, and palmitic acid).
Apart from being a food item, a variety of pharmaceutical products based on ingredients have also be developed and used in folk medicine. The principal components of P. edulis include polyphenols, triterpenes, and its glycosides, carotenoids, cyanogenic glycosides, polysaccharides, amino acids, essential oils, microelements, and so forth Zhang et al., 2013;Yuan et al., 2017;Hu et al., 2018). Among these compounds, the most reported are luteolin, apigenin, and quercetin derivatives. Most importantly, passion fruit contains nutritionally valuable compounds like vitamin C, dietary fiber, B vitamins, niacin, iron, phosphorus, and so forth. A wide range of in vitro and in vivo pharmacological studies have revealed various promising bioactivities of P. edulis, such as antioxidant, antimicrobial, antiinflammatory, anti-hypertensive, hepatoprotective and lungprotective activities, anti-diabetic, sedative, antidepressant activity, and anxiolytic-like actions (Nayak and Panda, 2012;Kinoshita et al., 2013;Silva et al., 2015;Dzotam et al., 2016;Zhang et al., 2016;Panelli et al., 2018). Most of these effects are consistent with those observed for P. edulis in traditional and folk medicine, and these pharmacological actions are thought to be mostly mediated via the existed bioactive components including polyphenol, triterpenes, and polysaccharides. Several researchers have reviewed the botany, chemistry, and pharmacological reports of the Passiflora genus (Dhawan et al., 2004;Correâ et al., 2016). However, to date, no comprehensive review concerning the information on the chemical and biological properties of P. edulis is available.
In this mini-review, we intend to systematically summarize the recent advances in knowledge about chemical and biological activities of different parts of P. edulis (fruit, stems, leaves, and peel). The extraction methods and purification procedures for polysaccharides, processing passion fruit for formulation and production of food product is also reviewed. Future research directions on how to better utilize and develop passion fruit are suggested. Table 1 lists the nutritional composition of purple and yellow passion fruit juice reported from the USDA Food Composition Database. The data show evidence that the purple and yellow passion fruit juice contain a high percentage of carbohydrate, Vitamin A, Vitamin C, minerals, and fiber. In general, the nutritional composition content in purple passion fruit was basically the same as that in yellow variety. In general, the passion fruit has a potential to become a functional food.

Protein and Amino Acids
The total protein content from fruit pulp of passion fruit is 0.80 mg/g (Araujo et al., 2003). Importantly, some proteins in passion fruit have promising antifungal properties. For example, Pe-AFP1 (5.0 kDa), a 2S-albumin-protein-like peptide purified from the seeds of passion fruit, is found to be able to inhibit the growth of filamentous fungi Trichoderma harzianum, Fusarium oxysporum, and Aspergillus fumigatus with a respective IC 50 values of 32, 34, and 40 mg/ml (Pelegrini et al., 2006). Free amino acids isolated from purple passion fruit mainly include leucine, valine, tyrosine, proline, threonine, glycine, aspartic acid, arginine, and lysine. Among them, lysine, threonine, leucine, and valine are indispensable amino acids for growth.

Minerals
Passion fruit is a very refreshing tropical fruit and full of minerals in fruit, juice, peel and seeds, which are known to be effective to human health. For instance, Fe, Zn, Mn, B, Cu, K, N, Ca, P, Mg, S, and Mo of skin and pulp and seeds of passion flower are 150, 41, 40, 25, 10, 3, 0.8, 0.4, 0.21, 0.15, 0.08, 0.08, and 110, 50, 16, 9, 6, 2, 1.4, 0.1, 0.25, 0.15, 0.08, and 0.12 ppm, respectively. We can consider passion fruit plant leaves as good resources of calcium and zinc due to the high content of both minerals. In the youngest leaves, the contents of N, P, K, and Zn are relatively high while the Ca, Mg, B, Cl, and Mn are relatively low (Freitas et al., 2007). Table 1 shows passion fruit juice is a source of minerals that naturally rich in Ca, Mn, P, and K, and so forth. However, the information on harmful elements of passion fruit is rather scarce.

Triterpenoids
Twenty nine triterpenoids varying in chemical structures have been isolated from fruits, leaves, stems, and roots of P. edulis (Bombardelli et al., 1975;Yoshikawa et al., 2000a;Yoshikawa et al., 2000b;Zhou et al., 2009;Wang et al., 2013;Yuan et al., 2017). Cycloartane triterpenoids have showed the significant protective effects against damage of PC 12 cell induced by glutamate, which can be used for the treatment of neurodegenerative disease (Xu et al., 2016). Cycloartane triterpenoids cyclopassiflosides IX and XI at 50 mg/kg displayed antidepressant-like effect .

Sulforaphanes and Carotenoids
Six sulforaphanes and 13 carotenoids have been isolated and identified in fruits of P. edulis (Winter et al., 1976;Engel and Tressl, 1991;Mercadante et al., 1998). Carotenoids from vegetables and fruit play important roles in physiological functions, and thus have health benefits including anti-obesity, antidiabetic, and anticancer activities, and so forth. (Chuyen and Eun, 2017).

Antioxidant Activity
Large amount studies highlight the potential of passion fruit as a valuable source of natural antioxidants which can eliminate free radicals or inhibit the activity of free radicals, thereby helping the body to maintain an adequate antioxidant status. The antioxidant and radical scavenging activities of the extracts from fruit, seed, peel, leaves, bark of P. edulis have been studied via ABTS (Zas and John, 2017), AAPH, DPPH, FRAP, ORAC, HOCI scavengers and ferrous ions assays in vitro, as well as several in vivo experiments (Rotta et al., 2019). The results showed that aqueous, ethanol, polyphenol-rich in particular extracts of leaf (Thomas et al., 2019), peel and seed from P. edulis demonstrate potential antioxidant and radical scavenging activities. P. edulis fruit showed a higher antioxidant activity (64% of DPPH reduced) than mango, pineapple, banana and 3-oxoretro-a-ionols, 3-oxo-7,8-dihydro -a-ionol, 3-hydroxy-1,1, 6-trimethyl-1,2,3, 4-tetrahydronaphthalene, vomifoliol, and dehydrovomifoliol, and so forth. Winterhalter, 1990 He et al.      et al., 2015). The in vivo treated the bark of P. edulis to obese male db/db mice could increase the antioxidant capacity of plasma, kidney, liver and adipose tissue, and reduce lipid oxidation of kidney and liver (Panelli et al., 2018). Furthermore, administration of P. edulis leaves, peel, and seeds to streptozotocin-induced diabetic rats showed antioxidant capacity by improving the anti-oxidants enzyme in animal visceral organs (da Silva et al., 2013;Kandandapani et al., 2015).

Analgesic Activity
Comparative studies showed that n-butanol extracts of P. edulis leaves had a dose-dependent analgesic activity in a thermal stimulation pain model (Nayak and Panda, 2012). In acetic acid-induced writhing, formalin-induced paw licking and response latency in the hot plate test, the polysaccharide of the dried fruit of the P. edulis reduced acetic acid induced writhing and formalin-induced paw licking, but it did not produced a significant increase in reaction time in the hot plate test, suggesting that the analgesic activity of polysaccharide is related to peripheral mechanisms . However, detailed and accurate data on the possible molecular mechanism and bioactive compounds are need to be carried out.

Anti-Inflammatory Activity
Anti-inflammatory activity of P. edulis extracts has been evaluated through in vivo tests like the inflammation induced by 2,4,6-trinitrobenzenesulphonic acid, dextran sodium sulphate carrageenan (Herawaty and Surjanto, 2017), substance P, histamine, bradykinin, and dextran sodium sulphate (Cazarin et al., 2016), and so forth. In a 2,4,6-trinitrobenzenesulphonic acid induced rat colitis model, the aqueous extract of P. edulis leaves reduced pro-inflammatory levels of IL-1b and TNF-a (Cazarin et al., 2015). In a dextran sodium sulphate caused mice colitis model, P. edulis peel flour reduced pro-inflammatory cytokine TNF-a, IL-1b, IL-6, IL-12, and IL-17 expression and decreased the expression of MCP-1 and ICAM-1 (Cazarin et al., 2016). This could be attributed to the presence of bioactive compounds like C-glycosyl flavonoids vicenin, orientin, isoorientin, vitexin and isovitexin. Intraperitoneal injection of the polysaccharide from the dried fruit of P. edulis at the dose of 3 mg/kg reduced mice paw oedema induced by the compound 48/80, carrageenan, histamine, serotonin, and prostaglandin E 2 , and significantly reduced vascular permeability, TNF-a and IL-1b level .

Antimicrobial Activity
The passion fruit possesses antifungal and antibacterial activity against fungi and bacteria which cause infectious diseases in human and plants. The peptide with close similarity to 2S albumins from passion fruit seeds has antifungal properties against Trichoderma harzianum, Fusarium oxysporum, Aspergillus fumigatus, Colletotrichum lindemuthianum, Kluyveromyces marxiannus, Candida albicans, Candida parapsilosis and Saccharomyces cerevisiae (Agizzio et al., 2003;Pelegrini et al., 2006;Ribeiro et al., 2012;Jagessar et al., 2017). The methanol extracts of pericarp of P. edulis inhibited the growth of different bacterial strains such as Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, Pseudomonas  aeruginosa, and Providencia stuartii with minimum inhibitory concentrations ranging from 128 to 1024 mg/ml. This could be due to the presence of bioactive compounds such as polyphenols triterpenes, and sterols contained in the methanol extracts . Indeed, in a systematic study, Ramaiya et al. (2014) showed that the total phenolic and antioxidant contents had significantly antibacterial properties. Oil from yellow passion fruit seeds showed antibacterial activity against Escherichia coli, Salmonella enteritidis, Staphylococcus aureus and Bacillus cereus. n-hexane, tocopherol, linoleic acid, unsaturated fatty acids were identified as major compounds in the oil (Pereira et al., 2019). However, in vivo and clinical studies are needed for confirmation.

Anti-Hypertensive Activity
The anti-hypertensive activity of both yellow and purple passion fruit products has been proved in spontaneously hypertensive rats. Oral administration of P. edulis peel extract reduced hemodynamic parameters, decreased serum nitric oxide level (Zibadia et al., 2007), and lowered blood pressure in spontaneously hypertensive rats (Ichimura et al., 2006;Lewis et al., 2013). This could be attributed to the polyphenols such as luteolin, luteolin-6-C-glucoside, quercetin, edulilic acid, ascorbic acid, piceatannol (Kinoshita et al., 2013) and anthocyanin, and so forth. which can mediate nitric oxide modulation and have potent vascular effects (Ichimura et al., 2006;Lewis et al., 2013;Konta et al., 2014). However, the exact mechanisms and compounds responsible for this effect need further investigation.

Hepatoprotective and Lung-Protective Activities
Oral administration of purple passion fruit peel extract showed hepatoprotection against chloroform (1 mmol)-induced rat liver injury (Zibadia et al., 2007), and showed noteworthy hepatoprotective activity against CCl 4 induced hepatotoxicity (Kavitha et al., 2016). In ethanol-induced liver injury, treated daily with fruit juices to mice for 15 days could protect ethanol-induced liver injury by decreasing AST and ALT in liver, and alleviating the inflammation, oxidative stress (Zhang et al., 2016). In addition, the passion fruit seed extract prevented non-alcoholic fatty liver disease by improving the liver hypertrophy and hepatic histology of the high-fat diet-fed rats (Ishihata et al., 2016). In a pulmonary fibrosis of C57BL/6J mice model induced by bleomycin, administration of passion fruit peel extract significantly reduced loss of body weight and mortality rate, decreased the count of inflammatory cells, macrophages, lymphocytes, and neutrophils, reduced MPO activity and restored bleomycin induced depletion of SOD activity.

Hypolipidemic Activity
Hyperlipidemia can directly cause some diseases that seriously endanger human health, such as atherosclerosis, coronary heart disease, pancreatitis, and so forth. Passion fruit plays an important role in preventing hyperlipidemia. The passion fruit juice at a dose of 580 mg/kg once a day for 30 consecutive days significantly reduced total cholesterol, triglyceride, and lowdensity lipoprotein cholesterol levels, and increased highdensity lipoprotein cholesterol level in diabetic Wistar rat offspring (Barbalho et al., 2011), and peel flour of P. edulis counteracted cumulative body weight gain, decreased adiposity and leptin level, increased adiponectin in diet-induced obesity in rat (Lima et al., 2016). Oral administration of pectin from P. edulis fruit peel 0.5-25 mg/kg for 5 days effectively decreased triglyceride levels in diabetic rats (Silva et al., 2011), and the insoluble fiber derived from seed of P. edulis decreased serum triglyceride and total cholesterol, liver cholesterol, and increased the cholesterol, total lipids, and bile acids levels in feces of golden Syrian hamsters (Chau and Huang, 2005).

Antidiabetic Activity
Diverse studies have demonstrated that peel flour, juice, and seeds of P. edulis showed antidiabetic potential effects by reducing glucose tolerance in diabetic mice, and rats. Oral administration of passion fruit juice at a dose of 580 mg/kg once a day for 30 consecutive days significantly reduced glucose in streptozotocin induced diabetic rat offspring (Barbalho et al., 2011), and administration of passion fruit seed or leaf extract also reduced the blood glucose levels of db/db mice, alloxan induced diabetes mellitus in Wistar albino rats or streptozotocin (STZ) induced diabetic rats (Kanakasabapathi and Gopalakrishnan, 2015;Panchanathan and Rajendran, 2015;Uchida-Maruki et al., 2015). Oral administration of pectin from P. edulis fruit peel at a dose of 0.5-25 mg/kg daily for 5 days lowered blood glucose in diabetic rats induced by alloxan, providing a new treatment for type 2 diabetes (Silva et al., 2011). Peel flour of P. edulis intake increased glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, improved the insulin sensitivity in high-fat diet-induced obesity rats by increasing the glucose disappearance rate (Lima et al., 2016), and also prevents insulin resistance induced by low-fructose-diet in rats. In addition, the leaf extract of P. edulis full of flavonoids also has a health benefit to the diabetic state, and show the prevent effect on the appearance of its complications Soares et al., 2020).

Antidepressant Activity
Antidepressant potential of stems and leaves extracts has been certified in vivo. Oral administration of ethanol extracts of the aerial parts (equal to 10 and 2 g/kg of the plant materials) of P. edulis to mice for 7 day exhibited antidepressant-like effect via reduced immobility time in the forced swim and tail suspension tests in mice. Further evidence showed that the cycloartane triterpenoid cyclopassiflosides IX and XI at the dosage of 50 mg/kg possessed an antidepressant-like effect, which indicated that those cycloartane triterpenoids may be the main responsible bioactive compounds of P. edulis . Oral administration of the aqueous (300 mg/kg), ethyl acetate (50 mg/kg), and butanol extracts (50 mg/kg) of P. edulis Sims fo edulis reduced the immobility time in the mice forced swimming test, which is similar to nortriptyline and fluoxetine. Particularly, ethyl acetate and butanol extract rich in flavonoids showed preferably the antidepressant effects, and that can be counteracted by p-chlorophenylalanine, a-methyl-DL-tyrosine chloride and sulpiride, suggesting this action is related exclusively to regulate serotonergic and dopaminergic transmission such as 5-HT, catecholamine and D 2 receptor (Ayres et al., 2017).

Anxiolytic-Like Activity
The fragrant fruits and their twigs and leaf of P. edulis Sims are most used as a folk medicine in treating anxiety in American countries. In vivo data suggest that varieties of crude extracts like butanolic, methanol, ethanol, hydro-ethanol, and aqueous extract showed anxiolytic-like effect in the model tested. The aqueous extract of P. edulis at 50, 100, and 150 mg/kg showed anxiolytic-like effects in the elevated plus-maze and inhibitory avoidance tests in rat. More importantly, administration of the aqueous extract of P. edulis did not disrupted rat memory process in an habituation to an open-field test, but diazepam impaired rat habituation with a simple modification of the openfield apparatus (Barbosa et al., 2008). The methanol extract of aerial parts of P. edulis Sims at an oral dose of 75 mg/kg showed anxiolytic activity on the elevated plus-maze model of anxiety in mice, but oral dose of 125 mg/kg did not evoke any significant activity. Whereas, oral at higher doses of 200 and 300 mg/kg showed a mild sedative effect (Dhawan et al., 2001). Pre-treatment with 50, 100, and 150 mg/kg hydroethanol extracts and 400 and 800 mg/kg of spraydried powders of P. edulis leaves also showed anxiolytic activity in the elevated plus-maze test in mice. It was suggested that the therapeutic effect of these extracts was due to the presence of a wide range of flavonoids such as isoorientin, orientin, luteolin, apigenin, and chrysin or their glycosides, and so forth (Petry et al., 2001;Coleta et al., 2006;Otify et al., 2015).

Sedative Activity
There is cumulative evidence to suggest that P. edulis possess sedative activity, which are certified its therapeutic applications in insomnia in traditional folk medicines. Oral administration of aqueous extracts of pericarp and the leaves (300 mg/kg, 600 mg/ kg and 1,200 mg/kg) of P. edulis f. flavicarpa Degener showed a rapid onset of action and a significant decrease dose-dependently in locomotor activity in C57BL/6J mice using radiotelemetry. It is noteworthy to mention that aqueous extracts of pericarp showed more significant effects on locomotor activity while compared to leaves extracts (Klein et al., 2014). 300 mg/kg n-BuOH and ethanolic extract of aerial part of P. edulis f. flavicarpa Degener hindered motor activity of mice, showing a sedative-like effect. Flavonoids, especially, isoorientin were identified as a major sedative constituent in the extract (Deng et al., 2010). The aqueous extracts mainly contain C-glycosylflavonoids isoorientin, vicenin-2, spinosin, and 6,8-di-C-glycosylchrysin. In addition, ethanolic extract is composed of flavonoids like isovetexin, apigenin-6-C-b-D-glucopyrano-4′-O-a-Lrhamnopyranoside, luteolin 6-C-b-D-chinovoside, and luteolin 6-C-b-D-fucoside (Zhou et al., 2009). Thus, the flavonoids may be responsible for the sedative activity of P. edulis f. flavicarpa Degener.

Antitumor Activity
Most of the pharmacological work has been carried out on the antitumor activity of P. edulis. In vitro, the different varieties of extracts of P. edulis showed cytotoxicity against HepG 2 (Aguilloń et al., 2018), MCF-7, SW480, SW620, Caco-2 Sandra et al., 2017;Mota et al., 2018), CCRF-CEM, CEM/ ADR5000, and HCT116 [p53(-/-)] . It was found that higher content of polyphenolic and polysaccharide contained in ethanolic extract may be related to the inhibition of matrix-metalloprotease MMP-2 and MMP-9 (Puricelli et al., 2003). In vivo, the ethanol extract of yellow passion fruit inhibited tumor growth with an inhibition rate of 48.5% and increased mice lifespan to nearly 42% in male Balb/c mice inoculated with Ehrlich carcinoma cells. This could be attributed to the presence of medium and long chain fatty acids such as lauric acid (Mota et al., 2018). Oral or intraperitoneal administration of the polysaccharide showed the inhibition of the growth of sarcoma 180 tumors with an inhibition ratio ranging from 40.59% to 48.73% (Silva et al., 2012).

CLINICAL EFFECTIVENESS IN HUMANS
Although the use of P. edulis has a key role in management of various ailments in folk medicine and in various preclinical experiments, the efficacy of this plants has not been explored in depth in human clinical trials. So far, few clinical trials of P. edulis have been conducted to determine if improved chronic diseases such as diabetes, hypertension, and asthma. An open, prospective, randomized clinical trial studies showed that combined use of the yellow passion fruit peel flour and hypoglycemic drugs like glyburide, metformin, and insulin, and so forth. exerted a favorable effect on insulin sensitivity during the 60 days period in type 2 diabetes mellitus patients (de Queiroz Mdo et al., 2012), but the single use of flour made from the rind of the yellow passion fruit over 56 days did not significantly improve glycemic control on type 2 diabetes patients (de Araujo et al., 2017). This seems to be inconsistent with the results of animal experiments, so it remains to verify the antiglycation effect using a multitude of reliable experimental probes and to explicit which type of chemical composition is mostly responsible for promoting the activity of hypoglycemic agents. In 28 days randomized, placebo-controlled, double-blind clinical trial, orally administered of purple passion fruit peel extract at 400 mg/day significantly decreased systolic and diastolic blood pressure by 30.9 and 24.6 mmHg, respectively (Zibadia et al., 2007). Oral administration of purple passion fruit peel 150 mg/day in 28 days clinical trial can effectively alleviate the clinical symptoms of cough by reducing wheeze and cough and improving shortness of breath in adults with asthma, and no adverse effects were found in this study (Watson et al., 2008). Meanwhile, oral administration of purple passion fruit peel 150 mg/day for 56 days in clinical trial substantially alleviated osteoarthritis symptoms, and its beneficial effects may be due to the anti-inflammatory properties (Farid et al., 2010). In general, these interesting studies may contribute to a better understanding of clinical efficacy of P. edulis. However, in consideration of the significant in-vitro and in vivo pharmacological activities of P. edulis, more randomized, double-blind, placebo-controlled and cross-over studies are urgently needed.

TOXICITY
Many researches show that passion fruit does not cause any harmful side effects. In vivo acute and subacute toxicity studies indicate that oral administration of the ethanol extract of unripen fruit peel of P. edulis at the dose of 550 mg/kg had no toxic effect on the rats. Administration of the aqueous extract of P. edulis leaf was found to be safe even at the dose of 2,000 mg/kg. Importantly, mice behavioral pattern and hematologic parameters including RBC, Hb, WBC, MCV, MCH, platelets, neutrophils and lymphocytes had no abnormal change (Anurangi and Shamina, 2018). The subacute study showed that the aqueous extract was safe on the bone marrow function and it was neither hepatotoxic nor nephrotoxic (Devaki et al., 2012). These results provide a basis to further explore the clinical uses of passion fruit. However, more and extensively studies are still needed on its bioavailability and toxicity in animals and humans.

PROCESSING AND APPLICATIONS
Usually, passion fruit with an intense aroma can be eaten directly. Passion fruit is liable to deteriorate and has a short shelf life. Packaging with high oxygen (90%) atmosphere can effectively inhibit respiration and peel shape, keep vitamin C and solubility solids content, and increase total phenols content in passion fruit, improving the postharvest quality of passion fruit (Chen et al., 2018). Different processing methods affected the composition and activity of passion fruit. Steaming and boiling compared to frying protect the health-promoting properties of passion fruit (Gunathilake et al., 2018b). Today, passion fruit has been processed into a range of products on the basis of the attractive health effects and full of phytonutrients. A wide range of products made with passion fruit has been developed including cake, ice cream, jam, jelly, yoghurt, compound beverage, tea, wine, vinegar, soup-stock, condiment sauce, and so on. Additionally, many kinds of passion fruit drink with a refreshing taste are being prepared combining with Chinese medicines including Lycium barbarum and Dendranthema morifolium, and so forth, and are suitable for people to drink in the light of the vitamin supplementation, strengthening immunity, nourishing skin, and resisting fatigue (Zhang, 2018). Seed oil of P. edulis may be developed as functional food such as tea cream with whitening and anti-wrinkle effects. The nutritional ingredients and biological properties of P. edulis provide a strong basis for the development of P. edulis based food products.
The pulp of passion fruit can be both eaten or commonly juiced. The juice is often added to other juices to enhance its aroma. The passion fruit peel accounts for about 51% the fruit wet weight. Because of the large amount of fruit juice production, many thousand tons of seeds, pulps, and peels as agricultural coproducts during juice extraction. Peels, as the major wastes, have become an important burden on the environment. With the development of economy and people's awareness of environmental protection, peel has been used extensively in the industrial production of pectin. It is a widely used functional food raw material with high value in reducing cholesterol levels, reducing hyperlipidemia, and hypertension, improving glucose tolerance and insulin response, helpful to gastrointestinal health and the prevention of some cancers. Pectin is used as a nutritional fiber delivery, gelling agent, and edible coating and stabilizer in the pharmaceutical, cosmetic and food industry, especially in the production of confectionery, jelly, and other products . Pectin-based edible coating plays a waterproof role in fruit preservation, which have the functions of preventing moisture transfer and flavor loss, and improving hardness. The production of commercial pectin from passion fruit peel, seeds and bagasse could not only eliminate the problem of waste, but also provide a new source for pectin industry.

CONCLUSIONS AND FUTURE RESEARCH DIRECTIONS
Passion fruit is most popular for its attractive nutritional and sensory qualities to the health and well beings of the worldwide consumer. Secondary metabolites in passion fruit have been attracting considerable attention because these compounds exert numerous health benefits and economic value, and thus have been used in nutrition, cosmetics and medicine. Passion fruit and its byproducts full of various chemical constituents and phytonutrients including polyphenols, dietary fiber, pectin, carotenes, and vitamin. The chemical constituents and properties of different kinds of passion fruit are diverse. Yellow passion fruit presented higher water and relatively lower nutritional components, while purple fruit presented higher content of vitamin C, vitamin A, fiber and calcium. Different plant parts (leaves, buds, peels, and pulp) and growth stages of P. edulis contain a variety of bioactive components such as total dietary and polyphenols. The yellow passion fruit presented higher content of pectin in peels, high content of carotene, quercetin, and kaempferol in pulps and higher values of total dietary fiber in seeds. The purple fruit was highlighted by a great value of anthocyanins in peels and seeds. Passion fruit peels as food waste account for 50% of the total fruit has also a high potential to obtain functional ingredients because it rich in biological active ingredients. Because of the unique bioactive constituents in passion fruit, diverse nutritional and medical benefits have been watched and recorded. The various extracts from different parts of P. edulis exhibited numerous pharmacological activities including antioxidant, analgesic and anti-inflammatory, antimicrobial, anti-hypertensive, hepatoprotective and lung-protective, anti-tumor, antidiabetic, hypolipidemic, antidepressant and anxiolytic-like capacities, and thus are used in phytotherapeutic remedies. In particular, acute toxicity and subacute toxicity studies have shown that a rationalized daily dose of passion fruit is probably safe for consumption. These outstanding results suggest that passion fruit may offer a range of health benefits, such as managing inflammatory and neurological disease, and also preventing some chronic diseases like hypertension and hyperlipidemia.
There are also research opportunities to better utilize passion fruit and its by-products for human consumption. Both passion fruit and its by-products are a rich source of polyphenols, so it is very important to optimization of appropriate processing methods to stabilize and improve the quality of these processed product. The structure and characteristics of polysaccharides in fruits remains to be studied. Pesticides may be present on the fruit and should be strictly monitored and controlled. Influence of genetic diversity, processing approach and living environment on chemical composition and nutritional value of passion fruit should be further explored. Studies on varieties of P. edulis are very limited, especially the confusion between P. edulis and P. incarnata remains, that need to be attracted special attention from botanist. The pharmacological activity reports of the P. edulis plant are mostly based on preliminary evaluation, and the models used lack appropriate standards or reasonable dosage. P. edulis has showed therapeutic potentials as in vitro anticancer agent against various tumor cell lines, but in vitro cytotoxic activities need to be supported with the in vivo studies and clinical trials to confirm its role as an anticancer agent in future. The structure-activity relationship and molecular mechanism of bioactive compounds or crude extracts of P. edulis will also be the focus of future research and practice. More importantly, clinical trial on P. edulis efficacy and safety are very scarce to support claims of efficacy.

AUTHOR CONTRIBUTIONS
YY, MW, MZ and JF obtained the literatures. FL, ZZ, and XH wrote the manuscript. XH, YL, and ZW gave ideas and edited the manuscript. All authors approved the paper for publication.