Syzygium jambos L. Alston: An Insight Into its Phytochemistry, Traditional Uses, and Pharmacological Properties

Medicinal plants have been used since ancient times for human healthcare as drugs, spices, and food additives. The progress in technology and medicine observed, the last decades, has improved the quality of life and healthcare but with worrisome drawbacks. Side effects caused by synthetic drugs for instance originate sometimes irreversible health disorders. Natural substances, in contrast, are biologically and environmentally friendly. Syzygium jambos L. (Alston) also known as rose apple conveys a long history as essential traditional medicine with a broad spectrum of application in various cultures. The plant discloses a diverse group of secondary metabolites and extracts that displayed major susceptibilities towards various health concerns especially stress-related and inflammatory diseases. Despite a rich literature about the plant, the chemistry and biology of S. jambos have not been comprehensively reviewed yet. Accordingly, we present herein a literature survey of rose apple which aims to draw the chemical identity of the plant and establish a consistent discussion on the respective biological application of plant extracts and their corresponding traditional uses. The present work could provide a scientific basis for future studies and necessary information for further investigations of new drug discovery.


INTRODUCTION
The renown of alternative medicines nowadays is appealing although progress in technology and medicine encountered the last decades has improved the quality of life and healthcare around the world. Corresponding drawbacks are quite worrisome. Side effects caused by synthetic drugs for instance hurt human health system, sometimes with irreversible impacts (van Wyk and Wink 2015). Natural substances, in contrast, are biologically and environmentally friendly as they are recognized by other organisms which facilitate their metabolisms. These substances are provided from plants, microorganisms, or animals with a pronounced interest since they constitute the main sources of foods and thus, our first resort in case of pain (van Wyk and Wink 2015).
Plants contain chemicals not essential for their metabolism rather for the fight against attacks and stress due to the plant habitats. These phytochemicals have shown distinct biological properties against numbers of illnesses (Iwu, 1993;van Wyk and Wink 2015). Both plants and compounds are of great interest in drug development to face new medical challenges.
Accordingly, numerous of research works have been conducted on plants from the genus Syzygium to elucidate its chemistry and pharmacology. Species of this genus, including S. jambos, offer edible fruits found under various formulation including juices, jellies, and jams (Sun et al., 2020). The decoction of these fruits serves to alleviate gastrointestinal disorders, wounds, syphilis, leprosy, as well as toothache (Chua et al., 2019). Reports have highlighted the occurrence of polyphenols, flavonoids, tannins, and sterols from various organs of S. jambos species. Meanwhile, plant extracts and compounds also claimed a broad spectrum of activities from antibacterial to anti-inflammatory activities through analgesic, antiviral, antidermatophyte, anticancer, and hepatoprotective properties (Sobeh et al., 2018). Two recent reviews very briefly highlighted the chemical composition, traditional uses and biological activities of the plant (Harsha et al., 2021;Subbulakshmi et al., 2021).
The present research survey tends to summarize the traditional uses, chemical constituents, and pharmacological properties of extracts and compounds from S. jambos in one document as much information as possible about this plant, which has many biological properties. This work could provide a scientific basis for future study and necessary information for further investigations of new drug discovery.

TAXONOMY AND BOTANICAL DESCRIPTION
The genus Syzygium contains approximately 1,200-1800 species, the majority of which are flowering plants (Khalaf et al., 2021). Its taxonomy has been disputed for long with that of the genus Eugenia (Mabberley, 2017). As a result, species of the later have been ranged in the genus Syzygium. Amongst them, S. malaccence, S. suborbiculare, S. paniculatum, S. aqueum, samarangense, and S. jambos (Sobeh et al., 2016;Cock and Cheesman, 2018). S. jambos L. Alston, synonym of Eugenia jambos, is native to Reunion Island, Central America (Guatemal), and South-East of Asia, especially in Nepal, Indonesia, Philippines, and Malaysia. It has been naturalized in India and claims various vernacular names in different cultures including malabar plum, plum rose, rose apple, and water apple (Maskey and Shah, 1982;Morton, 1987;Avila-Peña et al., 2007).
S. jambos belonging to the family Myrtaceae, is a medium sized tree reaching 7.5-12 m in height, Figure 1 (Morton, 1987). Due to its physical characteristics and the aroma of the fruits, the plant is often known as rose apple. It has a dense crown of slender with wide spreading branches. Leaves are opposite, lanceolate, and glabrous with 2.5-6.25 cm wide and 10-22 cm length. They are glossy and dark-green when mature while vibrant red when young. Flowers are in small terminal clusters, white or greenish white with a diameter of 5-10 cm. Usually, there are 4-5 flowers together in terminal clusters (Nawwar et al., 2016). The berries have a fleshy pericarp with 10-15 mm thick on the tree. They are sub-globose and whitish-to pinkish-yellow color. Every fruiting season, a mature rose apple tree produces about 35.57 g of fruit, with 7.16 cm length and 5.15 cm width. The epicarp of the fruit is thin, smooth, and reddish, while the mesocarp and endocarp are whitish and succulent, Figure 1 (Daly et al., 2016;Mangini et al., 2020).

PHYTOCHEMICAL COMPOSITION
Phenolic compounds are mainly present in the leaves of S. jambos. They are represented by flavonoids, ellagitannins, phloroglucinols, and phenolic acids,   Rocchetti et al., 2019;Slowing et al., 1994;Slowing et al., 1996;Sobeh et al., 2018). Flavonoids are the most abundant group of compounds while quercetin sounds to be the most abundant monomer in every organ of the plant, except the stem bark. It is found in both aglycone and saponin forms. Only flavone and chalcone-types of flavonoids occur in S. jambos (Reynertson et al., 2008). Some anthocyanidins have also been detected in the plant mainly, petunidin 3-O-glucoside, pelargonidin 3-O-(6″-malonyl-glucoside) and delphinidin 3-Ogalactoside (Rocchetti et al., 2019). Catechin has been identified from the leaves of the plant suggesting a tentative occurrence of non-hydrolysable tannins in the plant. As part of tannins, only ellagitannins (hydrolysable tannins) have been found in some plant extracts to date. Likewise, ellagic acid monomer derivatives have also been reported in the leaves and stem bark of the plant. Moreover, phenolic acids, listed as intermediates in the metabolism of flavonoids and ellagic acids like gallic acid and cinnamic acid, have also been alarmed in the leaves and fruit of S. jambos. Gallic acid is the most abundant and distributed phenolic acid in the plant. The other phenolic acids were either glycosylated benzoic acid or derivatives of phenylpropanoids. Phloroglucinols also occur in S. jambos leaves. Though only one report highlighted their presence in S. jambos, phloroglucinols are well distributed in Myrtaceae family. The seven compounds of this class were isolated from a Chinese species and no trace of one of this group of compounds was mentioned in the Egyptian or Brazilian varieties, Table 1; Figure 2 (Li et al., 2015).
Pentacyclic triterpenoids are also abundant in the plant especially in the leaves and stem bark. They belong to oleanane, ursane, lupane and friedelane subclasses. The major ones were betulinic acid and friedelin. Saponins of triterpenes have not yet been isolated except the readily available β-sitosterol glucoside, Table 1 (Kuiate et al., 2007;Li et al., 2015). Roots and flowers of the plant have not been investigated yet.
The essential oil of the plant leaves contain mostly volatile sesquiterpenes including δ-cadinene, cumaldehyde, β-himachalene, isocaryophyllene, and β-cedrene, Table 1 ( Khalaf et al., 2021). Linalool is one of the essential oil markers in the identification of the plant fruit. Indeed, linalool, cinnamyl alcohol, and geraniol are the main volatile terpenes in the extracts. Differences were observed in the volatile aromatic composition of fruits from the Brazilian, Malaysian, and Egyptian species. Linalool was found as the main compound in the Brazilian fruits while 3-phenylpropyl alcohol (Z)-3-hexen-1-ol and (Z)-cinnamaldehydes were identified as major compounds in the Malaysian and Egyptian ecospecies (Vernin et al., 1991;Wong and Lai, 1996;Guedes et al., 2004;Ghareeb et al., 2017).

TRADITIONAL USES
Rose apple carries a long history as essential traditional medicine with a broad spectrum of application in various cultures. In India, the fruit tonic helps to improve brain and liver health while fruit infusions convey diuretic property (Morton, 1987). Moreover, the juices from macerated leaves in water were used as a febrifuge (Maskey and Shah, 1982). Dysentery is also alleviated by the seeds together with diarrhea, and catarrh. Furthermore, the flowers are assumed to relieve fever (Baliga et al., 2017). The infusion of the powdered leaves is beneficial to diabetes (Maskey and Shah, 1982). In South American cultures, the seeds have an anesthetic property whereas leaf decoction is applied to sore eyes, and used as diuretic, expectorant and to treat rheumatism (Maskey and Shah, 1982). The decoction of the bark is administered to treat asthma, bronchitis, and hoarseness (Maskey and Shah, 1982). The plant is also used to treat hemorrhages, syphilis, leprosy, wounds, ulcers, and lung diseases due to its potency to relieve fever and pains. In China, each plant organ is used to treat digestive tract and tooth pains (Mahmoud et al., 2021;Reis et al., 2021).

BIOLOGICAL ACTIVITIES
The biological applications of S. jambos are rich and diverse. Isolates were screened in accordance with the traditional uses of the plant encountered worldwide. Mainly, plant extracts and compounds have presented antifungal, antibacterial, hepatoprotective, analgesic, antioxidant, anti-inflammatory, antidiabetic, anticancer, anti-pyretic activities, Figure 3. The main pharmacological characteristics of S. jambos are listed in Tables 2-4.

Toxicity Studies
To date, only few literatures have reported the toxicity of the plant. The leaf extract of S. jambos is safe at a dose up to 5 g/kg b.wt. assessed by the acute toxicity test (Dhanabalan and Devakumar, 2014). The toxicity of the methanol extract of S. jambos and its fraction were evaluated by shrimp lethality bioassay. Methanolic extract and carbon tetrachloride fraction displayed significant lethality with LC 50 6.97 and 13.61 µg/ml,   Slowing et al., (1994), Reynertson et al., (2008)  respectively. Whereas the chloroform and hexane fractions showed moderate to low lethality with LC 50 64.94 µg/ml and 257.6 µg/ml, respectively (Haque, 2015). In the same line, Ghareeb et al. (2016) tested different extracts and fraction obtained from the leaves and flowers against the brine shrimp Artemia salina, a useful tool to determine the toxicity of natural products. As a result, the n-butanol fraction of the leaves showed a strong toxicity with LC 50 50.11 µg/ml while the dichloromethane and petroleum ether fractions were less toxic (LC 50 446.65 µg/ml) (Ghareeb et al., 2016).
Toxicology safety evaluation is essential for plants applications and new drug development. However, the toxicological studies of extracts and compounds isolated from S. Jambos have not been fully explored yet. Therefore, further research in toxicity is needed to determine the suitability of the plant extracts and related compounds composition.
Moreover, silver nanoparticles synthetized from leaves and bark extracts of S. jambos showed higher antiplasmodial activity against chloroquine sensitive and resistant strains of Plasmodium falciparum (Dutta et al., 2017). The fatty compounds, ethyl linoleate, methyl linolenate and phytol, inhibited the QS-dependent pigment production in C. violaceum and lowered pyoverdine production in P. aeruginosa as well. Results were also confirmed by docking analysis (Musthafa et al., 2017). The above research confirmed the antimicrobial activity of S. jambos. However, it is worthy to note that the above studies focused on the in vitro evaluations. Consequently, these studies only give preliminary information about the activity of S. jambos. Therefore, further studies combining in vivo and in vitro need to be conducted to provide reliable basis for exploring new potentially and low toxic antimicrobial agents from the studied plant.

Antioxidant Activity
Several studies, both in vitro and in vivo, reported the antioxidant activity of S. jambos extracts and its phytochemicals. Bonfanti et al. (2013) demonstrated the potency of the leaf aqueous extract of S. jambos to inhibit the nitric oxide radical, the lipid peroxidation and the mitigation sodium-nitroprusside-induced oxidative stress in rats. The extract also showed a capacity to increase the GSH levels in rats (Sobeh et al., 2018). Furthermore, the bark extract inhibited lipid peroxidation and increased reduced glutathione (GSH) in pancreatic tissues of STZdiabetic rats (Mahmoud et al., 2021). S. jambos leaf extract abolished ROS production by endothelin-1 in human polymorphonuclear and mononuclear cell migration (Inostroza-Nieves et al., 2021). On the other hand, S. jambos rich phenolic and flavonoid fractions demonstrated good antioxidant activities as shown in Table 3. The chalcones phloretin 4′-O-methyl ether, myrigalones B and G were assessed for their antioxidant activity using DPPH radical. As a result, myrigalone B showed a significant capacity of scavenging radicals with an IC 50 of 3.8 µg/ml while the other compounds showed low to moderate activity (IC 50 > 30 µg/ml) (Jayasinghe et al., 2007). Moreover, 2,6-dihydroxy-4-methoxy-3,5dimethyldihydrochalcone showed anti-DPPH activity with an IC 50 value of 10.6 µg/ml while, the flavones, 4′methoxysideroxylin and 6-demethylsideroxylin, and phloroglucinols, jambones A-B, presented weak antioxidant activities in FRAP and DPPH radical scavenging activities (Li et al., 2015).

Neurological Activity
There are relatively few studies on neuroprotective effect of S. jambos. Bonfanti et al. (2013) investigated the effects of S. jambos in the inhibition of both AChE and BuCE, the two main enzymes in the occurrence of Alzheimer. As a result, the aqueous leaves extract of S. jambos showed significant AChE (IC 50 16.5 µg/ml) and BuCE (IC 50 15.2 µg/ml) inhibition potentials in support with the uses of the plant to alleviate Alzheimer disorders. Considering these findings, further investigations may improve the neuroprotective effect of S. jambos.

Anticancer Activity
In vitro anticancer activity of isolates from S. jambos was determined towards various cancer cell lines, providing data on the bioactivity of both extract and single compounds, Table 3. Methanolic extract of S. jambos leaves showed cytotoxic effects against liver cancer cell line, Hep G2 cells, by inducing apoptotic pathways (Thamizh Selvam et al., 2016). Moreover, another study evaluated the anticancer effects of the leaves along with other extracts on human melanoma (A375), epidermoid carcinoma (A431), cervical epithelial carcinoma (HeLa) and human embryonic kidney cells (HEK-293). They found that the extract showed low toxicity against HEK-293 cells but better effects against A431 and HeLa cells (IC 50 34.90-56.20 μg/ml) (Twilley et al., 2017). The hydrolysable tannins, 1-O-galloyl castalagin and casuarinin, exhibited significant cytotoxic activity against the human promyelocytic leukemia cell line HL-60 with IC 50 of 10.8-12.5 µM and showed moderate to low cytotoxicity on the human adenocarcinoma SK-HEP-1, normal cell lines of human lymphocytes and liver cell lines. Results were confirmed by DNA fragmentation assay and microscopic investigation of cells (Yang et al., 2000). The cytotoxic effects of the phenolic compounds, cis-3- Φmm ranging between 10 and 13.5 mm Petroleum ether Φmm ranging between 8.5 and 11.5 mm Dichloromethane Φmm ranging between 9 and 11.5 mm Ethyl acetate Φmm ranging between 11.5 and 13.5 mm n-Butanol Φmm ranging between 9.5 and 14.5 mm Aqueous Φmm ranging between 12.5 and 15.  (Li et al., 2015). The cytotoxic effect of quercetin-3-O-β-D-xylofuranosyl-(1 → 2)-α-L-rhamnopyranoside and myricetin-3-O-β-Dxylofuranosyl-(1 → 2)-α-L-rhamnopyranoside isolated from the CH 2 Cl 2 /MeOH fraction of the plant was evaluated against RW 264.7 cell lines. Both flavonoids demonstrated a moderate activity (IC 50 1.68 and 1.11 µM, respectively) . The cytotoxic effect of the nanoparticles synthetized from the leaf and bark extracts of S. jambos was assessed against HeLa and L6 cells using MTT assay. As a result, the nanoparticles were found to be non-toxic toward HeLa and L6 cell lines (Dutta et al., 2017). These investigations provided the anticancer potential of S. jambos, further in vivo, toxicological, and clinical studies are needed in future to guarantee efficiency and safety.

Anti-Inflammatory Effect
Inflammation and specifically low-grade inflammation play a vital role in many diseases. Natural products with antiinflammatory effects are promising targets for drug discovery. In vitro and in vivo models were applied to determine the antiinflammatory effects of crude extracts and pure compounds from S. jambos. In vitro studies showed that the ethanol leaf extract of S. jambos and the commercially available chemicals ursolic acid and myricitrin dramatically reduced the release of inflammatory cytokines IL 8 and TNF-α by 74-99% indicating anti acne effects (Sharma et al., 2013). A more recent study on two isolated glycosylated flavonoids, the quercetin-3-O-β-D-xylofuranosyl-(1 → 2)-α-L-rhamnopyranoside and myricetin-3-O-β-Dxylofuranosyl-(1 → 2)-α-L-rhamnopyranoside, isolated from the chloroform/methanol fraction of S. jambos showed that they reduced the production of TNF-α, with IC 50 values of 1.68 and 1.11 M, respectively in the RAW 264.7 cell line. In addition, at a dose of 5 mg/kg, the flavonoids reduced the levels of TNF-α, C-reactive protein, and fibrinogen in murine models (Apaza Ticona et al., 2021). In vivo studies showed that the ethanol extract of the leaves also exerted potent anti-inflammatory effects at a dose of 400 mg/kg in carrageenan and histamine edema rat models (Hossain et al., 2016). The soluble fraction of polysaccharide fraction of the plant also expressed a capacity to increase the secretion of TNF-α, IL-1β and IL-10 in a concentration-dependent manner (10-100 µg/ml). The aqueous extract of the plant attenuated the inflammatory response induced by LPS at a concentration of 100 µg/ml (Tamiello et al., 2018b). Furthermore, the bark extract inhibited pancreatic inflammation in STZ diabetic rat model where it dose-dependently suppressed the pro-inflammatory, TNF-α and increased the anti-inflammatory IL-10 levels (Mahmoud et al., 2021).

Hepatoprotective Activities
Liver is one of the largest and important organs in human body and performs numerous interrelated vital functions, such as metabolism, biotransformation, and detoxification of toxins. Consequently, liver diseases resulting from liver damage is a global problem. Herbal medicine has been used traditionally for the prevention of liver diseases (Islam et al., 2012). Preclinical studies have shown that extracts from different parts of S. jambos possess beneficial effect in liver related diseases, Table 4. The methanol extract of the leaves of the plant significantly modulated the levels of liver biochemical parameters ALT, AST, MDA, TB, TC, TG, GSH and SOD) in comparison with the positive control, silymarin, Table 4 ( Sobeh et al., 2018). Isolation of the compounds of the extract may led to the discovery of promising active constituents.

Antidiabetic Activity
Diabetes and diabetic complications are global health problem. Although many medicinal plants were investigated for their possible antidiabetic activities, there are relatively few studies on antidiabetic effect of S. jambos extracts. An in vitro study compared the inhibitory effects of ethanol extract of different organs of S. jambos on α-glycosidase and α-amylase activities, enzymes related to diabetes, and showed that the inhibitory effects against yeast and mice intestinal α-glucosidase activity was on the following order: seed ˃ stem ˃ leaf ˃ root ˃ flower ˃ flesh ˃ acarbose, while the inhibitory effect on α-amylase activity was  acarbose ˃ seed ˃ stem ˃ root ˃ leaf ˃ flesh ˃ flower (Wen et al., 2019). In vivo studies showed that the infusion of the combined leaves of S. jambos and S. cumini had no significant effect on blood glucose levels in a randomized double-blind clinical trial in non-diabetic and diabetic subjects (Teixeira et al., 1990). However a more recent study showed that the ethanol extract of leaves at two dose levels (374.5 mg/kg and 749 mg/kg, Po) lowered blood glucose levels in alloxan induced diabetic rabbits (Prastiwi et al., 2019). Moreover, an aqueous leaf extract from the plant showed better blood modulation potential of glucose over time, in diabetes genetic mouse models (Gavillán-Suárez et al., 2015). Recent studies have shown the protective effect of the bark extract on pancreatic β cells against streptozotocin-induced diabetes. The extract have also improved insulin signaling pathway in the liver and glycemic parameters and have suppressed pancreatic oxidative stress (Mahmoud et al., 2021). However, further studies need to be conducted to confirm the potential of S. jambos as a natural antidiabetic agent, as it can be incorporated into functional foods and nutraceutical products.

Antiurolithiatic Activity
The antiurolithiatic activity of the leaf extract of S. jambos, collected in India, was evaluated both in vitro and in vivo using ethylene glycol induced urolithiatic model in rats.
Results showed a capability of the extract to prevent the growth of urinary stones. However, further studies should be done to understand the mechanism and pharmacological action in preventing urolithiasis in susceptible populations (Deka et al., 2021).

DISCUSSION
The main chemicals found in S. jambos were phenolic compounds and triterpenoids. Phenolic compounds were the major constituents of the plant. They are made up of glycosylated flavonoid and ellagitannin derivatives. Plant extracts showed significant antibacterial activity, improving the potency of strong antibiotics like tetracycline, ciprofloxacin, erythromycin, or chloramphenicol. Likewise, both watersoluble fraction and organic extracts have shown significant capabilities in reducing radicals and heavy metal ions. In vivo anti-inflammatory activity of plant extracts has also been demonstrated with considerable endpoints. These biological characteristics of the plant could be related to their main chemical constituents. Flavonoids and ellagitannins are excellent free radical scavengers (Koagne et al., 2020). For this reason, they protect cells from aging and stress, and exerted antinociceptive activities. Indeed, S. jambos plant extracts have shown considerable anti-inflammatory activity towards some models. The analgesic potential has been ascribed to two glycosylate flavonols occurring in rose apple namely, myricetin-3-O-β-Dxylofuranosyl-(1 → 2)-α-L-rhamnopyranoside and quercetin 3-O-β-D-xylopyranosyl-(1→2)-α-L-rhamnopyranoside. However, no mechanism of action of the recorded biological activity was proposed yet. Nevertheless, both antioxidant and antiinflammatory activities encountered for S. jambos extracts and compounds are closely related. The anti-inflammatory potency of rose apple extracts is a key point in the uses of plant extracts to alleviate different illnesses. More importantly, the major constituents of S. jambos extracts, flavonoids and ellagitannins, are mostly glycosylated. They can then be found in large extent in the blood because of their water solubility. This parameter is quite important in drug development as it improves the therapeutic action of a drug. Accordingly, S. jambos constitutes a potential candidate to the development of potent traditional drugs against ROS and inflammation-induced illness.

CONCLUSION AND PERSPECTIVES
This review provides an up-to-date summary of S. jambos from the perspectives of its phytochemistry, pharmacology, traditional uses as well as toxicology. Phytochemical investigations have been focused on different organs of the plant, prepared with various organic and water solvents. These studies revealed the presence of flavonoids (flavones, chalcones, anthocyanins and  proanthocyanins), ellagitannins, phenolic acids, triterpenoids, volatiles compounds and fatty analogues. Compounds were either isolated following chromatographic techniques or identified by online methods like HPLC-MS/MS and GC-MS. Flavonoids and saponins as well as phenolic acids are the main constituents of the plant. Activities of the plant towards pathogens and cells are also diverse and rich, consecutive to the broad spectrum of applications of the plant in traditional medicine to alleviate some illnesses. Plant extracts showed considerable antiinflammatory activity and a synergistic effect to antibiotics activity of some popular drugs correlating the uses of the plant to relieve pains and infection. Extracts have also antiviral, anti-dermatophyte, hepatoprotective, and anticancer effects. Numerous compounds were isolated and initially screened for their bioactive potential. Further investigations are needed to complete the phytochemical profile, pharmacology mechanisms and pharmacokinetics studies of the plant. In the same line, toxicity study of S. jambos is indispensable in the future to assess the safety of the plant and its bioactive compounds to support possible future medicinal applications and before proceeding to the development of pharmaceutical formulations.

AUTHOR CONTRIBUTIONS
MAO and WBB drafted the manuscript; GTMB and MFM reviewed the manuscript; MS revised the manuscript and designed and conceived the study. All authors approve the final version.

FUNDING
The APC was paid by UM6P.