Lansium domesticum—A Fruit with Multi-Benefits: Traditional Uses, Phytochemicals, Nutritional Value, and Bioactivities

Lansium domesticum (Langsat, Meliaceae) is a tropical fruit mainly found in Southeast Asian countries, particularly in Thailand, Malaysia, Indonesia, and the Philippines. Traditionally, it is utilized as a folk treatment for eye inflammation, ulcers, diarrhea, dysentery, fever, spasms, flatulence, worms, insect bites, scorpion stings, and malaria. Additionally, it is utilized as a mosquito repellent, skin moisturizer and whitening agent. Pharmacological research showed that the plant has a wide array of bioactivities, including antimalarial, antifeedant, anti-aging, wound healing, antioxidant, cytotoxic, analgesic, antibacterial, antimutagenic, insecticidal, and larvicidal. The most commonly described activities were attributed to the presence of terpenoids and phenolics. Further, some studies reported the preparation of nanoparticles and pharmaceutical formulations from the plant. This review highlights the potential of L. domesticum as herbal medicine. It provides an overview about the reported data on L. domesticum from 1931 to November 2021, including nutritional value, traditional uses, phytoconstituents, and bioactivities, as well as nanoparticles and pharmaceutical formulations.


Introduction
Fruits, vegetables, and medicinal herbs are the richest sources of health-promoting compounds such as vitamins, β-carotene, minerals, flavonoids, phenolics, and polyphenolics that exert significant bioactivities [1,2]. Genus Lansium belongs to the Meliaceae family, which includes about 560 species and 50 genera that are widespread in tropical and subtropical regions [3]. Genus Lansium commonly recognized species are Lansium breviracemosum Kosterm., L. membranaceum (Kosterm.) Mabb., and L. domesticum Corrêa. [4]. This genus is represented by only one species, L. domesticum, in Peninsular Malaysia [4]. While in Java, it is represented by two species; L. domesticum Corrêa and L. humile Hassk., as well as a variety L. domesticum var. pubescens Koorders et Valeton have been recognized [5,6]. L. domesticum is a common evergreen Southeast Asian tree that occurs both in the wild or cultivated in these regions, where it represents one of the commonly cultivated fruits [7]. It has high market potential and adequate economic value in Southeast Asian countries. Thailand, Malaysia, Indonesia, and the Philippines are considered to be the main producers of L. domesticum. Additionally, the plant is cultivated in Burma, Vietnam, Puerto Rico, Sri Lanka, India, Hawaii, Surinam, and Australia [5,8,9]. L. domesticum Correa is a complicated aggregate species of different plant forms. It's four prevalent types are Duku, Dokong (longkong), Duku-langsat, and Langsat. Duku and Langsat are the two most common types. Duku-langsat, Langsat, and Duku are domestic to Peninsular Malaysia, however, Dokong is found in southern Thailand and has been cultured in Peninsular Malaysia for >10 years [5,7]. The Duku-langsat is an intermediate type, it is conventionally regarded as Table 1. Characteristics of the major distinct forms and varieties of L. domesticum.

Forms/Variety
Botanical Characteristics Ref.

Langsat
Fruits are bunched together ≈ 20 on one brown thick spike up to 20 cm length. Its fruit is oval or round ≈ 2-3 cm long and has a yellowish skin, which when peeled release a latex, showing up a translucent white flesh that is divided into segments and has 1-3 seeds. On ripping, the flesh is fairly aromatic and juicy with a sweet-acidic taste. [11] Duku Fruits are bunched together ≈ 8-12, on one brown thick spike up to 20 cm length. Duku fruit is featured from langsat fruit by its larger size (3-5 cm in diameter), round shape, and much thicker skin that is comparatively free from latex. Also, it is generally more aromatic and sweeter than langsat. [11] Dokong (Longkong) Fruits are occurred in bunches (25-30 fruits/bunch). Its fruit is globular with leathery, thick, and yellow skin, free of latex. The edible portion is juicy and fleshy is thin-skinned, nearly seedless, and free of latex, with uneven five-fragmented translucent white adhering aril. It has a nice aroma with a slightly sour and sweet taste. [12,13] Duku-langsat It is round, brownish-yellow, and intermediate in size. It has a sweet flesh and thinner skin than that of duku. [5] L. domesticum var. typica Inflorescence: rachises, young branchlets, under the surface of leaves, and calyx sparsely pubescent or sub-glabrous. Fruit: oblong-obovoid or ellipsoid, pericarp thin with little milky juice, seeds small, aril thick and smooth. [14] L. domesticum var. pubescens Koorders et Valeton Inflorescence: young branchlets, rachises, calyx densely pubescent, under the surface of leaves. Fruit: sub-globose, pericarp thick with milky copious juice, thin and sour aril, large seeds. [14] The plant has different synonyms; Aglaia domestica (Correa) Pellegrin, A. aquea (Jack) Kosterm., A. intricatoreticulata Kosterm., A. dookoo Griff., A. merrillii Elmer, A. steenisii Kosterm.  [5,15,16] (Table 2).
Its tree has a 40-50 ft height with long leaves which are dark green and pinnate with a glossy surface. The flowers are present in clusters on the old branches and trunk of the tree. They are mostly bisexual, small with a yellow-white color. The fruits grow in clusters and are small, round (3-5 cm diameter) with a leathery yellow skin that can be thin or thick. The fruit's flesh is translucent and juicy with six or five segments which have seeds. The fruits may be sweet or acidic relying on the growing conditions and variety [5]. The delicious, succulent, fruit aril is eaten fresh directly after peeling or can also be candied or preserved in syrup [5,17,18]. The jams, juices, sherbet, and ice creams are the most popular langsat products. On the contrary, the seeds and peel are the main byproducts after the flesh's consumption, neither of which are widely used. However, the seeds and peels are a rich pool of bio-metabolites [12]. In Indonesia, the fruit is a very popular dessert, and the peel was traditionally known to be toxic to domestic animals [19]. The plant extracts exhibited various biological activities, including antimalarial, antifeedant, anti-aging, wound healing antioxidant, cytotoxic, analgesic, antibacterial, antimutagenic, insecticidal, and larvicidal. Phytochemical studies of L. domesticum indicated that triterpenoids particularly onoceranoids with unusual and unrivaled skeleton, cycloartenoid, and tetranortriterpenoid are the main constituents reported from this plant that displayed remarkable bioactivities. In recent decades, herbal medicines have substantiated their publicity among consumers for both traditional and cultural reasons. Herbal medicines have been utilized for treating various ailments and diseases in many populations for thousands of years. They are considered the main treatment approach in many countries because of their safety, reliability, and affordability in comparison to synthetic ones that can cause adverse effects on human health. L. domesticum has immense role in providing medicinal and realistic value in many developing countries particularly in regions where medicine is unreachable, and the populations are in the need of healthcare. Thus, this review is aimed at describing and summarizing the studies on L. domesticum, including traditional uses, nutritional value, phytoconstituents, and bioactivities, as well as the production and season and nanoparticles and pharmaceutical formulations. The cited literature in the current work is dated from 1931 to November 2021.

Research Methodology
The reported data about L. domesticum was obtained through searching in various databases, including Web of Science, PubMed, Scopus, and Google scholar. Moreover, published papers in different publishers such as ACS, Elsevier, Bentham, Sage, Wiley, Taylor &Francis, Thieme Medical, and Springer were surveyed. Further, non-English papers, theses, conferences, and symposiums have been reviewed. The used keywords include

Traditional Uses of L. domesticum
The different parts of L. domesticum have various medicinal and non-medicinal uses in many nationalities ( Table 3). The peel is wealthy in non-toxic oleoresin that is utilized against diarrhea and fevers [8]. In Thailand, the peel and flesh have been used as facial toners, wash gels, and masks, as well as a skin moisturizer and whitening cream. Additionally, the seeds possess antifeedant and febrifugal capacities and pericarp is utilized for repelling mosquitoes [22,23]. L. domesticum bark was used by people in the Pakuli region of Palu for malaria treatment. Moreover, the boiled bark with water was utilized to reduce pain and fever [24]. Table 3. Non-medicinal and medicinal uses of L. domesticum.

Forms/Variety
Botanical Characteristics Ref.

Fruit peels
In Java, it is dried and burned as incense in the sick people's rooms and to repel mosquitoes. It is utilized to cure diarrhea and intestinal parasites.
Fruit peels are used as an arrow poison. [25,26] It is applied to the skin as a moisturizer and skin whitening cream. Borneo, it is utilized as talc powder by indigenous females of Dayak for skin protection from the sun. [10,27] Seeds Pulverized seeds mixed with water are utilized as a vermifuge for children. Also, they are utilized as a febrifuge. In Peninsular Malaysia, among the Sakai the bitter seeds were crushed and utilized for curing fevers. In the Philippines, pounded seeds mixed with water are used for deworming and ulcers. [22,23,28] Bark A poultice of bark used against scorpion stings. A decoction is taken for malaria and dysentery treatment in Java, Borneo, and Malaya. A tincture is useful as an anti-colic or anti-diarrhetic.
In Kenya, the bark is used for spleen and fever. In Borneo, bark stew water decoction is taken by rural communities as an antifertility medicine. [8,17,26,[29][30][31] Resin It halts diarrhea and intestinal spasms. The resin from the bark is given for swellings, flatulence, and spasm.

Forms/Variety Botanical Characteristics
Ref.

Leaf
Its juice is utilized as eye drops to eleminate inflammation. A decoction of leaves and bark has been taken for curing dysentery.
The Philippines used leaves for the control of mosquitoes. In Ibans in Sarawak, Malaysia leaves are used to treat fever. [26,32,33] Peel and flesh It is used as facial masks, wash gels, and toners. Peel is known to be toxic to domestic animals. [10,34] Wood tar It is used for blackening teeth. [5] Wood It is used for tool handles, house posts, and rafters [16] Bark and fruit The fruit skin's juice and bark are utilized as a Dyak arrow poison. [5] Seed and bark A decoction of seed and bark is used for the enlargement of spleen and fever in Kenya. [30] Stem The decoction of the langsat stems and bark of Pterocarpus indica assists treating dysentery. [35]

Nutritional Value of L. domesticum
The fruit tastes sweet and sour. It has a sour taste due to its low pH at about 3.85 that is aligns with the reported total acidity of fruit ≈1.04% [36]. Its taste has been resembled to a combination of grapefruit and grape and is considered excellent by most people. Its fructose, sucrose, and glucose contents are accountable for the sweet taste [37]. The fruit is a prosperous source of minerals, fats, protein, organic acids, carbohydrates, fiber, and vitamins. Various studies reported the evaluation of the nutritional value of this fruit. Chemical composition and mineral contents of flesh, peel, and seed of a fruit sample collected from Kuala Terengganu, Malaysia using ICP-OES (inductively couple plasma optical emission spectrometry) were previously evaluated [38]. The seeds had the highest crude protein (3.0 g/100 g), carbohydrates, and sodium, whereas the peels possessed high contents of crude fat, ash, calcium, potassium, and magnesium [38]. Furthermore, the seeds are rich in starch. Additionally, it was reported that the seeds and peels could have higher nutrient contents than pulp fruits [39]. In Thailand, the nutrient composition per100 g langsat fruit had energy (66 cal), moisture (82.9%), protein (0.9 g), fat (0.1 g), fibre (0.3 g), carbohydrate (15.3 g), Ca (5 mg), Fe (0.7 mg), P (35 mg), vitamin A (15 I.U.), vitamin B2 (0.02 mg), vitamin B1 (0.08 mg), niacin (0.1 mg), and vitamin C (46 mg) [40]. In addition, it was found that 100 g edible portion of duku showed 34 kcal energy, 90 g water, 0.4 g protein, 0.0 g fat, 8.2 g carbohydrate, 0.9 g fiber, 0.5 g ash, 10 mg Ca, 20 mg P, 1.0 mg Fe, 12 mg Na, 230 mg K, 0.05 mg vitamin B1, 0.02 mg vitamin B2, 0.5 mg niacin, and 13.4 mg vitamin C [41]. Meanwhile, 100 g longkong fruit flesh contained protein 1.0 g and crude fat 0.5 g, which are higher than that of duku and langsat fruit [18,42]. Moreover, 100 g of longkong contains water 84 g, fiber 0.8 g, carbohydrates 14.2 g, Ca 19 mg, ash 0.6 g, K 275 mg, and vitamins (B2, B1, and C). The energy value is 238 kJ/100 g [16,43,44]. It is noteworthy that sodium, magnesium, potassium, zinc, calcium, iron, and manganese are the major minerals in the fruit [12,45].

L. domesticum Enzymes
Enzymes are important biocatalysts in food biotechnology. Plant-derived enzymes (e.g., bromelain, invertase, amylase, papain, ficin, lipoxygenase, etc.) have played a remarkable role in various food industries, for example, dairy and bakery products, syrups, and alcoholic beverages. Besides, the plants can also be used as raw materials for enhancing the potential of the microbial enzyme that are employed in the food industry. L. domesticum fruit and pericarp are wealthy, with different active enzymes. On the other hand, these enzymes could contribute to the spoilage of the fruit. The fruits activated these enzymes for protection when they suffer from changes in the environment and/or storage temperature [12]. For example, oxidoreductases are activated when the peel or fruit is damaged. Phenylalanine ammonia-lyase, polyphenol oxidase, and peroxidase that are found in the pericarp oxidize the phenols to yield browning compounds [46,47]. Chitinase and β-1,3-glucanase are reported from the fruit peel that possessed antifungal potential towards Metarhizium guizhouense [48]. Polygalacturonase (PG) and pectin methylesterase (PME), as well as antioxidant enzymes: GPX (glutathione peroxidase), SOD (superoxide dismutase), and catalase (CAT) were detected in fully matured fruit that possessed high activities during fruit maturation [49]. Furthermore, the fruit had LOX (lipoxygenase) that is accountable for the polyunsaturated fatty acids deoxygenation and converting them into fragrance and signaling molecules for regulating leukotriene [50]. It was reported that polygalacturonase, pectin methylesterase, and cellulases rise the sugar profile in the fruit and decrease the firmness of the fruit during ripening [49].

Phytoconstituents of L. domesticum
The chemical investigation of various parts of L. domesticum resulted in the isolation of different chemical constituents; most of them have been isolated from the peels, seeds, and barks (Table 4). Their identification was carried out using various spectroscopic techniques, as well as X-ray and chemical means. A total of 112 compounds have been reported from L. domesticum (excluding nutrients such as amino acids, protein, and sugars), including various classes of triterpenoids (e.g., swietenine, onoceranoid, cycloatanoid, and tetranortriterpenoid), cardenolides, steroids, sesquiterpenes, organic acids, phenolics, and volatile compounds. It was reported that the fruit peel had an abundant level of reductive substances, glycosides, organic acids, alkaloids, flavonoids, and phenolics, but it had no saponins [51,52]. Phytochemical screening of the bark revealed the existence of anthraquinones, alkaloids, flavonoids, coumarins, cardiac glycosides, tannins, saponins, and iridoids [24]. Further, a toxic constituent such as lansium acid (6%) was detected in the peel [52,53]

Volatile Organic Compounds and Organic Acids
Volatile organic compounds (VOCs) are the small molecular weight lipophilic molecules with a low boiling point and volatility which result from the plant's secondary and primary metabolism [54]. They include alcohols, terpenes, alkanes, olefins, aldehydes, and fatty acid derivatives [55].

Phenolics
It was stated that the longkong peel and flesh had a high phenolic content that is affected by the initiation of the phenylalanine ammonia-lyase activity upon external stimuli leading to abundant phenolics production [12]. Ferulic (25), p-coumaric (26), and gallic (27) acids, ellagic acid (28), and a high level of tannins were reported in longkong fruit [20,59,93]. Further, the phytochemical analysis of the ethyl acetate (LDSK50-EA) and aqueous (LDSK50-H 2 O) fractions of longkong peels illustrated the presence of phenolics, mainly chlorogenic acid (29), rutin (30), and scopoletin (31) [51]. It is noteworthy to state that the pericarp possessed a higher flavonoid content than flesh, while the seeds have no flavonoids [53]. A high flavonoids yield was observed in the fruit extracted with hot H 2 O in comparison to other kinds of solvents [43]. Alimon et al., reported the presence of flavonoids in langsat, duku, and longkong [93]. It is noteworthy that many flavonoids are found in the fruit, however, only rutin (30), quercetin (32), and catechin (33)

Terpenoids
The peel was reported to contain a large quantity of latex that had lansic acid (34) as a major component of the latex that was isolated firstly in 1967 by Kiang et al., from the light petroleum peel extract [94]. Lansioside A (35), a novel seco-onoceran aminoglucoside triterpenoid was isolated from the EtOH extract of L. domesticum peel by SiO 2 CC. It had an acetyl group linked to the nitrogen atom, characterizing the existence of N-acetyl-Dglucosamine. Its configuration was established by NMR and chemical derivation, as well as optical rotation [60,63]. In another study, Nishizawa et al., obtained seco-onoceran triterpenoids; lansic acid (34) and lansiosides B and C (36 and 37) from the peel CH 2 Cl 2 fraction by SiO 2 CC. They gave the same aglycone methyl ester, methyl lansiolate (38) on methanolysis ( Figure 3) [63]. Lansiosides B and C (36 and 37) are β-D-glucopyranoside and β-D-xyloside, respectively [19]. Compound 35 was found to inhibit leukotriene D 4 -induced contraction of guinea pig ileum in vitro in a dose-dependent way (IC 50 2.4 × l0 6 g/mL, 2.4 ppm), while 36 and 37 were 10-fold less potent and 39 was inactive [19]. Dukunolide A (40), a tetranortriterpenoid with a novel 26-carbon skeleton was purified from n-hexane extract of duku seeds by SiO 2 CC and recrystallization. Its structure was established by NMR spectroscopic data and single-crystal X-ray diffraction [69]. Nishizawa et al., isolated and characterized dukunolides A (40), B (41), and C (42), as well as revising the structure of 40 using NMR; the absolute configuration was deduced by chemical method and X-ray analysis. Compound 40 possessed a UV bathochromic shift due to the α,β,γ,δ-dienolide system and cisring junctions at C-l/C-2 and C-5/C-10, whereas 41 had a C-8/C-9 epoxide and saturated doubly conjugated δ-lactone moieties at the γ,δ-positions. Compound 42 was similar to 40, with an additional secondary acetoxyl group at C-22 [70]. Further, the same authors in 1988 isolated dukunolides D-F (43-45) from the CH 2 Cl 2 extract of by SiO 2 CC using CH 2 Cl 2 /n-hexane or CH 2 Cl 2 /EtOAc as solvent system. Their structures were elucidated by NMR and the absolute configuration was deduced by X-ray analysis [72]. Dukunolides D (43) and E (44) were structurally similar to 40 and 41, respectively, with the absence of the 5,6-oxirane ring. Whilst dukunolide F (45) was assigned as stereoisomer of 44 [72] (Figure 3).

Anti-Malarial Activity
Malaria is a serious parasitic disease in tropical and subtropical regions all over the world, with 435,000 deaths and 219 million infections cited in 2017 [95]. The incidence of malaria has re-emerged in part due to several strains of P. falciparum becoming resistant to the available antimalarial agents. Thence, there is a crucial need for discovering new anti-malarial agents and for verifying the safety and efficiency of traditional medicinal plants that are utilized to fight this disease [96].
L. domesticum seeds and bark are traditionally known to be effective towards malaria parasite [30]. L. domesticum bark extracts were assessed for in vitro anti-plasmodial potential against chloroquine-resistant clone (W2) and -sensitive P. falciparum clone (D6). The bark extracts (Conc. 20 µg/mL) were notably active towards chloroquine-resistant clone W2 and exhibited selective potential towards chloroquine-sensitive P. falciparum clone D6 in the Kenyah malaria [30]. Further, the bark EtOAc fraction had a promising activity towards D6 and W2 P. falciparum clones (IC 50 3.45 and 5.61 µg/mL, respectively). On the other hand, it had no significant effect on parasite clearance on the P. bergheii-infected mice [68]. On the other hand, the skin and leaf aqueous extracts equally reduced parasite number of both drug-sensitive (3D7) and chloroquine-resistant (T9) P. falciparum. The skin extracts interrupted the parasite lifecycle, which proved the effectiveness of L. domesticum as a source of antimalarial agents towards P. falciparum chloroquine-resistant strains [17]. Additionally, the seeds CH 2 Cl 2 extract was found to significantly prohibit P. falciparum (IC 50 9.9 µg/mL) [65,85]. It was stated that lansiolic acid (39) had antimalarial potential [97]. Yapp et al., obtained 4-hydroxy-N-methylproline (57), a cyclic hydroxy-amino acid with trans carboxyl and hydroxyl groups as a crystal from the peel MeOH extract. This compound exhibited antimalarial potential towards chloroquine-resistant P. falciparum (T9) strain only at concentration >1.0 mg/mL [84].

Antifeedant, Insecticidal, and Larvicidal Activities
Natural pest controlling agents have been publicized as substitutes to synthetic chemicals for integrated pest management. These phytochemicals are known to pose little threat to human health or to the environment [99]. Recently, there has been a fast-growing interest in the use of more ecologically acceptable methods to protect the food supply from predatory insect attacks [100]. Antifeedants are compounds that either prevent insect feeding (feeding deterrent effect) or cause slowing or cessation of further feeding (feeding suppressant effect) [99,101]. They attract special attention owing to their potential utilization in integrated pest control systems [102].

Anti-Fertility Activity
The increase in the human population is one of the most critical problems throughout the world, especially in underdeveloped and developing countries [104]. The evaluation of the antifertility potential of the medicinal plant has been growing worldwide as a means of identifying safe and effective agents for controlling the population explosion [105]. L. domesticum bark water decoction was used by rural communities in East Kalimantan as an anti-fertility agent. The potential of water decoction of bark stew on uterus weight and estrous cycle in mice had been assessed [31]. The estrous cycle is the reproductive cycle in female mice that ranges from 4-5 days. The results revealed that H 2 O decoction of the bark had no remarkable effect on the uterine weight and estrous cycle in female mice. Therefore, the anti-fertility potential of the bark H 2 O decoction was not proven [31].

Antimutagenic Activity
Mutagens are agents that can invoke mutations [106]. They are not only included in carcinogenesis and genotoxicity but also the pathogenesis and inception of many chronic diseases, including neurodegenerative, cardiovascular, and hepatic disorders, chronic inflammation, arthritis, diabetes, and aging [107,108]. Natural antimutagenics are known to protect against the detrimental effects of mutagens. They include various plants and their active metabolites such as flavonoids, phenolics, coumarins, carotenoids, tannins, anthraquinones, saponins, and terpenoids [107].

Cytotoxic Activity
Cancer represents one of the major reasons for death globally [110]. Many of the available chemotherapies possess serious side effects, drug resistance, and none target specificity [111]. Thus, there is an emerging search to develop drugs from natural sources in order to overcome these drawbacks. Natural metabolites from diverse sources, including microorganisms, plants, and animals, present a great pool for the discovery of novel therapeutic candidates for treating this disease [112].
Moreover, the peel MeOH extract had toxicity against Artemia salina [61]. Further, the leaves MeOH extract (Conc. 200 µg/mL) exhibited Notch inhibitory potential by reducing luciferase activity to 30% and cell viability to 62% compared to those of the control [90].
Manosroi et al., assessed the cytotoxic capacities of cold and hot H 2 O, cold and hot MeOH, and cold and hot CHCl 3 extracts of eight L. domesticum parts (young fruits (YF), ripe fruits (RF), old leaves (OL), seeds (SE), young leaves (YL), peels (PE), stalk (ST), and branches (BR)] that were collected from three provinces (Satun, Narathiwat, and Yala) in the south of Thailand towards B 16 F 10 , KB, HepG2, and HT-29 using SRB assay. It is noteworthy that ripe fruits cold water extract (RFWC) had the highest percentage yield (59.38%). The hot and cold MeOH extract of stalks (STMH and STMC) showed the highest total flavonoid and phenolic contents. The young fruit cold (YFCC) and hot CHCl 3 (YFCH) extracts possessed cytotoxic potential (IC 50 < 1 mg/mL) towards all cancer cells. In apoptotic induction, YFCH displayed the highest apoptotic effectiveness towards KB with 13.84% at 0.5 mg/mL and towards HT-29 with 8.68% at 5 mg/mL. On the other hand, YFCC had the highest apoptotic potential towards KB cells (10.70% at 0.5 mg/mL) [43]. The YFCH exhibited the highest necrotic induction potential towards KB and B 16 F 10 cell lines (% necrosis 6.19 and 27.58% at 5 mg/mL, respectively) whereas YFCC had the highest potential towards KB, HT-29, HepG2, and B 16 F 10 cell lines at 5 mg/mL (% necrosis 45.36, 41.13, and 100%, respectively) [43].
Besides, Manosroi et al., stated that the young fruit hot (NYFCH) and cold chloroform (NYFCC) extracts from the Northern region exhibited antiproliferative effect towards KB cells (IC 50 603.45 and 765.06 µg/mL, respectively) in the SRB assay, compared to cisplatin (IC 50 12.72 µg/mL), fluorouracil (IC 50 12.94 µg/mL), doxorubicin (IC 50 0.82 µg/mL), and vincristine (IC 50 0.03 µg/mL). The triterpenoids in the chloroform extracts may be accountable for this effect [53]. Additionally, they had higher active MMP-2 inhibitory potential (53.03 and 31.30% for NYFCC and 49.40 and 21.72% for NYFCH) than all anticancer agents except cisplatin. The antioxidative triterpenes in hot chloroform extract inhibited matrix metalloproteases (MMPs), which regulate invasion and cellular motility of cancer cells, indicating that the NYFCH could be further developed to an oral anticancer agent [53].

Antioxidant Activity
Chronic illnesses such as diabetes, cancer, and cardiovascular and neurodegenerative diseases are featured by an incremented state of oxidative stress that may result from a decline in antioxidant defenses and/or reactive species (ROS) overproduction [116]. Natural compounds are known to have better antioxidant potential than synthetic antioxidants, making them an extremely attractive ingredient for commercial foods [117]. Despite the huge number of natural antioxidative agents, searching for new chemical entities with antioxidant potential remains a growing field. Klungsupya et al., reported that the peel 50% EtOAc fraction possessed potent antioxidant capacity [109]. Also, the EtOH-EtOAc (50:50%, v/v) and EtOH:H 2 O (50:50%, v/v) fractions showed potent O 2 -bullet and OH bullet scavenging activity in the photo-chemiluminescence assay. They had protective potential on H 2 O 2 -induced DNA damage on TK6 human lymphoblast cells (Conc. 25, 50, 100, and 200 µg/mL) in the comet assay [51]. Subandrate et al., reported that the seed extract (dose 100 mg/kg BW) had an antioxidant potential, where it increased GSH (glutathione) and lowered MDA (malondialdehyde) in alcohol-induced rats, therefore it prohibited free radicals and inhibited lipid peroxi-dation [118]. Moreover, the EtOAc fraction of the seeds exhibited a strong antiradical potential (IC 50 8.938 µg/mL) than water fraction, n-hexane fraction, and methanol extract (IC 50 13.898, 11.012, and 14.624 µg/mL, respectively) in comparison to vitamin C (IC 50 4.721 µg/mL). This effect was referred to its high phenolic and flavonoid contents (58.25 mg GAE/g and 75.123 mg QE/g, respectively) [119].
Manosroi et al., collected various parts of L. domesticum from Eastern and Northern Thailand and extracted them by the cold and hot methods using H 2 O, CHCl 3 , and MeOH. The hot seeds H 2 O extract from the Northern region (NSEWH) possessed the highest free radical scavenging (FRS) potential (SC 50 0.34 µg/mL) in the DPPH assay, compared to ascorbic acid (SC 50 0.08 µg/mL). On the other hand, the hot CHCl 3 extract of the young leaves from the Eastern region (EYLCH) had the potent lipid peroxidation inhibition (IPC 50 0.86 µg/mL), compared to α-tocopherol (IPC 50 0.03 µg/mL) in the modified ferricthiocyanate method. Additionally, the cold-H 2 O extract of the old leaves from the Northern region (NOLWC) exhibited the powerful metal ion chelating potential (MC 50 0.47 µg/mL), compared to EDTA (MC 50 0.06 µg/mL) in the ferrous ion chelating method. It is noteworthy that the extracts from the Northern region had higher FRS, metal ion chelating, and lipid peroxidation inhibition activity than those from the Eastern region. This might be attributed to the flavonoid and phenolic compounds in the extracts [53].

α-Glucosidase Inhibitory Activity
Diabetes continues to be a main health concern worldwide. It is featured by a defect in insulin action and/or secretion associated by hyperglycemia and disruption in lipid, carbohydrate, and protein metabolism [122,123]. The best therapeutic strategy for type-II diabetes is to lower hyperglycemia through retardation of the intake of glucose by repression of α-glucosidases and α-amylases, which are accountable for the di-and oligosaccharides breakdown into glucose [123].

Anti-Aging Activity
Aging is a process distinguished by the accumulation of the degenerative damages, ultimately leading to the death of an organism [124]. It is the highest risk factor for various age-linked disorders, such as diabetes, neurodegenerative disease, cancer, and stroke [125]. A wealth of research aims to develop therapies that delay age-related disorders in human. The 96% EtOH and EtOAc extracts from fruit peels (FP) and flesh (FF) of L. domesticum were assessed for the elastase and collagenase inhibitory activity. FP-EtOH and FP-EtOAc extracts exhibited the most potent elastase and collagenase inhibitory activity. Nevertheless, FF-EtOH extract possessed the highest tyrosinase inhibitory capacity. Therefore, the fruit flesh and peel extracts of L. domesticum could be a cosmetic active ingredient because of their anti-tyrosinase and anti-aging capacities [121].

Analgesic and Anti-Inflammatory Activities
Inflammation occurs in response to processes such as cell death, tissue injury, ischemia, cancer, and degeneration, leading to the synthesis and secretion of numerous inflammatory mediators [126]. Pain is a public health problem with considerable socioeconomic effects [127]. Its treatment needs analgesics including, anti-inflammatory agents that exhibit analgesic potential at maximum doses [128]. In this respect, the inhibition of NO (nitric oxide) and PGE2 (prostaglandin E2) production has been established as a potential therapy for different inflammatory disorders [126,129]. Several available analgesics and anti-inflammatory drugs possess adverse effects [130]. Accordingly, medicinal plants can represent a significant source of natural and safer new drugs for treating pain and inflammation [129]. Purification

Antibacterial Activity
Antibiotics represent one of the most substantial interventions in human medicine [131]. However, the world has witnessed an alarming rise in the failure of many antibiotics to treat bacterial infections due to the generation of antibiotic-resistant and antibiotic-tolerant persister cells and biofilms [132,133]. Natural products from various sources may contribute to the discovery of novel therapeutics for multi-drug resistant bacterial infections.
Marfori et al., isolated lansioside D (105) from acetone fraction of EtOAc extract of the fruit peel that exhibited pronounced antibacterial activity against S. aureus and B. subtilis with MICs 31.25 and 15.62 µg/mL, respectively. It was moderately active versus E. coli (MIC 250 µg/mL) and inactive against Candida lipolytica, Saccharomyces cerevisiae, Cladosporium herbarum, and Aspergillus niger [92].
The L. domesticum seeds extract showed antibacterial potential towards S. aureus and E. coli at concentration 1250 and 1000 µg/mL, respectively, in the dilution broth technique using Mueller-Hinton broth [28].
8.11. 5α-Reductase Inhibitory Activity 5α-Reductase is the key enzyme responsible for the biosynthesis of dihydrotestosterone (DHT) [134]. Its inhibitors are useful treatments for DHT-dependent disorders, including androgenic alopecia and hair growth, benign prostatic hyperplasia, and acne [135]. Lansiosides A-C isolated from dried peel possessed 5α-reductase inhibitory potential. They were effective in controlling male hormone-type baldness, acne, and prostate hypertrophy [58,64].

Wound Healing Activity
Fruits' phenolic compounds are known to exhibit wound healing potential and accelerate tissue regeneration through their antioxidant, anti-inflammatory, and antimicrobial capacities, as well as stimulation of angiogenic activities needed for wound re-epithelialization and granulation tissue formation [136,137]. Therefore, they may be favorable ingredients in nutraceutical preparations, functional foods, or cosmeceuticals [138]. L. domesticum had high phenolic contents.
It was reported that AgNPs have a wound healing potential for normal and burnrelated wounds because of their antifungal and antibacterial activities. Additionally, Shankar et al., reported that the incorporation of the L. domesticum peel extract AgNPs (0.1% w/w) in Pluronic F127 gels as a delivery system enhanced the wound healing potential. These AgNPs increased wound closure time, hydroxyproline and collagen content, and wound tensile strength (33.41 N/cm 2 ) without any inflammation. Finally, the enhanced biocompatibility and wound healing activity of L. domesticum AgNPs were attributed to its triterpenoids [139].
Metal oxide nanoparticles (NPs) have gained remarkable attention in the biomedical field [140]. L. domesticum peels triterpenoids along with amino-sugars (N-acetyl-Dglucosamine) have a strong stabilizing and reducing potential that can reduce the metal ions to nanoparticles by acting as capping agents [141]. Fruit peel extract of L. domesticum was used as a combined reducing and capping agent to develop eco-friendly gold (Au), silver (Ag), and gold-silver (Au-Ag) nanoparticles that were characterized by various physicochemical techniques. AgNPs inhibited the S. aureus and E. coli growth (MICs 16 and 8 µg/mL and MBCs 32 and 16 mg/mL, respectively), while Au-Ag-NPs had MICs 16 µg/mL for both S. aureus and E. coli. However, AuNPs did not display any antibacterial potential [142]. Further, the cytotoxicity and cellular activity of C2C12 cells in the presence of these NPs were assessed using MTT and Almar Blue assay, respectively. AgNPs showed decreased cellular activity (Conc. > 40 µg/mL), however, AuNPs (Conc. > 50 µg/mL) exhibited no difference in cellular activity. It is noteworthy that Au-Ag-NPs did not possess cytotoxic potential compared to AgNPs, revealing that the AuNPs content in Au-Ag-NPs prohibited the AgNPs-induced cellular damage and increased the cell viability [142].
Rahma et al., synthesized AgNPs using langsat leaf (LL) extract as the bio-reductor that were characterized by UV-Vis spectrophotometer. They significantly inhibited the E. coli and S. aureus growth (Conc. 6.25 and 12.5%, respectively) in the broth dilution method. Additionally, they displayed bactericidal potential towards E. coli (MBC 25%) but did not have bactericidal activity towards S. aureus [143].
Skin aging is a physiological process that can be induced by extrinsic and intrinsic factors [144,145]. Intrinsic aging takes place within tissue through the reduction in dermal cells, fibroblasts, and collagen production, while extrinsic aging can be produced by environmental factors, especially solar UV radiation, which leads to skin damage through the ROS (reactive oxygen species) generation [146,147]. The use of antioxidants can prevent aging [148]. Increase free radicals in the body will accelerate the production of elastase and collagenase enzymes, leading to an increase in the degradation of collagen which is the major component of connective tissue on the skin [149]. Based on the strong antioxidant activity of L. domesticum fruit peel, it was formulated in topical semisolid pharmaceutical preparations such as gel and cream with the EtOH extract of strawberry fruit and pomelo peel as anti-aging formula [150]. All formulas showed anti-aging potential through radical DPPH scavenging, anti-collagenase, anti-tyrosinase, and anti-elastase activities [150].
A combination of L. domesticum fruit extract and Hibiscus (Hibiscus rosa-sinensis) flower extract (LHE) caused 49.37% tyrosinase inhibition, which revealed that LHE had effectiveness as a lightening agent in cosmetics preparations [27]. After applying for 4 weeks in human skin, LHE contained lotion base significantly increased skin moisture content and reduced its melanin index in the efficacy test [27].

Safety of L. domesticum
The dermatological safety assessment of L. domesticum fruits EtOH extract was carried out clinically using ROPT (Repeated Opened Patch Test) and SCPT (Single Closed Patch Test) in >50 selected healthy volunteers. A lotion base containing 50 mg of extract was applied onto the chorioallantoic membrane and left for 20 s in contact and afterward any appearance of hemorrhage, hyperemia, and opacity on the membrane was reordered using HET-CAM (Hen's Egg Testing of Chorioallantoic Membrane) method. ROPT revealed that the extract did not produce any allergic skin reaction or irritation. SCPT exhibited no irritation or allergic skin reaction (Conc. 1% and 3%) in all volunteers, while 5% concentration produced irritation in 1.9% of all subjects [152][153][154]. Further, L. domesticum fruit extract and Hibiscus (Hibiscus rosa-sinensis) flower extract (LHE) lotion safety assessment by SCPT and HET-CAM indicated that LHE was safe for human eyes and skin and could be utilized as active an ingredient in cosmetics [10,27].

Conclusions
L. domesticum is a commonly consumed fruit with high nutritional value, low toxicity, and long-term traditional applications for treating various diseases. The current work summarized the reported data concerning its production and season, nutritional value, phytoconstituents, enzymes, biological activities, safety, nanoparticles, and pharmaceutical formulations. It was found that yields of various plant parts MeOH extracts are varied (5.71% for peels, 6.4% for seed, and 17.94% for pulp) [53,71,155]. These percentages would vary according to the tree, source of plant material, and time of collection, as well as the extraction condition, including the technique, type of solvent, time, and temperature [53,156]. A total of 112 compounds have been reported from L. domesticum, including terpenes, sterols, organic acids, flavonoids, coumarin, and volatile compounds ( Figure 12). These metabolites were isolated from the different parts of L. domesticum such as seeds, leaves, peels, bark, twigs, and fruits ( Figure 13). Triterpenoids (64 compounds) are the major metabolites reported from L. domesticum, including onoceranoid (35 compounds), tetranortriterpenoid (24 compounds), cycloartane (4 compounds), and swietenine (1 compound) triterpenoids and are frequently involved in various pharmacological actions. Most of the reported metabolites have been evaluated for their anticancer, antifeedant, insecticidal, antidiabetic, antimalarial, antimutagenic, and antibacterial abilities ( Figure 14). It is noteworthy that 94 and 95 showed potent notch inhibitory potential; therefore, they may be a candidate for anticancer or neural regenerative agents. Further, 38 and 73 had potent antimalarial effectiveness that could be further investigated for their possible use as antimalarial agents. However, the relative study of the relationship between the structure of these metabolites and bioactivity, as well as their biosynthetic pathways is limited. The emphasis of future work should be to conduct biosynthetic pathways, possible mechanisms, and pharmacological properties of L. domesticum and its metabolites.
Although the phytochemical screening of L. domesticum revealed the existence of anthraquinones, alkaloids, and iridoids, however, none of them have been isolated as pure metabolites. Limited studies reported the synthesis of metal nanoparticles (Au-and AgNPs) using L. domesticum that evaluated only for their antimicrobial and wound healing potential. Therefore, future research should focus on evaluating these NPs for other bioactivities and on developing protocols for implementing the biosynthesis of NPs using other metals, metal oxides, nitrides, and carbides. Some studies reported the preparation and biological evaluation of various pharmaceutical formulations such as gel, cream, and lotion using either L. domesticum extracts alone or in combination with other plant extracts that proved the traditional uses of L. domesticum as an anti-aging, lightening, and moisturizing agent in cosmetics preparations, as well as mosquito repellent. The topical safety studies of the fruit extract revealed its safety for topical uses. Thus, future research should focus on the comprehensive utilization of L. domesticum, the following strategies are suggested. First, there should be an emphasis on research concerned with the single metabolite's isolation and bioactivity evaluation rather than the crude extract. Second, metabolic pathways, structure-activity relationships, in-vivo pharmacological studies, and mechanisms of action of L. domesticum metabolites, particularly triterpenoids, require more attention. Third, research on the unstudied parts of L. domesticum that have been widely used in traditional medicine should be carried out to prove the folk use. Lastly, the toxicological evaluation of the extracts of other parts of L. domesticum is needed to estimate safety and reliable dosage in clinical applications. L. domesticum by-products (LDP) could represent wide opportunity for separating bioactive metabolites with various potential applications. Additionally, they could be a source of livestock feeds, fuel (bioethanol), or organic fertilizers [157,158]. Peels can also be utilized for the recovery of soluble dietary fibers and polyphenols [157,158]. The polyphenols recovery from the LDP can be achieved utilizing micro-, ultra-, and nanofiltration processes [159]. Therefore, proper use of these by-products will be a sustainable approach for improving health through the separation of health-promoting metabolites, as well as solving the environmental issues.