Sterqulia quadrifida R.Br: A Comprehensive Review of Ethnobotany, Phytochemistry, Pharmacology and Toxicology

Sterculia quadrifida, R.Br. is one of the plants that grows on the mainland of Timor, East Nusa Tenggra. Sterculia quadrifida, R.Br. commonly known as Peanut tree in English and faloak in Indonesian has various pharmacological activities and has been widely used in traditional medicine. This review article aimed to provide a comprehensive overview of the potential of the faloak plant as an herbal medicine by looking at various aspects such as ethnobotany, phytochemicals, pharmacology and toxicity. Literature searches are carried out in scientific databases that are accepted worldwide such as ScienceDirect, Scopus, PubMed, Springer Link, Wiley Online Library and advanced searches on Google scholars, books, abstracts, theses, scientific reports, and several non-impact and non-indexed journals with the search keywords "Sterculia quadrifida" or "Peanut tree" or "Red fruit kurajong" or "Faloak". From the various literature that has been collected, faloak has been shown to have pharmacological activities such as anticancer, antioxidant, antifungal, immunomodulatory, antiviral, antibacterial, antidiabetic, and antipyretic. The existence of this activity cannot be separated from the chemical compounds contained therein such as flavonoids, alkaloids, terpenoids, phenols, tannins and saponins. Faloak also has low toxicity with LD50> 5000 mg/kg body weight rats.

faloak was found on Pantar Island as many as 4.68 trees/hectare. The optimal growth of faloak occurs at an altitude of 0-450 masl, but can still be found at an altitude of 889 masl in Netpala Village, South Central Timor regency (Siswadi, 2015). The most potential faloak is found in Timor Island, which is spread from Belu Regency and West Timor Island / City and Kupang Regency . The most widely used part of the faloak tree is its bark, mainly to treat liver disease. In the market, faloak is sold for IDR 1,600/piece. The traders also sell faloak skin mixed with other simplicia at a price of IDR 5,000/can .

Morphology
Faloak tree can reach a height of up to 15 m or more, the crown is spread out, the bark is light gray, and secretes lymph when it is split. The flowering season is between April-June and the fruiting season is between June-October each year. The leaves are dark green and have an oval shape with a length of 5-12 cm and a width of 4-8 cm. The fruit has an oval shape like a star on the outer surface, yellow, red or orange in adulthood (Siswadi, 2015). The seeds are ellipsoid-shaped about 10 mm and covered with a thin black epidermis. When it is ripening, the faloak seeds are protected by the green skin of the fruit. After the flowering period ends at the age of 3-4 months the fruit skin will turn orange, which will then turn brown after 1-3 weeks later which indicates the seeds are old and the fruit skin opens into two parts. In one fruit there are usually between 4-8 seeds wrapped by a layer of black epidermis, with the position of the seeds in the fruit lined up and sticking to the skin of the fruit, they will be easily peeled when the seeds are old. The seeds are edible and taste like raw nuts (Siswadi et al., 2012).

Habitat
Faloak is a small tree that grows in rainforest, scrubs, and gallery forests. Faloak that grows in semi-arid land at an altitude of 0-900 masl can reach a height of up to 20 m. The faloak tree (Sterculia quadrifida, R.Br.) is one of the plants known to East Nusa Tenggara people that grows wildly in forest areas and around settlements that grow on rocky soil (Soeharto & Tenda, 2018). The climatic and tread conditions in the East Nusa Tenggara region which are classified as semi arid are thought to exert pressure on faloak growth, thus potentially producing a large secondary metabolites   (Siswadi & Saragih, 2017).

Propagation
Sterculia quadrifida can be propagated generatively by seed. The results revealed that pretreatment or scarification of Sterculia quadrifida seeds was needed to increase the rate of germination. In the planting process, the most suitable medium for planting Sterculia quadrifida seedlings is a combination medium of black soil (grumusol), sand, and manure with a ratio of 1:1:1 (Siswadi et al., 2012). In addition, Sterculia quadrifida can also be propagated by vegetative methods (shoot cuttings, stems and pruning gardens), but the vegetative development success is still low. Faloak has a hypogeal germination type and the scarification process can be done by soaking the seeds in cold water for 12 hours .

Traditional use
Traditionally, bark and roots extracts of Sterculia quadrifida have been commonly used to treat various diseases such as diabetes, liver and cancer (Lulan et al., 2018). Meanwhile, based on a survey conducted on people in East Nusa Tenggara, Faloak is most commonly used for the treatment of liver dysfunction (55%), stamina recovery (13%), treating back pain (7%), ulcers (7%), lumbago (6%), malaria (6%), and blood purifiers (6%) . The harvesting technique carried out by the community is by slicing or peeling tree bark with certain dimensions or sizes, then drying and boiling it using water. Some of the boiling processes use pure faloak stem bark, but some also use a mixture of other ingredients such as garlic, onion, turmeric, lemongrass, sand ginger, and cinnamon .

Phytochemical review
Faloak can be used in traditional medicine because it contains various secondary metabolites compounds such as terpenes, alkaloids, flavonoids, phenols, and tannins (Dillak et al., 2019). Flavonoids, terpenoids, alkaloids, phenolics and steroids have also been reported in other species of the genus Sterculia. Some other chemical elements that have also been reported from the Sterculia genus plant are sitosterol and betulinic acid from Sterculia striata isolates, sterculinine I and sterculinine II from Sterculia lychnophora isolates, and 1,6-diferuloyl glucose from Sterculia foetida isolates .

Alkaloid
The preliminary test results of chloroform extract of faloak bark showed a positive content of alkaloid compounds indicated by the presence of a white precipitate after being given Mayer's reagent. The separation results using PTLC were obtained by one fraction which was expressed as a single compound after being identified by two dimensional TLC which was suspected as an alkaloid compound. The results of the analysis by UV Spectrophotometry indicate the presence of I band at a wavelength of λ max 263,30 nm indicating the presence of a conjugated double bond which is thought to be an alkaloid compound (Firawati & Hidayat, 2017).

Flavonoid
Almost various studies that have been conducted have shown that faloak contains flavonoid compounds. Faloak bark contains natural antioxidant compounds, namely flavonoids and phenolic compounds that can protect the body from free radical attacks . Methanol extract of S. quadrifida showed a total flavonoid content of 661.85 mg equivalent to quercetin per 100 g extract and showed a high total phenolic content of 116.84 mg equivalent to gallic acid per 100 g extract (Lulan et al., 2018). Phytochemical screening on 70% ethanol extract showed that the plant parts of roots, bark, stems, leaves, fruits, and seeds contained flavonoid compounds. The highest total flavonoids were found in the bark of 62.76 mg/g, while the lowest was found in seeds (1.55 mg/g). Total flavonoids in the leaves and fruit are in the range of 11-12 mg/g (Dillak et al., 2019). Other studies also showed that the total flavonoids of 96% ethanol extract of faloak bark were 3.60 ± 0.35 mg QE/g sample (Munawaroh et al., 2018). While the water extract of faloak bark contains flavonoids in the form of epicatechin 875 mg/kg which is soluble in water and can be an antiviral candidate against HCV JFH1 (Dean et al., 2019).

Terpenoid
The presence of terpenoid compounds in faloak bark can be detected in four fractions namely acetone, ether, ethyl acetate, and hexane fractions . Terpenoids are formed from aisonapra and serve as plant protectors against insects. One class of terpenoids that act as antimicrobials are triterpenoids which are widely used to treat skin disorders, antifugus, insecticide, antibacterial and antiviral. Triterpenoids were at least selected into four groups including triterpane, steroids, glycosides and saponins (Robinson, 1995).

Phenolic
Phytochemical screening of ethanol extract 70% faloak showed that the plant parts of the roots, bark, leaves, fruit, and seeds contained phenolic compounds. The highest phenol (82.90 mg/g) is found in the roots, while the smallest phenol is in the seeds (2.89 mg/g) (Dillak et al., 2019). The water fraction of the faloak bark metanolic extract has a total phenolic content of 6.97 ± 0.17 mg gallic acid equivalent per gram . Fraction 2 has the largest total phenolic content of all fractions (34.16 ± 0.76 mg GAE) and has the highest antioxidant activity (Susanto, 2019). In addition to the previously mentioned compounds, the results of isolation of the active compounds from the faloak bark (Sterculia quadrifida, R.Br.) obtained three isolates which are derivates from gallic acid which have activity as antibiofilms (Rollando, 2017). Scopoletin is a phenolic compound that belongs to the coumarin compounds and is present in the most active fractions, namely hexane and ethyl acetate fractions where this compound is responsible for increasing the phagocytic activity of macrophages (Munawaroh et al., 2020).

Fatty Acid
Based on the measurements of H-NMR and C-NMR, it is suspected that the bioactive compounds in faloak seeds are derivatives of hydrolylated fatty acids. The results of faloak isolation was also found the presence of 3-hydroxyoctadecanoic acid compound which has antifungal properties against C. albicans (Ranta et al., 2012).

Pharmacological studies
Widely reported research on faloak is also associated with the potential of the bark as an antibacterial, antifungi, antitumor, antiviral and antioxidant agent. Plant extract studies of the genus Sterculia showed several biological activities such as antidiabetic activity of S. villosa, anti-inflammatory and anti-fertility activity of S. foetida, larvicidal activity of S. guttata, and antiproliferative activity of S. tavia (Lulan et al., 2018).

Antioxidant activity
Various studies have been conducted to look at the antioxidant activity of the faloak plant.  (Lulan et al., 2018). Faloak bark methanol extract and water fraction of Faloak bark methanol extract were reported to have antioxidant activity against DPPH with IC50 91.72% (Saefudin et al., 2013) and 45.63 ± 1.47 μg/mL , and both were classified as very strong antioxidant activities. In addition, faloak leaf methanol extract has IC50 value of 69.19% and is classified as a strong antioxidant activity (Saefudin et al., 2013). The extracts obtained from newly regrown bark have higher antioxidant activity than other parts. The IC50 value of new regrowed bark (2.51 μg/ml) is even stronger than the IC50 value of vitamin C (4.74 μg/ml) (Saragih & Siswadi, 2019). The antioxidant activity of S. quadrifida is also stronger than other plants such as Pterospermum reticulatum (182 μg/ml) and Pterospermum rubiginosum (166 μg/ml) (Jacob & Sreejith, 2019). Groups of compounds that are suspected to be strong influence on antioxidant activity (free radical redction) are phenolic and flavonoids compounds (Leliqia et al., 2020).
However, the opposite happened in the testing of faloak bark which was made into instant drinks and tested for antioxidant activity with DPPH resulting IC50 values of 2,307.77 ppm ± 58.20 ppm or 2,249.57-2,365.97 ppm which indicates weak antioxidants (Soeharto & Tenda, 2018  . Ethyl acetate fraction of 96% ethanol extract of faloak bark had the greatest cytotoxic activity against T47D breast cancer cells compared to hexane fraction and diethyl ether fraction with IC50 24.88 μg/mL and selectivity index value of 15.58. Ethyl acetate fraction accumulated T47D breast cancer cells in the S phase (27.43%) and was able to induce apoptosis so that it could be developed as a chemotherapy agent in improving the effectiveness of breast cancer treatment (Rollando & Prilianti, 2017). Another study showed that the ethyl acetate fraction had the highest cytotoxic activity against T47D, MCF7 and HepG2 cells with IC50 of 9.56; 7.62 ; 3.24 μg/mL while the selectivity index was 2.01; 2.52; 5.94 respectively .

Antifungal activity
The results of faloak bark isolation was also found the presence of 3-hydroxyoctadecanoic acid compound which has anti-fungal properties against C. albicans (Ranta et al., 2012).

Immunomodulatory activity
Decoction of faloak bark have been shown to have immunomodulatory activity in vivo, which can increase macrophage phagocytosis activity and nitric oxide production but cannot increase lymphocyte proliferation and production of IgG . Water extract, ethanol extract, and ethanol-water extract significantly increased macrophage phagocytosis but had no effect on lymphocyte proliferation in vitro . Ethyl acetate fraction at a concentration of 250 μg/mL is the active fraction of ethanolic extract of Faloak bark which has in vitro immunomodulatory activity of 51.94 ± 4.67% (Munawaroh et al., 2018). Scopoletin compounds were found in the most active fractions, namely the hexane and ethyl acetate fractions where these compounds are responsible for increasing the phagocytic activity of macrophages (Munawaroh et al., 2020).

Antivirus activity
Anti-Hepatitis C Virus (HCV) test results showed that water extracts, 70% ethanol extracts, and methanol extract were active against HCV with IC50 value of 6.06 μg/ml, 9.44 μg/ml, and 10.39 μg/ml, respectively. Fractionation of water extract as the most active extract produces seven fractions. Fractions 5 and 6 showed the highest activity with IC50 value of 7.60 μg/ml and 8.87 μg/ml, respectively. Furthermore, the cytotoxicity of these two active fractions did not show any toxicity with a value of CC50> 2,000 μg/ml. Methanol extract, 70% ethanol extract, water extract, fraction 5, and fraction 6 aqueous extract of faloak bark have potential activity as anti-HCV . Another study on faloak bark water extract also had the inhibitory power of HCV genotype 2a strain JFH1 with an IC50 value of 11.57 μg/mL and the toxicity of faloak bark water extract in Huh7it cell hepatocytes of CC50 >1000 μg/mL. The mechanism action of faloak bark water extract is by inhibiting all stages of the HCV life cycle.
The first stage is that the step entry has 93.97% inhibition, the post-entry step has 96.75% inhibition, and the combination step (entry and post-entry step) has 100% inhibition (Dean et al., 2019).

Antipyretic activity
Ethanol extract of faloak bark at doses of 150 mg/kg and 300 mg/kg has activity comparable to paracetamol, while the dose of 600 mg/kg has more optimal antipyretic activity than paracetamol dose 1.3 mg/20 g body weight (Yuliani et al., 2016). Compounds that can act as antipyretics are flavonoids and tannins (Faizah et al., 2021). both compounds are found in faloak plants.

Toxicity
Acute  (Siswadi & Saragih, 2018). Toxicity tests conducted on male wistar rats with standardized faloak bark ethanol extract at doses of 500 mg/kg body weight, 1000 mg/kg body weight, and 2000 mg/kg body weight showed that no deaths occurred after 14 days of treatment.
In general, there were no significant changes in animal behavior, body weight, food and water consumption compared to the control group. Histological observations found no sign of toxicity in vital organs. The LD50 value obtained from the acute toxicity test results of faloak ethanol extract (Sterculia quadrifida, R.Br.) is higher than 2000 mg/kg body weight and is categorized as having a low toxicity level (Noviyanah et al., 2021).

Conclusion
This review is useful for improving advanced knowledge about the therapeutic effects of activities. In addition, Faloak also has low toxicity with LD50 >5000 mg/kg body weight rats.
From various sources that have been collected, faloak has great potential as a traditional medicine and in the future, further evaluation can be carried out so that it can be developed into herbal products that can be utilized by the community at large.