Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346) review ARTICLE

Rhodomyrtus tomentosa Phytochemistry and Biological Activities: an Update Review

Evana Kamarudin1,Haida Zainol2, Tengku Shahrul Anuar1,3, Roslinah Hussain1

1 Department of Medical Laboratory Technology , Faculty of Health Sciences, Campus Puncak Alam, Universiti Techology MARA UiTM) , 43200 Puncak Alam, Selangor, Malaysia 2 Department of Crop Science, Faculty of Agriculture, Universiti Putra Malaysia,43400 Serdang,Malaysia 3 Integrative Pharmacogenomics Institute (iPROMISE) Campus Puncak Alam, Universiti Techology MARA UiTM) Malaysia, 43200 Puncak Alam, Selangor, Malaysia

ABSTRACT

Grounded by the wide ethnopharmacological application of natural product, medicinal uses and its phar- macological properties have been actively discovered. This paper undertakes a comprehensive and updated review on tomentosa leaves and its active compound – rhodomyrtone current state of research discovery. A search was conducted in PubMed, ScienceDirect, and Web of Science meeting the parameters and keywords of ‘Rhodomyrtus’, ‘R. tomentosa’ and ‘rhodomyrtone’. There are 147 articles published since 1975 about Rhodomyr- tus’s pharmacological activities and their isolated compounds. Numerous studies exist showed increased interest in the therapeutic properties of this , mainly for its active ingredients, which include rhodomyrtone. This arti- cle provides an updated review on phytochemistry studies and pharmacological activities including antimicrobial, anti-inflammatory, antioxidant and anticancer activities of R. tomentosa leaves and rhodomyrtone as major active constituent. Key words : Rhodomytus tomentosa leaves, Rhodomyrtone, Biological activity, Phytochemical

Corresponding Author: in Indonesia and “Downy Rose Myrtle” in most of the Evana Kamarudin, ????? western countries. Email: [email protected] Tel:: +603-32584532 R. tomentosa is an evergreen that can grow up to two meters tall. R. tomentosa is undemanding plant INTRODUCTION species that can grow in any type and condition of and also can grow very well under fully sunlight (Aiton) Hassk plant belonging condition (5). The leaves of R. tomentosa are arranged to the family. R.tomentosa is native to in opposite arrangement with five to seven centimetres southern and South-East country including , long and 3.5 centimetres wide. It also has three-veined , Malaysia, , Thailand, Vietnam and from the base, oval, obtuse to sharp pointed at the Indonesia (1,2). R. tomentosa synonym names include tip with an entire margin. The ’s surface is glossy Cynomyrtus tomentosa (Aiton) Scriv, tomentosa green on the upper surface and soft, dense and hairy Aiton, Myrtus canescens Lour. and Rhodomyrtus grey appearance on the underside of the leaves. Due tomentosa var. tomentosa. However, Rhodomyrtus to the appearance of the leaves surface, “tomentose” is tomentosa (Aiton) Hassk is the only accepted name given as a name of this plant species (6). The of (3). Basically, the word of Rhodomyrtus is derived R. tomentosa are solitary or in cluster of two to three from Greek words which “Rhodon” give the meaning with 2.5 to 3 centimetres in diameter, five which of red and “myrtose” give the meaning or myrtle (4). are tinged white on the outside with purplish-pink or According to the Invasive Species Compendium (https:// all pink in colour. The of R. tomentosa are edible www.cabi.org/ISC), R. tomentosa is known by different and have an ellipsoid shape (1-1.5 cm in diameter) with local name such as “Kemunting” or “Karamunting” in persistent calyx. The mature fruits have purplish-black Malaysia, “Phruat” in Thailand, “Harendong Sabrang” skin colour and soft, sweet and purple in colour flesh.

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Meanwhile, the unripe fruits have green skin colour Paracetamol and nonsteroidal anti-inflammatory drugs with an astringent taste. The fruits contain many deltoid are well-known antipyretics that are capable of inducing (1.5 mm in diameter) that are located in six to liver and kidney toxicity (11).On the other hand, natural medicine such as Azadirachta indica, Centella asiatica, and Piper betel with antipyretic properties can be used Table 1. Scientific classification of Rhodomyrtus Tomen- tosa with lower side effects (12). Scientific classifi- cation Nevertheless, the toxicity level of herbal and natural medicine need to be determined accurately. Information Domain Eukaryota on the traditional formulation and use of the herbal Kingdom Plantae medicines should be satisfactory to avoid possible Phylum Phylum toxicity from the medicinal plants. Manufacturers of Subphy- Angiospermae herbal medicines should consider standardization of lum the products while patrons of herbal medicines need Class Dicotyledonae to inform their health-care providers about any herbal Order products they use to ensure effective and safe care. Since Family Myrtaceae ancient time, medicinal plants have been utilized due to Genus Rhodomyrtus its wide range of bioactive compounds that responsible for numerous therapeutic activities to prevent and cure Species Rhodomyrtus tomentosa various types of disease (13). According to Lai et al., (14) Scientific Name Rhodomyrtus tomentosa (Aiton) Hassk the leaves, buds, roots and fruits of R. tomentosa have Country : Common Name : been used as traditional medicine in Malaysia and China Ceylon hill cherry; Ceylon hill goose- since a long time ago. Unripe fruits of R. tomentosa are berry used to treat diarrhoea and the ripened fruits are used to Cambodia sragan boost one’s immune system (14) . Indigestion, gastralgia, China kong nim hepatitis, enterogastritis, and rheumatoid arthritis China/Hong barley bues are all traditionally treated with R. tomentosa (15). Kong In Thailand, Bangladesh and Vietnam, R. tomentosa Germany filzige Rosenmyrte has been prescribed in the treatment of inflammatory Indonesia: harendong sabrang bowel diseases, diarrhoea, dysentery, abscesses and haemorrhage (16). In Singapore, the leaves are used as Malaysia Karamunting; kemunting pain killer, the roots are used to soothe heartburn and Thailand phruat the seeds are used as tonic and anti-venom for snake USA/ downy myrtle; downy rose myrtle; bite (17). Nowadays, the study on medicinal plants as a ratberry source of alternative medicine including R. tomentosa Vietnam sim has gained attention globally. Its proven potential drug discovery from natural medicine or herbs, for example, eight pseudo-lobules and divided by thin false septa (7). taxol for anti-cancer, reveals that plant-derived anti- The of R. tomentosa is presented in Table 1. cancer drugs are Paclitaxel (Taxol®) (18). The cytotoxic activity of this taxane dipertene found in extracts from MATERIALS AND METHODS the bark of Taxus brevifolia Nutt. (Western yew) from natural product drugs of plant origin. In addition to low Worldwide, 80% of the population still relies on side effects, medicinal plants are given more attention traditional medicine for their primary health care because of their low cost, there is also a wide range of strategy (8). Based on WHO report, the highest usage bioactive compounds which are responsible for various of traditional medicine was the South-East Asia Region pharmacological activities (19). Hence, the present (91%), followed by the European Region (85%), the review article is aimed to provide detail on scientific Eastern Mediterranean Region (81%), the Region of evidence on phytochemistry and pharmacological the Americas (54%), the African Region (49%) and the activities of R. tomentosa leaves. Western Pacific Region (41%) (9). Example of diseases treated using traditional medicine includes Clinacanthus PHYTOCHEMICAL STUDIES nutans traditionally used as natural medicine in Over the past 45 years, there has been an overall trend Malaysia, Indonesia, and Thailand to treat certain towards rising R. tomentosa publication rates. This conditions such as skin rashes and scorpion and insect plant’s interest is translated into high number of research bites, diabetes mellitus, fever and diuretics (9). Another papers published since 2010, an average of five each example of a medicinal plant, Stevia rebaudiana leaves, year, a number that tends to increase, as shown in Fig.1. has a potential mode of actions in controlling type 2 Phytochemical compounds from R. tomentosa leaves diabetes (10). Nature-based medicine is more preferable mainly composed of triterpenoids, flavonoids, phenols than modern medicine due to lower side effects risk. and meroterpenoids as the primary components listed in

334 Mal J Med Health Sci 17(SUPP3): 333-342, Jun 2021 Fig. 1: Number of published papers in Rhodomyrtus tomentosa since Fig. 2: Chemical structure of rhodomyrtone (20) the 1969s until 30 Mei 2020 according to the databases searched in PubMed, ScienceDirect and Web of Science.

Table 2. Compounds of R.tomentosa leaves Compounds Classification Source Extraction Method Ref. (Wai-Haan & Man- Lupeol, -amyrin, amyrenonol, 1 β β- Terpenoid Leaves Petrol Extract Moon, 1976), (Hui et and botulin al., 1975) 3 -hydroxy-21 -hop-22(29)-en- (Wai-Haan & Man- 2 β α Terpenoid Leaves Petrol Extract, Acidic -95% Ethanol 30-al Moon, 1976) 95% Ethanol - n-hexane - ethyl ace- 3 Rhodomentones A and B Terpenoid Leaves (H.-X. Liu et al., 2016) tate Tomentosenol A, 4S-focifolidione, 95% Ethanol - n-hexane - ethyl ace- (H. X. Liu, Zhang, et al., 4 Terpenoid Leaves and 4R-focifolidione tate 2016)

95% EtOH,petroleum ether, chloro- 5 Tomentodione E Terpenoid Leaves (J. Liu et al., 2018) form, ethyl acetate and n-butanol

Rhodomyrtials A and B, tomentodi- 95% EtOH ,successively partitioned (Y. L. Zhang et al., 6 Terpenoid Leaves ones A–D with PE, CH2Cl2 and EtOAc 2016)

95% EtOH,successively partitioned (Y. L. Zhang et al., 7 Tomentodiones E–G Terpenoid Leaves with PE, CH2Cl2, and EtOAc 2017)

Rhodomyrtosone A, rhodomyrto- successively extracted at room tem- (A. Hiranrat & Ma- 8 sone B, rhodomyrtosone C, Phenolics Leaves perature with CH2Cl2, Me2CO and MeOH habusarakam, 2008) and rhodomyrtosone D

The air-dried ground leaves of R. tomentosa (2.1 kg) were successively extracted at room temperature with (A. Hiranrat et al., Tomentosones A and B, rhodomyr- CH2Cl2, Me2CO, and MeOH (3 × 9 Phenolics Leaves 2012), (W. Hiranrat et tosones G and H 6 L, each 3 days)The dried-ground al., 2017) leaves of R. tomentosa (1 kg) were macerated with hexane for three days twice

The air-dried leaves of R. tomentosa (12.5 kg) was pulverized and extract- (Y.-B. Zhang et al., 10 Tomentodiones N T Phenolics Leaves ed using supercritical fuid CO2 in a − 2018) supercritical extraction equipment to give a crude extract

Myricetin 3-O-α-L-furanoarabino- side, myricetin (Hou, A.; Wu, Y.; Liu, 11 Flavanoid Leaves 3-O-β-D-glucoside, and myricetin 1999) 3-O-α-L-rhamnoside (Dachriyanus et al., 12 Rhodomyrtone Phenolics Leaves Ethyl acetate 2002) Piceatannol 4t-O- -D-glucopyra- 13 β Flavanoid Leaves (Chuantao et al., 1997) noside Tomentosin, pedunculagin, casuari- 13 Tannin Leaves (Chuantao et al., 1997) in, and castalagin

-pinene, -pinene, and The leaf essential oils were obtained (Liu Yanze , Hou Aijun , 14 α β Essential oils Leaves aromadendrene by steam distillation with cohobation Ji Chunru, 1998)

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Table 2. Among the abundant phytochemical compounds 6.2 and MBC value of 6.2-50 μg/mL (30). Antimicrobial that are present in R. tomentosa, Rhodomyrtone[6,8- ability of R. tomentosa extract and rhodomyrtone on dihydroxy-2,2,4,4-tetramethyl-7-(3-methyl-1-oxobutyl)- S. agalactiae was ruled out in the same year by Na- 9-(2meth-ylpropyl)-4,9-dihydro-1H xan-thene -1,3(2H)- Phatthalung which can be an option in aquaculture di-one] is an active compound from this plant (Fig. 2) to prevent and control streptococcal infection (31). that has been extensively studied by researcher and Another study in 2013, additional effects on bacterial tested for its biological activities (7). virulence displayed by rhodomyrtone-treated S. aureus via DnaK and/or σB, resulting in reducing pigmentation PHARMACOLOGICAL STUDIES ON R. tomentosa a dose-dependent and increase in the susceptibility of

Main pharmacological data on R. tomentosa articles the pathogen to H2O2 and singlet oxygen killing (32) . covered the antibacterial activities of both R. tomentosa In the same year, Leejae and colleaque (33) concluded leaves and rhodomyrtone, followed by anti-inflammatory, that the bacterial cell membrane and subsequent cell antioxidant, anti tumor and other biological activities lysis were not the main target of rhodomyrtone against discussed in the following paragraphs. antibiotic-resistant pathogens of epidemic meticillin- resistant Staphylococcus aureus (EMRSA), vancomycin- intermediate S. aureus and vancomycin-resistant PHARMACOLOGICAL ACTIVITIES enterococcal strains (33). 1. Antimicrobial Activity The first report on antibacterial effect of R. tomentosa In 2014, Limsuwan et al., (34) proved that S. aureus , based on literature search start from a study by Streptococcus mutans and C. albicans respectively Dachirinus in 2002 (21), who found the active compound showed inhibitory effect with MIC values of 31.25, 15.62, rhodomyrtone as antibacterial candidate. Limsuwan and 1000 µg/ mL after treated with rhodomyrtone and and colleague (22) in year 2008, their study revealed R. R. tomentosa leaf extract. The author suggests that the tomentosa extracts had MIC of 0.24–7.81 mg mL-1 vastly extract and compound might be a potential preventive inhibited bio-film formation with also strong inhibition and therapeutic agent in oral diseases (34). Remarkable on quorum sensing on Streptococcus pyogenes (22). In bactericidal effects with MIC and MBC values ranged 2010, The R. tomentosa ethanolic leaves extract formed from 16 to 32 µg/mL and 128 to 512 µg/mL, respectively large inhibition zones in Bacillus cereus with 16 to 64 for proven the ability of R. tomentosa ethanolic leaves minimum inhibitory concentration (MIC) and minimum extract as a bio-control agent against L. monocytogenes bactericidal concentration (MBC) of 32 to 256 mg/mL to prevent the incidence of L. monocytogenes food (23). Saising and his colleagues revealed rhodomytone contamination (35). The previous work of Saising (36) was better at inhibiting staphylococcal biofilm formation extends the idea that rhodomyrtone exhibits activity than vancomycin (24). In the same year, proteomic against biofilm-forming staphylococci. Their subsequent study been carried out to study the anti-infective and study revealed the reduction in atl and ica transcription antibacterial activity of rhodomyrtone, which further signals in response to rhodomyrtone treatment (36). R. elucidate the mechanisms behind rhodomyrtone’s tomentosa leaves ethanolic extract displayed MIC and action upon S. pyogenes (25). MBC values ranged from 16–64 μg/mL and 64–N128 μg/ mL, respectively against all of staphylococcal isolates. Sianglum et al., (26) succeeded in demonstrating that In addition, rhodomyrtone was found to be effective ethanolic extract from R. tomentosa leaf is able to against staphylococci and significantly decreased inhibit both methicillin-resistant Staphylococcus aureus the adherence of the bacterial cells to tissues (37). In (MRSA) and S. aureus. Proteomic techniques provide another antimicrobial study, revealed that tomentosone insight on the effect of rhodomyrtone into MRSA C and the known acylphloroglucinol rhodomyrtone extracellular protein expression by interfere with WalK/ exhibited significant antimicrobial activity against WalR (YycG/YycF) system by downregulating the cell Staphylococcus aureus with MICs of 3.66 and 1.83 μg/ wall hydrolysis of both immunodominant antigen A mL (-1 ) respectively (38). (IsaA) and staphylococcal secretory antigen (SsaA) (27). Odenina et al., (39) observed that rinse method of R. In the following year, with the use of microarray tomentosa ethanolic leaves as a potent bio-additive analysis the effects of rhodomyrtone exposure were agent was more effective to reduce L. monocytogenes examined on the gene transcriptional profile of MRSA contamination in chicken meat. Molecular docking and this was achieved by silencing of 64 genes and study by Saeloh et al .,(40), revealed that a cofactor free induction of 35 genes (28). Limsuwan et al., (29) study dihydrofolate reductase (DHFR) and a ligand filamenting showed a significant antibacterial properties of both temperature-sensitive Z (FtsZ) proteins responsible for rhodomyrtone and R. tomentosa ethanolic leaves extract MRSA inhibition. against 47 and 14 clinical isolates of S. pyogenes. R. tomentosa acetone extract capped with silver In 2016, another antibacterial study on the leaf extract of nanoparticles exhibited profound antibacterial activity R. tomentosa been explored, which showed the efficacy against staphylococcal infections with MIC value 3.1- against Salmonella typhi and Propionibacterium acnes

336 Mal J Med Health Sci 17(SUPP3): 333-342, Jun 2021 with an inhibitory activity of 0.19–0.50, compared anucleated cells in Streptococcus suis (51). R.tomentosa to that of the reference drug, chloramphenicol (41). and rhodomyrtone continued to be explore for its Pronounced antibacterial effect of R. tomentosa antimicrobial properties. Despite its high potential as a ethanolic leaves extract (EER) against the Nile tilapia new antibiotic, the mechanism of how rhodomyrtone fish model infected with Streptococcus agalactiae and kills pathogens is not yet fully understood. Overall Streptococcus iniae with MICs ranging from 7.8 to findings on the antibacterial activities come with a 6 2.5 µg/mL been reported, additionally induction of similar outcome in the agreement of the leaves and

H2O2, S. agalactiae cells pre- treated with EER increased rhodomyrtone as a promising antibacterial agent. It the sensitivity of S. agalactiae cells to oxidative stress, is noted that both rhodomyrtone and R.tomentosa and mortality of Nile tilapia reduced (42). Srisuwan leaves possess good antimicrobial activities that have (39) utilised the efficiency of the extract in inhibiting been utilized to various implementation, from food the growth of human HaCaT cells and determined the production to fishery farm. The use of acne product from presence of alterations in the bacterial morphology. It’s R.tomentosa due to antimicrobial effect that readily in stated that MRSA has decreased cytotoxicity at least 50% the plant. Soon, the use of rhodmyrtone as a promising through the use of R. tomentosa. Study demonstrated antimicrobial drug is for seen. that. R. tomentoso acetone extract (RAE) capped with nanoparticles of silver and Au-Ag-Alloy have increased 2. Anti-Inflammatory Activities antibacterial activity against E. coli (43). The first article reported on the anti-inflammatory activity of R. tomentosa was discovered by Jeong et In vitro experiments, in silico s and studies in vivo are al., (52) R. tomentosa methanol leaves extract (Rt-ME used to evaluate the molecular interaction between ) inhibited lipopolysaccharide-activated RAW264.7 rhodomyrtone and FtsZ. Free FtsZ state changes occurred cells and peritoneal macrophages production of NO in both the S- and R- states compared to the natural three and prostaglandin E2 in a dose-dependent manner by states of FtsZ (ligand-free, GDP-, and GTP-binding states) directly targeting Syk/Src and IRAK1/IRAK4 inactivate (44). Another study on the antimicrobial effect of R. both nuclear factor (NF)-κB and activator protein (AP)- tomentosa extract using Nile talipia as subject revealed 1 pathways. Zhang and colleagues (53) demonstrate strong antimicrobial activity towards S. agalactiae and S. decrease NO production from LPS-induced RAW 264.7 iniae with MIC values ranging from 7.8 to 62.5 µg/mL, cells with the IC50 values of 3.8–74.3 µM, an anti- important fish pathogens causing streptococcosis. Their inflammatory effect of phloroglucinol derivatives from study has reinforced the view that R. tomentosa could R. tomentosa leaves. In another promising study showed play a significant role in controlling streptococcosis (42). R. tomentosa exerted anti-inflammatory activity in Rosli and colleagues (45) showed that the methanol rainbow trout model by mediating the expression of the extract of R. tomentosa exhibited strong inhibitory immune-related genes’ (54) . Na-Phatthalung et al.,(55) properties against Escherichia coli and S. aureus with showcasing the rhodomyrtone effect, the concentrations an inhibition zone of 10 mm. In 2018, Srisuwan et al., of IL-1β, IL-8, and TNF-α in head kidney macrophages (46) revealed the potency of rhodomyrtone impact on were enhanced, while IL-10 and TGF-β expression were C. difficile cell lysis, defective cell division and spore induced. In earlier study by Chorachoo and colleaques formation. In the same year, research by Sianglum (47) (56) demonstrated the ability of rhodomyrtone to demonstrate the damaging effects of rhodomyrtone suppress TNF-α expression in monocytes stimulated on MRSA by bacterial cell disruption, holes in cell with heat-killed methicillin-resistant Staphylococcus surface, and bulge formations. Contra findings on aureus (MRSA).In addition, rhodomyrtone have also antibiotic activity presented by Mordmuang et al., (48) shown ability to significantly inhibit the transcription whereby R. tomentosa leaves ethanolic extract showed and expression of inflammatory mediators from TNF-α a promising antibacterial ability in vitro, although its and IL-17A stimulated skin organ cultures via NF-κB, effectiveness in vivo was reduced. Docking analysis ERK, JNK, and p38 signalling pathways suppression. In yielded rhodomyrtone’s effect on the single point vivo data showed rhodomyrtone act as therapeutic agent mutation in farR [regulator of fatty acid (FA) promotes against psoriasis through the inhibition of keratinocyte hyper-virulence (49). hyperproliferation which could possibly be used for other inflammatory cytokine-mediated diseases (57). Sigma factor B (SigB) controls the expression of S. aureus Different approaches to anti-inflammatory activities genes which include virulence factor production and can be found in six different papers, each of which secretion through the membrane vesicle production uses a different subject to test for the anti-inflammatory system. Research suggests that rhodomyrtone inhibits effect, such as rainbrown trout, microorganisms, and S. aureus SigB activity at exponential growth rates and skin cultured organs. However, more data is needed inhibits hemolytic activity within membranes (50). to improve understanding of the molecular mechanism Recent finding in year 2020, prove that rhodomyrtone of anti-inflammatory activities of both compound and involves the early stage in bacterial cell division leaves. process by incomplete nucleoid segregation and septum misplacement, leading to the generation of 3. Antioxidant Activity

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Under the influence of oxidative stress, a hundred different that R. tomentosa and several isolated compounds have types of human diseases occur as a consequence of antitumor effects on multiple models (53). Presented anti peroxidation of membrane lipids, protein modification, cancer activities data limited to the effect of anti-cancer depletion of NAD, cytoskeletal disruption, and DNA derived from the rhodomyrtone, compound that present damage (58). Antioxidants from natural products have in the R.tomentosa leaves only. More information on the been shown to play a role in preventing and treating molecular mechanism of anti-cancer activity, as well as diseases caused by undesired free radical effects (59). an in vivo model, is needed. R. tomentosa leaves extract shows significant inhibitory effect on lipid peroxides equal to 0.93 0.07 mM gallic 5. Other Pharmacological Activities acid at 100 µg/mL. The extract reduced Fe3+ to Fe2+, Chai et al., (66) conclude rhodomyrtone inhibits and we found this to be equivalent to 10.8 ± 1.12 mM impairments in spatial memory, decreases dendritic gallic acid and 30.5 ± 5.22 mM ellagic acid at 1 mg/mL spines, inhibition of glycogen synthase kinase-3β (60). In another study, R. tomentosa extract exhibited activity and decreases brain-derived neurotrophic factor protective effects against CCl4-induced reduction in and postsynaptic density protein 95 in chronically antioxidant enzyme SOD, CAT, and GPx in blood, liver, stressed mice. In addition, rhodomyrtone treatment and kidneys. The improvement of enzyme activities at resulted in the reversal of apoptosis-associated protein a rate of 0.8 g/kg of body weight is similar to the effect Bax and cleaved-caspase 3. In another study, a of α-tocopherol at a rate of 0.1 g/kg of body weight. petroleum ether extract from the stems and leaves of R. The flavonoid rich extract increased the activities of tomentosa exhibited a significant degree of inhibition of antioxidant enzymes in mice’s serums such as SOD, acetylcholinesterase (81% , 500 μg/mL) (67). Hasibuan GSH-Px, and CAT (60). The aqueous alcoholic extract and colleagues (68) reported R. tomentosa aqueous of R. tomentosa leaves has shown ulcer healing and leaf extract’s anti-diabetic activity, the administration protective abilities comparable to that of omeprazole of R. tomentosa aqueous extract at 100 mg/kg was in acetic acid-induced gastric ulcers in rats. Likewise, effective in decreasing blood sugar levels in alloxan- a 400 mg/kg dose of the extract had a significant ability induced diabetic mice (68). According to Geetha to enhance CAT and SOD, as well as decrease lipid et al., (53) the potent anti-ulcerogenic activity of an peroxidation, in a manner similar to that of omeprazole aqueous alcoholic (70%) extract of R. tomentosa at 20 mg/kg (61). Research by Abd Hamid and colleague indicated by a reduction in ulcer index, an increase (62) conclude that the methanol fraction exhibited the in levels of superoxide dismutase and catalase, and a most significant antioxidant activities in vitro with EC50 decrease in lipid peroxidation. Jeenkeawpieam et al., values of 110.25, 53.84 and 58.62 μg/mL respectively (69) reported R. tomentosa was effective against five in DPPH, CUPRAC and β-carotene bleaching. The anti- human pathogenic fungi strain, therefore the author oxidant activities of the R.tomentosa leaves are limited, conclude that R. tomentosa extract was a good source to date, there is no paper published reporting on the for endophytic fungi that produce antifungal natural rhodomyrtone antioxidant activity. Different solvent use products (69). Saising and Voravuthikunchai revealed and type of extraction method of the R.tomentosa, thus that R. tomentosa ethanol extract and rhodomyrtone give different reported antioxidant activities. More data had very low cytotoxicity value of more than 200 mg/ on the anti-oxidant activities are required to justify and mL, which is safe to be applied topical therapeutics for prove antioxidant properties of both R.tomentosa leaves acne (70). Other pharmacological activities are limited extract and rhodomyrtone. to only one published paper reported with anti-diabetic, anti-ulcer activities, anti-acne and anti-fungal properties. All of R.tomentosa and rhodomyrtone other promising 4. Anticancer Activity properties can be investigated and unravelled. Rhodomyrtone from R. tomentosa leaves has been reported as a promising natural anticancer agent with the CONCLUSIONS ability to suppress cell viability of HaCaT keratinocyte cells in vitro at concentrations of 2–32 µg/mL after 24, This article summarized the R. tomentosa leaves’ 48, and 72 h treatments, with no skin irritation observed pharmacological activities, and rhodomyrtone as an in vivo, suggesting the potential to develop as a natural active compound derived from the R. tomentosa leaves anti psoriasis agent (63). In another study, rhodomyrtone according to literatures. Overall, R.tomentosa leaves markedly inhibited A431 cell migration in a dose- and and rhodomyrtone merits careful study on clinical time-dependent manner with an IC50 value of 8.04 ± 0.11 efficacy especially as antimicrobial drug. Humans focus µg/mL (64). In earlier study by Tayeh et al., (65) showed health information pertaining to R. tomentosa leaves rhodomyrtone reduced cell metastasis by inhibiting and rhodomyrtone are still under study to determine matrix metalloproteinase (MMP)-2/9 expression through their clinical value. Thus, the review will provide the inhibiting extracellular signal-regulated kinase 1/2 researchers with an in-depth view of R. tomentosa leaves (ERK1/2), p38 and focal adhesion kinase (FAK) signalling and rhodomyrtone are promising sources for modern pathways via nuclear factor-kappa B (NF-κB) activities medicine’s development. Based on the current review, (65). In the same year 2017, some studies have revealed the antibacterial activity of the rhodomyrtone have

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