Journal of Pharmaceutical Science and Application Volume 3, Issue 1, Page 40-49, June 2021 E-ISSN : 2301-7708

A REVIEW OF PHYTOCHEMICAL AND PHARMACOLOGICAL STUDIES OF retrofractum Vahl.

Ni Komang Sri Lumbung Artha Wardani1, Ni Putu Eka Leliqia1*

1Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Udayana University

Corresponding author email: [email protected]

ABSTRACT Background: Javanese ( Vahl.) is a that commonly found in Southeast Asia and is empirically used to treat various diseases. It is known that the phytochemical content in is one factor responsible for its pharmacology activities. The study of the pharmacological effects of herbal ingredients both pre-clinically and clinically is an attempt to prove their empirical properties. Aims: This review article aims to provide information to academics and the public regarding phytochemical studies and pharmacological activity that have been carried out regarding the Javanese long pepper plant. Methods: Article preparation was carried out through literature studies from various national scientific journals, international journals, and online reference books. Javanese long pepper data search system was based on chemical content and pharmacological activity studies either in vitro, in vivo, or clinical trials. Results: Phytochemical studies have shown that the plant parts of Javanese long pepper contain compounds such as , saponins, tannins, flavonoids, steroids, triterpenoid, and glycosides. Based on studies of its pharmacological activity, Javanese long pepper has been reported to have antimicrobial, antioxidant, cytotoxic, analgesic, androgenic, aphrodisiac, antihyperlipidemic, antihyperuricemic, lowering leukocyte count, antileishmanial and immunostimulant effects. Conclusion: The efficacy of Javanese long pepper has been scientifically proven to have pharmacological effects either through in vitro or clinical studies which can be taken into consideration for the development of traditional medicinal products.

Keywords: Javanese Long Pepper, Piper retrofractum, Phytochemical, Pharmacology activity

INTRODUCTION Currently, people tend to change their traditional medicine. This plant is native to lifestyle towards a “back to nature”. Southeast Asia and is known as Globally, people are starting to use hihatsumodoki in Japan. These plants are traditional herbal medicines to maintain widely cultivated in and their health. There are 40,000 types of Thailand[2]. Javanese long pepper in medicinal plants that have been known in Indonesia are found in Java, Sumatra, Bali, the world, and 30,000 of them are found in Nusa Tenggara, and Kalimantan, where the Indonesia. Based on this, 90% of medicinal main production center of this plant is on plants are found in the Asian region[1]. The Madura[3]. Javanese long pepper plant (Piper The Javanese long pepper plant is retrofractum Vahl.) is one of the herbal closely related to the pepper plant and is ingredients that can be developed into included in family[4]. The traditional medicinal products in Indonesia. of Javanese long pepper, namely Javanese long pepper has long been kingdom plantae; magnoliphyta division; known as a plant that is widely used as magnoliopside class; order; 40 DOI : https://doi.org/10.24843/JPSA.2021.v03.i01.p05 Wardani and Leliqia Volume 3, Issue 1, Page 40-49, June 2021

piperaceae family; piper genus; and the Piper retrofractum, then it is further species Piper retrofractum[5]. Based on its selected to obtain data related to its morphology, Javanese long pepper is a phytochemical content and climbing plant. The leaves are round, pharmacological activity. lanceolate, and wide; green to dark green. The fruit has varying shapes and sizes RESULTS AND DISCUSSIONS ranging from small lengths (cylindrical), Javanese long pepper (Piper flat length (filiform), elliptical (conical), retrofractum Vahl.) are known to have and short round (globular). The stem is pharmacological activities. The type of round and large; has a diameter of ± 5-7 cm; chemical content of this plant plays an length of the main stem 2.93-9.82 cm; The important role in determining its color of the stem varies greatly from black, pharmacological effect. Phytochemical brown to blackish brown[6]. screening and isolation of chemical Traditionally, the Javanese long pepper compounds from Javanese long pepper is plant is used for the treatment of digestive one way to obtain information about the function disorders, asthma, hypertension, chemical content and isolate compounds. influenza, and for treating flatulence[7]. The pharmacological effect of an herbal Based on its empirical properties, many ingredient can be determined through studies have been carried out related to the preclinical tests which include in vitro and pharmacological effects of Piper in vivo testing, as well as through clinical retrofractum plants. Several studies trials. In vitro testing is carried out to revealed that the phytochemical contained determine the efficacy of these herbal in this plant has pharmacological activities, ingredients so that they can predict and including antimicrobial[8], antioxidant[9], determine the mechanism of the compound cytotoxic[10], analgesic[11], androgenic[12], to work with target receptors. This test is aphrodisiac[13], antihyperlipidemic[14], carried out outside the body of a living thing antihiperuricemia[15], reducing the number such as in bacterial cultures, isolated cells, of leukocytes[16], antileishmanial[17], and or isolated organs. In vivo testing is carried immunostimulants[18]. out to see the behavior of the test animals so The increasing number of scientific that they can provide information about studies regarding the phytochemical their biological system after being given the content and pharmacological activities of test material[19]. According to BPOM RI Javanese long pepper is expected to provide (2015), clinical trials are studies using information to the public about the potential humans as subjects to find or confirm of this plant as a traditional medicine. In clinical, pharmacological and/or other addition, this article can be used by pharmacodynamic effects, and/or researchers as a consideration in developing identifying any unwanted reactions, and/or Javanese chili research for the treatment of studying absorption, distribution, diseases. metabolism and excretion to ensure the safety and/or effectiveness of the product METHODS studied[20]. The method used in this review article was a literature study. Literature was Chemical Content collected from original articles published in The fruit, leaves, stems, and roots of national and international scientific journals Javanese long pepper contain alkaloids, online through searches on the Scopus saponins, tannins, flavonoids, steroids, portal and Google Scholar. Literature can triterpenoid, and glycosides[21]. The results also be in the form of a reference book. The of phytochemical screening conducted by main keyword used is the name of the plant Krisnawan et al. (2017), showed that the

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aqueous extract of Javanese long pepper shown by a study conducted by Jamal et al., leaves positively contained flavonoids and (2013). The activity test was carried out in saponins[22]. Yuliatmoko and Febria (2018) vitro with the diffusion method to see the also reported that dried leaves of Javanese inhibitory diameter and the dilution method long pepper contain terpenoid to determine the value of the minimum compounds[23]. Research by Insanu et al., inhibitory concentration (MIC) of the test (2017) revealed that Javanese long pepper sample against bacteria. The results showed leaf extract contains flavonoids, tannin, that essential oils with a concentration of quinone, and steroid/triterpenoid 50% proved to have antibacterial activity compounds[24]. against Bacillus subtilis (NBRC 3134), Several studies had been succeeded in Micrococcus luteus (NBRC 14218), isolating the chemical compounds from Staphylococcus aureus (NBRC 14276) with Javanese long pepper. This plant is known an inhibitory diameter of 8.5; 8.0; and 9.7 to contain , chavicin, palmatic acid, mm; but it had no effect on Eschericia coli tetrahydropiperic acid, 1-undecylenyl-3, 4- (NBRC 14237). It is also known that the methylledioxy benzene, piperidine, essential oil from the leaves of Javanese essential oils, N-isobutyldeka-trans-4- long pepper has a MIC value of 2% (v/v) dienamid, and sesamin[4]. Jamal et al., against B. subtilis. Tetramethylcyclo (2013) reported that there are 4 main [5.3.1.0 (4.11)] undec-8-ene, germacrene components of the essential oil of Javanese D, Ar-turmerone, and benzyl benzoate were long pepper leaves, namely germacrene D known as main components of essential oils (24.20%), tetramethylcyclo [5.3.1.0 (4.11)] contained in Javanese long pepper leaves in undec-8-ene (17.73%), Ar-turmerone this study. Cell leakage testing and (11.55%) and benzyl benzoate (6.28%). observation by Scanning Electron Meanwhile, 3 other sesquiterpene, namely Microscopy (SEM) were carried out on B. α-cubebene (3.55%), β-cubebene (2.59%), subtilis. Exposure of B. subtilis bacterial and β-cadinene (2.49%) as well as cells with essential oil of Javanese long sesquiterpene alcohol curlone (2.67%) and pepper leaves at a concentration of 2% and derivatives of phenyl propanoate, 2- 4% caused cell leakage of cellular methoxy-4- (2-propenyl) –phenol (2.05%) metabolites such as proteins and nucleic showed a content between 2-4%[8]. acids, as well as ions from metals (K+ and Amad et al., (2016) also stated that Ca2+). SEM observations showed that there other compounds have been isolated from were morphological changes in these Javanese long pepper fruit, namely bacterial cells[8]. Gauthier (2006) explains piperine, methyl piperate, sylvatin, and that the leak is thought to affect changes in piperlonguminine[25]. According to the bacterial morphology that can inhibit cell findings reported by Bodiwala et al. (2007), wall synthesis. Ion leakage is caused by there are 3 compounds produced by n- damage to cell membranes and increased hexane and methanol extracts from the stem membrane permeability. Damage to the cell of Javanese long pepper. The results of the membrane will make it easier for organic isolation showed that the n-hexane extract acids to penetrate the cytoplasmic of Javanese long pepper stems contained membrane and cause changes in membrane sesamin (lignans) and pellitorine (amide) stability which eventually leads to ion compounds. Meanwhile, methanol extract leakage[26]. contains piplartine (amide) compounds[17]. Panphut et al., (2020) reported that Javanese long pepper fruit which were Antimicrobial Activity extracted with several solvents such as The leaves of Javanese long pepper are acetonitrile, methanol n-hexane, known to have antibacterial activity as isopropanol, and dichloromethane had

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antimicrobial activity with a range of these results, aqueous extract with a inhibition zone diameters 0.5–8.0 mm. The concentration of 20-65% were categorized acetonitrile extract showed antimicrobial as having weak activity, while aqueous activity against E. coli, B. subtilis, extract with a concentration of 80% was Enterococcus faecalis, Klebsiella categorized as having moderate activity[22]. pneumoniae, Pseudomonas aeruginosa, Pan et al., (2009) stated that there are three Salmonella typhi, S. aureus, Vibrio categories of inhibitory power, the weak parahaemolyticus XN89, Vibrio activity with an inhibition diameter of 0 mm paraparahaemolyticus 5HP, and Candida – 3mm, a moderate activity with an albicans with MIC values of 36.0; 71.50; inhibition diameter of 3 mm – 6 mm and the 4,50; 143.50; 143.50; 9.0; 71.50; 71.50; third category is strong with an inhibition 71.50; and 1.0 mg/mL. Methanolic extract diameter of > 6 mm[28]. also showed antimicrobial activity against Amad et al., (2016) revealed that E. coli, B. subtilis, E. faecalis, K. Javanese long pepper fruit had an anti- pneumoniae, P. aeruginosa, S. typhi, S. tuberculosis effect. In vitro testing on the aureus, V. parahaemolyticus XN89, V. bacterium Mycobacterium tuberculosis paraparahaemolyticus 5HP, and C. strain H37Ra showed that the methanol albicans with MIC value of 22.50; 5,50; extract and the isolates contained therein, 45.0; 90.0; 179.50; 11.0; 45.0; 45.0; 22.50; namely piperlonguminine and piperine, had 0.50 mg/mL. The n-hexane extract only antibacterial activity. The MIC value of the showed activity against C. albicans with a methanol extract was 25 µg/mL, while MIC value of 2.50 mg/mL. Isopropanol piperlonguminine and piperine had weaker extract showed antimicrobial activity activity with MIC values of 50.0 µg/mL. against E. coli, B. subtilis, E. faecalis, S. Two other compounds that have also been typhi, S. aureus, V. parahaemolyticus isolated from methanol extract, namely XN89, V. paraparahaemolyticus 5HP, and sylvatine and methyl piperate, did not have C. albicans with MIC values of 18.0; 9.0; antibacterial activity[25]. 71.50; 9.0; 35.50; 71.50; 18.0; and 10.0 mg/mL; and dichloromethane extracts Antioxidant Activity showed antimicrobial activity against E. Based on research conducted by Jadid coli, B. subtilis, E. faecalis, S. typhi, S. et al. (2016), Javanese long pepper that was aureus, V. parahaemolyticus XN89, V. extracted with several solvents had paraparahaemolyticus 5HP, and C. antioxidant activity. The activity was albicans with MIC values of 80.0; 80.0; determined using using DPPH method. The 40.0; 10.0; 80.0; 80.0; 40.0; and 18.0 IC50 value obtained from the n-hexane mg/mL. Based on this study, it is known extract was 57.66 μg/mL; ethyl acetate of that the bioactive compound Javanese long 66.12 μg/mL; and methanol 101.74 μg/mL. pepper which was extracted with methanol In this study, the antioxidant activity was had better potential against pathogenic classified into 3 categories. Strong [27] microorganisms . antioxidant activity had a range of IC50 The results of research conducted by values of 10-50 μg/mL; moderate Krisnawan et al. (2017), reported that the antioxidants have an IC50 value range of 50- aqueous extract of Javanese long pepper 100 μg/mL, and weak antioxidants have IC leaves various concentrations also had values >100 µg/mL. Based on these antibacterial activity against S. aureus. The categories, n-hexane and ethyl acetate extract with a concentration of 20%, 35%, extracts were classified as antioxidants with 50%, 65%, and 80% had an inhibitory moderate activity, while methanol extracts diameter of 1.40 mm; 2.38 mm; 2.88 mm; were classified as weak antioxidants[9]. 2.76 mm; 4.49 mm respectively. Based on

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Mulia et al., (2016) conducted a study to 70% ethanol extract of Javanese long comparing the antioxidant activity of pepper fruit from various regions in Javanese long pepper fruit extracts from Indonesia. The results of the cytotoxic test Pamekasan and Karangasem. The results on MCF-7 breast cancer cells showed that showed that samples from Pamekasan had the extracts from Paranggupito 1 (Central weaker antioxidant activity (IC50 288.037 Java), Paranggupito 2 (Central Java), μg/mL) than samples from Karangasem Girintontro (Central Java), Air Naningan 1 (IC50 285.61 μg/mL). However, based on (Lampung), and Air Naningan 2 (Lampung) the IC50 value, the antioxidant activity of had a value IC50 successively 80.43; both samples is still relatively weak[29]. 126.09; 181.52; 54.35; 4.35 μg/mL. These results indicate that the Javanese long Cytotoxic Activity pepper from Air Naningan 2 have the best Javanese long pepper extract has been cytotoxic activity. Further testing on MCF- shown to have a cytotoxic activity against 7 breast cancer cells given the extract from Artemia salina Leach shrimp larvae, MCF- Air Naningan 2 with a concentration of 250 7 breast cancer cells, HeLa cell line μg/mL showed that the cancer cells were (continuous cell line derived from cervical severely damaged[30]. cancer epithelial cells), T47D breast cancer Based on research conducted by cells and lung cancer cells (SCLC-H22 and Ekowati et al. (2011), it is known that 96% NCI-H187). According to findings reported ethanol extract of Javanese long pepper fruit by Clarasati et al., (2016), extract and had cytotoxic activity against HeLa cells fractions of Javanese long pepper fruit had with an IC50 value of 47.409 µg/mL and cytotoxic activity against Artemia salina against T47D with an IC50 value of 92.38 Leach shrimp larvae. The LC50 value of µg/mL. Ekowati et al., (2011) also 95% ethanol extract, n-hexane fraction, combined this extract with red ethyl acetate fraction, and aqueous fraction rhizome. The results showed increased were 44.05 μg/mL; 70.79 μg/mL; 79.43 cytotoxic activity against HeLa and T47D μg/mL; and 112.2 μg/mL respectively. cells when the two ingredients were Extracts and fractions of Javanese long combined, with smaller IC50 values for the pepper were stated to have cytotoxic two test cells, namely 33 µg/mL and 53 [31] activity because they had an LC50 value µg/mL. Compound that role play in the lower than 1,000 μg/mL[10]. cytotoxic activity of this plant is piperine Mulia et al., (2016) reported that ( group). The piperin can protect Javanese long pepper fruit extract from cells from cancer by binding to proteins in Karangasem and Pamekasan had cytotoxic mitochondria and triggering apoptosis activity against MCF-7 breast cancer cells. without damaging normal cells, through The treatment of various concentrations of increased activity of antioxidant enzymes Javanese long pepper extract from the two such as superoxide dismutase, catalase, and regions were able to have effect on these glutathione peroxidase. In addition, cells. There was a decrease in the IC50 value piperine can inhibit NFkB so that it can with increasing concentration. Samples prevent tumor formation through TNF-α from Karangasem and Pamekasan had and inhibit the angiogenesis process[32,33]. cytotoxic activity with IC50 values of Amad et al., (2016) reported that the 63.283 μg/mL and 83.662 μg/mL. Based on methanol extract of Javanese long pepper these data, the cytotoxic activity of both fruit and their isolates (piperine and samples is classified as active because the piperlonguminine) had cytotoxic activity [29] IC50 value is in the 50-100 μg/mL range . against lung cancer cells [SCLC-H22 and Hasan et al. (2016) also researched on NCI-H187 (ATCC CRL-5840)]. The MCF-7 breast cancer cells that was exposed cytotoxic activity can be shown based on

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the percentage value of the growth Aphrodisiac inhibition of the test cells. The methanol Tominik (2018) examined the extract of Javanese long pepper with a aphrodisiac effect of the Javanese long concentration of 5 µg/mL also had a % pepper fruit extract. The administration of inhibitory value of SCLC-H22 and NCI- extract at a dose of 210 mg/kg BW to albino H187 lung cancer cells of 38.83 and mice (Mus musculus) for 36 days was able 96.71%, respectively. Piperine with a to increase diameter of the seminferus concentration of 25 µg/mL had a % tubule, the weight of the testis, the core inhibitory value against SCLC-H22 and Leydig diameter, the thickness of the NCI-H187 lung cancer cells of 7.68 and germinal seminiferous tubular epithelium, 15.58%, respectively. Meanwhile, Sertoli cells, the Leydig cell count, the piperlonguminine with a concentration of spermatogenesis index, and the associate 25 µg/mL had a % inhibitory value against cell significantly (p<0.05). The increase in SCLC-H22 and NCI-H187 lung cancer spermatogenic cells is thought to be due to cells of 11.59 and 15.04%. The IC50 value an increase in metabolism in the body. This was only obtained in the methanol extract causes an increase in energy for protein of 20.98 µg/mL against NCI-H187[25]. synthesis which affects the spermatogenesis process when mitotic division increases[13]. Analgesic According to findings reported by Evacuasiany et al., (2010) revealed that Rahmawati and Bachri (2012), an infusion the ethanol extract of Javanese long pepper that contained combination of Piper fruit at a dose of 3 g/kg BW given to mice retrofractum at a dose of 210 mg/kg BW, orally had analgesic activity equivalent to Centella asiatica at a dose of 546 mg/kg acetosal at a dose of 0.42 g/kg BW. The BW, and Curcuma domestica at a dose of ethanol extract at doses of 0.75 g/kg BW 910 mg/kg BW gave aphrodisiac effect to and 1.5 g/kg BW also showed analgesic male rats. This infusion was orally activity but this activity was still weaker administered for 7 days simultaneously. than acetosal. The analgesic effect is The effect was indicated by sexual behavior thought to be due to decreased intensity (introduction, coitus and climbing prostaglandin synthesis so that inhibit frequency). The male rat that was given an sensitivity to pain responses[11]. infusion had higher sexual behavior intensity than control group significantly Androgenic (p<0.05). This is thought to be due to the Based on research conducted by piperine content of Javanese long Moeloek et al., (2010), the fruit extract of pepper[34]. Muslichah (2011) also reported Javanese long pepper had androgenic that the piperine content of the Javanese activity that has been tested clinically. The long pepper fruit extract at a dose of 1.6 100 mg/day extract given to several male mg/kg BW and an insoluble fraction of n- hypogondism patients for 60 days had an hexane free of piperine from javanese long androgenic effect. Its effect was indicated pepper fruit at a dose of 29.10 mg/kg BW by an increase in testosterone levels in 78% which given to male rats for 27 days orally of the total number of patients (9 patients). had an aphrodisiac effect[35]. However, the androgenic effect of the extract was categorized as weak androgenic Antihyperlipidemia because it was unable to significantly Based on research conducted by reduce follicle stimulating hormone and Mustofa et al. (2014), the ethanol extract of luteinizing hormone levels (p <0.05)[12]. 97% Javanese long pepper fruit had the potential to be an antihyperlipidemic. This was indicated by the ability of this extract

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to influence the lipid profile and histology leukocytes in Wistar rats with traumatic of the coronary arteries of male white rats ulcers. Piperine was thought to be an active (Rattus norvegicus) which were given a compound that plays a role in its activity. high-fat diet for 49 days orally. In the Piperine is known to stimulate salivary negative control group, the treatment of a flow, where an increase in salivary pH can high-fat diet in the test animals showed an affect the increase in buffer activity in increased lipid profile of total cholesterol, saliva. In addition, piperine is thought to aid Low Density Lipoprotein (LDL) and in the healing process of lesions because it triglyceride levels and significantly has antipyretic, analgesic, antifungal, and decreased High Density Lipoprotein (HDL) antibacterial properties[35]. compared to normal controls (p<0.05). In addition, a high-fat diet also causes the Antileishmanial intactness of endothelial cells and can even Bodiwala et al., (2007) reported that be found atherosclerotic plaques some extracts of Javanese long pepper stem accompanied by thickening of the aortic had antileishmanial activity which was wall. Meanwhile, in the treatment group tested in vitro against Leismania donovani where the test animals were given a high-fat promastigotes. The IC50 values of acetone, diet along with the extract at a dose of 40 ethyl acetate, n-hexane, and methanol mg/kg BW showed a decrease in total extracts were 3.5; 45; 5; 7.5 µg/mL. In this cholesterol, LDL and triglyceride levels as study also obtained 3 isolates from the well as a significant increase in HDL levels extract of n-hexane and methanol. The compared to negative controls (p<0.05). In results of the isolation showed that the n- the histology of the coronary arteries, it hexane extract contained sesamin and showed that the endothelial cells were intact pellitorin. While the methanol extract but not atherosclerotic plaques are formed contained piplartine. Further testing of the on the walls of the blood vessels[14]. isolates showed that only piplartine was known to be active and gave an IC50 value Antihyperuricemia of 7.5 µM. Antileishmanial was also carried Fitriani et al. (2018), tested the out in vivo using infected hamsters by antihyperuricemia activity of herbal observing the amastigotes of Leismania combination containing Javanese long donovani. Piplartine at a dose of 30 mg/kg pepper fruit, broadleaf plantain (Plantago BW given intra-peritoneally for 10 days major), and (Apium graveolens). significantly reduced the spleen parasitic Administration of this combination at a burden and spleen weight (P <0.05)[16]. dose of 2 g/kg BW to male white rats for 7 days orally, were able to reduce uric acid Immunostimulants levels. Flavonoids were thought to be According to the findings reported by responsible for this activity[15]. In addition, Roseno et al. (2019), it is known that the this study also reported that giving these ethanol extract of Javanese long pepper fruit at doses of 2, 3, 4, and 5 g/kg BW had at a dose of 280 mg/kg BW given to test no effect on kidney function and liver animals orally for 6 days has function tested on white rats for 14 days[36]. immunomodulatory activity as an immunostimulant. In this case, the Decreased Number of Leukocytes immunostimulant activity of Piper A research by Nurhidayah et al., (2019) retrofractum extract had a higher revealed that the methanol extract of phagocytosis index value compared to the Javanese long pepper fruit with a comparison group of phytopharmaca concentration of 100% given topically was immunostimulants of 1.5x; and able to effective in reducing the number of increase peripheral blood neutrophil levels

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which play an important role in the process Characteristics and Antioxidant of phagocytosis[36]. Capacities of Hihatsumodoki (Piper retrofractum Vahl.) Fresh Fruit at CONCLUSION Three Edible Maturity Stages. J Food Based on the results of phytochemical Sci Technol. 2018; 55(4): 1295–1305. studies, the Javanese long pepper plant 3. Sudarmaji L, Hayati A, dan Rahayu T. (Piper retrofractum Vahl.) contains Studi Etnobotani Tanaman Cabe Jamu phytochemical compounds of alkaloids, (Piper retrofractum Vahl.) Di Desa flavonoids, essential oils, saponins, Gapura Timur Kecamatan Gapura terpenoids, tannins, quinones, Kabupaten Sumenep. e-Jurnal Ilmiah steroids/triterpenoids, lignans and amides. Biosaintropis (Bioscience-Tropic). Javanese long pepper has also been shown 2019; 4: 26-32. to have pharmacological effects either 4. Haryudin W, dan Rostiana O. Stabilitas through in vitro, in vivo, or clinical studies. Karakter Morfologi 10 Aksesi Cabe Activities that have been tested in vitro Jawa (Piper retrofractum Vahl.) di were antimicrobial, antioxidant, and Kebun Percobaan Cikampek. Bul. cytotoxic; activities that have been tested in Littro. 2011; 22(1): 13-22. vivo are analgesic, aphrodisiac, 5. Boangmanalu RK, dan Zuhrotun A. antihyperlipidemic, anti-hyperuricemia, Review Artikel: Potensi Khasiat Obat and decreased leukocyte count; The activity Tanaman Marga Piper: Piper nigrum which has been tested in vitro and in vivo L., Piper retrofractum Vahl., Piper was antileishmanial; The activity that has betle Linn., L. dan Piper been clinically tested was androgenic. crocatum Ruiz & Pav. Farmaka. 2018; These activities are inseparable from the 16(3): 204-212. chemical content in the Javanese long 6. Haryudin W, dan Rostiana O. pepper. Karateristik Morfologi Tanaman Cabe Jawa (Piper retrofractum Vahl.) di CONFLICT OF INTEREST Beberapa Sentra Produksi. Bul. Littro. In the preparation of this article, there 2009; 20(1): 1-10. is no conflict or interest. This article is 7. Chaveerach A, Mokkamul P, Sudmoon written independently without the R, and Tanee T. Ethnobotany of the involvement of other parties who could Genus Piper (Piperaceae) in Thailand. improperly influence this article. Ethnobotany Research & Applications. 2006; 4: 223-231. ACKNOWLEDGEMENT 8. Jamal Y, Irawati P, Fathoni A, and Thank you to all parties, especially Agusta A. Chemical Constituents and from the Pharmacy Study Program of the Antibacterial Effect of Essential Oil of Faculty of Mathematics and Natural Javaneese Pepper Leaves (Piper Sciences, Udayana University who have retrofractum Vahl.). Media provided a lot of assistance in the process of Litbangkes. 2013; 23(2): 65-72. making this article. 9. Jadid N, Hidayati D, Hartanti SR, Arraniry BA, Rachman RY, and REFERENCES Wikanta W. Antioxidant Activities of 1. Salim Z, dan Munadi E. Info Komoditi Different Solvent Extracts of Piper Tanaman Obat. Jakarta: Badan retrofractum Vahl. using DPPH Assay. Pengkajian dan Pengembangan Proceeding of International Biology Perdagangan; 2017. Conference. 2016. 2. Takahashi M, Hirose N, Ohno S, 10. Clarasati MB, Fitrianingsih SP, dan Arakaki M, dan Wada K. Flavor Suwendar. Uji Sitotoksik Ekstrak dan

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26. Gauthier, E. Minyak Atsiri Jilid I, Lung Cancer with Reference to Lipid Penerjemah S, Ketaren. Jakarta: Peroxidation and Antioxidant System Universitas Indonesia Press; 2006. in Swiss Albino Mice. Fitoterapia. 27. Panphut W, Budsabun T, and 2003; 74: 109-115. Sangsuriya P. In Vitro Antimicrobial 34. Rahmawati N, and Bachri MS. The Activity of Piper retrofractum Fruit Aphrodisiac Effect and Toxicity of Extracts against Microbial Pathogens Combination Piper retrofractum L, Causing Infections in Human and Centella asiatica, and Curcuma Animals. International Journal of domestica Infusion. Health Science Microbiology. 2020; 1-6. Indones. 2012; 3(1): 19-22. 28. Pan X, Chen F, Wu T, Tang H, and 35. Muslichah, S. Potensi Afrodisiak Zhao Z. The Acid, Bile Tolerance, and Kandungan Aktif Buah Cabe Jawa Antimicrobial Property of (Piper retrofractum Vahl) Pada Tikus Lactobacillus acidophilus NIT. Food Jantan Galur Wistar. Jurnal Agrotek. Control. 2009; 20: 598-602. 2011; 5(2): 11-20. 29. Mulia K, Hasan AEZ, and Suryani. 36. Fitriani U, Dewi TF, dan Wijayanti. Total Phenolic, Anticancer and Analisis Fungsi Hati dan Fungsi Ginjal Antioxidant Activity of Ethanol pada Tikus Setelah Pemberian Ramuan Extract of Piper retrofractum Vahl Cabe Jawa, Daun Sendok dan Seledri. from Pamekasan and Karang Asem. Pros Sem Nas Masy Biodiv Indon. Current Biochemistry. 2016; 3(2): 80- 2019; 5(2): 263-266. 90. 30. Hasan AEZ, Suryani, Mulia K, Setiyono A, and Silip JJ. Antiproliferation Activities of Indonesian Java Chili, Piper retrofractum Vahl., Against Breast Cancer Cells (MCF-7). Der Pharmacia Lettre. 2016; 8(18): 141-147. 31. Ekowati H, Septiyaningsih, and Harwoko. An Extract of Zingiber officinale and Piper retrofractum Combination and Its Effect to Cancer Cell Line. Indonesian Journal of Cancer Chemoprevention. 2011; 2(1): 173-181. 32. Pradeep CR, and Kuttan G. Piperine is a Potent Inhibitor of Nuclear Factor-nB (NF-nB), c-Fos, CREB, ATF-2 and Proinflammatory Cytokine Gene Expression in B16F-10 Melanoma Cells. International Immunopharmacology. 2004; 4: 1795 – 1803. 33. Selvendiran K, Singh JPV, Krishnan KB, and Sakthisekaran D. Cytoprotective Effect of Piperine Against Benzowaxpyrene Induced

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