Activity and potential of Phyllantus niruri L. and Phyllantus urinaria L. as Hepatitis B virus inhibitors: A narrative review of the SANRA protocol

Year 2024, Volume: 28 Issue: 1, 335 - 350, 28.06.2025

I Made Dwi Mertha Adnyana , Budi Utomo Shifa Fauziyah Dwinka Syafira Eljatin Muhamad Frendy Setyawan Lesty Helda Marsel Sumah Citra Al Karina

Abstract

Terna plants are used by Indonesians as raw materials for herbal and traditional medicine, including Phyllantus niruri L. and Phyllantus urinaria L. Therefore, this study aimed to explore, analyze and compile the activities and potential of Phyllantus niruri L. and Phyllantus urinaria L. as agents of hepatitis B virus (HBV) inhibitors using a narrative review approach. It was conducted based on the Scale for the Assessment of Narrative Review Articles (SANRA) by establishing inclusion and exclusion criteria. The study selected and reviewed 15 out of 38 articles. The Phyllantus genus is a group of seasonal herbs containing bioactive compounds and activity as HBV Inhibitors. In this study, 23 compounds were identified in the two species, including Nirtetralin, Phyllanthin, Niranthin, Hinokinin, Ellagic acid, Ethanol, Phyllanthosterol, Ethyl brevifolincarboxylate, Tenofovir, Quercetin, Quercitrin, Astragalin, Repanducinic acid, Corilagin, Gallic acid, Aloe-emodin-8-O-β-D-glucopyranoside, Catechin, D-glucopyranoside, Ethyl gallate, Protocatequatic acid, Chebulanin, Albibrissinoside B, and (-)-Epicatechin. Meanwhile, the activity in inhibiting cells infected with HBV was reported in vitro, in vivo, ex vivo, and in silico. The mechanism of bioactive compounds as HBV inhibitors focuses on suppression, blocking, and inhibiting the synthesis, secretion, and expression of HBsAg, HBcAg, and HbeAg in test media. The results showed that Meniran red and green bioactive compounds have the potential to be developed as raw materials as herbal medicine with promising prospects as commercial drug candidates.

Keywords

Anti hepatitis B Virus , meniran , medicinal plants , therapeutic agents , traditional medicine

References

• [1] Li C, Bi X. Clinical characteristics of hepatitis in pregnancy in pregnant women with chronic hepatitis B virus infection and evaluation of the efficacy of antiviral therpy. Indian J Pharm Sci. 2021;83(3):180–185. http://dx.doi.org/10.36468/pharmaceutical-sciences.spl.273
• [2] Siswanto. Epidemiologi Penyakit Hepatitis. 1st ed. Samarinda: Mulawarman University Press; 2020. pp.74. https://repository.unmul.ac.id/bitstream/handle/123456789/6028/BukuSisHepatitis%28Edited%29.pdf?sequence=1&isAllowed=y .
• [3] Kementerian Kesehatan Republik Indonesia. Profil Kesehatan Indonesia 2021. Jakarta; 2022.
• [4] Nazarian Z, Rafieian M. Effective medicinal plants in treating Hepatitis B. Int J Pharm Sci Res. 2018;2(9):3589–3596. https://doi.org/10.13040/IJPSR.0975-8232.9(9).3589-96
• [5] Basavaraju M. Phyllanthus Niruri L. A Holistic Medicinal Plant with Modern Therapeutics. 1st ed. Medicinal Plants. Bangalore, India: Scientist R Academy; 2022.
• [6] Firdayani, Riswoko A, Helianti I. Inhibition of SARS-Cov-2 proteases by medicinal plant bioactive constituents: Molecular docking simulation. In: IOP Conference Series: Earth and Environmental Science. 2022. p. 012054. https://doi.org/10.1088/1755-1315/976/1/012054
• [7] WHO. Guidelines on good herbal processing practices for herbal medicines. 50. Expert Committee on Specifications for Pharmaceutical Preparations; 2018. Pp. 81–152. https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/production/trs1010-annex1-herbal-processing.pdf?sfvrsn=80b60ae5_0.
• [8] Sen S, Chakraborty R. Herbal medicine in India: Indigenous knowledge, practice, innovation and its value. Herbal Medicine in India: Indigenous Knowledge, Practice, Innovation and its Value. 2019. Pp.1–620. https://doi.org/10.1007/978-981-13-7248-3.
• [9] Adnyana IMDM, Sudaryati NLG, Sitepu I. Toxicity of Legiayu incense as insecticide and larvicide against Aedes aegypti mosquitoes mortality. Indones J Pharm. 2021;32(4):524–521. https://doi.org/10.22146/ijp.1814
• [10] Muderawan IM, Budiawan IM, Giri MKW, Atmaja INB. Usada: The Ethnomedicine of Balinese Society. Int J Ayurvedic Herbal Med. 2020;10(6):3893–3905. https://doi.org/10.31142/ijahm/v10i6.04.
• [11] Abuga I, Sulaiman SF, Abdul Wahab R, Ooi KL, Abdull Rasad MSB. Phytochemical constituents and antibacterial activities of 45 Malay traditional medicinal plants. J Herb Med. 2022;32(July 2021):100496. https://doi.org/10.1016/j.hermed.2021.100496
• [12] Geethangili M, Ding ST. A review of the phytochemistry and pharmacology of Phyllanthus urinaria L. Front Pharmacol. 2018;9(1109):1–20. https://doi.org/10.3389/fphar.2018.01109
• [13] Adnyana IMDM, Sumarya IM, Sudaryati NLG. Efficacy and toxicity of Parasayu incense ash as a larvicide for the eradication of Aedes aegypti (Diptera: Culicidae) mosquito larvae. J Res Pharm. 2022;26(6):1805–1813. http://dx.doi.org/10.29228/jrp.271.
• [14] Hasan, Kurniawan A, Moh.Padri, Asnawati F, Ulfah AAN, Zain IA, Sari intan ariesta p, Azis dwi yuliana, Akhmad W, Indriani S, Wahyuni AR. Atlas Tumbuhan Sulawesi Selatan. 1st ed. Makassar: Program Studi Biologi, Jurusan Biologi Fakultas Matematika Dan Ilmu Pengetahuan Alam Universitas Negeri Makassar; 2014. Pp.141–142. http://eprints.unm.ac.id/17603/1/Buku%20atlas%20vegetasi%20pattunuang.pdf.
• [15] Kuttan R, Harikumar KB. Phyllanthus species: scientific evaluation and medicinal applications. 1st ed. United States: CRC Press; 2011. https://doi.org/10.1201/b11380.
• [16] Nisar MF, He J, Ahmed A, Yang Y, Li M, Wan C. Chemical components and biological activities of the genus Phyllanthus: A review of the recent literature. Molecules. 2018;23:2567. https://doi.org/10.3390/molecules23102567
• [17] Sarma K, Borkakoty B, Parida P, Jakharia A, Dey D, Biswas D, Panda D, K. Modi M, K. Mohapatra P, Mahanta J. In Silico identification of natural lead molecules from the genus of Phyllanthus against Hepatitis B Virus reverse transcriptase. Nat Prod J. 2016;6(4):292–304. http://dx.doi.org/10.2174/2210315506666160822095818
• [18] Moharana M, Pattanayak SK, Khan F. Computational efforts to identify natural occurring compounds from Phyllanthus niruri that target hepatitis B viral infections : DFT, docking and dynamics simulation study. J Indian Chem Soc. 2022;99(9):100662. https://doi.org/10.1016/j.jics.2022.100662
• [19] Han N, Ye Q, Guo Z, Liang X. Metabolomics analysis of differential chemical constituents and α-glucosidase inhibiting activity of Phyllanthus urinaria L. root, stem, leaf and fruit. Nat Prod Res. 2023;37(4):642-645.https://doi.org/10.1080/14786419.2022.2069766
• [20] Arbab AH, Parvez MK, Al-Dosari MS, Al-Rehaily AJ. In vitro evaluation of novel antiviral activities of 60 medicinal plants extracts against hepatitis B virus. Exp Ther Med. 2017;14(1):626–634. https://doi.org/10.3892/etm.2017.4530
• [21] Perera WPRT, Liyanage JA, Dissanayake KGC, Gunathilaka H, Weerakoon WMTDN, Wanigasekara DN, Fernando WSK, Rajapaksha RMH, Liyanage RP, Perera BT. Antiviral potential of selected medicinal herbs and their isolated natural products. Biomed Res Int. 2021;2021:7872406. https://doi.org/10.1155/2021/7872406
• [22] Wu Y, Lu Y, Li S yu, Song Y han, Hao Y, Wang Q. Extract from Phyllanthus urinaria L. inhibits hepatitis B virus replication and expression in hepatitis B virus transfection model in vitro. Chin J Integr Med. 2015;21(12):938–943. https://doi.org/10.1007/s11655-015-2076-7
• [23] Chen Y, Zhu J. Anti-HBV effect of individual traditional Chinese herbal medicine in vitro and in vivo: An analytic review. J Viral Hepat. 2013;20(7):445–452. https://doi.org/10.1111/jvh.12112
• [24] Liu X, Ma C, Liu Z, Kang W. Natural products: Review for their effects of Anti-HBV. Biomed Res Int. 2020;2020:3972390. https://doi.org/10.1155/2020/3972390
• [25] Siddiqui MH, Alamri SA, Al-Whaibi MH, Hussain Z, Ali HM, El-Zaidy ME. A mini-review of anti-hepatitis B virus activity of medicinal plants. Biotechnol Biotechnol Equip. 2017;31(1):9–15. https://doi.org/10.1080/13102818.2016.1240593
• [26] Xia Y, Luo H, Liu JP, Gluud C. Phyllanthus species for chronic hepatitis B virus infection. Cochrane Database of Syst Rev. 2011; 2011;(4):CD008960. https://doi.org/10.1002/14651858.CD008960.pub2
• [27] Kothari S, Gohil D, Sangar V, Patil M, Sasibhushan V, Chowdhary A. In-Vitro evaluation of the anti-Hepatitis (HBV) and hepato-protective activity of herbal extracts. Int J Pharm Sci Rev Res. 2014;24(1):96–100. https://globalresearchonline.net/journalcontents/v24-1/17.pdf.
• [28] Ahmad I, Mun’im A, Luliana S, Elya B, Azminah A, Yanuar A, Artha Y, Negishi O. Isolation, elucidation, and molecular docking studies of active compounds from Phyllanthus niruri with angiotensin-converting enzyme inhibition. Pharmacogn Mag. 2018;14(58):604. https://dx.doi.org/10.4103/pm.pm_151_18
• [29] Ezzat MI, Okba MM, Ahmed SH, El-Banna HA, Prince A, Mohamed SO, Ezzat SM. In-depth hepatoprotective mechanistic study of Phyllanthus niruri: In vitro and in vivo studies and its chemical characterization. PLoS One. 2020;15(1):e0226185. https://doi.org/10.1371/journal.pone.0226185
• [30] Shin MS, Kang EH, Lee YI. A flavonoid from medicinal plants blocks hepatitis B virus-e antigen secretion in HBV-infected hepatocytes. Antiviral Res. 2005;67(3):163–168. https://doi.org/10.1016/j.antiviral.2005.06.005
• [31] Firdayani, Kusumaningrum S, Miranti YR. Potency of plant bioactive compounds from the genus Phyllanthus as Hepatitis B Virus replication inhibitor. J Bioteknol Biosains Indones (JBBI). 2017;4(2):85. https://doi.org/10.29122/jbbi.v4i2.2589
• [32] Sabdoningrum EK, Hidanah S, Chusniati S, Soeharsono. Characterization and phytochemical screening of meniran (Phyllanthus niruri Linn) extract’s nanoparticles used ball mill method. Pharmacogn J. 2021;13(6):1568–1572. 10.5530/pj.2021.13.200
• [33] ITIS. Genus Phyllanthus [Internet]. Integrated Taxonomic Information System (ITIS). 2022 [cited 2022 Jul 15]. Available from: https://www.itis.gov/servlet/SingleRpt/SingleRpt
• [34] Handayani V, Nurfadillah N. Pharmacognostic study of green meniran herb (Phyllanthus niruri L.) and red meniran herb (Phyllanthus urinaria L.). J Fitofarmaka Indones. 2016;1(1):18–23. https://doi.org/10.33096/jffi.v1i1.196
• [35] Paithankar VV, Raut KS, Charde RM, Vyas VJ. Phyllanthus niruri: A magic Herb. Res Pharm. 2011;1(4):1–9. https://updatepublishing.com/journal/index.php/rip/article/view/215.
• [36] Aldi Y, Novelin F, Handayani D. Activity of multiple subfractions of Meniran Herb (Phyllanthus niruri Linn.) on phagocytosis activity and capacity of macrophages. Scientia: J Pharm Health. 2015;5(2):92. https://doi.org/10.36434/scientia.v5i2.28 .
• [37] Kardinan A. Tanaman Penghasil Minyak Atsiri (In English: Essential oil-producing plants). Agromedia Pustaka, Jakarta; 2013.
• [38] Salsabila S, Hartati R, al Muqarrabun LMR, Qomaladewi NP, Haniffadli A, Rosandy AR, Chahyadi A, Elfahmi E. Isolation of bioactive compounds with tyrosinase inhibitory activity from the methanol extract of meniran herb (Phyllanthus niruri Linn.). Curr Res Biosci Biotechnol. 2022;3(2):196–201. https://doi.org/10.5614/crbb.2022.3.2/GOO6ZULV
• [39] Kamruzzaman HM, Hoq MO. A review on ethnomedicinal, phytochemical and pharmacological properties of Phyllanthus niruri. J Med Plants Stud. 2016;4(6):173–180.
• [40] Du G, Xiao M, Yu S, Wang M, Xie Y, Sang S. Phyllanthus urinaria: A potential phytopharmacological source of natural medicine. Int J Clin Exp Med. 2018;11(7):6509–6520.
• [41] Maheshika Dahanayake J, Kamal Perera P, Galappaththy P, Arawwawala M. A mini-review on therapeutic potentials of Phyllanthus niruri Linn. Trends Phytochem Res. 2020;4(3):2020–2101.
• [42] Kumar B, Kumar S, Madhusudanan KP. Phytochemistry of Plants of Genus Phyllanthus. First edit. Phytochemistry of Plants of Genus Phyllanthus. United States: CRC Press, Taylor & Francis Group, LLC; 2020. https://doi.org/10.1201/9781003014867
• [43] Adnyana IMDM, Sudaryati NLG. Phytochemical analysis of the antioxidant compounds of Baper tea and its potential as an immunomodulatory agent and candidate for standardized herbal medicine. Trends Sci. 2023;20(1):6391. https://doi.org/10.48048/tis.2023.6391
• [44] PubChem. PubChem Compound database [Internet]. National Library of Medicine (NLM) -National Center for Biotechnology Information (NCBI. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/#query=phyllanthus urinaria&tab=substance
• [45] Wei W, Li X, Wang K, Zheng Z, Zhou M. Lignans with anti-hepatitis B virus activities from Phyllanthus niruri L. Phytother Res. 2012;26(7):964–968. https://doi.org/10.1002/ptr.3663
• [46] Liu S, Wei W, Shi K, Cao X, Zhou M, Liu Z. In vitro and in vivo anti-hepatitis B virus activities of the lignan niranthin isolated from Phyllanthus niruri L. J Ethnopharmacol. 2014;155(2):1061–1067. https://doi.org/10.1016/j.jep.2014.05.064
• [47] Tong GD, Zhang X, Zhou DQ, Wei CS, He JS, Xiao CL, Liu XL, Zheng YJ, Chen SN, Tang HH. Efficacy of early treatment on 52 patients with preneoplastic hepatitis B virus-associated hepatocellular carcinoma by compound Phyllanthus urinaria L. Chin J Integr Med. 2014;20(4):263–271. https://doi.org/10.1007/s11655-013-1320-7
• [48] Wahyuni TS, Permanasari AA, Widyawaruyanti A, Hotta H, Aoki-Utsubo C, Hafid AF. Antiviral activity of indonesian medicinal plants against hepatitis B virus. Pharmacogn J. 2020;12(5):1108–1114. http://dx.doi.org/10.5530/pj.2020.12.157.
• [49] Huang RL, Huang YL, Ou JC, Chen CC, Hsu FL, Chang C. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro. Phytother Res. 2003;17(5):449–453. https://doi.org/10.1002/ptr.1167
• [50] Li Y, Li X, Wang JK, Kuang Y, Qi MX. Anti-hepatitis B viral activity of Phyllanthus niruri L (Phyllanthaceae) in HepG2/C3A and SK-HEP-1 cells. Trop J Pharm Res. 2017;16(8):1873–1879. https://doi.org/10.4314/tjpr.v16i8.17
• [51] Mohan M, James P, Valsalan R, Nazeem P. Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA polymerase. Bioinformation. 2015;11(9):426–431. https://doi.org/10.6026/97320630011426.
• [52] Jung J, Kim NK, Park S, Shin HJ, Hwang SG, Kim K. Inhibitory effect of Phyllanthus urinaria L. extract on the replication of lamivudine-resistant hepatitis B virus in vitro. BMC Complement Altern Med. 2015;15:255. https://doi.org/10.1186/s12906-015-0792-3
• [53] Liang QP, Wu C, Xu TQ, Jiang XY, Tong GD, Wei CS, Zhou GX. Phenolic constituents with antioxidant and antiviral activities from Phyllanthus urinaria Linnea. Indian J Pharm Sci. 2019;81(3):424–430. https://doi.org/10.36468/pharmaceutical-sciences.526.
• [54] Shanmugam B, Shanmugam KR, Ravi S, Reddy KS. Exploratory studies of (-)-Epicatechin, a bioactive compound (-)-Epicatechin of Phyllanthus niruri on hepatic stress markers and lipid metabolic profiles in D-galactosamine induced hepatitis in aged rats. Pharmacogn Mag. 2017;13(Suppl 1):S56-S62. https://doi.org/10.4103/0973-1296.203973.
• [55] Liu S, Wei W, Li Y, Lin X, Shi K, Cao X, Zhou M. In vitro and in vivo anti-hepatitis B virus activities of the lignan nirtetralin B isolated from Phyllanthus niruri L. J Ethnopharmacol. 2014;157:62–68. https://doi.org/10.1016/j.jep.2014.09.019
• [56] Huang D, Yang B, Yao Y, Liao M, Zhang Y, Zeng Y, Zhang F, Wang N, Tong G. Autophagic inhibition of caveolin-1 by compound Phyllanthus urinaria L. activates ubiquitination and proteasome degradation of β-catenin to suppress metastasis of Hepatitis B-associated hepatocellular carcinoma. Front Pharmacol. 2021;12:659325. https://doi.org/10.3389/fphar.2021.659325
• [57] Li Y, Jiang M, Li M, Chen Y, Wei C, Peng L, Liu X, Liu Z, Tong G, Zhou D, He J. Compound Phyllanthus urinaria L inhibits HBV-related HCC through HBx-SHH pathway axis inactivation. Evid Based Complement Alternat Med. 2019;2019:1635837. https://doi.org/10.1155/2019/1635837
• [58] Siew YY, Yew HC, Neo SY, Seow SV, Lew SM, Lim SW, Lim CSES, Ng YC, Seetoh WG, Ali A, Tan CH, Koh HL. Evaluation of anti-proliferative activity of medicinal plants used in Asian traditional medicine to treat cancer. J Ethnopharmacol. 2019;235(10):75–87. https://doi.org/10.1016/j.jep.2018.12.040
• [59] Singh A, Rana S, Singh R. Wild and cultivated vegetables of the Indian Himalaya and their use as vegetables and in traditional medicine. Int J Veg Sci. 2020;26(4):385–407. https://doi.org/10.1080/19315260.2019.1638480
• [60] Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines. 2018;5(3):93. https://doi.org/10.3390/medicines5030093
• [61] Luliana S, Desnita R, Martien R, Nurrochmad A. Total flavonoid contents and in silico study of flavonoid compounds from Meniran (Phyllanthus niruri L.) toward alpha-amylase and alpha-glucosidase enzyme. Pharmaciana. 2019;9(1):1–10. http://dx.doi.org/10.12928/pharmaciana.v9i1.10416
• [62] Baethge C, Goldbeck-Wood S, Mertens S. SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:5. https://doi.org/10.1186/s41073-019-0064-8
• [63] Darwin M, Mamondol MR, Sormin SA, Nurhayati Y, Tambunan H, Sylvia D, Adnyana IMDM, Prasetiyo B, Vianitati P, Gebang AA. Quantitative approach research method. 1st ed. Tambunan TS, editor. Bandung: CV Media Sains Indonesia; 2021. Pp.192.