The Phytochemistry profile of Piper betle extract and its Activity Against Hepatitis C Virus
Keywords:
Hepatitis C Virus, Piper betle, Medicinal plants, Simeprevir, Ribavirin, Medicine.
Abstract
Hepatitis C virus (HCV) is an RNA virus that is easy to mutate and high risk of resistance. The vaccine for HCV has not been provided yet, and the current treatment is very expensive. To provide alternative and complementary antiviral from plants, this study evaluated the activities of Piper betle (P. betle) against HCV and its combination with existing antiviral drugs, Ribavirin and Simeprevir. The antiviral inhibition was identified by in vitro culture using Huh7it-1 cells and JFH1a HCV. Moreover, the phytochemistry profile was also determined by Thin Layer Chromatography (TLC) and High-Performance Liquid Chromatography (HPLC). The result showed that the ethanol extract of P. betle was possess strong activity with an IC50 value of 0.08 ± 0.028 µg/mL. The mechanism of action revealed the extract dominantly inhibit in the post-entry steps. Furthermore, the combination of P. betle extract with simeprevir increased its anti-HCV activity, however, no effect was observed in the combination with ribavirin. The Western blotting analysis was shown inhibition of NS3 protein levels in a dose-dependent manner. Phytochemistry evaluation was shown for the extract containing flavonoids, polyphenols, and alkaloids. These results suggested that the ethanolic extract of P. betle could be a good candidate for the development or an alternative to anti-HCV drugs.
Keywords: Hepatitis C Virus, Piper betle, Medicinal plants, Simeprevir, Ribavirin, Medicine.
References
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Ouwerkerk-Mahadevan, S., Snoeys, J., Peeters, M., Beumont-Mauviel, M., & Simion, A. (2016). Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir. Clinical Pharmacokinetics, 55(2), 197–208. https://doi.org/10.1007/s40262-015-0314-y
Permanasari, A. A., Aoki-Utsubo, C., Wahyuni, T. S., Tumewu, L., Adianti, M., Widyawaruyanti, A., Hotta, H., & Hafid, A. F. (2021). An in vitro study of an Artocarpus heterophyllus substance as a hepatitis C antiviral and its combination with current anti-HCV drugs. BMC Complementary Medicine and Therapies, 21(1), 1–15. https://doi.org/10.1186/s12906-021-03408-w
Sabir, S. M., Zeb, A., Mahmood, M., Abbas, S. R., Ahmad, Z., & Iqbal, N. (2021). Phytochemical analysis and biological activities of ethanolic extract of Curcuma longa rhizome. Brazilian Journal of Biology, 81(3), 737–740. https://doi.org/10.1590/1519-6984.230628
Salehi, B., Zakaria, Z. A., Gyawali, R., Ibrahim, S. A., Rajkovic, J., Shinwari, Z. K., Khan, T., Sharifi-Rad, J., Ozleyen, A., Turkdonmez, E., Valussi, M., Tumer, T. B., Fidalgo, L. M., Martorell, M., & Setzer, W. N. (2019). Piper species: A comprehensive review on their phytochemistry, biological activities and applications. In Molecules (Vol. 24, Issue 7). https://doi.org/10.3390/molecules24071364
Syahidah A, Saad CR, Hassan MD, Rukayadi Y, Norazian MH, Kamarudin MS. Phytochemical analysis, identification and quan-tification of antibacterial active compounds in betel leaves, Piper betle methanolic extract. Pakistan J Biol Sci. 2017;20(2):70-81.
Tagrida, M., & Benjakul, S. (2021). Betel (: Piper betle L.) leaf ethanolic extracts dechlorophyllized using different methods: antioxidant and antibacterial activities, and application for shelf-life extension of Nile tilapia (Oreochromis niloticus) fillets. RSC Advances, 11(29), 17630–17641. https://doi.org/10.1039/d1ra02464g
Wahyuni, T. S., Permanasari, A. A., Tumewu, L., AtyWidyawaruyant, A. W., & Hafid, A. F. (2021). Qualitative and quantitative analysis of 70% ethanol extract from Ruta angustifolia for developing anti-hepatitis c agents. Pharmacognosy Journal, 13(3), 682–687. https://doi.org/10.5530/pj.2021.13.87
Yu, Y., Jing, J. F., Tong, X. K., He, P. L., Li, Y. C., Hu, Y. H., Tang, W., & Zuo, J. P. (2014). Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease. Acta Pharmacologica Sinica, 35(8), 1074–1081. https://doi.org/10.1038/aps.2014.55
Beran, R. K., & Pyle, A. M. (2008). Hepatitis C viral NS3-4A protease activity is enhanced by the NS3 helicase. J Biol Chem, 283(44), 29929-29937. doi:10.1074/jbc.M804065200
Pradat, Pierre, Virlogeux, Victor, Gagnieu, Marie-Claude, Zoulim, Fabien, & Bailly, François. (2014). Ribavirin at the Era of Novel Direct Antiviral Agents for the Treatment of Hepatitis C Virus Infection: Relevance of Pharmacological Monitoring. Advances in Hepatology, 2014, 493087. doi:10.1155/2014/493087
Susiloningrum, D., Permanasari, A. A., Adianti, M., Tumewu, L., Wahyuni, T. S., Tanjung, M., . . . Hafid, A. F. (2020). The alkaloid fraction from Melicope latifolia leaves inhibits hepatitis C Virus. Pharmacognosy Journal, 12(3), 535-540. doi:10.5530/pj.2020.12.81
Wahyuni, T. S., Permatasari, A. A., Widiandani, T., Fuad, A., Widyawaruyanti, A., Aoki-Utsubo, C., & Hotta, H. (2018). Antiviral activities of Curcuma genus against hepatitis C virus. Nat Prod Commun, 13(12), 1579-1582. doi:10.1177/1934578x1801301204
Wahyuni, T. S., Utsubo, C. A., & Hotta, H. (2016). Promising Anti-Hepatitis C Virus Compounds from Natural Resources. Nat Prod Commun, 11(8), 1193-1200. https://pubmed.ncbi.nlm.nih.gov/30725589/
Wahyuni, T. S., Permanasari, A. A., Widyawaruyanti, A., Hafid, A. F., Fuchino, H., Kawahara, N., & Hotta, H. (2020). Enhancement of anti-hepatitis c virus activity by the combination of chalepin from ruta angustifolia and current antiviral drugs [Article]. Southeast Asian Journal of Tropical Medicine and Public Health, 51(1), 18-25. https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107797013&partnerID=40&md5=c2bb2b1a440609336be64b9a474c0a6c
Wahyuni, T. S., Permatasari, A. A., Widiandani, T., Fuad, A., Widyawaruyanti, A., Aoki-Utsubo, C., & Hotta, H. (2018). Antiviral activities of curcuma genus against hepatitis C virus [Article]. Nat Prod Commun, 13(12), 1579-1582. https://doi.org/10.1177/1934578x1801301204
Wahyuni, T. S., Tumewu, L., Permanasari, A. A., Apriani, E., Adianti, M., Rahman, A., Widyawaruyanti, A., Lusida, M. I., Fuad, A., Soetjipto, Nasronudin, Fuchino, H., Kawahara, N., Shoji, I., Deng, L., Aoki, C., & Hotta, H. (2013). Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus. Virol J, 10, 259. https://doi.org/10.1186/1743-422x-10-259
Widyawaruyanti, A., Tanjung, M., Permanasari, A. A., Saputri, R., Tumewu, L., Adianti, M., Aoki-Utsubo, C., Hotta, H., Hafid, A. F., & Wahyuni, T. S. (2021). Alkaloid and benzopyran compounds of Melicope latifolia fruit exhibit anti-hepatitis C virus activities [Article]. BMC Complementary Medicine and Therapies, 21(1), Article 27. https://doi.org/10.1186/s12906-021-03202-8
Beran, R. K., & Pyle, A. M. (2008). Hepatitis C viral NS3-4A protease activity is enhanced by the NS3 helicase. J Biol Chem, 283(44), 29929-29937. https://doi.org/10.1074/jbc.M804065200
Bhalerao, S. A., Verma, D. R., Gavankar, R. V., Teli, N. C., Rane, Y. Y., Didwana, V. S., & Trikannad, A. A. (2013). Phytochemistry, Pharmacological Profile and Therapeutic Uses of Piper Betle Linn.â An Overview. Journal of Pharmacognosy and Phytochemistry, 1, 10-19. https://www.rroij.com/open-access/phytochemistry-pharmacological-profile-and-therapeutic-uses-of-piper-betle-linn--an-overview-.php?aid=34176
Chaudhari, R., Fouda, S., Sainu, A., & Pappachan, J. M. (2021). Metabolic complications of hepatitis C virus infection. World Journal of Gastroenterology, 27(13), 1267–1282. https://doi.org/10.3748/wjg.v27.i13.1267
Feld, J. J., Jacobson, I. M., Sulkowski, M. S., Poordad, F., Tatsch, F., & Pawlotsky, J. M. (2017). Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. Liver International, 37(1), 5–18. https://doi.org/10.1111/liv.13212
Halake, K., & Lee, J. (2017). Functional hyaluronic acid conjugates based on natural polyphenols exhibit antioxidant, adhesive, gelation, and self-healing properties. Journal of Industrial and Engineering Chemistry, 54(April 2017), 44–51. https://doi.org/10.1016/j.jiec.2017.04.018
Izquierdo, L., Helle, F., François, C., Castelain, S., Duverlie, G., & Brochot, E. (2014). Simeprevir for the treatment of hepatitis C virus infection. Pharmacogenomics and Personalized Medicine, 7(1), 241–249. https://doi.org/10.2147/PGPM.S52715
Kanda, T., Nakamoto, S., Wu, S., & Yokosuka, O. (2014). New treatments for genotype 1 chronic hepatitis C - focus on simeprevir. Therapeutics and Clinical Risk Management, 10(1), 387–394. https://doi.org/10.2147/TCRM.S50170
Kausar, S., Said Khan, F., Ishaq Mujeeb Ur Rehman, M., Akram, M., Riaz, M., Rasool, G., Hamid Khan, A., Saleem, I., Shamim, S., & Malik, A. (2021). A review: Mechanism of action of antiviral drugs. International Journal of Immunopathology and Pharmacology, 35. https://doi.org/10.1177/20587384211002621
Kumar, A., Hossain, R. A., Yost, S. A., Bu, W., Wang, Y., Dearborn, A. D., Grakoui, A., Cohen, J. I., & Marcotrigiano, J. (2021). Structural insights into hepatitis C virus receptor binding and entry. Nature, 598(7881), 521–525. https://doi.org/10.1038/s41586-021-03913-5
Mejer, N., Galli, A., Ramirez, S., Fahnøe, U., Benfield, T., & Bukh, J. (2020). Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent. Virology, 540(August 2019), 132–140. https://doi.org/10.1016/j.virol.2019.09.014
Nayaka, N. M. D. M. W., Sasadara, M. M. V., Sanjaya, D. A., Yuda, P. E. S. K., Dewi, N. L. K. A. A., Cahyaningsih, E., & Hartati, R. (2021). Piper betle (L): Recent review of antibacterial and antifungal properties, safety profiles, and commercial applications. Molecules, 26(8), 1–21. https://doi.org/10.3390/molecules26082321
Ouwerkerk-Mahadevan, S., Snoeys, J., Peeters, M., Beumont-Mauviel, M., & Simion, A. (2016). Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir. Clinical Pharmacokinetics, 55(2), 197–208. https://doi.org/10.1007/s40262-015-0314-y
Permanasari, A. A., Aoki-Utsubo, C., Wahyuni, T. S., Tumewu, L., Adianti, M., Widyawaruyanti, A., Hotta, H., & Hafid, A. F. (2021). An in vitro study of an Artocarpus heterophyllus substance as a hepatitis C antiviral and its combination with current anti-HCV drugs. BMC Complementary Medicine and Therapies, 21(1), 1–15. https://doi.org/10.1186/s12906-021-03408-w
Sabir, S. M., Zeb, A., Mahmood, M., Abbas, S. R., Ahmad, Z., & Iqbal, N. (2021). Phytochemical analysis and biological activities of ethanolic extract of Curcuma longa rhizome. Brazilian Journal of Biology, 81(3), 737–740. https://doi.org/10.1590/1519-6984.230628
Salehi, B., Zakaria, Z. A., Gyawali, R., Ibrahim, S. A., Rajkovic, J., Shinwari, Z. K., Khan, T., Sharifi-Rad, J., Ozleyen, A., Turkdonmez, E., Valussi, M., Tumer, T. B., Fidalgo, L. M., Martorell, M., & Setzer, W. N. (2019). Piper species: A comprehensive review on their phytochemistry, biological activities and applications. In Molecules (Vol. 24, Issue 7). https://doi.org/10.3390/molecules24071364
Syahidah A, Saad CR, Hassan MD, Rukayadi Y, Norazian MH, Kamarudin MS. Phytochemical analysis, identification and quan-tification of antibacterial active compounds in betel leaves, Piper betle methanolic extract. Pakistan J Biol Sci. 2017;20(2):70-81.
Tagrida, M., & Benjakul, S. (2021). Betel (: Piper betle L.) leaf ethanolic extracts dechlorophyllized using different methods: antioxidant and antibacterial activities, and application for shelf-life extension of Nile tilapia (Oreochromis niloticus) fillets. RSC Advances, 11(29), 17630–17641. https://doi.org/10.1039/d1ra02464g
Wahyuni, T. S., Permanasari, A. A., Tumewu, L., AtyWidyawaruyant, A. W., & Hafid, A. F. (2021). Qualitative and quantitative analysis of 70% ethanol extract from Ruta angustifolia for developing anti-hepatitis c agents. Pharmacognosy Journal, 13(3), 682–687. https://doi.org/10.5530/pj.2021.13.87
Yu, Y., Jing, J. F., Tong, X. K., He, P. L., Li, Y. C., Hu, Y. H., Tang, W., & Zuo, J. P. (2014). Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease. Acta Pharmacologica Sinica, 35(8), 1074–1081. https://doi.org/10.1038/aps.2014.55
Beran, R. K., & Pyle, A. M. (2008). Hepatitis C viral NS3-4A protease activity is enhanced by the NS3 helicase. J Biol Chem, 283(44), 29929-29937. doi:10.1074/jbc.M804065200
Pradat, Pierre, Virlogeux, Victor, Gagnieu, Marie-Claude, Zoulim, Fabien, & Bailly, François. (2014). Ribavirin at the Era of Novel Direct Antiviral Agents for the Treatment of Hepatitis C Virus Infection: Relevance of Pharmacological Monitoring. Advances in Hepatology, 2014, 493087. doi:10.1155/2014/493087
Susiloningrum, D., Permanasari, A. A., Adianti, M., Tumewu, L., Wahyuni, T. S., Tanjung, M., . . . Hafid, A. F. (2020). The alkaloid fraction from Melicope latifolia leaves inhibits hepatitis C Virus. Pharmacognosy Journal, 12(3), 535-540. doi:10.5530/pj.2020.12.81
Wahyuni, T. S., Permatasari, A. A., Widiandani, T., Fuad, A., Widyawaruyanti, A., Aoki-Utsubo, C., & Hotta, H. (2018). Antiviral activities of Curcuma genus against hepatitis C virus. Nat Prod Commun, 13(12), 1579-1582. doi:10.1177/1934578x1801301204
Wahyuni, T. S., Utsubo, C. A., & Hotta, H. (2016). Promising Anti-Hepatitis C Virus Compounds from Natural Resources. Nat Prod Commun, 11(8), 1193-1200. https://pubmed.ncbi.nlm.nih.gov/30725589/
Wahyuni, T. S., Permanasari, A. A., Widyawaruyanti, A., Hafid, A. F., Fuchino, H., Kawahara, N., & Hotta, H. (2020). Enhancement of anti-hepatitis c virus activity by the combination of chalepin from ruta angustifolia and current antiviral drugs [Article]. Southeast Asian Journal of Tropical Medicine and Public Health, 51(1), 18-25. https://www.scopus.com/inward/record.uri?eid=2-s2.0-85107797013&partnerID=40&md5=c2bb2b1a440609336be64b9a474c0a6c
Wahyuni, T. S., Permatasari, A. A., Widiandani, T., Fuad, A., Widyawaruyanti, A., Aoki-Utsubo, C., & Hotta, H. (2018). Antiviral activities of curcuma genus against hepatitis C virus [Article]. Nat Prod Commun, 13(12), 1579-1582. https://doi.org/10.1177/1934578x1801301204
Wahyuni, T. S., Tumewu, L., Permanasari, A. A., Apriani, E., Adianti, M., Rahman, A., Widyawaruyanti, A., Lusida, M. I., Fuad, A., Soetjipto, Nasronudin, Fuchino, H., Kawahara, N., Shoji, I., Deng, L., Aoki, C., & Hotta, H. (2013). Antiviral activities of Indonesian medicinal plants in the East Java region against hepatitis C virus. Virol J, 10, 259. https://doi.org/10.1186/1743-422x-10-259
Widyawaruyanti, A., Tanjung, M., Permanasari, A. A., Saputri, R., Tumewu, L., Adianti, M., Aoki-Utsubo, C., Hotta, H., Hafid, A. F., & Wahyuni, T. S. (2021). Alkaloid and benzopyran compounds of Melicope latifolia fruit exhibit anti-hepatitis C virus activities [Article]. BMC Complementary Medicine and Therapies, 21(1), Article 27. https://doi.org/10.1186/s12906-021-03202-8
Published
2024-03-25
How to Cite
Wahyuni, T. S., Tumewu, L., Permanasari, A. A., Utsubo, C. A., Widyawaruyanti, A., & Hafid, A. F. (2024). The Phytochemistry profile of Piper betle extract and its Activity Against Hepatitis C Virus. Indonesian Journal of Pharmacy, 35(1), 74-82. https://doi.org/10.22146/ijp.7071
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Research Article
