Dipeptidyl peptidase-4 inhibition of Peronema canescens Jack leaves and stems: Bioassay-guided fractionation, compound profiling by LC-MS/MS, and interaction mechanism

Berna Elya Roshamur Cahyan Forestrania Najihah Mohd Hashim Nita Triadisti   

Open Access   

Published:  May 09, 2024

DOI: 10.7324/JAPS.2024.161007

Sungkai (Peronema canescens Jack) has been used for generations as a traditional antidiabetic drug for the Borneo people, but scientific data as a dipeptidyl peptidase-4 (DPP-4) inhibitor has never been reported. This study aims to obtain the most active chromatographic fraction as a DPP-4 inhibitor and the profile of the compounds contained. Bioassay-guided fractionation was used in this study and bioassays using spectrofluorometric principles. Compound profiling is carried out using ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (UPLC-ESI-QToF-MS/MS), and molecular docking is used to investigate interactions between compounds and DPP-4. The study found that the most effective extracts were ethyl acetate and methanol extracts from the leaves, which showed inhibitory percentages of 70.0% ± 0.7233% and 59.69% ± 1.9394%, respectively, at a concentration of 100 μg/ml. The fractionation produces the most active fraction, the second fraction from P. canescens methanol extract (FPSM2 fraction), with a percent inhibition of 88.28% ± 2.1204%. The compounds contained in FPSM2 were identified through UPLC-ESI-QToF-MS/MS, including pectolinarigenin, glycitein, formononetin, latifoline, 3-oxo-alpha-ionol, moracin M, and loliolide. Assay results showed that P. canescens has been shown to have inhibitory activity against DPP-4, suggesting that this plant has excellent potential to be developed as a DPP-4 inhibitor.

Keyword:     Peronema canescens Jack dipeptidyl peptidase-4 (DPP-4) bioassay-guided fractionation UPLC-ESI-QToF-MS/MS compound profiling


Elya B, Forestrania RC, Hashim NM, Triadisti N. Dipeptidyl peptidase-4 inhibition of Peronema canescens Jack leaves and stems: Bioassay-guided fractionation, compound profiling by LC-MS/MS, and interaction mechanism. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.161007

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text


1. Widyawati T, Yusoff NA, Bello I, Asmawi MZ, Ahmad M. Bioactivity-guided fractionation and identification of antidiabetic compound of Syzygium polyanthum (Wight.)'s leaf extract in streptozotocin-induced diabetic rat model. Molecules. 2022;27(20):6814. https://doi.org/10.3390/molecules27206814

2. Manalo RAM, Arollado EC, Heralde FM. Anti-hyperglycemic fraction from Alternanthera sessilis L. leaves gets elucidated following bioassay-guided isolation and mass spectrometry. Braz J Pharm Sci. 2023;59:e21283. https://doi.org/10.1590/s2175-97902023e21283

3. Ong KL, Stafford LK, McLaughlin SA, Boyko EJ, Vollset SE, Smith AE, et al. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2023;402(10397):203-34. https://doi.org/10.1016/S0140-6736(23)01301-6

4. Boyko EJ, Esztergalyos B, Gautam S, Helman B, Pinkepank M, Randi A, et al., editors. IDF diabetes atlas, Brussels, Belgium. 10th ed. IDF; 2021. vol. 64, 665-76 pp.

5. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):1-34. https://doi.org/10.3390/ijms21176275

6. Zhou H, Liao J, Ou J, Lin J, Zheng J, Li Y, et al. Bioassay-guided isolation of Fenghuang Dancong tea constituents with α-glucosidase inhibition activities. Front Nutr. 2022;9(4):1050614. https://doi.org/10.3389/fnut.2022.1050614

7. Wu M, Yang Q, Wu Y, Ouyang J. Inhibitory effects of acorn (Quercus variabilis Blume) kernel-derived polyphenols on the activities of α-amylase, α-glucosidase, and dipeptidyl peptidase IV. Food Biosci [Internet]. 2021;43(April):101224. https://doi.org/10.1016/j.fbio.2021.101224

8. Shaikh S, Lee E, Ahmad K, Ahmad S, Lim J, Choi I. A comprehensive review and perspective on natural sources as dipeptidyl peptidase-4 inhibitors for management of diabetes. Pharmaceuticals. 2021;14(591):1-18. https://doi.org/10.3390/ph14060591

9. Chalichem NSS, Jupudi S, Yasam VR, Basavan D. Dipeptidyl peptidase-IV inhibitory action of Calebin A: an in silico and in vitro analysis. J Ayurveda Integr Med [Internet]. 2021;12(4):663-72. https://doi.org/10.1016/j.jaim.2021.08.008

10. Kato E, Uenishi Y, Inagaki Y, Kurokawa M, Kawabata J. Isolation of rugosin A, B and related compounds as dipeptidyl peptidase-IV inhibitors from rose bud extract powder. Biosci Biotechnol Biochem [Internet]. 2016;80(11):2087-92. https://doi.org/10.1080/09168451.2016.1214533

11. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of clinical endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2020 executive summary. Endocr Pract [Internet]. 2020;26(1):107-39. https://doi.org/10.4158/CS-2019-0472

12. Jao CL, Hung CC, Tung YS, Lin PY, Chen MC, Hsu KC. The development of bioactive peptides from dietary proteins as a dipeptidyl peptidase IV inhibitor for the management of type 2 diabetes. BioMedicine. 2015;5(3):9-15. https://doi.org/10.7603/s40681-015-0014-9

13. Cian RE, Nardo AE, Garzón AG, Añon MC, Drago SR. Identification and in silico study of a novel dipeptidyl peptidase IV inhibitory peptide derived from green seaweed Ulva spp. hydrolysates. Lwt. 2022;154:112738. https://doi.org/10.1016/j.lwt.2021.112738

14. Latief M, Sari PM, Fatwa LT, Tarigan IL, Rupasinghe HPV. Antidiabetic activity of Sungkai (Peronema canescens Jack) leaves ethanol extract on the male mice induced alloxan monohydrate. Pharmacol Clin Pharm Res. 2021;6(2):64-74. https://doi.org/10.15416/pcpr.v6i2.31666

15. Triadisti N, Sauriasari R, Elya B. Antioxidant activity of fractions from Garcinia hombroniana Pierre leaves extracts. Pharmacogn J. 2018;10(4):682-5. https://doi.org/10.5530/pj.2018.4.112

16. Cayman Chemical Company. DPP (IV) inhibitor screening assay Kit, Michigan, United States. Cayman Chemical Company; 2017.

17. Zhang Z, Wallace MB, Feng J, Stafford JA, Skene RJ, Shi L, et al. Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV. J Med Chem. 2011;54(2):510-24. https://doi.org/10.1021/jm101016w

18. Bitencourt-Ferreira G, de Azevedo WF. Docking screens for drug discovery. 1st ed. In: de Azevedo WF, editor. Molegro Virtual Docker for Docking. Molegro Virtual Docker for Docking. New York, NY: Humana New York NY; 2019. vol. XVII, 286 p. https://doi.org/10.1007/978-1-4939-9752-7_10

19. Maigoda T, Judiono J, Purkon DB, Haerussana ANEM, Mulyo GPE. Evaluation of Peronema canescens leaves extract: fourier transform infrared analysis, total phenolic and flavonoid content, antioxidant capacity, and radical scavenger activity. Open Access Maced J Med Sci. 2022;10(A):117-24. https://doi.org/10.3889/oamjms.2022.8221

20. Dillasamola D, Aldi Y, Wahyuni FS, Rita RS, Dachriyanus, Umar S, et al. Study of Sungkai (Peronema canescens, Jack) leaf extract activity as an immunostimulators with in vivo and in vitro methods. Pharmacogn J. 2021;13(6):1397-407. https://doi.org/10.5530/pj.2021.13.177

21. Sarian MN, Ahmed QU, Mat So'Ad SZ, Alhassan AM, Murugesu S, Perumal V, et al. Antioxidant and antidiabetic effects of flavonoids: a structure-activity relationship based study. Biomed Res Int. 2017;2017:1-14. https://doi.org/10.1155/2017/8386065

22. Tran N, Pham B, Le L. Bioactive compounds in anti-diabetic plants : from herbal medicine to modern drug discovery. Biology (Basel). 2020;9(252):1-31. https://doi.org/10.3390/biology9090252

23. Salleh NH, Zulkipli IN, Yasin HM, Ja F, Ahmad N, Amir W, et al. Systematic review of medicinal plants used for treatment of diabetes in human clinical trials : an ASEAN perspective. Hindawi-Evid Based Complement Altern Med. 2021;2021(Article ID 5570939):1-10. https://doi.org/10.1155/2021/5570939

24. Triadisti N, Rahayu S, Zamzani I. Metabolite profiling of Ficus deltoidea's most active fraction as anti-Candida albicans using UPLC-QToF-MS/MS. J Young Pharm. 2021;13(1):58-62. https://doi.org/10.5530/jyp.2021.13.13

25. Mahayasih PGMW, Elya B, Hanafi M. Alpha-glucosidase inhibitory activity of Garcinia lateriflora Blume leaves. J Appl Pharm Sci. 2017;7(10):100-4.

26. Zhang S, Ma Y, Ma R, Wang Q, Dang J. Combination of medium- and high-pressure liquid chromatography for isolation of L-tryptophan (Q-marker ) from Medicago sativa extract. Separations. 2022;9(9):1-11. https://doi.org/10.3390/separations10010001

27. Nikoletta. A short notes on column chromatography. J Chromatogr Res [Internet]. 2021;4(1):1. Available from: https://www.scitechnol.com/peer-review/a-short-notes-on-column--chromatography-vUfW.php?article_id=18544

28. Wolfender JL, Marti G, Thomas A, Bertrand S. Current approaches and challenges for the metabolite profiling of complex natural extracts. J Chromatogr A. 2015;1382(February 2015):136-64. https://doi.org/10.1016/j.chroma.2014.10.091

29. Grata E, Guillarme D, Glauser G, Boccard J, Carrupt PA, Veuthey JL, et al. Metabolite profiling of plant extracts by ultra-high-pressure liquid chromatography at elevated temperature coupled to time-of-flight mass spectrometry. J Chromatogr A. 2009;1216(30):5660-8. https://doi.org/10.1016/j.chroma.2009.05.069

30. Li SL, Song JZ, Choi FFK, Qiao CF, Zhou Y, Han QB, et al. Chemical profiling of radix paeoniae evaluated by ultra-performance liquid chromatography/photo-diode-array/quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal. 2009;49(2):253-66. https://doi.org/10.1016/j.jpba.2008.11.007

31. Kury?owicz A. The role of isoflavones in type 2 diabetes prevention and treatment-a narrative review. Int J Mol Sci. 2021;22(1):1-31. https://doi.org/10.3390/ijms22010218

32. Ahmed QU, Ali AHM, Mukhtar S, Alsharif MA, Parveen H, Sabere ASM, et al. Medicinal potential of isoflavonoids: polyphenols that may cure diabetes. Molecules. 2020;25(23):1-19. https://doi.org/10.3390/molecules25235491

33. Pan J, Zhang Q, Zhang C, Yang W, Liu H, Lv Z, et al. Inhibition of dipeptidyl peptidase-4 by flavonoids: structure-activity relationship, kinetics and interaction mechanism. Front Nutr. 2022;9(May):1-17. https://doi.org/10.3389/fnut.2022.892426

34. Sewidan N, Khalaf RA, Mohammad H, Hammad W. In-vitro studies on selected Jordanian plants as dipeptidyl peptidase-IV inhibitors for management of diabetes mellitus. Iran J Pharm Res. 2020;19(4):95-102.

35. Kwon RH, Thaku N, Timalsina B, Park SE, Choi JS, Jung HA. Inhibition mechanism of components isolated from Morus alba branches on diabetes and diabetic complications via experimental and molecular docking analyses. Antioxidants. 2022;11(2):1-22. https://doi.org/10.3390/antiox11020383

36. Zhang M, Chen M, Zhang HQ, Sun S, Xia B, Wu FH. In vivo hypoglycemic effects of phenolics from the root bark of Morus alba. Fitoterapia [Internet]. 2009;80(8):475-7. https://doi.org/10.1016/j.fitote.2009.06.009

37. Jung M, Park M, Lee H, Kang YH, Kang E, Kim S. Antidiabetic agents from medicinal plants. Curr Med Chem. 2006;13(10):1203-18. https://doi.org/10.2174/092986706776360860

38. Grabarczyk M, Wi?ska K, M?czka W, Potaniec B, Anio? M. Loliolide-the most ubiquitous lactone. Folia Biol Oecol. 2015;11:1-8. https://doi.org/10.1515/fobio-2015-0001

39. Song JH, Lee D, Lee SR, Yu JS, Jang TS, Nam JW, et al. Identification of bioactive heterocyclic compounds from mulberry and their protective effect against streptozotocin-induced apoptosis in INS-1 cells. Mol Med Rep. 2018;17(4):5982-7. https://doi.org/10.3892/mmr.2018.8582

40. Thissera B, Visvanathan R, Khanfar MA, Qader MM, Hassan MHA, Hassan HM, et al. Sesbania grandiflora L. Poir leaves: a dietary supplement to alleviate type 2 diabetes through metabolic enzymes inhibition. S Afr J Bot [Internet]. 2020;130(February):282-99. https://doi.org/10.1016/j.sajb.2020.01.011

41. Sharma D, Kumar S, Kumar S, Kumar D. DPP-IV inhibitors from natural sources: an alternative approach for treatment and management of diabetes. Indian J Nat Prod Resour. 2019;10(4):227-37.

42. Beidokhti MN, Lobbens ES, Rasoavaivo P, Staerk D, Jäger AK. Investigation of medicinal plants from Madagascar against DPP-IV linked to type 2 diabetes. S Afr J Bot [Internet]. 2018;115:113-9. https://doi.org/10.1016/j.sajb.2018.01.018

43. Akhtar N, Jafri L, Green BD, Kalsoom S, Mirza B. A multi-mode bioactive agent isolated from Ficus microcarpa L. Fill. With therapeutic potential for type 2 diabetes mellitus. Front Pharmacol. 2018;9(NOV):1-12. https://doi.org/10.3389/fphar.2018.01376

44. Gu L, Tian T, Xia L, Chou G, Wang Z. Rapid isolation of a dipeptidyl peptidase IV inhibitor from Fritillaria cirrhosa by thin-layer chromatography-bioautography and mass spectrometry-directed autopurification system. J Planar Chromatogr-Mod TLC. 2019;32(6):447-51. https://doi.org/10.1556/1006.2019.32.6.1

45. Morikawa T, Ninomiya K, Akaki J, Kakihara N, Kuramoto H, Matsumoto Y, et al. Dipeptidyl peptidase-IV inhibitory activity of dimeric dihydrochalcone glycosides from flowers of Helichrysum arenarium. J Nat Med. 2015;69(4):494-506. https://doi.org/10.1007/s11418-015-0914-8

Article Metrics
54 Views 14 Downloads 68 Total



Similar Articles

Related Search

By author names