Antidiabetic Activity of Averrhoa bilimbi L. Fruit Extracts and the Identification of Active Compounds Using LC-MS and In silico Methods
Keywords:
Antidiabetic activity, Averrhoa bilimbi L, in vitro, in silico, LC-MS
Abstract
Patients with diabetes mellitus require drugs that do not cause side effects in long-term use. In this era, many people use herbal medicine to treat diabetes mellitus. One species we can use as herbal medicine is Averrhoa bilimbi L., a plant whose fruit is known as belimbing wuluh and is used because it has value as an alternative medicine. This study aims to determine the antidiabetic activity of the active fraction of Averrhoa bilimbi L. fruit in vitro and in silico and to obtain the active compounds contained in the fruit fraction of starfruit (A. bilimbi L.) using Liquid Chromatography Mass Spectrometer (LC-MS). Sixteen organic compounds were identified using LC-MS analysis of the n-hexane fraction, which had the highest IC50 (7.03 μg/mL) antidiabetic activity compared to ethyl acetate (102.77 μg/mL) and n-butanol (181.65 μg/mL). In silico molecular docking, analysis was performed for all identified compounds to support the antidiabetic characteristics further. Computational predictions in this investigation revealed that two A. bilimbi fruit compounds with the greatest RT value, namely 2,3,4,5,6-pentaphenylbenzazocine (-16.0 kcal/mol) and Thraustochytroside A (-6.2 kcal/mol), exhibited higher binding affinity values than miglitol (-5.4 kcal /mol). This indicates that both compounds have promising futures as α-glucosidase inhibitor alternatives for treating diabetic disorders.
References
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Bhuyan, P., Ganguly, M., Baruah, I., Borgohain, G., Hazarika, J., & Sarma, S. (2022). Alpha glucosidase inhibitory properties of a few bioactive compounds isolated from black rice bran: combined in vitro and in silico evidence supporting the antidiabetic effect of black rice. RSC Advances, 12(35), 22650–22661. https://doi.org/10.1039/d2ra04228b
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Hidayatullah, A., Putra, W. E., Sustiprijatno, S., Widiastuti, D., Salma, W. O., & Heikal, M. F. (2023). Molecular Docking and Molecular Dynamics Simulation-Based Identification of Natural Inhibitors against Druggable Human Papilloma Virus Type 16 Target. Trends in Sciences, 20(4), 4891. https://doi.org/10.48048/tis.2023.4891
Jokiaho, A. J., Winchester, M., & Donovan, C. M. (2022). N-Hydroxyethyl-1-Deoxynojirimycin (Miglitol) Restores the Counterregulatory Response to Hypoglycemia Following Antecedent Hypoglycemia. Diabetes, 71(5), 1063–1072. https://doi.org/10.2337/db21-0859
Kashtoh, H., & Baek, K. H. (2022). Recent Updates on Phytoconstituent Alpha-Glucosidase Inhibitors: An Approach towards the Treatment of Type Two Diabetes. Plants, 11(20). https://doi.org/10.3390/plants11202722
Khoo, H. E., Azlan, A., Kong, K. W., & Ismail, A. (2016). Phytochemicals and Medicinal Properties of Indigenous Tropical Fruits with Potential for Commercial Development. Evidence-Based Complementary and Alternative Medicine, 2016. https://doi.org/10.1155/2016/7591951
Khwaja, N. U. D., & Arunagirinathan, G. (2021). Efficacy and Cardiovascular Safety of Alpha Glucosidase Inhibitors. Current Drug Safety, 16(2), 122–128. https://doi.org/10.2174/1574886315666201217100445
Kulzer, B., Albus, C., Herpertz, S., Kruse, J., Lange, K., Lederbogen, F., & Petrak, F. (2021). Psychosocial Factors and Diabetes. Experimental and Clinical Endocrinology and Diabetes, 129, S91–S105. https://doi.org/10.1055/a-1284-6524
Kurup, S. B., & Mini, S. (2017). Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. Journal of Food and Drug Analysis, 25(2), 360–368. https://doi.org/10.1016/j.jfda.2016.06.007
Lau, W. K., Noruddin, N. A. A., Ariffin, A. H., Mahmud, M. Z., Noor, M. H. M., Amanah, A., Hamzah, M. F., & Zafarina, Z. (2019). Novel discovery of Averrhoa bilimbi ethanolic leaf extract in the stimulation of brown fat differentiation program in combating diet-induced obesity. BMC Complementary and Alternative Medicine, 19(1), 243. https://doi.org/10.1186/s12906-019-2640-3
Mayanti, T., Sinaga, S. E., & Supratman, U. (2022). Phytochemistry and biological activity of Lansium domesticum Corr. species: a review . Journal of Pharmacy and Pharmacology, September, 1–20. https://doi.org/10.1093/jpp/rgac057
Muthu, N., Lee, S. Y., Phua, K. K., & Bhore, S. J. (2016). Nutritional, Medicinal and Toxicological Attributes of Star-Fruits (Averrhoa carambola L.): A Review. Bioinformation, 12(12), 420–424. https://doi.org/10.6026/97320630012420
Nugroho, A. E., Andrie, M., Warditiani, N. K., Siswanto, E., Pramono, S., & Lukitaningsih, E. (2012). Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.) Nees and andrographolide in high-fructose-fat-fed rats. Indian Journal of Pharmacology, 44(3), 377–381. https://doi.org/10.4103/0253-7613.96343
Pradono, J., Delima, D., Kusumawardani, N., Dany, F., & Kristanto, Y. (2020). Contribution of Metabolic Syndrome in Controlling Diabetes Mellitus According to Gender in Indonesia (RISKESDAS 2018). Global Journal of Health Science, 13(1), 46. https://doi.org/10.5539/gjhs.v13n1p46
Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K., Shaw, J. E., Bright, D., & Williams, R. (2019). Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Research and Clinical Practice, 157, 107843. https://doi.org/10.1016/j.diabres.2019.107843
Setyawan, H. Y., Sukardi, S., & Nareswari, B. F. (2021). The phytochemical potential of Averrhoa bilimbi - A review. IOP Conference Series: Earth and Environmental Science, 733(1). https://doi.org/10.1088/1755-1315/733/1/012091
Shurrab, N. T., & Arafa, E. S. A. (2020). Metformin: A review of its therapeutic efficacy and adverse effects. Obesity Medicine, 17(January). https://doi.org/10.1016/j.obmed.2020.100186
Sinaga, S. E., Mayanti, T., Naini, A. A., Harneti, D., Nurlelasari, N., Maharani, R., Farabi, K., Supratman, U., Fajriah, S., & Azmi, M. N. (2022). Sesquiterpenoids from the Stem Bark of Lansium domesticum Corr . Cv . Kokossan and Their Cytotoxic Activity against MCF-7 Breast Cancer Cell Lines. Indonesian Journal of Chemistry, 22(4), 1035–1042. https://doi.org/10.22146/ijc.72742
Thompson, A., Cooper, J., & Ingram Jr. BT - Forest Products Journal, L. L. (2006). Distribution of terpenes in heartwood and sapwood of loblolly pine. 56(7–8), 46+. https://link.gale.com/apps/doc/A149986357/AONE?u=anon~f551fc74&sid=googleScholar&xid=10b7a46a
Wang, J., Lu, S., Sheng, R., Fan, J., Wu, W., & Guo, R. (2020). Structure-Activity Relationships of Natural and Synthetic Indole-Derived Scaffolds as α-Glucosidase Inhibitors: A Mini-Review. Mini-Reviews in Medicinal Chemistry, 20(17), 1791–1818. https://doi.org/10.2174/1389557520666200619121003
Widiastuti, D., Sinaga, S. E., Warnasih, S., Pujiyawati, E., Salam, S., & Putra, W. E. (2023). Identification of Active Compounds from Averrhoa bilimbi L . ( Belimbing Wuluh ) Flower using LC-MS and Antidiabetic Activity Test using in vitro and in silico Approaches. Trends in Sciences, 20(8), 1–9. https://doi.org/https://doi.org/10.48048/tis.2023.6761
Xu, X., Liang, T., Wen, Q., Lin, X., Tang, J., Zuo, Q., Tao, L., Xuan, F., & Huang, R. (2014). Protective effects of total extracts of averrhoa carambola l. (oxalidaceae) roots on streptozotocin-induced diabetic mice. Cellular Physiology and Biochemistry, 33(5), 1272–1282. https://doi.org/10.1159/000358695
Xue, Q., Liu, X., Russell, P., Li, J., Pan, W., Fu, J., & Zhang, A. (2022). Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock. Ecotoxicology and Environmental Safety, 233, 113323. https://doi.org/10.1016/j.ecoenv.2022.113323
Al-Abdullah, E. S., Al-Tuwaijri, H. M., Hassan, H. M., Al-Alshaikh, M. A., Habib, E. E., & El-Emam, A. A. (2015). Synthesis, antimicrobial and hypoglycemic activities of novel N-(1-adamantyl)carbothioamide derivatives. Molecules, 20(5), 8125–8143. https://doi.org/10.3390/molecules20058125
Artanti, N., Maryani, F., Dewi, R. T., Handayani, S., Dewijanti, I. D., Meilawati, L., Filaila, E., & Udin, L. Z. (2019). in vitro Antidiabetic, Antioxidant and Cytotoxic Activities of Syzygium cumini Fractions from Leaves Ethanol Extract. Indonesian Journal of Cancer Chemoprevention, 10(1), 24. https://doi.org/10.14499/indonesianjcanchemoprev10iss1pp24-29
Bakun, P., Czarczynska-Goslinska, B., Goslinski, T., & Lijewski, S. (2021). In vitro and in vivo biological activities of azulene derivatives with potential applications in medicine. Medicinal Chemistry Research, 30(4), 834–846. https://doi.org/10.1007/s00044-021-02701-0
Bhuyan, P., Ganguly, M., Baruah, I., Borgohain, G., Hazarika, J., & Sarma, S. (2022). Alpha glucosidase inhibitory properties of a few bioactive compounds isolated from black rice bran: combined in vitro and in silico evidence supporting the antidiabetic effect of black rice. RSC Advances, 12(35), 22650–22661. https://doi.org/10.1039/d2ra04228b
Chae, S. Y., Jin, C. H., Shin, J. H., Son, S., Kim, T. H., Lee, S., Youn, Y. S., Byun, Y., Lee, M. S., & Lee, K. C. (2010). Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs. Journal of Controlled Release, 142(2), 206–213. https://doi.org/10.1016/j.jconrel.2009.10.025
Eruygur, N., Koçyiğit, U. M., Taslimi, P., Ataş, M., Tekin, M., & Gülçin. (2019). Screening the in vitro antioxidant, antimicrobial, anticholinesterase, antidiabetic activities of endemic Achillea cucullata (Asteraceae) ethanol extract. South African Journal of Botany, 120, 141–145. https://doi.org/10.1016/j.sajb.2018.04.001
Hedrington, M. S., & Davis, S. N. (2019). Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes. Expert Opinion on Pharmacotherapy, 20(18), 2229–2235. https://doi.org/10.1080/14656566.2019.1672660
Hidayatullah, A., Putra, W. E., Rifa’i, M., Sustiprijatno, Widiastuti, D., Heikal, M. F., Susanto, H., Salma, W. O., & Mulyadi, H. (2022). Molecular Docking and Dynamics Simulation Studies to Predict Multiple Medicinal Plants’ Bioactive Compounds Interaction and Its Behavior on the Surface of DENV-2 E Protein. Karbala International Journal of Modern Science, 8(3), 531–542. https://doi.org/10.33640/2405-609X.3237
Hidayatullah, A., Putra, W. E., Sustiprijatno, S., Widiastuti, D., Salma, W. O., & Heikal, M. F. (2023). Molecular Docking and Molecular Dynamics Simulation-Based Identification of Natural Inhibitors against Druggable Human Papilloma Virus Type 16 Target. Trends in Sciences, 20(4), 4891. https://doi.org/10.48048/tis.2023.4891
Jokiaho, A. J., Winchester, M., & Donovan, C. M. (2022). N-Hydroxyethyl-1-Deoxynojirimycin (Miglitol) Restores the Counterregulatory Response to Hypoglycemia Following Antecedent Hypoglycemia. Diabetes, 71(5), 1063–1072. https://doi.org/10.2337/db21-0859
Kashtoh, H., & Baek, K. H. (2022). Recent Updates on Phytoconstituent Alpha-Glucosidase Inhibitors: An Approach towards the Treatment of Type Two Diabetes. Plants, 11(20). https://doi.org/10.3390/plants11202722
Khoo, H. E., Azlan, A., Kong, K. W., & Ismail, A. (2016). Phytochemicals and Medicinal Properties of Indigenous Tropical Fruits with Potential for Commercial Development. Evidence-Based Complementary and Alternative Medicine, 2016. https://doi.org/10.1155/2016/7591951
Khwaja, N. U. D., & Arunagirinathan, G. (2021). Efficacy and Cardiovascular Safety of Alpha Glucosidase Inhibitors. Current Drug Safety, 16(2), 122–128. https://doi.org/10.2174/1574886315666201217100445
Kulzer, B., Albus, C., Herpertz, S., Kruse, J., Lange, K., Lederbogen, F., & Petrak, F. (2021). Psychosocial Factors and Diabetes. Experimental and Clinical Endocrinology and Diabetes, 129, S91–S105. https://doi.org/10.1055/a-1284-6524
Kurup, S. B., & Mini, S. (2017). Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. Journal of Food and Drug Analysis, 25(2), 360–368. https://doi.org/10.1016/j.jfda.2016.06.007
Lau, W. K., Noruddin, N. A. A., Ariffin, A. H., Mahmud, M. Z., Noor, M. H. M., Amanah, A., Hamzah, M. F., & Zafarina, Z. (2019). Novel discovery of Averrhoa bilimbi ethanolic leaf extract in the stimulation of brown fat differentiation program in combating diet-induced obesity. BMC Complementary and Alternative Medicine, 19(1), 243. https://doi.org/10.1186/s12906-019-2640-3
Mayanti, T., Sinaga, S. E., & Supratman, U. (2022). Phytochemistry and biological activity of Lansium domesticum Corr. species: a review . Journal of Pharmacy and Pharmacology, September, 1–20. https://doi.org/10.1093/jpp/rgac057
Muthu, N., Lee, S. Y., Phua, K. K., & Bhore, S. J. (2016). Nutritional, Medicinal and Toxicological Attributes of Star-Fruits (Averrhoa carambola L.): A Review. Bioinformation, 12(12), 420–424. https://doi.org/10.6026/97320630012420
Nugroho, A. E., Andrie, M., Warditiani, N. K., Siswanto, E., Pramono, S., & Lukitaningsih, E. (2012). Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.) Nees and andrographolide in high-fructose-fat-fed rats. Indian Journal of Pharmacology, 44(3), 377–381. https://doi.org/10.4103/0253-7613.96343
Pradono, J., Delima, D., Kusumawardani, N., Dany, F., & Kristanto, Y. (2020). Contribution of Metabolic Syndrome in Controlling Diabetes Mellitus According to Gender in Indonesia (RISKESDAS 2018). Global Journal of Health Science, 13(1), 46. https://doi.org/10.5539/gjhs.v13n1p46
Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K., Shaw, J. E., Bright, D., & Williams, R. (2019). Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Research and Clinical Practice, 157, 107843. https://doi.org/10.1016/j.diabres.2019.107843
Setyawan, H. Y., Sukardi, S., & Nareswari, B. F. (2021). The phytochemical potential of Averrhoa bilimbi - A review. IOP Conference Series: Earth and Environmental Science, 733(1). https://doi.org/10.1088/1755-1315/733/1/012091
Shurrab, N. T., & Arafa, E. S. A. (2020). Metformin: A review of its therapeutic efficacy and adverse effects. Obesity Medicine, 17(January). https://doi.org/10.1016/j.obmed.2020.100186
Sinaga, S. E., Mayanti, T., Naini, A. A., Harneti, D., Nurlelasari, N., Maharani, R., Farabi, K., Supratman, U., Fajriah, S., & Azmi, M. N. (2022). Sesquiterpenoids from the Stem Bark of Lansium domesticum Corr . Cv . Kokossan and Their Cytotoxic Activity against MCF-7 Breast Cancer Cell Lines. Indonesian Journal of Chemistry, 22(4), 1035–1042. https://doi.org/10.22146/ijc.72742
Thompson, A., Cooper, J., & Ingram Jr. BT - Forest Products Journal, L. L. (2006). Distribution of terpenes in heartwood and sapwood of loblolly pine. 56(7–8), 46+. https://link.gale.com/apps/doc/A149986357/AONE?u=anon~f551fc74&sid=googleScholar&xid=10b7a46a
Wang, J., Lu, S., Sheng, R., Fan, J., Wu, W., & Guo, R. (2020). Structure-Activity Relationships of Natural and Synthetic Indole-Derived Scaffolds as α-Glucosidase Inhibitors: A Mini-Review. Mini-Reviews in Medicinal Chemistry, 20(17), 1791–1818. https://doi.org/10.2174/1389557520666200619121003
Widiastuti, D., Sinaga, S. E., Warnasih, S., Pujiyawati, E., Salam, S., & Putra, W. E. (2023). Identification of Active Compounds from Averrhoa bilimbi L . ( Belimbing Wuluh ) Flower using LC-MS and Antidiabetic Activity Test using in vitro and in silico Approaches. Trends in Sciences, 20(8), 1–9. https://doi.org/https://doi.org/10.48048/tis.2023.6761
Xu, X., Liang, T., Wen, Q., Lin, X., Tang, J., Zuo, Q., Tao, L., Xuan, F., & Huang, R. (2014). Protective effects of total extracts of averrhoa carambola l. (oxalidaceae) roots on streptozotocin-induced diabetic mice. Cellular Physiology and Biochemistry, 33(5), 1272–1282. https://doi.org/10.1159/000358695
Xue, Q., Liu, X., Russell, P., Li, J., Pan, W., Fu, J., & Zhang, A. (2022). Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock. Ecotoxicology and Environmental Safety, 233, 113323. https://doi.org/10.1016/j.ecoenv.2022.113323
Published
2024-06-10
How to Cite
Widiastuti, D., Sinaga, S. E., Warnasih, S., Syahputri, Y., Saputri, N. B., Sustiprijatno, & Putra, W. E. (2024). Antidiabetic Activity of Averrhoa bilimbi L. Fruit Extracts and the Identification of Active Compounds Using LC-MS and In silico Methods. Indonesian Journal of Pharmacy, 35(2), 282–291. https://doi.org/10.22146/ijp.7746
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Research Article
