Ficus deltoidea var. kunstleri Extract Administration in Hypercholesterolaemic, Atherosclerotic Rabbits: Effects on Organ Function, Morphology, and Atherosclerosis Development
Keywords:
kunstleri, safety, efficacy, New Zealand White rabbits, atherosclerosis, Ficus deltoideaAbstract
Ficus deltoidea (FD) is used in traditional Malay medicine to treat various ailments and has been shown to be safe in toxicity studies. However, the information on the safety and efficacy of FD in the atherosclerosis-induced animal model is limited. This study aims to investigate the safety of FD var. kunstleri (FDK) extract on high cholesterol diet (HCD)-induced atherosclerotic rabbits and its efficacy in treating atherosclerosis. New Zealand White rabbits were randomly divided into two groups: G1 (1% HCD for 4 weeks) and G2 (1% HCD for 8 weeks). Each group was randomised into FDK700 (700 mg FDK/kg/day for G1 and G2), FDK800 (800 mg FDK/kg/day for G2), simvastatin (5 mg/kg/day) and placebo. The body weight, blood pressure, serum biochemistry and histopathological examination were obtained to assess any toxicity signs. Fasting lipid profile, soluble c-reactive protein (sCRP) level and atherosclerotic plaque formation were compared between treated and placebo groups to evaluate treatment efficacy. Results: No significant differences were observed in all safety parameters between the treated and placebo groups (p<0.05). FDK treatment did not show significant differences in all parameters evaluated in both treatment arms. In conclusion, FDK extract up to 800 mg/kg is safe for use in atherosclerotic rabbits. It has neutral effects on lipid profile, inflammation and atherosclerosis formation.
Downloads
Metrics
References
Ab Azis, N., Agarwal, R., Ismail, N.M., Ismail, N.H., Kamal, M.S.A., Radjeni, Z. & Singh, H.J. 2019. Blood pressure lowering effect of Ficus deltoidea var kunstleri in spontaneously hypertensive rats: Possible involvement of renin-angiotensin-aldosterone system, endothelial function and anti-oxidant system. Molecular Biology Reports, 46(3): 2841-2849. DOI: https://doi.org/10.1007/s11033-019-04730-w
Abdel-Rahman, R.F., Ezzat, S.M., Ogaly, H.A., Abd-Elsalam, R.M., Hessin, A.F., Fekry, M.I., Mansour, D.F. & Mohamed, S.O. 2020. Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: A new insight into its antidiabetic mechanism. Journal of Nutritional Science, 9. DOI: https://doi.org/10.1017/jns.2019.40
Abdullah, N., Karsani, S. & Aminudin, N. 2008. Effects of Ficus deltoidea extract on the serum protein profile of simultaneously hypertensive rats (SHR). Proteomics and Bioinformatics, S2. DOI: https://doi.org/10.4172/jpb.s1000111
Adam, Z., Khamis, S., Ismail, A. & Hamid, M. 2012. Ficus deltoidea: A Potential Alternative Medicine for Diabetes Mellitus. Evidence-Based Complementary and Alternative Medicine, 2012: 632763. DOI: https://doi.org/10.1155/2012/632763
Afzan, A., Kasim, N., Ismail, N.H., Azmi, N., Ali, A.M., Mat, N. & Wolfender, J.-L. 2019. Differentiation of Ficus deltoidea varieties and chemical marker determination by UHPLC-TOFMS metabolomics for establishing quality control criteria of this popular Malaysian medicinal herb. Metabolomics, 15: 1-11. DOI: https://doi.org/10.1007/s11306-019-1489-2
Alfon, J., Pueyo Palazon, C., Royo, T. & Badimon, L. 1999. Effects of statins in thrombosis and aortic lesion development in a dyslipemic rabbit model. Thrombosis and Haemostasis, 81(5): 822-827. DOI: https://doi.org/10.1055/s-0037-1614576
Ariff, A.M., Bakar, N.A.A., Muid, S.A., Omar, E., Ismail, N.H., Ali, A.M., Kasim, N.A.M. & Nawawi, H.M. 2020. Ficus deltoidea suppresses endothelial activation, inflammation, monocytes adhesion and oxidative stress via NF-κB and eNOS pathways in stimulated human coronary artery endothelial cells. BMC Complementary Medicine and Therapies, 20(1): 1-13.
Bakar, N.A., Muid, S.A., Omar, E., Ahmad, R., Ismail, N., Kasim, N.M., Ali, A. & Nawawi, H.M. 2017. Effects of Ficus deltoidea variants on inflammatory, endothelial nitric oxide synthase (ENOS) and endothelin-1 expression in stimulated human coronary artery endothelial cells. International Journal of Cardiology, 249: S13. DOI: https://doi.org/10.1016/j.ijcard.2017.09.064
Bergheanu, S., Bodde, M. & Jukema, J. 2017. Pathophysiology and treatment of atherosclerosis. Netherlands Heart Journal, 25(4): 231-242. DOI: https://doi.org/10.1007/s12471-017-0959-2
Bunawan, H., Amin, N.M., Bunawan, S.N., Baharum, S.N. & Mohd Noor, N. 2014. Ficus deltoidea Jack: a review on its phytochemical and pharmacological importance. Evidence-Based Complementary and Alternative Medicine, 2014. DOI: https://doi.org/10.1155/2014/902734
Cho, K.-h., Kim, H.-j., Kamanna, V.S. & Vaziri, N.D. 2010. Niacin improves renal lipid metabolism and slows progression in chronic kidney disease. Biochimica et Biophysica Acta (BBA)-General Subjects, 1800(1): 6-15. DOI: https://doi.org/10.1016/j.bbagen.2009.10.009
Choo, C., Sulong, N., Man, F. & Wong, T. 2012. Vitexin and isovitexin from the leaves of Ficus deltoidea with in-vivo α-glucosidase inhibition. Journal of Ethnopharmacology, 142(3): 776-781. DOI: https://doi.org/10.1016/j.jep.2012.05.062
Corti, R., Fayad, Z.A., Fuster, V., Worthley, S.G., Helft, G., Chesebro, J., Mercuri, M. & Badimon, J.J. 2001. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation, 104(3): 249-252. DOI: https://doi.org/10.1161/01.CIR.104.3.249
Dornas, W.C., Oliveira, T.T., Augusto, L.E. & Nagem, T.J. 2010. Experimental atherosclerosis in rabbits. Arquivos Brasileiros de Cardiologia, 95(2): 272-278. DOI: https://doi.org/10.1590/S0066-782X2010001200020
Duff, G.L. 1935. Experimental cholesterol arteriosclerosis and its relationship to human arteriosclerosis. Archives of Pathology, 20: 81-304.
Fabbrini, E., Mohammed, B.S., Korenblat, K.M., Magkos, F., McCrea, J., Patterson, B.W. & Klein, S. 2010. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. The Journal of Clinical Endocrinology & Metabolism, 95(6): 2727-2735. DOI: https://doi.org/10.1210/jc.2009-2622
Fan, J., Kitajima, S., Watanabe, T., Xu, J., Zhang, J., Liu, E. & Chen, Y.E. 2015. Rabbit models for the study of human atherosclerosis: From pathophysiological mechanisms to translational medicine. Pharmacology & Therapeutics, 146: 104-119. DOI: https://doi.org/10.1016/j.pharmthera.2014.09.009
Farsi, E., Ahmad, M., Hor, S.Y., Ahamed, M.B.K., Yam, M.F. & Asmawi, M.Z. 2014. Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats. BMC Complementary and Alternative Medicine, 14(1): 220. DOI: https://doi.org/10.1186/1472-6882-14-220
Farsi, E., Shafaei, A., Hor, S.Y., Ahamed, M.B.K., Yam, M.F., Asmawi, M.Z. & Ismail, Z. 2013. Genotoxicity and acute and subchronic toxicity studies of a standardized methanolic extract of Ficus deltoidea leaves. Clinics, 68(6): 865-875. DOI: https://doi.org/10.6061/clinics/2013(06)23
Finking, G. & Hanke, H. 1997. Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed rabbit as a model for atherosclerosis research. Atherosclerosis, 135(1): 1-7. DOI: https://doi.org/10.1016/S0021-9150(97)00161-5
Gil-Pulido, J. & Zernecke, A. 2017. Antigen-presenting dendritic cells in atherosclerosis. European Journal of Pharmacology, 816: 25-31. DOI: https://doi.org/10.1016/j.ejphar.2017.08.016
Ham, C.P., Uzar, F., Abdul-Rahman, P.S., Abdullah, N. & Aminudin, N. 2020. Alterations of cholesterol lowering-related proteins in the serum of hypercholesterolemic-induced rats treated with Ficus deltoidea. Sains Malaysiana, 49(5): 1055-1066. DOI: https://doi.org/10.17576/jsm-2020-4905-10
Ilyanie, Y., Wong, T.W. & Choo, C.Y. 2011. Evaluation of hypoglycemic activity and toxicity profiles of the leaves of Ficus deltoidea in rodents. Journal of Complementary and Integrative Medicine, 8(1). DOI: https://doi.org/10.2202/1553-3840.1469
Kalman, D.S., Schwartz, H.I., Feldman, S. & Krieger, D.R. 2013. Efficacy and safety of Elaeis guineensis and Ficus deltoidea leaf extracts in adults with pre-diabetes. Nutrition Journal, 12: 36. DOI: https://doi.org/10.1186/1475-2891-12-36
Kamal, M.S.A., Ismail, N.H., Satar, N.A., Azis, N.A., Radjeni, Z., Mohammad Noor, H.S., Kasim, N. & Singh, H. 2019. Standardized ethanol-water extract of Ficus deltoidea Angustifolia reduces blood pressure in spontaneously hypertensive rats. Clinical and Experimental Hypertension, 41(5): 444-451. DOI: https://doi.org/10.1080/10641963.2018.1506467
Lei, X. & Yang, Y. 2020. Vitexin and an HMG-Co A reductase inhibitor prevent the risks of atherosclerosis in high-fat atherogenic diet fed rats. Journal of King Saud University-Science, 32(3): 2088-2095. DOI: https://doi.org/10.1016/j.jksus.2020.01.037
Liu, Q., Yuan, B., Lo, K.A., Patterson, H.C., Sun, Y. & Lodish, H.F. 2012. Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism. Proceedings of the National Academy of Sciences, 109(36): 14568-14573. DOI: https://doi.org/10.1073/pnas.1211611109
Misbah, H., Aziz, A.A. & Aminudin, N. 2013. Antidiabetic and antioxidant properties of Ficus deltoidea fruit extracts and fractions. BMC Complementary and Alternative Medicine, 13: 118. DOI: https://doi.org/10.1186/1472-6882-13-118
Mohammad Noor, H.S., Ismail, N.H., Kasim, N., Mediani, A., Mohd Zohdi, R., Ali, A.M., Mat, N. & Al-Mekhlafi, N.A. 2020. Urinary metabolomics and biochemical analysis of antihyperglycemic effect of Ficus deltoidea Jack varieties in streptozotocin-nicotinamide-induced diabetic rats. Applied Biochemistry and Biotechnology, 192: 1-21. DOI: https://doi.org/10.1007/s12010-020-03304-y
Mohd Ariff, A., Abu Bakar, N.A., Omar, E., Ismail, N.H., Ali, A.M., Mohd Kasim, N.A. & Mohd Nawawi, H. 2020. Ficus deltoidea suppresses endothelial activation, inflammation, monocytes adhesion and oxidative stress via NF-κB and eNOS pathways in stimulated human coronary artery endothelial cells. BMC Complementary Medicine and Therapies, 20(1): 1-13. DOI: https://doi.org/10.1186/s12906-020-2844-6
Morgantini, C., Trifirò, S., Tricò, D., Meriwether, D., Baldi, S., Mengozzi, A., Reddy, S. & Natali, A. 2018. A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects. Nutrition, Metabolism and Cardiovascular Diseases, 28(6): 575-581. DOI: https://doi.org/10.1016/j.numecd.2018.03.005
Nair, A.B. & Jacob, S. 2016. A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2): 27. DOI: https://doi.org/10.4103/0976-0105.177703
Niimi, M., Chen, Y., Yan, H., Wang, Y., Koike, T. & Fan, J. 2020. Hyperlipidemic rabbit models for anti-atherosclerotic drug development. Applied Sciences, 10(23): 8681. DOI: https://doi.org/10.3390/app10238681
Noor, H.S.M., Ismail, N.H., Kasim, N., Zohdi, R.M. & Ali, A.M. 2016. Hypoglycemic and glucose tolerance activity of standardized extracts Ficus deltoidea varieties in normal rats. Journal of Medicinal Plants Studies, 4: 275-279.
Nugroho, R.A., Aryani, R., Manurung, H., Rudianto, R., Prahastika, W., Juwita, A., Alfarisi, A.K., Pusparini, N.A.O. & Lalong, A. 2020. Acute and subchronic toxicity study of the ethanol extracts from Ficus deltoidea leaves in male mice. Open Access Macedonian Journal of Medical Sciences, 8(A): 76-83. DOI: https://doi.org/10.3889/oamjms.2020.3989
Omar, M.H., Mullen, W. & Crozier, A. 2011. Identification of proanthocyanidin dimers and trimers, flavone C-Glycosides, and antioxidants in Ficus deltoidea, a Malaysian herbal tea. Journal of Agricultural and Food Chemistry, 59(4): 1363-1369. DOI: https://doi.org/10.1021/jf1032729
Ramkumar, S., Raghunath, A. & Raghunath, S. 2016. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiologica Sinica, 32(6): 631-639.
Wolf, M.P. & Hunziker, P. 2020. Atherosclerosis: insights into vascular pathobiology and outlook to novel treatments. Journal of Cardiovascular Translational Research, 13(5): 744-757. DOI: https://doi.org/10.1007/s12265-020-09961-y
Woon, S.M., Seng, Y.W., Ling, A.P., Chye, S.M. & Koh, R.Y. 2014. Anti-adipogenic effects of extracts of Ficus deltoidea var. deltoidea and var. angustifolia on 3T3-L1 adipocytes. Journal of Zhejiang University-SCIENCE B, 15(3): 295-302. DOI: https://doi.org/10.1631/jzus.B1300123
Yanni, A.E. 2004. The laboratory rabbit: an animal model of atherosclerosis research. Laboratory Animals, 38(3): 246-256. DOI: https://doi.org/10.1258/002367704323133628
Yu, Q., Li, Y., Waqar, A.B., Wang, Y., Huang, B., Chen, Y., Zhao, S., Yang, P., Fan, J. & Liu, E. 2012. Temporal and quantitative analysis of atherosclerotic lesions in diet-induced hypercholesterolemic rabbits. Journal of Biomedicine and Biotechnology, 2012: 506159. DOI: https://doi.org/10.1155/2012/506159
Zakaria, Z.A., Hussain, M.K., Mohamad, A.S., Abdullah, F.C. & Sulaiman, M.R. 2012. Anti-inflammatory activity of the aqueous extract of Ficus deltoidea. Biological Research For Nursing, 14(1): 90-97. DOI: https://doi.org/10.1177/1099800410395378
Published
How to Cite
Issue
Section
Any reproduction of figures, tables and illustrations must obtain written permission from the Chief Editor (wicki@ukm.edu.my). No part of the journal may be reproduced without the editor’s permission
