Hypoglycemic and antioxidant potential of Myrcia splendens extract in diabetic rat models
Heloiza Cruz de Oliveira; Débora Delwing-Dal Magro; Scheila Medeiros; Karol Arias Fernandes; Michele Debiasi Alberton; Lucas Wippel; Vendelino Crisóstomo Salomon; Henrique César Bischoff; Liz Caroline de Oliveira Camilo; Camila Reinert; Anna Lydia Schuster; Sheila Wayszceyk; Katherine Plautz; Daniela Delwing-de Lima
Abstract
We verified the effects of the subchronic administration of the ethyl acetate extract (EAE), acquired through the leaves of Myrcia splendens, on the changes caused by DMI and DMII induced by the administration of alloxan and streptozotocin-nicotinamide, respectively, on hyperglycemia, hypertriglyceridemia (HTG) and oxidative stress in the blood and kidneys of rats. The results showed increased levels of glucose and triglycerides in both models. In the DMI and DMII models, the EAE partially reversed the hyperglycemia and completely reversed the HTG. Alloxan-induced DMI increased TBA-RS and decreased CAT, SOD, and GSH-Px activities. Streptozotocin-nicotinamide-induced DMII increased TBA-RS, reduced total sulfhydryl content, increased CAT, and decreased GSH-Px activities in the blood of rats. Subchronic administration of EAE reversed the increase in TBA-RS levels, the reduction of total sulfhydryl content, and the alterations in CAT, SOD, and GSH-Px activities in both experimental models. Otherwise, alloxan increased TBA-RS levels, carbonyl protein content, SOD and GSH-Px activities, and streptozotocin-nicotinamide decreased CAT activity, as well as GSH-Px activity in the kidney. Additionally, treatment with EAE abolished the increase in TBA-RS and protein carbonyl content, as well as the alterations in SOD, CAT, and GSH-Px activities caused by diabetes models. Finally, the effects of the subchronic administration of EAE are inherent to the presence of phenolic compounds, such as gallic and ellagic acids, in the extract. Further studies are needed to identify whether EAE obtained from Myrcia splendens should be used as an adjuvant treatment in individuals with DM in order to minimize adverse effects caused by currently used medications.
Keywords
References
Aebi, H. (1984). Catalase in vitro. Methods in Enzymology, 105, 121-126. http://doi.org/10.1016/S0076-6879(84)05016-3. PMid:6727660. Aishwarya, V., Solaipriya, S., & Sivaramakrishnan, V. (2021). Role of ellagic acid for the prevention and treatment of liver diseases. Phytotherapy Research, 35(6), 2925-2944. http://doi. org/10.1002/ptr.7001. PMid:33368795.
Aksenov, M. Y., & Markesbery, W. R. (2001). Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neuroscience Letters, 302(2-3), 141-145. http://doi.org/10.1016/S0304- 3940(01)01636-6. PMid:11290407.
American Diabetes Association – ADA. (2013). Diagnosis and classification of Diabetes Mellitus. Diabetes Care, 36(Suppl 1), S67-S74. http://doi.org/10.2337/dc13-S067. PMid:23264425.
American Diabetes Association – ADA. (2017). 2. Classification and diagnosis of diabetes: standards of medical care in diabetes – 2018. Diabetes Care, 41(Suppl 1), S13-S27. http://doi.org/10.2337/ dc18-S002.
Arumugam, G., Manjula, P., & Paari, N. (2013). A review: antidiabetic medicinal plants used for diabetes mellitus. Journal of Acute Disease, 2(3), 196-200. http://doi.org/10.1016/S2221- 6189(13)60126-2.
Basting, R. T., Nishijima, C. M., Lopes, J. A., Santos, R. C., Périco, L. L., Laufer, S., Bauer, S., Costa, M. F., Santos, L. C., Rocha, L. R. M., Vilegas, W., Santos, A. R. S., Santos, C., & HirumaLima, C. A. (2014). Antinociceptive, anti-inflammatory and gastroprotective effects of a hydroalcoholic extract from the leaves of Eugenia punicifolia (Kunth) DC. in rodents. Journal of Ethnopharmacology, 157, 257-267. http://doi.org/10.1016/j. jep.2014.09.041. PMid:25311275.
Berlett, B. S., & Stadtman, E. R. (1997). Protein oxidation in aging, disease, and oxidative stress. The Journal of Biological Chemistry, 272(33), 20313-20316. http://doi.org/10.1074/jbc.272.33.20313. PMid:9252331.
Bhadri, N., Sinha, S., & Jain, S. (2020). Protective effects of ellagic acid in experimental diabetes via modulating NF-κB and insulin signaling pathways in diabetic rats. Journal of Diabetes and Metabolic Disorders, 19(2), 1235-1244. http://doi.org/10.1007/ s40200-020-00581-y.
Budoff, M. (2016). Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. The American Journal of Cardiology, 118(1), 138-145. http://doi.org/10.1016/j. amjcard.2016.04.004. PMid:27184174.
Cascaes, M., Guilhon, G., Andrade, E., Zoghbi, M., & Santos, L. (2015). Constituents and pharmacological activities of Myrcia (Myrtaceae): a review of an aromatic and medicinal group of plants. International Journal of Molecular Sciences, 16(10), 23881- 23904. http://doi.org/10.3390/ijms161023881. PMid:26473832.
Custodio, B. V., & Lima, D. D. D. (2018). Evaluation of the hypoglycemic and antioxidant potential of ethyl acetate extract from dolphins of the species of Myrcia splendens in an animal model of type II diabetes (16 p.). Joinville: Joinville Region University.
Diao, M., Liang, Y., Zhao, J., Zhang, J., & Zhang, T. (2022). Complexation of ellagic acid with α-lactalbumin and its antioxidant property. Food Chemistry, 372, 131307. http://doi.org/10.1016/j. foodchem.2021.131307. PMid:34634588.
Domingueti, C. P., Dusse, L. M. S., Carvalho, M. D. G., de Sousa, L. P., Gomes, K. B., & Fernandes, A. P. (2016). Diabetes mellitus: the linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. Journal of Diabetes and Its Complications, 30(4), 738-745. http://doi.org/10.1016/j. jdiacomp.2015.12.018. PMid:26781070.
D’Souza, J. J., D’Souza, P. P., Fazal, F., Kumar, A., Bhat, H. P., & Baliga, M. S. (2014). Antidiabetic effects of the Indian indigenous fruit Emblica officinalis Gaertn: active constituents and modes of action. Food & Function, 5(4), 635-644. http://doi.org/10.1039/ c3fo60366k. PMid:24577384.
Evtyugin, D. D., Magina, S., & Evtuguin, D. V. (2020). Recent advances in the production and applications of ellagic acid and its derivatives: a review. Molecules, 25(12), 2745. http://doi. org/10.3390/molecules25122745. PMid:32545813.
Ferreira, M. J. P., Emerenciano, V. P., Cabrol-Bass, D., & Ferreira, A. G. (2014). Chemosystematic studies of Myrcia (Myrtaceae): Distribution of triterpenes, steroids, flavonoids, and acetophenone derivatives. Biochemical Systematics and Ecology, 56, 223-231. Gaschler, M. M., & Stockwell, B. R. (2017). Lipid peroxidation in cell death. Biochemical and Biophysical Research Communications, 482(3), 419-425. http://doi.org/10.1016/j.bbrc.2016.10.086. PMid:28212725.
Gülçin, L., Huyut, Z., Elmastaş, M., & Aboul-Enein, H. Y. (2010). Radical scavenging and antioxidant activity of tannic acid. Arabian Journal of Chemistry, 3(1), 43-53. http://doi.org/10.1016/j. arabjc.2009.12.008.
Hemmingsen, B., Richter, B., & Metzendorf, M. I. (2021). (Ultra-)longacting insulin analogues for people with type 1 diabetes mellitus. Cochrane Database of Systematic Reviews, 3(3), CD013498. http://doi.org/10.1002/14651858.CD013498. PMid:33662147.
Hurrle, S., & Hsu, W. H. (2017). The etiology of oxidative stress in insulin resistance. Biomedical Journal, 40(5), 257-262. http:// doi.org/10.1016/j.bj.2017.06.007. PMid:29179880.
Ighodaro, O. M., Adeosun, A. M., & Akinloye, O. A. (2018). Alloxaninduced diabetes, a common model for evaluating the glycemiccontrol potential of therapeutic compounds and plants extracts in experimental studies. Medicine, 97(52), e13411.
Inzucchi, S. E., & Matthews, D. R. (2015). Response to comments on Inzucchi et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the study of diabetes. Diabetes Care 2015;38:140-149. Diabetes Care, 38(8), e128-e129. http://doi. org/10.2337/dc15-0812. PMid:26207068.
Johnson, E. L. (2019). Standards of Medical Care in Diabetes – 2019 abridged for primary care providers. Clinical Diabetes, 37(1), 11-34. PMid:30705493.
Kábelová, A., Malínská, H., Marková, I., Oliyarnyk, O., Chylíková, B., & Šeda, O. (2021). Ellagic acid affects metabolic and transcriptomic profiles and attenuates features of metabolic syndrome in adult male rats. Nutrients, 13(3), 804. http://doi. org/10.3390/nu13030804. PMid:33671116.
Kanter, J. E., & Bornfeldt, K. E. (2016). Impact of Diabetes Mellitus. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(6), 1049-1053. http://doi.org/10.1161/ATVBAHA.116.307302. PMid:27225786.
Kar, A., Choudhary, B. K., & Bandyopadhyay, N. G. (2003). Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. Journal of Ethnopharmacology, 84(1), 105-108. http://doi.org/10.1016/S0378-8741(02)00144-7. PMid:12499084.
Li, Y. H., Ueng, K. C., Jeng, J. S., Charng, M. J., Lin, T. H., Chien, K. L., Wang, C. Y., Chao, T. H., Liu, P. Y., Su, C. H., Chien, S. C., Liou, C. W., Tang, S. C., Lee, C. C., Yu, T. Y., Chen, J. W., Wu, C. C., & Yeh, H. I. (2017). 2017 Taiwan lipid guidelines for high-risk patients. Journal of the Formosan Medical Association, 116(4), 217-248. http://doi.org/10.1016/j.jfma.2016.11.013. PMid:28242176.
Lima, A. B., Delwing-de Lima, D., Vieira, M. R., Poletto, M. Z., Delwing-Dal Magro, D., Barauna, S. C., Alberton, M. D., Pereira, E. M., Pereira, N. R., Salamaia, E. M., & Siebert, D. A. (2017). Hypolipemiant and antioxidant effects of Eugenia brasiliensis in an animal model of coconut oil-induced hypertriglyceridemia. Biomedicine and Pharmacotherapy, 96, 642-649. http://doi. org/10.1016/j.biopha.2017.10.047. PMid:29035830.
Lorenzi, M., & Cagliero, E. (1991). Pathobiology of endothelial and other vascular cells in diabetes mellitus. Call for data. Diabetes, 40(6), 653-659. http://doi.org/10.2337/diab.40.6.653. PMid:2040380.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 193(1), 265-275. http://doi.org/10.1016/ S0021-9258(19)52451-6. PMid:14907713.
Mahmoud, A. M., Ahmed, O. M., Ashour, M. B., & Abdel-Moneim, A. (2019). Gallic acid and p-coumaric acid attenuate type 2 diabetesinduced neurodegeneration through modulation of the NF-κB signaling pathway. Food and Chemical Toxicology, 126, 315-329. Marklund, S. (1985). Pyrogallol autooxidation. In R. A. Greenwald (Ed.), Handbook of methods for oxygen radical research. Boca Raton: Greenwald Press.
Medeiros, S., Maia, T. P., Lima, A. B., Pscheidt, L. C., Delmonego, L., Vincenzi, K. L., Custodio, B. V., Delwing-Dal Magro, D., Barauna, S. C., Alberton, M. D., Pereira, E. M., & Delwing-de Lima, D. (2021). Hypolipidemic, hypoglycemiant and antioxidant effects of Myrcia splendens (Sw.) DC in an animal type 2 diabetes model induced by streptozotocin. Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, 20(2), 132-146. http://doi. org/10.37360/blacpma.21.20.2.11.
Moresco, H. H., Pereira, M., Bretanha, L. C., Micke, G. A., Pizzolatti, M. G., & Brighente, I. M. C. (2014). Myricitrin is the main constituent of two species of Myrcia. Journal of Applied Pharmaceutical Science, 4(2), 1-7. http://doi.org/10.7324/ JAPS.2014.40201.
Murray-Smith, C., Brummitt, N. A., Oliveira-Filho, A. T., Bachman, S. P., Moat, J., Lughadha, E. M. N., & Lucas, E. J. (2009). Plant diversity hotspots in the Atlantic coastal forests of Brazil. Conservation Biology, 23(1), 151-163. http://doi.org/10.1111/ j.1523-1739.2008.01075.x. PMid:18950472.
Naraki, K., Ghasemzadeh Rahbardar, M., Ajiboye, B. O., & Hosseinzadeh, H. (2023). The effect of ellagic acid on the metabolic syndrome: a review article. Heliyon, 9(11), e21844. http://doi.org/10.1016/j.heliyon.2023.e21844. PMid:38027887.
National Research Council. (1996). Guide for the care and use of laboratory animals. Washington, D.C.: National Academy Press. Orgah, J. O., He, S., Wang, Y., Jiang, M., Wang, Y., Orgah, E. A., Duan, Y., Zhao, B., Zhang, B., Han, J., & Zhu, Y. (2020). Pharmacological potential of the combination of Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua) for diabetes mellitus and its cardiovascular complications. Pharmacological Research, 153, 104654. http://doi.org/10.1016/j.phrs.2020.104654. PMid:31945473.
Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351-358. http://doi.org/10.1016/0003- 2697(79)90738-3. PMid:36810.
Paganelli, C. J., Siebert, D. A., Vitali, L., Micke, G. A., & Alberton, M. D. (2020). Quantitative analysis of phenolic compounds in crude extracts of Myrcia splendens leaves by HPLC-ESI-MS/ MS. Rodriguésia, 71, e00552019. http://doi.org/10.1590/2175- 7860202071045.
Päivärinta, E., Pajari, A. M., Törrönen, R., & Mutanen, M. (2006). Ellagic acid and natural sources of ellagitannins as possible chemopreventive agents against intestinal tumorigenesis in the min mouse. Nutrition and Cancer, 54(1), 79-83. http://doi. org/10.1207/s15327914nc5401_9. PMid:16800775.
Pillay, J., Armstrong, M. J., Butalia, S., Donovan, L. E., Sigal, R. J., Vandermeer, B., Chordiya, P., Dhakal, S., Hartling, L., Nuspl, M., Featherstone, R., & Dryden, D. M. (2015). Behavioral programs for type 2 diabetes mellitus. Annals of Internal Medicine, 163(11), 848-860. http://doi.org/10.7326/M15-1400. PMid:26414227.
Raghu, G., Jakhotia, S., Yadagiri Reddy, P., Anil Kumar, P., & Bhanuprakash Reddy, G. (2016). Ellagic acid inhibits non-enzymatic glycation and prevents proteinuria in diabetic rats. Food & Function, 7(3), 1574-1583. http://doi.org/10.1039/C5FO01372K. PMid:26902315.
Ravi, K., Ramachandran, B., & Subramanian, S. (2004). Protective effect of Eugenia jambolana seed kernel on tissue antioxidants in streptozotocin-induced diabetic rats. Biological & Pharmaceutical Bulletin, 27(8), 1212-1217. http://doi.org/10.1248/bpb.27.1212. PMid:15305024.
Ravi, K., Rajasekaran, S., & Subramanian, S. (2005). Antihyperlipidemic effect of Eugenia jambolana seed kernel on streptozotocin-induced diabetes in rats. Food and Chemical Toxicology, 43(9), 1433-1439. http://doi.org/10.1016/j.fct.2005.04.004. PMid:15964674.
Reznick, A. Z., & Packer, L. (1994). Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods in Enzymology, 233, 357-363. PMid:8015470.
Ríos, J. L., Giner, R., Marín, M., & Recio, M. (2018). A pharmacological update of ellagic Acid. Planta Medica, 84(15), 1068-1093. http:// doi.org/10.1055/a-0633-9492. PMid:29847844.
Scio, E., Mendes, R. F., Motta, E. V. S., Bellozi, P. M. Q., Aragão, D. M. O., Mello, J., Fabri, R. L., Moreira, J. R., Assis, I. V. L., & Bouzada, M. L. M. (2012) Antimicrobial and antioxidant activities of some plant extracts. In V. Rao (Ed.), Phytochemicals as nutraceuticals: global approaches to their role in nutrition and health. London: IntechOpen.
Sheela, N., Jose, M. A., Sathyamurthy, D., & Kumar, B. N. (2013). Effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats. Iranian Journal of Kidney Diseases, 7(2), 117-123. PMid:23485535.
Sobral, M., & Duarte de Souza, M. A. (2015). Thirteen new Amazonian Myrtaceae. Phytotaxa, 238(3), 201-229. https://ui.adsabs. harvard.edu
Su, L. J., Zhang, J. H., Gomez, H., Murugan, R., Hong, X., Xu, D., Jiang, F., & Peng, Z. Y. (2019). Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxidative Medicine and Cellular Longevity, 2019, 5080843. http:// doi.org/10.1155/2019/5080843. PMid:31737171.
Umesalma, S., & Sudhandiran, G. (2010). Ellagic acid prevents rat colon carcinogenesis induced by azoxymethane through inhibition of NF-κB and Wnt/β-catenin signaling pathways. European Journal of Cancer Prevention, 19(2), 166-173. http://doi.org/10.1097/ CEJ.0b013e328334e4a8.
Valaiyapathi, B., Gower, B., & Ashraf, A. P. (2020). Pathophysiology of type 2 diabetes in children and adolescents. Current Diabetes Reviews, 16(3), 220-229. http://doi.org/10.2174/157339981466 6180608074510. PMid:29879890.
Vareda, P. M. P., Saldanha, L. L., Camaforte, N. A. D. P., Violato, N. M., Dokkedal, A. L., & Bosqueiro, J. R. (2014). Myrcia bella leaf extract presents hypoglycemic activity via PI3k/Akt insulin signaling pathway. Evidence-Based Complementary and Alternative Medicine, 2014(1), 543606. http://doi.org/10.1155/2014/543606. PMid:24872834.
Wendel, A. (1981). Glutathione peroxidase. Methods in Enzymology, 77, 325-333. http://doi.org/10.1016/S0076-6879(81)77046-0. PMid:7329310.
Wiesner, P., & Watson, K. E. (2017). Triglycerides: a reappraisal. Trends in Cardiovascular Medicine, 27(6), 428-432. http://doi. org/10.1016/j.tcm.2017.03.004. PMid:28438398.
Wong, T. S., Mohamed Tap, F., Hashim, Z., Abdul Majid, F. A., Zakaria, N. H., Siahaan, P., & Mogadem, A. (2022). Dual actions of gallic acid and andrographolide trigger AdipoR1 to stimulate insulin secretion in a streptozotocin-induced diabetes rat model. Journal of Traditional and Complementary Medicine, 13(1), 11-19. http://doi.org/10.1016/j.jtcme.2022.09.002. PMid:36685073.
Xu, Y., Tang, G., Zhang, C., Wang, N., & Feng, Y. (2021). Gallic acid and diabetes mellitus: its association with oxidative stress. Molecules, 26(23), 7115. http://doi.org/10.3390/molecules26237115. PMid:34885698.
Yaribeygi, H., Butler, A. E., Barreto, G. E., & Sahebkar, A. (2018a). Antioxidative potential of antidiabetic agents: a possible protective mechanism against vascular complications in diabetic patients. Journal of Cellular Physiology, 234(3), 2436-2446. http://doi.org/10.1002/jcp.27278. PMid:30191997.
Yaribeygi, H., Mohammadi, M. T., & Sahebkar, A. (2018b). Crocin potentiates the antioxidant defense system and improves oxidative damage in liver tissue in diabetic rats. Biomedicine and Pharmacotherapy, 98, 333-337. http://doi.org/10.1016/j. biopha.2017.12.077. PMid:29274590.
Yaribeygi, H., Mohammadi, M., & Sahebkar, A. (2018c). PPAR-α agonist improves hyperglycemia-induced oxidative stress in pancreatic cells by potentiating antioxidant defense system. Drug Research, 68(6), 355-360. http://doi.org/10.1055/s-0043-121143. PMid:29433142.
Yaribeygi, H., Farrokhi, F. R., Butler, A. E., & Sahebkar, A. (2019). Insulin resistance: review of the underlying molecular mechanisms. Journal of Cellular Physiology, 234(6), 8152-8161. http://doi. org/10.1002/jcp.27603. PMid:30317615.
Yaribeygi, H., Sathyapalan, T., Atkin, S. L., & Sahebkar, A. (2020). Molecular mechanisms linking oxidative stress and Diabetes Mellitus. Oxidative Medicine and Cellular Longevity, 2020, 8609213. http://doi.org/10.1155/2020/8609213. PMid:32215179.
Zahoor, M., Bari, W. U., Zeb, A., & Khan, I. (2020). Toxicological, anticholinesterase, antilipidemic, antidiabetic and antioxidant potentials of Grewia optiva Drummond ex Burret extracts. Journal of Basic and Clinical Physiology and Pharmacology, 31(2), 20190220. http://doi.org/10.1515/jbcpp-2019-0220. PMid:31926084.
Zhang, W., Chen, X., & Huang, L. (2019). Gallic acid ameliorates high glucose-induced insulin resistance via attenuating oxidative stress. Food Science and Biotechnology, 28(2), 555-561. http:// doi.org/10.1007/s10068-018-0493-x.
Submitted date:
05/21/2024
Accepted date:
01/30/2025
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email