Macaranga tanarius Reduces the Expression of Vascular Endothelial Growth Factor and Tumor Necrosis Factor-Alpha in Diabetic Retinopathic Rats
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Abstract
Diabetic retinopathy (DR), a microvascular consequence of diabetes mellitus, leads to blindness in the elderly due to damage to the retinal blood barrier. Macaranga tanarius (L.) Mull. Argument. Leaves (MT) include prenylflavonoids and other bioactive substances that are advantageous for managing diabetes mellitus. This study aimed to evaluate the efficacy of MT as an alternative treatment for DR by reducing levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α). Rats were divided into five groups (n=5 per group): Group I (diabetic control, NA-CMC 1%), Group II (positive control, glibenclamide 0.45 mg/Kg BW orally), and Groups III to V received ethanol extract of MT orally at doses of 0.64, 1.28, and 1.92 g/Kg BW, respectively. All groups were induced with STZ-NA (45 and 110 mg/kg BW intraperitoneally) and subsequently rested for four weeks before receiving treatment once daily for four weeks, after which the rats were confirmed to have diabetes mellitus with fasting blood glucose (FBG) levels ≥250 mg/dL. FBG was evaluated on days 3, 31, and 59, while TNF-α and VEGF levels were tested on days 31 and 59 using blood samples obtained from the orbital sinus. MT extract at a dosage of 1.92 g/kg BW can enhance body weight (p˂ 0.05), induce a 17.10% drop in FBG levels (comparable to glibenclamide's effect of 17.03%), and achieve a 57.06% and 52.39% decrease in TNF-α and VEGF levels, respectively, outperforming the other four groups. MT extract from these results proved to be an effective alternative treatment for DR in DM rats induced with STZ-NA.
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1. Dwivedi M, Pandey AR. Diabetes Mellitus and Its Treatment: An Overview. J Adv Pharmacol. 2020;1(1):48–58.
2. Hsu YC, Chang CC, Hsieh CC, Shih YH, Chang HC, Lin CL. Therapeutic Potential of Extracts from Macaranga tanarius (MTE) in Diabetic Nephropathy. Plants. 2023;12(3).
3. Wahidin M, Achadi A, Besral B, Kosen S, Nadjib M, Nurwahyuni A, Ronoatmodjo S, Rahajeng E, Pane M, Kusuma D. Projection of diabetes morbidity and mortality till 2045 in Indonesia based on risk factors and NCD prevention and control programs. Sci Rep 2024;14(1):1–17. Available from: https://doi.org/10.1038/s41598-024-54563-2
4. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S, Boyko EJ, Magliano D. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:1–23.
5. Wahyuningsih AS, Yunus A, Purwanto B, Wasita B, Pamungkasari EP, Nurwati I, Soetrisno S. Blood Sugar Levels in terms of Differences in Intervention Time Duration for Corncob Ethanol Extract in Male Wistar Rats as a Model Of Diabetes Mellitus. Trop J Nat Prod Res. 2024;8(12):9451–9455.
6. Damanik EB, Manafe DRT, Kareri DGR. The Effect of Red Betel Leaf (Piper crocatum) Ethanol Extract on the Histopathological Eye Image of Alloxan-Induced Diabetic Rat (Rattus norvegicus). Trop J Nat Prod Res. 2024;8(4):6771–6774.
7. Ajani RA, Oboh G, Adefegha SA, Akindahunsi AA. Free Polyphenol Contents, Antioxidant Activity and Inhibition of Enzymes Linked with Type-2-Diabetes of Bread Produced from Cocoa Powder Flavoured Improved Variety Cassava-Wheat Composite Flours. Trop J Nat Prod Res. 2022;6(2):227–235.
8. Hou Y, Cai Y, Jia Z, Shi S. Risk factors and prevalence of diabetic retinopathy: A protocol for meta-analysis. Med (United States). 2020;99(42):E22695.
9. Wong TY, Cheung CMG, Larsen M, Sharma S, Simó R. Diabetic retinopathy. Nat Rev Dis Prim. 2016;2: 16012. https://doi.org/10.1038/nrdp.2016.12l).
10. Ucgun NI, Zeki-Fikret C, Yildirim Z. Inflammation and diabetic retinopathy. Mol Vis. 2020;26:718–21.
11. Kusuhara S, Fukushima Y, Ogura S, Inoue N, Uemura A. Pathophysiology of diabetic retinopathy: The old and the new. Diabetes Metab J. 2018;42(5):364–376.
12. Xu M, Fan R, Fan X, Shao Y, Li X. Progress and Challenges of Anti-VEGF Agents and Their Sustained-Release Strategies for Retinal Angiogenesis. Drug Des Devel Ther. 2022;16:3241–3262.
13. Nam SH, Yamano A, Kim JA, Lim J, Baek SH, Kim JE, Kwon TG, Saito Y, Teruya T, Choi SY, Kim YK. Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways. Int Endod J. 2021;54(7):1142–1154.
14. Nakashima K, Miyashita H, Yoshimitsu H, Fujiwara Y, Nagai R, Ikeda T. Prenylflavonoids isolated from Epimedii Herba show inhibition activity against advanced glycation end-products. Front Chem. 2024;12:1–13.
15. Natsume N, Yonezawa T, Saito Y, Woo JT, Teruya T. Prenylflavonoids from fruit of Macaranga tanarius promote glucose uptake via AMPK activation in L6 myotubes. J Nat Med. 2021;75(4):813–823.
16. Salama R, Abdelaziz SAM. Retinal Protective Effect of Avocado Soybean (ASB) Versus Glibenclamide in Streptozotocin-Induced Diabetic Rats. Egypt J Histol. 2024;47(1):1–25.
17. Estefania KV, Silalahi J, Sumaiyah S, Satria D. Formulation and Evaluation of Cream Turmeric Extract Preparations from Turmeric Rhizomes (Curcuma domestica Val.). Indones J Pharm Clin Res. 2022;5(1):01–9.
18. Nurcahyo H, Sumiwi SA, Halimah E, Wilar G. Total Flavonoid Levels of Ethanol Extract and Ethyl Acetate Fraction Dry Shallots (Allium cepa L. var. Garden Onion of Brebes) with Maceration Methods Using UV-Vis Spectrophotometry. Syst Rev Pharm. 2020;11(10):286–289.
19. Caputo L, Amato G, de Bartolomeis P, De Martino L, Manna F, Nazzaro F, De Feo V, Barba AA. Impact of drying methods on the yield and chemistry of Origanum vulgare L. essential oil. Sci Rep. 2022;12(1):1–11.
20. Lapidot-Cohen T, Rosental L, Brotman Y. Liquid Chromatography–Mass Spectrometry (LC-MS)-Based Analysis for Lipophilic Compound Profiling in Plants. Curr Protoc Plant Biol. 2020;5(2):1–18.
21. Ghasemi A, Jeddi S. Streptozotocin As a Tool for Induction of Rat Models of Diabetes: a Practical Guide. EXCLI J. 2023;22:274–294.
22. Khanra R, Bhattacharjee N, Dua TK, Nandy A, Saha A, Kalita J, Manna P, Dewanjee S. Taraxerol, a pentacyclic triterpenoid, from Abroma augusta leaf attenuates diabetic nephropathy in type 2 diabetic rats. Biomed Pharmacother. 2017;94:726–41. Available from: http://dx.doi.org/10.1016/j.biopha.2017.07.112
23. Cruz PL, Moraes-Silva IC, Ribeiro AA, Machi JF, de Melo MDT, dos Santos F, da Silva MB, Strunz CMC, Caldini EG, Irigoyen MC. Nicotinamide attenuates streptozotocin-induced diabetes complications and increases survival rate in rats: role of autonomic nervous system. BMC Endocr Disord. 2021;21(1):1–10.
24. Tang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy. Neural Regen Res. 2023;18(5):976–982.
25. Adki KM, Kulkarni YA. Paeonol attenuates retinopathy in streptozotocin-induced diabetes in rats by regulating the oxidative stress and polyol pathway. Front Pharmacol. 2022;13(September):1–8.
26. Talbot SR, Biernot S, Bleich A, van Dijk RM, Ernst L, Häger C, Helgers SOA, Koegel B, Koska I, Kuhla A, Miljanovic N, Müller-Graff FT, Schwabe K, Tolba R, Vollmar B, Weegh N, Wölk T, Wolf F, Wree A, Zieglowski L, Potschka H. Defining body-weight reduction as a humane endpoint: a critical appraisal. Lab Anim. 2020;54(1):99–110.
27. Lee SW. Regression analysis for continuous independent variables in medical research: statistical standard and guideline of Life Cycle Committee. Life Cycle. 2022;2:1–8.
28. Nanda A, Mohapatra DBB, Mahapatra APK, Mahapatra APK, Mahapatra APK. Multiple comparison test by Tukey’s honestly significant difference (HSD): Do the confident level control type I error. Int J Stat Appl Math. 2021;6(1):59–65.
29. Chien YH, Yu YH, Ye SR, Chen YW. Antibacterial and Antioxidant Activity of the Fruit of Macaranga tanarius, the Plant Origin of Taiwanese Green Propolis. Antioxidants. 2022;11(7). Doi:10.3390/antiox11071242
30. Gali S, Kundu A, Sharma S, Ahn MY, Puia Z, Kumar V, Kim IS, Kwak JH, Palit P, Kim HS. Therapeutic potential of bark extracts from Macaranga denticulata on renal fibrosis in streptozotocin-induced diabetic rats. J Toxicol Environ Heal - Part A Curr Issues 2024;00(00):1–23. Doi:10.1080/15287394.2024.2394586
31. Solikhah TI, Setiawan B, Ismukada DR. Antidiabetic activity of papaya leaf extract (Carica Papaya L.) isolated with maceration method in alloxan-induces diabetic mice. Syst Rev Pharm. 2020;11(9):774–778.
32. Potrebić MS, Pavković ŽZ, Srbovan MM, Đmura GM, Pešić VT. Changes in the Behavior and Body Weight of Mature, Adult Male Wistar Han Rats after Reduced Social Grouping and Social Isolation. J Am Assoc Lab Anim Sci. 2022;61(6):615–623.
33. Chandran R, Primelazhagan T, Shanmugam S, Thankarajan S. Antidiabetic activity of Syzygium calophyllifolium in Streptozotocin-Nicotinamide induced Type-2 diabetic rats. Biomed Pharmacother. 2016;82:547–554.
34. Pasaribu SF, Wiboworini B, Kartikasari LR. Effect of Germinated Black Rice Krisna Extract on Fasting Blood Glucose and Body Weight in Diabetes Mellitus Rats. Int J Nutr Sci. 2021;6(4):194–200.
35. Ebrahimi B, Azizi H, Sarkarizi HK, Bahrami-Taghanaki H, Rajabzadeh A. Comparing the effect of electroacupuncture and glibenclamide on blood glucose level and histological markers of pancreas in streptozotocin-induced diabetic rats. Altern Ther Health Med. 2020;26:12–19.
36. Azzahra AA, Sujono TA. Science Midwifery Testantidiabetic activity of a combination of 70% ethanol extract of meniran leaves (Phyllanthus Niruri L.) and glibenclamide in male white Wistar rats induced by alloxan. Sci Midwifery. 2024;12(1):2721–9453.
37. Wei H, Qiao L, Wang L, Luo M, Di M, Hui Z, LiangM, Jing W, Hai L. Phytochemistry and pharmacology of natural prenylated flavonoids. Vol. 46, Archives of Pharmacal Research. Pharmaceutical Society of Korea; 2023. 207–272 p.
38. Gandhi GR, Bruno A, Vasconcelos S, Wu D, Li H, Antony PJ, Li H, Geng F, Gurgel RQ, Narain N. Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications : A Systematic Review of In Vitro and In Vivo Studies. 2020;
39. Salleh WMNHW, Razak NZA, Ahmad F. Phytochemicals and biological activities of Macaranga hosei and Macaranga constricta (Euphorbiaceae). Marmara Pharm J. 2017;21(4):881–888.
40. Segun P, Gbadebo M, Adebowale M, Olufolabo K, Fred-Jaiyesimi A. Investigation of the anti-inflammatory and hypoglycaemic effects of Macaranga hurifolia beille (Eurphorbiaceae) extract on Wistar albino rats. Acta Pharm Sci. 2019;57(4):93–102.
41. Elsadek MF, Ahmed BM. Effect of sakuranin on carbohydrate-metabolizing enzyme activity modifications in streptozotocin-nicotinamide-induced diabetic wistar rats. Saudi J Biol Sci . 022;29(3):1402–1406. Doi:10.1016/j.sjbs.2021.11.035
42. Sasongko H, Rohman A, Nurrochmad A, Nugroho AE. Biochemical And Triglyceride-Glucose Index (Tyg) Profile In High Doses Streptozotocin-Nicotinamide Produce Diabetes Mellitus In Rats Model. Trop J Nat Prod Res. 2024;8(6):7499–7503.
43. Panjaitan RGP, Astuti A. Antidiabetic Activity of the Leaf Extract of Eurycoma Longifolia Jack. in Streptozotocin-Nicotinamide Induced Diabetic Model. Pharmacogn J. 2021;13(6):1582–1588.
44. Rehman H ur, Ullah K, Rasool A, Manzoor R, Yuan Y, Tareen AM, Kaleem I, Riaz N, Hameed S, Bashir S. Comparative impact of streptozotocin on altering normal glucose homeostasis in diabetic rats compared to normoglycemic rats. Sci Rep. 2023;13(1):1–6. Available from: https://doi.org/10.1038/s41598-023-29445-8
45. Berdugo M, Delaunay K, Naud M, Moulin A, Savoldelli M, Picard É, Radet L, Jonet L, Djerada Z, Berdugo M, Delaunay K, Naud M, Guegan J, Moulin A. The antidiabetic drug glibenclamide exerts direct retinal neuroprotection To cite this version : HAL Id : inserm-02980520. 2020;
46. Shahinozzaman M, Taira N, Ishii T, Halim MA, Hossain MA, Tawata S. Anti-inflammatory, anti-diabetic, and anti-Alzheimer’s effects of prenylated flavonoids from Okinawa propolis: An investigation by experimental and computational studies. Molecules. 2018;23(10):1–18.
47. Garaulet M, Lopez-Minguez J, Dashti HS, Vetter C, Hernández-Martínez AM, Pérez-Ayala M, Baraza JC, Wang W, Florez JC, Scheer FAJL, Saxena R. Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial. Diabetes Care. 2022;45(3):512–519.
48. Liu KF, Niu CS, Tsai JC, Yang CL, Peng WH, Niu HS. Comparison of area under the curve in various models of diabetic rats receiving chronic medication. Arch Med Sci. 2022;18(4):1078–1087.
49. Alema NM, Periasamy G, Sibhat GG, Tekulu GH, Hiben MG. Antidiabetic activity of extracts of Terminalia brownii fresen. Stem bark in mice. J Exp Pharmacol. 2020;12:61–71.
50. Jiang B, Geng Q, Li T, Mohammad Firdous S, Zhou X. Morin attenuates STZ-induced diabetic retinopathy in experimental animals. Saudi J Biol Sci [Internet]. 2020;27(8):2139–2142. Doi:10.1016/j.sjbs.2020.06.001
51. Abu-Yaghi NE, Abu Tarboush NM, Abojaradeh AM, Al-Akily AS, Abdo EM, Emoush LO. Relationship between Serum Vascular Endothelial Growth Factor Levels and Stages of Diabetic Retinopathy and Other Biomarkers. J Ophthalmol. 2020;2020.
52. Zhang M, Zhou M, Cai X, Zhou Y, Jiang X, Luo Y, Hu Y, Qiu R, Wu Y, Zhang Y, Xiong Y. VEGF promotes diabetic retinopathy by upregulating the PKC/ET/NF-κB/ICAM-1 signaling pathway. Eur J Histochem. 2022;66(4).
53. Cheng R, Ma J xing. Angiogenesis in Diabetes and Obesity. Rev Endocr Metab Disord. 2016;16(1):67–75.
54. Ansari P, Tabasumma N, Snigdha NN, Siam NH, Panduru RVNRS, Azam S, Hannan, JMA, Abdel-Wahab YHA. Diabetic Retinopathy: An Overview on Mechanisms, Pathophysiology and Pharmacotherapy. Diabetology. 2022;3(1):159–175.
55. Khaloo P, Qahremani R, Rabizadeh S, Omidi M, Rajab A, Heidari F, Farahmand G, Bitaraf M, Mirmiranpour H, Esteghamati A, Nakhjavani M. Nitric oxide and TNF-α are correlates of diabetic retinopathy independent of hs-CRP and HbA1c. Endocrine [Internet]. 2020;69(3):536–541. Doi:10.1007/s12020-020-02353-x
56. Pitale PM, Gorbatyuk MS. Diabetic Retinopathy: From Animal Models to Cellular Signaling. Int J Mol Sci. 2022;23(3):1–22.
57. Zhou Z, Ju H, Sun M, Chen H. Review Article Serum Vascular Endothelial Growth Factor Levels Correlate with Severity of Retinopathy in Diabetic Patients : A Systematic Review and Meta-Analysis. 2019;2019:1-15. Doi:10.1155/2019/9401628
58. Zou Y, Zhou C, Xu H, Yu J, Ye P, Zhang H, Chen S, Zhao J, Le S, Cui J, Jiang L, Wu J, Xia J. Glibenclamide ameliorates transplant-induced arteriosclerosis and inhibits macrophage migration and MCP-1 expression. Life Sci [Internet]. 2020;241:117141. Available from: https://doi.org/10.1016/j.lfs.2019.117141
59. Amir Rawa MS, Nurul Azman NA, Mohamad S, Nogawa T, Wahab HA. In Vitro and In Silico Anti-Acetylcholinesterase Activity from Macaranga tanarius and Syzygium jambos. Molecules. 2022;27(9):1–11.
60. Lv W, Wang X, Xu Q, Lu W. Current Topics in Medicinal Chemistry. Curr Top Med Chem. 2020;20(1):37–56.
61. Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. 2020;37(xxxx):101799.
62. Park S, Sim KS, Hwangbo Y, Park SJ, Kim YJ, Kim JH. Naringenin and Phytoestrogen 8-Prenylnaringenin Protect against Islet Dysfunction and Inhibit Apoptotic Signaling in Insulin-Deficient Diabetic Mice. Molecules. 2022;27(13). Doi:10.3390/molecules27134227
63. Ogundajo AL, Tom Ashafa AO. Chemical profiling, antioxidant and carbohydrate-metabolizing enzymes inhibitory potential of fractions from the leaves of Macaranga bateri Mull-Arg. Trans R Soc South Africa. 2019;74(1):27–37. Doi: 10.1080/0035919X.2018.1552213
64. Megawati, Hariyanti, Pebriani R, Fajriah S. Inhibition activity of -glucosidase enzyme, phenolic content, and toxicity of Mara (Macaranga tanarius (L.) Mull. Arg) Leaf. IOP Conf Ser Mater Sci Eng. 2021;1011(1).