POTENTIAL FOR DIABETIC WOUND HEALING WITH HYDROGEL PATCH OF NEEM LEAF EXTRACT (AZADIRACHTA INDICA)
DOI:
https://doi.org/10.22159/ijap.2025v17i2.53310Keywords:
Azadirachta indica, Anti-inflammatory, Hydrogel patch, Diabetic wound healingAbstract
Objective: Disruptions in the wound healing process occur because of two main factors in diabetes: high blood sugar levels and chronic inflammation. This study evaluated the effectiveness of hydrogel patches containing neem leaf extract in the healing of diabetic wounds.
Methods: The experimental method used a post-test control group design that included extract preparation, phytochemical screening, hydrogel patch preparation, stability testing, and testing of hyperglycemic rats by observing wound size, histopathology, and TNF-α and TGF-β cytokine levels on days 7, 14, and 21.
Results: The neem leaf extract contains secondary metabolites that support anti-inflammatory and wound-healing activities. Stability tests showed that the hydrogel patch met the standards for organoleptic properties, weight uniformity, and moisture absorption. The group given NLEHP (Neem Leaf Extract Hydrogel Patch) showed a decrease in wound area (0.5±0.1 cm2) not significantly different from the non-diabetic group with a reduction (0.5±0.1 cm2) (p>0.05) and significantly different from the negative group with a decrease (1.1±0 cm2) (p<0.05). Histopathological analysis of skin thickness of the NLEHP group (19.2±1.6 μm) was not significantly different from the non-diabetic group (18.2±0.8 μm) (p>0.05) and significantly higher than the negative control group (10.7±2.4 μm) (p<0.05). The TNF-α levels showed a significant increase (p<0.05) in the negative control group, whereas the non-diabetic and NLEHP groups showed a non-significant decrease (p>0.05). The levels of TGF-β progressively increased in the non-diabetic and NLEHP groups, unlike the decline observed in the negative control.
Conclusion: These results indicate that the neem leaf extract hydrogel patch is an effective alternative for diabetic wound healing therapy.
References
Yang L, Rong GC, WU QN. Diabetic foot ulcer: challenges and future. World J Diabetes. 2022;13(12):1014-34. doi: 10.4239/wjd.v13.i12.1014, PMID 36578870.
Saputra MK, Masdarwati M, Lala NN, Tondok SB, Pannyiwi R. Analysis of the occurrence of diabetic wounds in people with diabetes mellitus. fulltext PDF. 2023;12(1):143-9. doi: 10.35816/jiskh.v12i1.915.
Liu ZW, Zhang YM, Zhang LY, Zhou T, LI YY, Zhou GC. Duality of interactions between TGF-Β and TNF-Α during tumor formation. Front Immunol. 2021;12:810286. doi: 10.3389/fimmu.2021.810286, PMID 35069596.
Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB. The role of tumor necrosis factor-alpha (TNF-Α) in autoimmune disease and current TNF-Α inhibitors in therapeutics. Int J Mol Sci. 2021;22(5):2719. doi: 10.3390/ijms22052719, PMID 33800290.
Wang HL, Wang L, Zhao CY, Lan HY. Role of TGF-beta signaling in beta cell proliferation and function in diabetes. Biomolecules. 2022;12(3):373. doi: 10.3390/biom12030373, PMID 35327565.
Nasrine A, Narayana S, Gulzar Ahmed M, Sultana R, Noushida N, Raunak Salian T. Neem (Azadirachta indica) and silk fibroin associated hydrogel: boon for wound healing treatment regimen. Saudi Pharm J. 2023;31(10):101749. doi: 10.1016/j.jsps.2023.101749, PMID 37663591.
Batra N, Kumar VE, Nambiar R, De Souza C, Yuen A, LE U. Exploring the therapeutic potential of neem (Azadirachta indica) for the treatment of prostate cancer: a literature review. Ann Transl Med. 2022;10(13):754. doi: 10.21037/atm-22-94, PMID 35957716.
Zhang S, GE G, Qin Y, LI W, Dong J, Mei J. Recent advances in responsive hydrogels for diabetic wound healing. Mater Today Bio. 2022 Dec 1;18:100508. doi: 10.1016/j.mtbio.2022.100508, PMID 36504542.
Wardani VK, Saryanti D. Papaya seed ethanol extract transdermal patch formulation (Carica papaya L.) with hydroxypropyl methylcellulose base (HPMC). Med J. 2021;4:38.v4i1.43613.
Sharma P, Aggarwal A, Tandon S. Review article enhancing transdermal delivery of poorly water-soluble NSAIDs: effective strategies. Int J Curr Pharm Sci. 2024;16(6):1-5. doi: 10.22159/ijcpr.2024v16i6.5070.
Jacob S, Nair AB, Shah J, Sreeharsha N, Gupta S, Shinu P. Emerging role of hydrogels in drug delivery systems tissue engineering and wound management. Pharmaceutics. 2021;13(3):357. doi: 10.3390/pharmaceutics13030357, PMID 33800402.
Novriyanti R, Putri NE, Rijai L. Phytochemical screening and antioxidant activity test of lime peel ethanol extract (Citrus aurantifolia) using the DPPH method. Proceeding Mulawarman Pharm Conf. 2022;15(1):165-70. doi: 10.25026/mpc.v15i1.637%0A1.
Dubale S, Kebebe D, Zeynudin A, Abdissa N, Suleman S. Phytochemical screening and antimicrobial activity evaluation of selected medicinal plants in Ethiopia. J Exp Pharmacol. 2023 Feb 8;15:51-62. doi: 10.2147/JEP.S379805, PMID 36789235.
Muhtadi M, Haryoto H, Azizah T, Suhendi A, Yen KH. Antidiabetic and antihypercholesterolemic activities of citrus sinensis peel: in vivo study. Natl J Physiol Pharm Pharmacol. 2015;5(5):382-5. doi: 10.5455/njppp.2015.5.2807201561.
Rusnedy R, Febrina M, Sari CP. Uji aktivitas wound healing ekstrak etanol buah Averrhoa bilimbiL. (Belimbing Wuluh) pada mencit putih jantan (Mus musculus). Pharmacon. 2023;20(1):50-60. doi: 10.23917/pharmacon.v20i1.22677.
Hanistya R, Samlan K. Formulation and physical characteristics of hydrogel plaster preparations of Ciplukan leaf extract (Physalis angulata L.) and cinnamon bars (Cinnamomum burmannii). J Muhammadiyah Med Lab Technol. 2021;4:201.v4i2.11151.
Bin JW, Muthia R, Kartini K, Setiawan F, Juhrah S, Yulida N. Formulation and evaluation of transdermal patches from Eleutherine bulbosa Urb. bulb extract with plasticizer variations. Int J Appl Pharm. 2024;16(1):94-7. doi. 10.22159/ijap.2024v16i1.46421.
Wahyuni AS, Munawaroh R, Dai M. Antidiabetic mechanism of ethanol extract of black rice bran on diabetic rats. Natl J Physiol Pharm Pharmacol. 2016;6(2):106-10. doi: 10.5455/njppp.2015.5.1111201590.
Rahati S, Kamalinezhad M, Ebrahimi A, Eshraghian M, Pishva H. Accelerated wound healing induced by spinach extract in experimental model diabetic rats with streptozotocin. Sci Rep. 2023;13(1):14933. doi: 10.1038/s41598-023-42033-0, PMID 37696865.
Maan P, Yadav KS, Yadav NP. Wound healing activity of Azadirachta indica a. juss stem bark in mice. Pharmacogn Mag. 2017;13 Suppl 2:S316-20. doi: 10.4103/0973-1296.210163, PMID 28808399.
Muhtadi M, Haryoto H, Azizah T, Suhendi A, Yen K. Antidiabetic and antihypercholesterolemic activities of Citrus sinensis peel: in vivo study. Natl J Physiol Pharm Pharmacol. 2015;5(5):382-5. doi: 10.5455/njppp.2015.5.2807201561.
Salrian AA, Behzadi A, Oloumi MM, Farajli Abbasi M, Delshad S, Moghadaszadeh M. Amplification of wound healing by propolis and honey ointment in healthy and diabetic rat models; histopathological and morphometric findings. Arch Razi Inst. 2022;77(5):1673-81. doi: 10.22092/ARI.2022.357191.1991, PMID 37123150.
Gunawan SA, Berata IK, Wirata IW. Histopathology of skin on incision wound healing of white rats after administration of extracellular matrix (ECM) derived from pig urinary bladder. Indones Med Veterinus. 2019;8:313-24. doi: 10.19087/imv.2019.8.3.313.
Masson Meyers DS, Andrade TA, Caetano GF, Guimaraes FR, Leite MN, Leite SN. Experimental models and methods for cutaneous wound healing assessment. Int J Exp Pathol. 2020;101(1-2):21-37. doi: 10.1111/iep.12346, PMID 32227524.
Chagas MD, Behrens MD, Moragas Tellis CJ, Penedo GX, Silva AR, Goncalves DE Albuquerque CF. Flavonols and flavones as potential anti‐inflammatory, antioxidant and antibacterial compounds. Oxid Med Cell Longev. 2022;2022(1):9966750. doi: 10.1155/2022/9966750, PMID 36111166.
Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. doi: 10.1017/jns.2016.41, PMID 28620474.
Al Ishaq RK, Abotaleb M, Kubatka P, Kajo K, Busselberg D. Flavonoids and their anti-diabetic effects: cellular mechanisms and effects to improve blood sugar levels. Biomolecules. 2019;9(9):430. doi: 10.3390/biom9090430, PMID 31480505.
Wati DP, Ilyas S. Renoprotective potential of flavonoids rich against doxorubicin-induced in animal models: a review. Int J App Pharm. 2024;16(6):28-37. doi: 10.22159/ijap.2024v16i6.51741.
Souza CR, Bezerra WP, Souto JT. Marine alkaloids with anti-inflammatory activity: current knowledge and future perspectives. Mar Drugs. 2020;18(3):147. doi: 10.3390/md18030147, PMID 32121638.
Yadav JP, Verma A, Pathak P, Dwivedi AR, Singh AK, Kumar P. Phytoconstituents as modulators of NF-κB signalling: investigating the therapeutic potential for diabetic wound healing. Biomed Pharmacother. 2024;177:117058. doi: 10.1016/j.biopha.2024.117058, PMID 38968797.
Berry CE, Brenac C, Gonzalez CE, Kendig CB, LE T, An N. Natural compounds and biomimetic engineering to influence fibroblast behavior in wound healing. Int J Mol Sci. 2024;25(6):3274. doi: 10.3390/ijms25063274, PMID 38542247.
Shita AD, Dharmayanti AW, Meilawaty Z, Lestari M, Mazaya IM. Increasing fibroblasts and gingival collagen density in periodontitis rats by using cassava leaf extract. J Taibah Univ Med Sci. 2023;18(6):1321-8. doi: 10.1016/j.jtumed.2023.05.006, PMID 37293131.
Kalalinia F, Amiri N, Mehrvarzian N, Fazly Bazzaz BS, Iranshahi M, Shahroodi A. Topical green tea formulation with anti-hemorrhagic and antibacterial effects. Iran J Basic Med Sci. 2020;23(8):1085-90. doi: 10.22038/ijbms.2020.41397.9782, PMID 32952956.
Alzohairy MA. Therapeutics role of Azadirachta indica (neem) and their active constituents in diseases prevention and treatment. Evid Based Complement Alternat Med. 2016;2016:7382506. doi: 10.1155/2016/7382506, PMID 27034694.
Nagini S. Neem limonoids as anticancer agents: modulation of cancer hallmarks and oncogenic signaling. Enzymes. 2014;36:131-47. doi: 10.1016/B978-0-12-802215-3.00007-0, PMID 27102702.
Jayalakshmi M. Effect of neem leaves extract irrigation on the wound healing outcome in nurse managed diabetic foot ulcers. Natl J Physiol Pharm Pharmacol. 2020;11(1):1. doi: 10.5455/njppp.2021.10.09238202008092020.
Treichel TL, DO Prado TD, DO Amaral AS, DE Sousa Gomes Y, DA Rocha Pinto L, Martins GT. Use of ointment or aqueous extract of neem (Azadirachta indica) for the repair of experimental skin lesions in sheep. Am J Plant Sci. 2020;11(5):693-706. doi: 10.4236/ajps.2020.115051.
Patel DP, Setty CM, Mistry GN, Patel SL, Patel TJ, Mistry PC. Development and evaluation of ethyl cellulose-based transdermal films of furosemide for improved in vitro skin permeation. AAPS Pharm Sci Tech. 2009;10(2):437-42. doi: 10.1208/s12249-009-9224-3, PMID 19381831.
Gounden V, Singh M. Hydrogels and wound healing: current and future prospects. Gels. 2024;10(1):43. doi: 10.3390/gels10010043, PMID 38247766.
Deng X, Gould M, Ali MA. A review of current advancements for wound healing: biomaterial applications and medical devices. J Biomed Mater Res B Appl Biomater. 2022;110(11):2542-73. doi: 10.1002/jbm.b.35086, PMID 35579269.
Hatting M, Tavares CD, Sharabi K, Rines AK, Puigserver P. Insulin regulation of gluconeogenesis. Ann N Y Acad Sci. 2018;1411(1):21-35. doi: 10.1111/nyas.13435, PMID 28868790.
Lenzen S. The mechanisms of alloxan and streptozotocin-induced diabetes. Diabetologia. 2008;51(2):216-26. doi: 10.1007/s00125-007-0886-7, PMID 18087688.
American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care. 2021;44 Suppl 1:S15-33. doi: 10.2337/dc21-S002, PMID 33298413.
Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2019;99(1):665-706. doi: 10.1152/physrev.00067.2017, PMID 30475656.
Wulandari D, Noviyanti NP, Wardani L, Yowani SC. Efektivitas nanoemulgel kombinasi ekstrak daun mimba dan lidah buaya untuk terapi skabies. JMPI. 2023;9(2):461-74. doi: 10.35311/jmpi.v9i2.403.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314-21. doi: 10.1038/nature07039, PMID 18480812.
Berlanga Acosta JA, Guillen Nieto GE, Rodriguez Rodriguez N, Mendoza Mari Y, Bringas Vega ML, Berlanga Saez JO. Cellular senescence as the pathogenic hub of diabetes-related wound chronicity. Front Endocrinol (Lausanne). 2020;11:573032. doi: 10.3389/fendo.2020.573032, PMID 33042026.
Panichakul T, Ponnikorn S, Tupchiangmai W, Haritakun W, Srisanga K. Skin anti-aging potential of Ipomoea pes-caprae ethanolic extracts on promoting cell proliferation and collagen production in human fibroblasts (CCD-986sk cells). Pharmaceuticals (Basel). 2022;15(8):969. doi: 10.3390/ph15080969, PMID 36015117.
Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49(1):35-43. doi: 10.1159/000339613, PMID 22797712.
Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care. 2015;4(3):119-36. doi: 10.1089/wound.2013.0485, PMID 25785236.
Ruslie RH, Darmadi D. Administration of neem (Azadirachta indica A. Juss) leaf extract decreases TNF-α and IL-6 expressions in dextran sodium sulphate induced colitis in rats. J Adv Vet Anim Res. 2020;7(4):744-9. doi: 10.5455/javar.2020.g476, PMID 33409321.
Rajendran P, Renu K, Abdallah BM, Ali EM, Veeraraghavan VP, Sivalingam K. Nimbolide: promising agent for prevention and treatment of chronic diseases (recent update). Food Nutr Res. 2024;68:1-14. doi: 10.29219/fnr.v68.9650.
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