SYNERGISTIC POTENTIAL OF NIGELLA SATIVA L. AND TRIGONELLA FOENUM-GRAECUM: INTEGRATED NETWORK PHARMACOLOGY FOR DIABETIC WOUND HEALING

Authors

  • MAHARANI RETNA DUHITA Department Biology Faculty of Science and Technology Universitas Islam Negeri Maulana Malik Ibrahim Malang, Malang, Indonesia https://orcid.org/0000-0002-1651-2903
  • RETNO SUSILOWATI Department Biology Faculty of Science and Technology Universitas Islam Negeri Maulana Malik Ibrahim Malang, Malang, Indonesia
  • SITI QURROTUL AINI Department Biology Faculty of Science and Technology Universitas Islam Negeri Maulana Malik Ibrahim Malang, Malang, Indonesia https://orcid.org/0009-0004-9483-0204
  • RAHMI ANNISA Department of Pharmacy Faculty of Medicine and Health Science Universitas Islam Negeri Maulana Malik Ibrahim Malang, Malang, Indonesia

DOI:

https://doi.org/10.22159/ijap.2024v16i6.51718

Keywords:

DW, Network pharmacology, N. sativa L, T. foenum-graecum

Abstract

Objective: Diabetes Mellitus (DM) is a metabolic disorder marked by elevated blood glucose levels, and one of the issues linked to DM involves the development of Diabetic Wounds (DW). DW is susceptible to infection and develops into chronic wounds if not treated properly. This study aimed to investigate the network pharmacology of N. sativa L. and T. foenum-graecum, emphasizing on their potential as DW treatment candidates.

Methods: Various databases were used in this study, including PubChem, Dr. Duke's phytochemistry and Ethnobotany, and KNApSAcK Family. Swiss Target Prediction and Way2Drug PASS Online were utilized for biological activity and protein target prediction. The DW pathway's protein-protein interactions were examined with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Cards, and STRING databases. STRING was used to predict the metabolite's action. The relationship between metabolites and target proteins was predicted using STITCH, and Cytoscape was used to visualize the network.

Result: The results showed that ten active ingredients (five active ingredients in N. sativa L. and five active ingredients in T. foenoem-graecum) contributed to DW healing by affecting Tumor Necrosis Factor (TNF), Interleukin-1beta (IL1B), JUN, Caspase 3 (CASP3), Interleukin-6 (IL-6), Alpha Kinase Threonine-1 (AKT1), Vascular Endothelial Growth Factor-A (VEGFA), and Mitogen-Activated Protein Kinase 3 (MAPK3) genes. Furthermore, the ten active ingredients correlated with twenty-eight intracellular proteins, resulting in a mechanism involving eight DW signalling pathways.

Conclusion: Based on network pharmacology analysis, we determine that N. sativa L. and T. foenoem-graecum combination can potentially treat DW.

Downloads

Download data is not yet available.

References

Shailaja K, Abraham A, Bhargavi B, Devika R. Influence of pharmaceutical care activities on knowledge attitude and practice (KAP) among diabetic patients in a Tertiary Care Hospital. Int J Pharm Pharm Sci. 2020;12(5):36-40. doi: 10.22159/ijpps.2020v12i5.36984.

Arman E, AA, Dafriani P, Almasdy D. Combined effect of topical application of virgin coconut oil (vco) and black cumin oil (nigella sativa) on the upregulation of vegf gene expression and wound healing in diabetic ulcerated rats. Int J App Pharm. 2024;16(1):35-40. doi: 10.22159/ijap.2024.v16s1.07.

Marchianti AC, Prameswari MC, Sakinah EN, Ulfa EU. The enhancement of collagen synthesis process on diabetic wound by Merremia mammosa (Lour.) extracts fraction. Int J Pharm Pharm Sci. 2019 Feb;11(2):47-50. doi: 10.22159/ijpps.2019v11i2.30170.

Maslova E, Eisaiankhongi L, Sjoberg F, McCarthy RR. Burns and biofilms: priority pathogens and in vivo models. NPJ Biofilms Microbiomes. 2021;7(1):73. doi: 10.1038/s41522-021-00243-2, PMID 34504100.

Giannopoulos S, Armstrong EJ. Diabetes mellitus: an important risk factor for peripheral vascular disease. Expert Rev Cardiovasc Ther. 2020;18(3):131-7. doi: 10.1080/14779072.2020.1736562, PMID 32129693.

Lipsky BA, Senneville E, Abbas ZG, Aragon Sanchez J, Diggle M, Embil JM. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3280. doi: 10.1002/dmrr.3280, PMID 32176444.

Sukmawan YP, Alifiar I, Nurdianti L, Ningsih WR. Wound healing effectivity of the ethanolic extracts of Ageratum conyzoides L. leaf (white and purple flower type) and Centella asiatica and astaxanthin combination gel preparation in an animal model. Turk J Pharm Sci. 2021;18(5):609-15. doi: 10.4274/tjps.galenos.2021.34676, PMID 34719189.

Ivanalee AS, Yudaniayanti IS, Yunita MN, Triakoso N, Hamid IS, Saputro AL. Efektivitas sugar dressing (100% Gula) dalam meningkatkan kepadatan kolagen pada proses penyembuhan luka bakar buatan pada kulit tikus putih (Rattus norvegicus) jantan. J Med Vet. 2018;1(3):134. doi:10.20473/jmv.vol1.iss3.2018.134-141.

Nourbar E, Mirazi N, Yari S, Rafieian Kopaei M, Nasri H. Effect of hydroethanolic extract of Nigella sativa L. on skin wound healing process in diabetic male rats. Int J Prev Med. 2019;10:18. doi: 10.4103/ijpvm.IJPVM_276_18, PMID 30820305.

Bahar M, Yusmaini H. Efek antimikroba ekstrak lidah buaya (aloe vera) terhadap isolat bakteri penyebab acne vulgaris secara in vitro. Jurnal Kedokteran Dan Kesehatan. 2017;11(2). doi: https://doi.org/10.33533/jpm.v11i2.222.

Susilowati R, Rohmanningrum UM. Effective combination of Nigella sativa and Trigonella foenum graecum seed extract on wound healing in diabetic mice. J Biodjati. 2023 May;8(1):106-16. doi: 10.15575/biodjati.v8i1.19968.

Tan X, Pei W, Xie C, Wang Z, Mao T, Zhao X. Network pharmacology identifies the mechanisms of action of tongxie anchang decoction in the treatment of irritable bowel syndrome with diarrhea predominant. Evid Based Complement Alternat Med. 2020 Nov 17;2020:2723705. doi: 10.1155/2020/2723705, PMID 33281910.

Chandran U, Mehendale N, Patil S, Chaguturu R, Patwardhan B. Network pharmacology. Innovative Approaches in Drug Discovery. 2017;127-64. doi: 10.1016/B978-0-12-801814-9.00005-2.

Firzannida F, Bagaskara S, Savira SS, Fadnurrahim A, Rofida S. Network pharmacology of black cumin (Nigella sativa L.) as a candidate of OMAI in colorectal cancer: in silico study. Indones J Biotechnol. 2022;27(2):87-98. doi: 10.22146/ijbiotech.70699.

Corso M, Perreau F, Mouille G, Lepiniec L. Specialized phenolic compounds in seeds: structures functions and regulations. Plant Sci. 2020 Jul;296:110471. doi: 10.1016/j.plantsci.2020.110471.

Savithramma N, Yugandhar P, Prasad KS, Ankanna S, Chetty KM. Ethnomedicinal studies on plants used by yanadi tribe of Chandragiri reserve forest area Chittoor district Andhra Pradesh India. J Intercult Ethnopharmacol. 2016;5(1):49-56. doi: 10.5455/jice.20160122065531, PMID 27069725.

Sallehuddin N, Nordin A, Idrus BT HJ Ruszymah, Fauzi MB. Nigella sativa and its active compound thymoquinone accelerate wound healing in an in vivo animal model: a comprehensive review. Int J Environ Res Public Health. 2020 Jun;17(11):4160. doi: 10.3390/ijerph17114160, PMID 32545210.

Szabo K, Gesztelyi R, Lampe N, Kiss R, Remenyik J, Pesti Asboth G. Fenugreek (Trigonella foenum-Graecum) seed flour and diosgenin preserve endothelium-dependent arterial relaxation in a rat model of early-stage metabolic syndrome. Int J Mol Sci. 2018 Mar;19(3):798. doi: 10.3390/ijms19030798, PMID 29534453.

VS, PS, AR. Antimicrobial activity of Trigonella foenum-Graecum L. (Fenugreek). Eur J Exp Bio. 2017 Jan;7(1):1-4. doi: 10.21767/2248-9215.100004.

Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV. Prediction of the biological activity spectra of organic compounds using the pass online web resource. Chem Heterocycl Comp. 2014 Jun;50(3):444-57. doi: 10.1007/s10593-014-1496-1.

Ramadhan DS, Fakih TM, Arfan A. Activity prediction of bioactive compounds contained in Etlingera elatior against the SARS-CoV-2 main protease: an in silico approach. Borneo J Pharm. 2020;3(4):235-42. doi: 10.33084/bjop.v3i4.1634.

Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. Swiss target prediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res. 2024 Jul 1;42:32-8. doi: 10.1093/nar/gku293, PMID 24892161.

Altman T, Travers M, Kothari A, Caspi R, Karp PD. A systematic comparison of the MetaCyc and KEGG pathway databases. BMC Bioinformatics. 2013;14:112. doi: 10.1186/1471-2105-14-112, PMID 23530693.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta Cepas J. String v11: protein-protein association networks with increased coverage supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-13. doi: 10.1093/nar/gky1131, PMID 30476243.

Szklarczyk D, Santos A, Von Mering C, Jensen LJ, Bork P, Kuhn M. Stitch 5: augmenting protein chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016;44(D1):D380-4. doi: 10.1093/nar/gkv1277, PMID 26590256.

Doncheva NT, Morris JH, Gorodkin J, Jensen LJ. Cytoscape stringapp: network analysis and visualization of proteomics data. J proteome Res. 2019 Feb;18(2):623-32. doi: 10.1021/acs.jproteome.8b00702.

Hadian Y, Bagood MD, Dahle SE, Sood A, Isseroff RR. Interleukin-17: a potential target for chronic wounds. Mediators Inflamm. 2019 Nov;2019:1297675. doi: 10.1155/2019/1297675, PMID 31827374.

FU J, Huang J, Lin M, Xie T, You T. Quercetin promotes diabetic wound healing via switching macrophages from M1 to M2 polarization. J Surg Res. 2020;246:213-23. doi: 10.1016/j.jss.2019.09.011, PMID 31606511.

Rodrigues HG, Vinolo MA, Sato FT, Magdalon J, Kuhl CM, Yamagata AS. Oral administration of linoleic acid induces new vessel formation and improves skin wound healing in diabetic rats. PLoS One. 2016 Oct;11(10):e0165115. doi: 10.1371/journal.pone.0165115, PMID 27764229.

Majumder S, McGeachy MJ. IL-17 in the pathogenesis of disease: good intentions gone awry. Annu Rev Immunol. 2021;39:537-56. doi: 10.1146/annurev-immunol-101819-092536, PMID 33577346.

Stachura A, Khanna I, Krysiak P, Paskal W, Wlodarski P. Wound healing impairment in type 2 diabetes model of leptin-deficient mice a mechanistic systematic review. Int J Mol Sci. 2022;23(15):8621. doi: 10.3390/ijms23158621, PMID 35955751.

Cooper PO, Haas MR, Noonepalle SK, Shook BA. Dermal drivers of injury-induced inflammation: contribution of adipocytes and fibroblasts. Int J Mol Sci. 2021;22(4):1933. doi: 10.3390/ijms22041933, PMID 33669239.

Hohmann MS, Habiel DM, Coelho AL, Verri WA, Hogaboam CM. Quercetin enhances ligand-induced apoptosis in senescent idiopathic pulmonary fibrosis fibroblasts and reduces lung fibrosis in vivo. Am J Respir Cell Mol Biol. 2019;60(1):28-40. doi: 10.1165/rcmb.2017-0289OC, PMID 30109946.

Kmail A, Said O, Saad B. How thymoquinone from Nigella sativa accelerates wound healing through multiple mechanisms and targets. Curr Issues Mol Biol. 2023;45(11):9039-59. doi: 10.3390/cimb45110567, PMID 37998744.

Wang X, LI W, LU S, MA Z. Modulation of the wound healing through noncoding RNA interplay and GSK-3β/NF-κB signaling interaction. Int J Genomics. 2021 Aug;2021:9709290. doi: 10.1155/2021/9709290, PMID 34485505.

Khalid M, Petroianu G, Adem A. Advanced glycation end products and diabetes mellitus: mechanisms and perspectives. Biomolecules. 2022 Apr;12(4):542. doi: 10.3390/biom12040542, PMID 35454131.

Zheng SY, Wan XX, Kambey PA, Luo Y, HU XM, Liu YF. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes. 2023;14(4):364-95. doi: 10.4239/wjd.v14.i4.364, PMID 37122434.

Jiang M, Wang X, Wang P, Peng W, Zhang B, Guo L. Inhibitor of RAGE and glucose-induced inflammation in bone marrow mesenchymal stem cells: effect and mechanism of action. Mol Med Rep. 2020;22(4):3255-62. doi: 10.3892/mmr.2020.11422, PMID 32945430.

Yehualashet AS. Toll-like receptors as a potential drug target for diabetes mellitus and diabetes-associated complications. Diabetes Metab Syndr Obes. 2020 Dec;13:4763–77. doi: 10.2147/DMSO. S274844.

Suryavanshi SV, Kulkarni YA. NF-κβ: a potential target in the management of vascular complications of diabetes. Front Pharmacol. 2017 Nov 7;8:798. doi: 10.3389/fphar.2017.00798, PMID 29163178.

QI M, Zhou Q, Zeng W, WU L, Zhao S, Chen W. Growth factors in the pathogenesis of diabetic foot ulcers. Front Biosci (Landmark Ed). 2018;23(2):310-7. doi: 10.2741/4593, PMID 28930549.

Zulkefli N, Che Zahari CN, Sayuti NH, Kamarudin AA, Saad N, Hamezah HS. Flavonoids as potential wound healing molecules: emphasis on pathways perspective. Int J Mol Sci. 2023 Feb;24(5):4607. doi: 10.3390/ijms24054607, PMID 36902038.

Published

07-11-2024

How to Cite

DUHITA, M. R., SUSILOWATI, R., AINI, S. Q., & ANNISA, R. (2024). SYNERGISTIC POTENTIAL OF NIGELLA SATIVA L. AND TRIGONELLA FOENUM-GRAECUM: INTEGRATED NETWORK PHARMACOLOGY FOR DIABETIC WOUND HEALING. International Journal of Applied Pharmaceutics, 16(6), 345–351. https://doi.org/10.22159/ijap.2024v16i6.51718

Issue

Section

Original Article(s)