Aronia melanocarpa Fenolik Bileşiklerinin PON1 Merkezli Lipid Metabolizması ve Antioksidan Savunmadaki Rolü: ADMET ve Moleküler Docking Yöntemlerini Kullanan Entegre Bir Yaklaşım

Yıl 2025, Cilt: 30 Sayı: 3, 974 - 989, 24.12.2025

Serim Tuna Koç , Aslı Akyüz , Duygu Yaşar Şirin

https://doi.org/10.53433/yyufbed.1753059

Öz

Oksidatif stresin zararlı etkilerini azaltmak amacıyla vücut çeşitli savunma mekanizmaları geliştirmiştir ve antioksidanlar bu mekanizmalarda merkezi bir rol oynamaktadır. Aronia melanocarpa, özellikle fenolik bileşikler açısından zengin olması sayesinde güçlü antioksidan ve anti-inflamatuvar etkiler sergiler. Paraoksonaz 1 (PON1), karaciğerde sentezlenen ve yüksek yoğunluklu lipoprotein partiküllerine bağlanarak dolaşımda bulunan bir enzimdir ve lipid peroksitleri hidrolize ederek antioksidan etkiler gösterir. Bu mekanizma sayesinde, ateroskleroz, diyabet ve kanser gibi çeşitli patolojik durumlarla ilişkili oksidatif hasarın azaltılmasında kritik bir rol oynar ve bu nedenle umut verici bir terapötik hedef olarak kabul edilir. Bu çalışmada, Aronya meyvesinde doğal olarak bulunan fenolik bileşiklerin PON1 geni ile ilişkili biyolojik hedefler üzerindeki potansiyel etkileri in siliko yaklaşımlar kullanılarak araştırılmıştır. Her bir fenolik bileşiğin potansiyel hedefleri biyoinformatik platformlar aracılığıyla belirlenmiştir. Elde edilen genler, GO ve zenginleştirme analizleri yoluyla fonksiyonel olarak sınıflandırılmış ve sonuçlar SR Plot kullanılarak görselleştirilmiştir. PON1 proteini ile etkileşime giren genler STRING veritabanı kullanılarak belirlenmiştir. Seçilen fenolik bileşiklerin farmakokinetik özellikleri ADMETLab platformu ile değerlendirilmiş ve naringenin ile trans-ferulik asit en umut verici aday bileşikler olarak tanımlanmıştır. Belirlenen fenolik bileşiklerin, PON1 ile ilişkili hub genler tarafından kodlanan proteinlerle moleküler etkileşimleri CB-Dock2 ile yapılan moleküler doking analizleriyle incelenmiştir. Sonuçlar, kateşin, izorhamnetin, naringenin, kuersetin ve rutin’in PON1 sinyal yolunu modüle edebileceğini, bu yolla oksidatif stresi azaltarak lipid metabolizmasını iyileştirebileceğini göstermektedir. Bu bulgular, söz konusu bileşiklerin farmakolojik ajan adayları olarak potansiyel taşıdığını ortaya koymaktadır.

Anahtar Kelimeler

Aronia melanocarpa , Ağ farmakolojisi , PON1 gen yolağı

Proje Numarası

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Role of Aronia melanocarpa Phenolic Compounds in PON1-Centered Lipid Metabolism and Antioxidant Defense: An Integrated Approach Utilizing ADMET and Molecular Docking

Öz

To mitigate the harmful effects of oxidative stress, the body has evolved a range of defense mechanisms, with antioxidants playing a central role. Aronia melanocarpa exhibits strong antioxidant and anti-inflammatory effects due to its rich content of bioactive compounds, especially phenolic compounds. Paraoxonase 1 (PON1) is a liver-synthesized enzyme that circulates in the bloodstream by binding to high-density lipoprotein particles and exerts antioxidant effects by hydrolyzing lipid peroxides. Through this mechanism, it plays a critical role in mitigating oxidative damage implicated in various pathological conditions, including atherosclerosis, diabetes, and cancer, thereby representing a promising therapeutic target. In the present study, the potential effects of phenolic compounds naturally present in Aronia fruit on biological targets associated with the PON1 gene were investigated using in silico approaches. The potential targets of each phenolic compound were identified through bioinformatics platforms. The genes obtained were functionally classified through GO and enrichment analyses, with results visualized using the SR Plot. PON1 protein-interacting genes were identified using the STRING database. The pharmacokinetic properties selected phenolic compounds were evaluated using the ADMETLab platform, which identified naringenin and trans-ferulic acid as the most promising candidate compounds. The molecular interactions of the identified phenolic compounds with the proteins encoded by PON1 related hub genes were analyzed through molecular docking using the CB-Dock2. Results indicate that catechin, isorhamnetin, naringenin, quercetin, and rutin may modulate the PON1 signaling pathway, contributing to reduced oxidative stress and improved lipid metabolism. These findings suggest their potential pharmacological agent candidates.

Anahtar Kelimeler

Aronia melanocarpa , Network pharmacology , PON1 gene pathway

Etik Beyan

The authors state that no ethical committee approval or legal/special permission was required for the materials and methods employed in this study.

Proje Numarası

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Kaynakça

• Abudayyak, M., Boran, T., Tukel, R., Oztas, E., & Özhan, G. (2020). The Role of PON1 Variants in Disease Susceptibility in a Turkish Population. Global medical genetics, 7(2), 41–46. https://doi.org/10.1055/s-0040-1715568
• Ashiq, S., & Ashiq, K. (2021). The Role of Paraoxonase 1 (PON1) Gene polymorphisms in coronary artery disease: A systematic review and Meta-Analysis. Biochemical genetics, 59(4), 919–939. https://doi.org/10.1007/s10528-021-10043-0
• Bushmeleva, K., Vyshtakalyuk, A., Terenzhev, D., Belov, T., Nikitin, E., & Zobov, V. (2023). Aronia melanocarpa flavonol extract—Antiradical and immunomodulating activities analysis. Plants (Basel, Switzerland), 12(16), 2976. https://doi.org/10.3390/plants12162976
• Cannon, M., Stevenson, J., Stahl, K., Basu, R., Coffman, A., Kiwala, S., McMichael, J. F., Kuzma, K., Morrissey, D., Cotto, K., Mardis, E. R., Griffith, O. L., Griffith, M., & Wagner, A. H. (2024). DGIdb 5.0: rebuilding the drug-gene interaction database for precision medicine and drug discovery platforms. Nucleic acids research, 52(D1), D1227–D1235. https://doi.org/10.1093/nar/gkad1040
• Daina, A., Michielin, O., & Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic acids research, 47(W1), W357–W364. https://doi.org/10.1093/nar/gkz382
• Davis, A. P., Wiegers, T. C., Sciaky, D., Barkalow, F., Strong, M., Wyatt, B., Wiegers, J., McMorran, R., Abrar, S., & Mattingly, C. J. (2024). Comparative toxicogenomics database’s 20th anniversary: update 2025. Nucleic Acids Research.
• Durrington, P. N., Bashir, B., Soran, H. (2023). Paraoxonase 1 and atherosclerosis. Frontiers in cardiovascular medicine, 10, 1065967. https://doi.org/10.3389/fcvm.2023.1065967
• Go, M. Y., Kim, J., Jeon, C. Y., & Shin, D. W. (2024). Functional activities and mechanisms of Aronia melanocarpa in our health. Current Issues in Molecular Biology, 46(8), 8071–8087. https://doi.org/10.3390/cimb46080477
• Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., Bridgland, A., Meyer, C., Kohl, S. A. A., Ballard, A. J., Cowie, A., Romera-Paredes, B., Nikolov, S., Jain, R., Adler, J., Back, T., & Hassabis, D. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596(7873), 583–589. https://doi.org/10.1038/s41586-021-03819-2
• Jurendić, T., & Ščetar, M. (2021). Aronia melanocarpa Products and By-Products for Health and Nutrition: A Review. Antioxidants (Basel, Switzerland), 10(7), 1052. https://doi.org/10.3390/antiox10071052
• Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, BA., Thiessen, PA., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, EE. (2025). PubChem 2025 update. Nucleic Acids Research, 53 (D1), D1516–D1525. https://doi.org/10.1093/nar/gkae1059
• Koc, S. T. (2025). Kapsüllenmiş ve kapsülsüz aronya (Aronia melanocarpa) ekstraktının sıçanların PON1 geni mRNA ekspresyonu, karaciğer dokularındaki PON1 enzim aktivitesi ve aterosklerozis üzerine etkisinin araştırılması. (Doktora Tezi), Trakya Üniversitesi, Fen Bilimleri Enstitüsü, Edirne, Türkiye.
• Liu, Y., Yang, X., Gan, J., Chen, S., Xiao, Z. X., & Cao, Y. (2022). CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic acids research, 50(W1), W159–W164. https://doi.org/10.1093/nar/gkac394
• Lucas, S. A. M., Graham, A. M., Presnell, J. S., & Clark, N. L. (2023). Highly dynamic gene family evolution suggests changing roles for PON genes within Metazoa. Genome Biology and Evolution, 15(2), evad011. https://doi.org/10.1093/gbe/evad011
• Medina-Díaz, I. M., Ponce-Ruíz, N., Rojas-García, A. E., Zambrano-Zargoza, J. F., Bernal-Hernández, Y. Y., González-Arias, C. A., Barrón-Vivanco, B. S., & Herrera-Moreno, J. F. (2022). The relationship between cancer and paraoxonase 1. Antioxidants (Basel, Switzerland), 11(4), 697. https://doi.org/10.3390/antiox11040697
• Otocka-Kmiecik A. (2022). Effect of Carotenoids on Paraoxonase-1 Activity and Gene Expression. Nutrients, 14(14), 2842. https://doi.org/10.3390/nu14142842
• Ren, Y., Frank, T., Meyer, G., Lei, J., Grebenc, J. R., Slaughter, R., Gao, Y. G., & Kinghorn, A. D. (2022). Potential benefits of black chokeberry (Aronia melanocarpa) fruits and their constituents in improving human health. Molecules (Basel, Switzerland), 27(22), 7823. https://doi.org/10.3390/molecules27227823
• Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research, 13(11), 2498–2504. https://doi.org/10.1101/gr.1239303
• Sherman, B. T., Panzade, G., Imamichi, T., & Chang, W. (2024). DAVID Ortholog: an integrative tool to enhance functional analysis through orthologs. Bioinformatics (Oxford, England), 40(10), btae615. https://doi.org/10.1093/bioinformatics/btae615
• Steele, L., Furlong, C. E., Richter, R. J., Marsillach, J., Janulewicz, P. A., Krengel, M. H., Klimas, N. G., Sullivan, K., & Chao, L. L. (2024). PON1 Status in Relation to Gulf War Illness: Evidence of Gene-Exposure Interactions from a Multisite Case-Control Study of 1990-1991 Gulf War Veterans. International journal of environmental research and public health, 21(8), 964. https://doi.org/10.3390/ijerph21080964
• Szklarczyk, D., Santos, A., von Mering, C., Jensen, L. J., Bork, P., & Kuhn, M. (2016). STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic acids research, 44(D1), D380–D384. https://doi.org/10.1093/nar/gkv1277
• Szklarczyk, D., Kirsch, R., Koutrouli, M., Nastou, K., Mehryary, F., Hachilif, R., Annika, G. L., Fang, T., Doncheva, N. T., Pyysalo, S., Bork, P., Jensen, L. J., & von Mering, C. (2023). The STRING database in 2023: Protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Research, 51(D1), D638–D646.
• Tang, D., Chen, M., Huang, X., Zhang, G., Zeng, L., Zhang, G., Wu, S., & Wang, Y. (2023). SRplot: A free online platform for data visualization and graphing. PloS one, 18(11), e0294236. https://doi.org/10.1371/journal.pone.0294236
• Vavlukis, M., Vavlukis, A., Krsteva, K., & Topuzovska, S. (2022). Paraoxonase 1 gene polymorphisms in lipid oxidation and atherosclerosis development. Frontiers in genetics, 13, 966413. https://doi.org/10.3389/fgene.2022.966413
• Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., & Cao, D. (2021). ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic acids research, 49(W1), W5–W14. https://doi.org/10.1093/nar/gkab255