Syzygium polyanthum bioactive compounds in polycystic ovary syndrome

J. Pharm. Pharmacogn. Res., vol. 10, no. 4, pp. 725-736, July-August 2022.

Original Article

Anti-inflammatory and antioxidant potential of Syzygium polyanthum (Wight) Walp. bioactive compounds in polycystic ovary syndrome: An in silico study

[Potencial anti-inflamatorio y antioxidante de compuestos bioactivos de Syzygium polyanthum (Wight) Walp. en el síndrome de ovario poliquístico: Un estudio in silico]

Renny Aditya1,4, Budi Santoso2*, Widjiati Widjiati3

1Doctoral Program of Medical Science, Faculty of Medicine, University of Airlangga, Surabaya, Indonesia.

2Department of Obstetrics and Gynecology, Faculty of Medicine, University of Airlangga, Surabaya, Indonesia.

3Department of Veterinary Anatomy, Faculty of Veterinary Medicine, University of Airlangga, Surabaya, Indonesia.

4Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Lambung Mangkurat, Banjarmasin, Indonesia.

*E-mail: budi.santoso@fk.unair.ac.id

Abstract

Context: Polycystic ovary syndrome (PCOS) is significantly associated with inflammation and oxidative stress. Syzygium polyanthum is a plant rich in pharmacological properties. Aims: To evaluate the anti-inflammation and antioxidant potential of S. polyanthum bioactive compounds using in silico approach.

Methods: The S. polyanthum was extracted using the ultrasound-assisted extraction (UAE) method, and the bioactive compounds were screened using Liquid Chromatography–High Resolution Mass Spectrometry (LC-HRMS) analysis. This study predicted the biological activity of S. polyanthum compounds using PASS Online server. Before docking, we analyzed the protein-protein interactions (PPIs) network of TNFα, NF-kB, SOD, and KEAP1. The molecular docking was done using Autodock Vina in PyRx software and visualized using Discovery Studio. Probability to be active (Pa) was determined.

Results: The bioactive compounds found in S. polyanthum and used in this study were deoxyphomalone, NCGC00169066-01, and phloretin with retention times [min] of 0.886, 0.907, and 8.323, respectively. The predicted biological activity of compounds and controls were anti-inflammatory, immunosuppressant, TNF expression inhibitor, immunomodulatory and HIF1α expression inhibitor (Pa>0.5 for all S. polyanthum compounds and Pa<0.5 for SPD304, MG-132, and MDF). Based on PPIs network analysis, TNFα, NF-kB, SOD, and KEAP1 are associated. The molecular docking analysis showed that deoxyphomalone, NCGC00169066-01, and phloretin had inhibition potential against TNFα and NF-kB, and activation potential against SOD, due to several residues involved in the interaction of compounds-protein was the same as the interaction of inhibitor (SPD-304 and MG-132) and activator (gallic acid) control against the protein. The residues may have the same inhibition or activation mechanism as the control. However, S. polyanthum bioactive compounds may still have inhibition potential against KEAP1 through Ala548 residue that is also involved in the interaction of DMF-KEAP1.

Conclusions: The bioactive compounds of S. polyanthum showed anti-inflammation and antioxidant potential, which may have a good effect in the treatment of PCOS, yet still need to be confirmed in vitro or in vivo research.

Keywords: antioxidant; inflammation; molecular docking; polycystic ovary syndrome; Syzygium polyanthum.

Resumen

Contexto: El síndrome de ovario poliquístico (SOP) está significativamente asociado con la inflamación y el estrés oxidativo. Syzygium polyanthum es una planta rica en propiedades farmacológicas. Objetivos: Evaluar el potencial anti-inflamatorio y antioxidante de los compuestos bioactivos de S. polyanthum utilizando un enfoque in silico.

Métodos: S. polyanthum se extrajo mediante el método de extracción asistida por ultrasonido (UAE), y los compuestos bioactivos se seleccionaron mediante análisis de cromatografía líquida-espectrometría de masas de alta resolución (LC-HRMS). Este estudio predijo la actividad biológica de los compuestos de S. polyanthum utilizando el servidor PASS Online. Antes del acoplamiento, analizamos la red de interacciones proteína-proteína (PPI) de TNFα, NF-kB, SOD y KEAP1. El acoplamiento molecular se realizó con Autodock Vina en el software PyRx y se visualizó con Discovery Studio. Se determinó la probabilidad de estar activo (Pa).

Resultados: Los compuestos bioactivos encontrados en S. polyanthum y utilizados en este estudio fueron desoxifomalona, ​​NCGC00169066-01 y floretina con tiempos de retención [min] de 0,886; 0,907 y 8,323, respectivamente. La actividad biológica predicha de los compuestos y controles fue anti-inflamatoria, inmunosupresora, inhibidora de la expresión de TNF, inmunomoduladora e inhibidora de la expresión de HIF1α (Pa>0,5 para todos los compuestos de S. polyanthum y Pa<0,5 para SPD304, MG-132 y MDF). Según el análisis de red de PPI, se asocian TNFα, NF-kB, SOD y KEAP1. El análisis de acoplamiento molecular mostró que la desoxifomalona, ​​NCGC00169066-01 y la floretina tenían potencial de inhibición contra TNFα y NF-kB, y potencial de activación contra SOD, debido a que varios residuos involucrados en la interacción de compuestos-proteína eran los mismos que la interacción del inhibidor (SPD-304 y MG-132) y activador (ácido gálico) controlan contra la proteína. Los residuos pueden tener el mismo mecanismo de inhibición o activación que el control. Sin embargo, los compuestos bioactivos de S. polyanthum aún pueden tener un potencial de inhibición contra KEAP1 a través del residuo Ala548 que también está involucrado en la interacción de DMF-KEAP1.

Conclusiones: Los compuestos bioactivos de S. polyanthum mostraron potencial anti-inflamatorio y antioxidante, lo que puede tener un buen efecto en el tratamiento del SOP, pero aún debe confirmarse en investigaciones in vitro o in vivo.

Palabras Clave: acoplamiento molecular; antioxidante; inflamación; síndrome de ovario poliquistico; Syzygium polyanthum.

Citation Format: Aditya R; Santoso B; Widjiati W (2022) Anti-inflammatory and antioxidant potential of Syzygium polyanthum (Wight) Walp. bioactive compounds in polycystic ovary syndrome: An in silico study. J Pharm Pharmacogn Res 10(4): 725–736.
References

Amini L, Tehranian N, Movahedin M, Tehrani FR, Ziaee S (2015) Antioxidants and management of polycystic ovary syndrome in Iran: A systematic review of clinical trials.  Iran J Reprod Med 13(1): 1-8.

Arulselvan P, Fard MT, Tan WS, Gothai S, Fakurazi S, Norhaizan ME, Kumar SS (2016) Role of antioxidants and natural products in inflammation. Oxid Med Cell Longev 2016: 5276130.

Gao L, Gu Y, Yin X (2016) High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis. PloS One 11(10): e0164021

González F (2012) Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 77(4): 300-305.

Hartanti L, Yonas SMK, Mustamu JJ, Wijaya S, Setiawan HK, Soegianto L (2019) Influence of extraction methods of bay leaves (Syzygium polyanthum) on antioxidant and HMG-CoA reductase inhibitory activity. Heliyon 5(4): e01485.

He Z, Wang Y, Zhuan L, Li Y, Tang ZO, Wu Z, Ma Y (2021) MIF-mediated NF-κB signaling pathway regulates the pathogenesis of polycystic ovary syndrome in rats. Cytokine 146: 155632.

Ibáñez L, Oberfield SE, Witchel S, Auchus RJ, Chang RJ, Codner E, Dabadghao P, Darendeliler F, Elbarbary NS, Gambineri A, Garcia Rudaz C, Hoeger KM, López-Bermejo A, Ong K, Peña AS, Reinehr T, Santoro N, Tena-Sempere M, Tao R, Yildiz BO, Alkhayyat H, Deeb A, Joel D, Horikawa R, de Zegher F, Lee PA (2017) An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr 88: 371-395.

Ismail A, Ahmad WANW (2019) Syzygium polyanthum (Wight) Walp: A potential phytomedicine. Pharmacogn J 11(2): 429-438.

Kalliolias GD, Ivashkiv LB (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12(1): 49-62.

Lagunin AA, Dubovskaja VI, Rudik AV, Pogodin PV, Druzhilovskiy DS, Gloriozova TA, Filimonov DA, Sastry NG, Poroikov VV (2018) CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds. PLoS One 13(1): e0191838.

Li M, Huang W, Jie F, Wang M, Zhong Y, Chen Q, Lu B (2019) Discovery of Keap1− Nrf2 small− molecule inhibitors from phytochemicals based on molecular docking. Food Chem Toxicol 133: 110758.

Liu T, Zhang L, Joo D, Sun SC (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2: 17023.

Ma B, Lucas B, Capacci A, Lin EYS, Jones JH, Dechantsreiter M, Richter K (2020) Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators. Bioorg Med Chem Lett 30(4): 126852.

Mascret A, Mouhsine H, Attia G, Cabrera D, Benchekroun M, Gizzi P, Zerrouki C, Fourati N, Zagury JF, Veitía MS, Port M (2021) New contributions to the drug profile of TNFα inhibitor SPD304: Affinity, selectivity and ADMET considerations. Eur J Pharmacol 907: 174285.

Mohammadi M (2019) Oxidative stress and polycystic ovary syndrome: a brief review. Int J Prev Med 10: 86.

Nafisah W, Pinanti HN, Christina YI, Rifa’i M, Djati MS (2021) Computational biological activity and pharmacological properties analysis for anti-cancer Cyperus rotundus bioactive compounds. AIP Conf Proc 2353: 030118.

Palazon A, Goldrath AW, Nizet V, Johnson RS (2014) HIF transcription factors, inflammation, and immunity. Immunity 41(4): 518-528.

Pandey PK, Ahmed B, Khan HA, Bala M, Prasad J (2019) In silico molecular docking and comparative in-vitro analysis of ethyl 3, 4, 5-trihydroxybenzoate and its derivative isolated from Hippophae rhamnoides leaves as free radical scavenger and anti-inflammatory compound. Pharmacogn Mag 15(64): 313.

Prabhu YD, Borthakur A, Subeka AG, Vellingiri B, Gopalakrishnan AV (2021) Increased pro-inflammatory cytokines in ovary and effect of γ-linolenic acid on adipose tissue inflammation in a polycystic ovary syndrome model. J of Reprod Immunol 146: 103345.

Rani R, Hajam YA, Kumar R, Bhat RA, Rai S, Rather MA (2022) A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome  (PCOS). Phytomedicine Plus 2(1): 100161.

Regidor PA, Mueller A, Sailer M, Gonzalez Santos F, Rizo JM, Moreno Egea F (2020) Chronic inflammation in PCOS: The potential benefits of specialized pro-resolving lipid mediators (SPMs) in the improvement of the resolutive response. Int J Mol Sci 22(1): 384.

Rosenfield RL, Ehrmann DA (2016) The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 37(5): 467-520.

Rudnicka E, Suchta K, Grymowicz M, Calik-Ksepka A, Smolarczyk K, Duszewska AM, Meczekalski B (2021) Chronic low grade inflammation in pathogenesis of pcos. Int J Mol Sci 22(7): 3789.

Sever MJ, Janež A, Dolžan V (2019) Interplay between oxidative stress and chronic inflammation in PCOS: The role of genetic variability in PCOS risk and treatment responses. In (Ed.), Polycystic Ovarian Syndrome. IntechOpen. https://doi.org/10.5772/ intechopen.88698.

Shao Y, Cheng Z, Li X, Chernaya V, Wang H, Yang XF (2014) Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction-a novel mechanism for maintaining vascular function. J Hematol Oncol 7(1): 80.

Sulaiman MA, Al-Farsi YM, Al-Khaduri MM, Saleh J, Waly MI (2018) Polycystic ovarian syndrome is linked to increased oxidative stress in Omani women. Int J Womens Health 10: 763-771.

Suzuki K, Tominaga T, Ruhee RT, Ma S (2020) Characterization and modulation of systemic inflammatory response to exhaustive exercise in relation to oxidative stress. Antioxidants 9(5): 401.

Tosatti JAG, Sóter MO, Ferreira CN, Silva IFO, Cândido AL, Sousa MO, Reis FM, Gomes KB (2020) The hallmark of pro-and anti-inflammatory cytokine ratios in women with polycystic ovary syndrome. Cytokine 134: 155187.

Uçkan K, Demir H, Turan K, Sarıkaya E, Demir C (2022) Role of oxidative stress in obese and nonobese PCOS patients. Int J Clin Pract 2022: 4579831.

Victor VM, Rovira-Llopis S, Bañuls C, Diaz-Morales N, Martinez de Marañon A, Rios-Navarro C, Alvarez A, Gomez M, Rocha M, Hernández-Mijares A (2016) Insulin resistance in PCOS patients enhances oxidative stress and leukocyte adhesion: Role of myeloperoxidase. PLoS One 11(3): e0151960.

Wang Y, Chen Y, Zhang X, Lu Y, Chen H (2020) New insights in intestinal oxidative stress damage and the health intervention effects of nutrients: A review. J Funct Food 75: 104248

Witchel SF, Oberfield SE, Peña AS (2019) Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc 3(8): 1545-1573.

Zhang W, Xu W, Chen W, Zhou Q (2018) Interplay of autophagy inducer rapamycin and proteasome inhibitor MG132 in reduction of foam cell formation and inflammatory cytokine expression. Cell Transplant 27(8): 1235-1248.

Zuo T, Zhu M, Xu W (2016) Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev 2016: 8589318.

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