Andaliman fruit (Zanthoxylum acanthopodium DC.) Improves Physiological Condition in Preeclamptic Rat through Angiotensin II Receptor Type 1 Inhibition

Muhammad Shafala Safa, Azmi Noer, Fatchiyah Fatchiyah

Abstract


Background: Preeclampsia (PE) is a severe pregnancy complication involving the AT1R overactivation. Andaliman fruit showed potential for managing preeclampsia, but their effects on the renin-angiotensin system are not well-known. This study aimed to virtually analyze angiotensin II type 1 receptor (AT1R) inhibition by Andaliman Fruit (Zanthoxylum acanthopodium DC.) bioactive compounds and evaluated the effect through an in vivo approach.

Methods: The AT1R protein structure was modeled from the AT1R gene, and computational analysis was performed to identify potential molecules to inhibit AT1R. Wistar rats (n=25) were divided into five groups: normal pregnancy, PE pregnancy, PE + candesartan 5 mg/kg, PE + Andaliman 100 mg/kg BW, and PE + Andaliman 200 mg/kg BW. Blood pressure and proteinuria levels were measured on days 5, 13, and 21 of pregnancy. Serum and kidney Angiotensin-Converting Enzyme (ACE) levels were measured by ELISA, and kidney TNF-alpha levels by dot blotting.

Results: Kaempferol was indicated as the most potential compound to inhibit AT1R. In the late gestation period, Andaliman treatment significantly improved the blood pressure (124.5 mmHg) compared to the PE group (174.1 mmHg) (P < 0.01). Proteinuria level showed improvement in a dose-dependent manner. Serum and kidney ACE levels were downregulated significantly (P < 0.05) at the highest dose of Andaliman (17.6 and 19.9 ng/mL), as well as the kidney TNF-alpha expression (12,503,447 INT/mm2).

Conclusion: The study result found bioactive compounds from Andaliman possibly inhibited AT1R to return the blood pressure to normal level, improved proteinuria condition, and lowered the ACE and TNF-alpha protein levels.

Keywords: ACE, Andaliman, AT1R, Preeclampsia, TNF-alpha


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References


Khan B, Allah Yar R, Khakwani AK, Karim S, Arslan Ali H. Preeclampsia Incidence and Its Maternal and Neonatal Outcomes with Associated Risk Factors. Cureus, (2022); 14(11): e31143.

Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circulation Research, (2019); 124(7): 1094–1112.

Bisson C, Dautel S, Patel E, Suresh S, Dauer P, Rana S. Preeclampsia pathophysiology and adverse outcomes during pregnancy and postpartum. Frontiers in Medicine, (2023); 10: 1144170.

Sharma DD, Chandresh NR, Javed A, Girgis P, Zeeshan M, Fatima SS, et al. The Management of Preeclampsia: A Comprehensive Review of Current Practices and Future Directions. Cureus, (2024); 16(1): e51512.

Oarowski M, Karpiski TM, Szulc M, Wielgus K, Kujawski R, Wolski H, et al. Plant Phenolics and Extracts in Animal Models of Preeclampsia and Clinical Trials—Review of Perspectives for Novel Therapies. Pharmaceuticals, (2021); 14(3): 269-289.

Situmorang PC, Ilyas S, Hutahaean S. Study of Combination of Nanoherbal Andaliman (Zanthoxylum acanthopodium) and Extra Virgin Olive Oil (EVOO) Effects in the Expression of Malondialdehyde (MDA), Heat Shock Protein-70 (HSP70) and Placental Histology of Preeclamptic Rats. Pharmaceutical Sciences, (2019); 25(3): 205–220.

Barus MNG, Syafruddinilyas, Sitepu M, Bachtiar A. Andaliman Fruit Extract (Zanthoxylum acanthopodium) And It’s Effect on Preeclampsia as Anti-Inflammatory. International Journal of Current Pharmaceutical Research, (2020); 12(2): 75–77.

Situmorang PC, Ilyas S, Hutahaean S. Effect of Combination of Nano Herbal Andaliman (Zanthoxylum acanthopodium DC.) and Extra Virgin Olive Oil (EVOO) to Kidney Histology of Preeclampsia Rats. IOP Conference Series: Earth and Environmental Science, (2019); 305(1): 012081.

Situmorang PC, Ilyas S, Hutahaean S, Rosidah R. Effect of Nanoherbal Andaliman (Zanthoxylum acanthopodium) and Extra Virgin Olive Oil Combination on Preeclamptic Rats Liver Histology. Open Access Macedonian Journal of Medical Sciences, (2019); 7(14): 2226–2231.

Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin–angiotensin system: Basic and clinical aspects—A general perspective. Endocrinología, Diabetes y Nutrición, (2022); 69(1): 52–62.

Kawai T, Forrester SJ, O’Brien S, Baggett A, Rizzo V, Eguchi S. AT1 receptor signaling pathways in the cardiovascular system. Pharmacological Research, (2017); 125: 4–13.

Lumbers ER, Delforce SJ, Arthurs AL, Pringle KG. Causes and Consequences of the Dysregulated Maternal Renin-Angiotensin System in Preeclampsia. Frontiers in Endocrinology, (2019); 10(563): 1-13.

Leal CRV, Costa LB, Ferreira GC, Ferreira ADM, Reis FM, Simões E Silva AC. Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review. Pregnancy Hypertension, (2022); 28: 15–20.

De Lange-Jacobs P, Shaikh-Kader A, Thomas B, Nyakudya TT. An Overview of the Potential Use of Ethno-Medicinal Plants Targeting the Renin–Angiotensin System in the Treatment of Hypertension. Molecules, (2020); 25(9): 2114.

Simaratanamongkol A, Umehara K, Noguchi H, Panichayupakaranant P. Identification of a new angiotensin-converting enzyme (ACE) inhibitor from Thai edible plants. Food Chemistry, (2014); 165: 92–97.

Reddy R, Baijnath S, Moodley R, Moodley J, Naicker T, Govender N. South African medicinal plants displaying angiotensin-converting enzyme inhibition: Potential use in the management of preeclampsia. Journal of Ayurveda and Integrative Medicine, (2022); 13(2): 100562.

Safa MS, Noer A, Fatchiyah F. Virtual screening of Zanthoxylum acanthopodium DC. fruit bioactive compounds as natural angiotensin-converting enzyme inhibitors. Berkala Penelitian Hayati, (2024); 30(2): 56-66.

Fatchiyah, Arumingtyas EL, Widyarti S, Rahayu S. Biologi Molekular: Prinsip Dasar Analisis. (2011). Erlangga.

Bare Y, Marhendra A, Sasase T, Fatchiyah F. Differential Expression of IL-10 Gene and Protein in Target Tissues of Rattus norvegicus Strain Wistar Model Type 2 Diabetes Mellitus (T2DM). Acta Informatica Medica, (2018); 26(2): 87-92.

Sawal HA, Nighat S, Safdar T, Anees L. Comparative In Silico Analysis and Functional Characterization of TANK-Binding Kinase 1–Binding Protein 1. Bioinformatics and Biology Insights, (2023); 17: 117793222311648.

Moektiwardoyo M, Muchtaridi M, Halimah E. Chemical Composition and Locomotor Activity of Andaliman Fruits (Zanthoxylum acanthopodium DC.) Essential Oil on Mice. International Journal of Pharmacy and Pharmaceutical Sciences, (2014); 6(2): 124-130.

Rienoviar, Heliawati L, Khoiriyah A. Aktivitas Antioksidan dan Identifikasi Senyawa Aktif dalam Ekstrak Buah Andaliman (Zanthoxylum acanthopodium DC.). Warta Industri Hasil Pertanian, (2019); 36(2): 124-130.

Sibero MT, Siswanto AP, Murwani R, Frederick EH, Wijaya AP, Syafitri E, et al. Antibacterial, cytotoxicity and metabolite profiling of crude methanolic extract from andaliman (Zanthoxylum acanthopodium) fruit. Biodiversitas Journal of Biological Diversity, (2020); 21(9): 4147-4154.

Widyananda MH, Fatchiyah F, Muflikhah L, Ulfa SM, Widodo N. Computational examination to reveal Kaempferol as the most potent active compound from Euphorbia hirta against breast cancer by targeting AKT1 and ER. Egyptian Journal of Basic and Applied Sciences, (2023); 10(1): 753–767.

Wong F, Krishnan A, Zheng EJ, Stärk H, Manson AL, Earl AM, et al. Benchmarking AlphaFold-enabled molecular docking predictions for antibiotic discovery. Molecular Systems Biology, (2022); 18(9): e11081.

Silalahi S, Megaputri TR, Daisy. Effect of extraction solvent on total flavonoid content of andaliman fruit (Zanthoxylum acanthopodium DC). Pro Food, (2019); 5(2): 540–543.

Simanullang RH, Ilyas S, Hutahaean S, Rosidah. Effect of Andaliman (Zanthoxylum acanthopodium DC.) Methanol Extract on Rat’s Kidney and Liver Histology Induced by Benzopyrene. Pakistan Journal of Biological Sciences, (2021); 24(2): 274–281.

Mao LM, Qi XW, Hao JH, Liu HF, Xu QH, Bu PL. In vitro, ex vivo and in vivo anti-hypertensive activity of Chrysophyllum cainito L. extract. (2015); 8(10): 17912–17921.

Mashat BH, Awad MM, Amin AH, Osman YAM. Sensitivity and Reliability of Two Antibodies in Detecting E. coli in Meat and Water. Archives of Pharmacy Practice, (2022); 13(3): 33–40.

Caminero Gomes Soares A, Marques Sousa GH, Calil RL, Goulart Trossini GH. Absorption matters: A closer look at popular oral bioavailability rules for drug approvals. Molecular Informatics, (2023); 42(11): e202300115.

Vilar S, Costanzi S. Predicting the Biological Activities Through QSAR Analysis and Docking-Based Scoring: Membrane Protein Structure and Dynamics. (2012); 914: 271-284. Humana Press.

Ali A, Johnstone EKM, Baby B, See HB, Song A, Rosengren KJ, et al. Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor. International Journal of Molecular Sciences, (2020); 22(1): 209.

Vaou N, Stavropoulou E, Voidarou C, Tsakris Z, Rozos G, Tsigalou C, et al. Interactions between Medical Plant-Derived Bioactive Compounds: Focus on Antimicrobial Combination Effects. Antibiotics, (2022); 11(8): 1014.

Moetty DAA, Mahmoud MA, Ebtesam MI. Protective Effect of Angiotensin II Type 1-Receptor-Blocker on Diabetic Nephropathy in Rats: Role of Nephrin. The Medical Journal of Cairo University, (2020); 88(12): 2081–2089.

Trojacanec J, Pavlovska K, Gjorgjievska K, Kolovchevski N, Shikole E, Labachevski B, et al. Nephroprotective Effects of Candesartan on Diabetic Nephropathy in Rats. Journal of Morphological Sciences, (2023); 6(3): 21–33.

Shirai K, Watanabe K, Ma M, Wahed MII, Inoue M, Saito Y, et al. Effects of angiotensin-II receptor blocker candesartan cilexetil in rats with dilated cardiomyopathy. Molecular and Cellular Biochemistry, (2005); 269(1): 137–142.

Soga M, Kamal FA, Watanabe K, Ma M, Palaniyandi S, Prakash P, et al. Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats. International Journal of Cardiology, (2006); 110(3): 378–385.

Azhari MB, Febriani H, Syukriah S. The effect of ethanol extract of Andaliman (Zanthoxylum acanthopodium DC.) on kidney damage in tartrazine-induced rats. Sains Medika: Jurnal Kedokteran dan Kesehatan, (2022); 13(2): 70-74.

Koka V, Huang XR, Chung ACK, Wang W, Truong LD, Lan HY. Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway. The American Journal of Pathology, (2008); 172(5): 1174–1183.

Bulsara KG, Patel P, Makaryus AN. Candesartan. StatPearls Publishing, (2024).

Park S, Bivona BJ, Kobori H, Seth DM, Chappell MC, Lazartigues E, et al. Major role for ACE-independent intrarenal ANG II formation in type II diabetes. American Journal of Physiology-Renal Physiology, (2010); 298(1): F37–F48.

LaMarca BD, Ryan MJ, Gilbert JS, Murphy SR, Granger JP. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Current Hypertension Reports, (2007); 9(6): 480–485.

Sabio G, Davis RJ. TNF and MAP kinase signalling pathways. Seminars in Immunology, (2014); 26(3): 237–245.

Al-Khayri JM, Sahana GR, Nagella P, Joseph BV, Alessa FM, Al-Mssallem MQ. Flavonoids as Potential Anti-Inflammatory Molecules: A Review. Molecules, (2022); 27(9): 2901.

Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia—Pathophysiology and Clinical Presentations. Journal of the American College of Cardiology, (2020); 76(14): 1690–1702.

Gatford KL, Andraweera PH, Roberts CT, Care AS. Animal Models of Preeclampsia: Causes, Consequences, and Interventions. Hypertension, (2020); 75(6): 1363–1381.

Li Y, Yang N, Wang B, Niu X, Cai W, Li Y, et al. Effect and mechanism of prophylactic use of tadalafil during pregnancy on L-NAME-induced preeclampsia-like rats. Placenta, (2020); 99: 35–44.

Zhu J, Mori T, Huang T, Lombard JH. Effect of high-salt diet on NO release and superoxide production in rat aorta. American Journal of Physiology-Heart and Circulatory Physiology, (2004); 286(2): H575–H583.

Bankir L, Perucca J, Norsk P, Bouby N, Damgaard M. Relationship between Sodium Intake and Water Intake: The False and the True. Annals of Nutrition and Metabolism, (2017); 70(Suppl. 1): 51–61.

Tyurenkov IN, Perfilova VN, Smirnov AV, Reznikova LB, Poroyskaya AV, Verovsky VE. Features of endothelial dysfunction and morphofunctional changes of the uteroplacental complex in experimentally induced pre-eclampsia. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health, (2016); 6(4): 423–430.

Beauséjour A, Auger K, St-Louis J, Brochu M. High-sodium intake prevents pregnancy-induced decrease of blood pressure in the rat. American Journal of Physiology-Heart and Circulatory Physiology, (2003); 285(1): H375–H383.

Ilyas S, Situmorang PC. Role of Heat Shock Protein 70 (HSP-70) after Giving Nanoherbal Haramonting (Rhodomyrtus tomentosa) in Preeclamptic Rats. Pakistan Journal of Biological Sciences, (2021); 24(1): 139–145.

Wu H, Liang Y, Zheng Y, Bai Q, Zhuang Z, A L, et al. Up-Regulation of Intrarenal Renin-Angiotensin System Contributes to Renal Damage in High-Salt Induced Hypertension Rats. Kidney and Blood Pressure Research, (2014); 39(6): 526–535.

Darby M, Martin JN, LaMarca B. A complicated role for the renin–angiotensin system during pregnancy: highlighting the importance of drug discovery. Expert Opinion on Drug Safety, (2013); 12(6): 857–864.

Hogan T, Dharmaraj S, Sivashankar S. Fetal renin-angiotensin system blockade: two case reports. Infant, (2021); 17(2): 79-82.

Oh KT, Namgoong MK, Yoo YM, Lee BK. Angiotensin II Receptor Blocker Fetopathy with Persistent Pulmonary Hypertension, Hypocalvaria, Nephrogenic Diabetes Insipidus, Transient Pseudohypoaldosteronism and Polycythemia. Perinatology, (2021); 32(1): 48-53.




DOI: https://doi.org/10.62940/als.v13i2.3580

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