J. Pharm. Pharmacogn. Res., vol. 13, no. 4, pp. 979-990, Jul-Aug 2025.

DOI: https://doi.org/10.56499/jppres24.2134_13.4.979

Original Article

Effect of Rhodomyrtus tomentosa (Aiton) Hassk. on aortic hyperglycemia via JAK family expression

[Efecto de Rhodomyrtus tomentosa (Aiton) Hassk. sobre la hiperglucemia aórtica a través de la expresión de la familia JAK]

Putri Cahaya Situmorang1*, Rony Abdi Syahputra2, Etti Sartina Siregar1, Mimmy Sari Syah Putri3, Trina Ekawati Tallei4, Eka Setiawan1

1Department of of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, Indonesia.

2Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia.

3Department of Mathematics, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, Indonesia.

4Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado, Indonesia.

*E-mail: putri.cahaya@usu.ac.id

Abstract

Context: Hyperglycemia is a significant contributor to the development of atherosclerosis and is a major risk factor. The process initiates with the phosphorylation of JAK1 and JAK2, subsequently leading to the activation of STAT3, which results in atherosclerotic damage to vascular endothelial cells. Rhodomyrtus tomentosa is an antioxidant botanical in traditional medicine with the capacity to mitigate oxidative stress.

Aims: To analyze JAK family expression in aorta tissue after administration of R. tomentosa.

Methods: A Completely Randomized Design (CRD) was utilized to test Wistar rats in six groups: K+: alloxan-induced diabetes, K-: untreated animals, and K0: diabetic rats + metformin. Groups K1, K2, and K3 received R. tomentosa at 100, 150, and 200 mg/kg BW. R. tomentosa was taken orally for two weeks. Next, the animals were dissected to take the aorta for analysis of immunohistochemistry with JAK family expression and also for analysis of the lumen and thickness of the aorta.

Results: Hyperglycemic aortic tissue alters histologically, changing lumen size and tunica intima thickness and also media tunica layers. Foam cells produce fat and plaque streaks that thicken and restrict blood channel lumens. This restriction can slow blood flow. R. tomentosa restored lumen size similar to the untreated group. JAK1 and JAK2 inhibit pro-inflammatory protein function; however, JAK3 expression in aortic tissue decreases when R. tomentosa dosage increases.

Conclusions: Hyperglycemic aortic tissue has histological modifications, such as changes in lumen diameter and hypertrophy of the tunica intima and media, resulting in foam cell development, lipid streaks, and plaque-induced vascular constriction. Administering R. tomentosa restores lumen size and modulates JAK protein expression, with JAK1 and JAK2 levels inhibiting pro-inflammatory proteins, while JAK3 expression diminishes with increasing dosage.

Keywords: aortic; JAK1; JAK2; JAK3; plant extract.

PDF Download

Resumen

Contexto: La hiperglucemia contribuye significativamente al desarrollo de la aterosclerosis y es un factor de riesgo importante. El proceso se inicia con la fosforilación de JAK1 y JAK2, que posteriormente conduce a la activación de STAT3, lo que produce daño aterosclerótico a las células endoteliales vasculares. Rhodomyrtus tomentosa es un antioxidante botánico en la medicina tradicional con la capacidad de mitigar el estrés oxidativo.

Objetivos: Analizar la expresión de la familia JAK en el tejido de la aorta después de la administración de R. tomentosa.

Métodos: Se utilizó un diseño completamente aleatorizado (CRD) para evaluar ratas Wistar en seis grupos: K+: diabetes inducida por aloxano, K-: animales no tratados y K0: ratas diabéticas + metformina. Los grupos K1, K2 y K3 recibieron R. tomentosa a 100, 150 y 200 mg/kg de peso corporal. R. tomentosa se tomó por vía oral durante dos semanas. A continuación, se diseccionaron los animales para extraer la aorta para el análisis de inmunohistoquímica con la expresión de la familia JAK y también para el análisis del lumen y el grosor de la aorta.

Resultados: El tejido aórtico hiperglucémico se altera histológicamente, cambiando el tamaño del lumen y el grosor de la túnica íntima y también las capas de la túnica media. Las células espumosas producen estrías de grasa y placa que engrosan y restringen los lúmenes de los canales sanguíneos. Esta restricción puede ralentizar el flujo sanguíneo. R. tomentosa restauró el tamaño del lumen de manera similar al grupo no tratado. JAK1 y JAK2 inhiben la función de la proteína proinflamatoria; sin embargo, la expresión de JAK3 en el tejido aórtico disminuye cuando aumenta la dosis de R. tomentosa.

Conclusiones: El tejido aórtico hiperglucémico presenta modificaciones histológicas, como cambios en el diámetro del lumen e hipertrofia de la túnica íntima y media, lo que resulta en el desarrollo de células espumosas, estrías lipídicas y constricción vascular inducida por placa. La administración de R. tomentosa restaura el tamaño del lumen y modula la expresión de la proteína JAK; los niveles de JAK1 y JAK2 inhiben las proteínas proinflamatorias, mientras que la expresión de JAK3 disminuye con el aumento de la dosis.

Palabras Clave: aórtica; extracto de planta; JAK1; JAK2; JAK3.

PDF Download
 
Citation Format: Situmorang PC, Syahputra RA, Siregar ES, Putri MSS, Tallei TE, Setiawan E (2025) Effect of Rhodomyrtus tomentosa (Aiton) Hassk. on aortic hyperglycemia via JAK family expression. J Pharm Pharmacogn Res 13(4): 979–990. https://doi.org/10.56499/jppres24.2134_13.4.979
References

Al-Qahtani AA, Alhamlan FS, Al-Qahtani AA (2024) Pro-Inflammatory and anti-inflammatory interleukins in infectious diseases: A comprehensive review. Trop Med Infect Dis 9(1): 13. https://doi.org/10.3390/tropicalmed9010013

Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R (2021) The JAK-STAT pathway: An emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur Heart J 42(42): 4389-4400. https://doi.org/10.1093/eurheartj/ehab447

Burgos-Morón E, Abad-Jiménez Z, Marañón AM, Iannantuoni F, Escribano-López I, López-Domènech S, Salom C, Jover A, Mora V, Roldan I, Solá E, Rocha M, Víctor VM (2019) Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: The battle continues. J Clin Med 8(9): 1385. https://doi.org/10.3390/jcm8091385

Collotta D, Franchina MP, Carlucci V, Collino M (2023) Recent advances in JAK inhibitors for the treatment of metabolic syndrome. Front Pharmacol 14: 1245535. https://doi.org/10.3389/fphar.2023.1245535

Detsi A, Kavetsou E, Kostopoulou I, Pitterou I, Pontillo ARN, Tzani A, Christodoulou P, Siliachli A, Zoumpoulakis P (2020) Nanosystems for the encapsulation of natural products: The case of chitosan biopolymer as a matrix. Pharmaceutics 12(7): 669. https://doi.org/10.3390/pharmaceutics12070669

Harrison DA (2012) The JAK/STAT pathway. Cold Spring Harb Perspect Biol 4(3): a011205. https://doi.org/10.1101/cshperspect.a011205

Higashi Y (2022) Roles of Oxidative stress and inflammation in vascular endothelial dysfunction-related disease. Antioxidants (Basel) 11(10): 1958. https://doi.org/10.3390/antiox11101958

Hu X, Li J, Fu M, Zhao X, Wang W (2021) The JAK/STAT signaling pathway: from bench to clinic. Sig Transduct Target Ther 6: 402. https://doi.org/10.1038/s41392-021-00791-1

Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza AL, Vandenbroeck K (2022) Pathophysiology of atherosclerosis. Int J Mol Sci 23(6): 3346. https://doi.org/10.3390/ijms23063346

Liu Y, Wang W, Zhang J, Gao S, Xu T, Yin Y (2023) JAK/STAT signaling in diabetic kidney disease. Front Cell Dev Biol 11: 1233259. https://doi.org/10.3389/fcell.2023.1233259

Li R, Zhang Y, Rasool S, Geetha T, Babu JR (2019) Effects and underlying mechanisms of bioactive compounds on type 2 diabetes mellitus and Alzheimer's disease. Oxid Med Cell Longev 2019: 8165707. https://doi.org/10.1155/2019/8165707

Karp NA, Fry D (2021) What is the optimum design for my animal experiment? BMJ Open Sci 5(1): e100126. https://doi.org/10.1136/bmjos-2020-100126

Kolaszyńska O, Lorkowski J (2023) Symmetry and asymmetry in atherosclerosis. Int J Occup Med Environ Health 36(6): 693-703. https://doi.org/10.13075/ijomeh.1896.02171

Maharani A, Sujarwoto, Praveen D, Oceandy D, Tampubolon G, Patel A (2019) Cardiovascular disease risk factor prevalence and estimated 10-year cardiovascular risk scores in Indonesia: The SMARThealth Extend study. PloS One 14(4): e0215219. https://doi.org/10.1371/journal.pone.0215219

Malek TR, Castro I (2010) Interleukin-2 receptor signaling: At the interface between tolerance and immunity. Immunity 33(2): 153–165. https://doi.org/10.1016/j.immuni.2010.08.004

Mazière C, Conte MA, Mazière JC (2001) Activation of JAK2 by the oxidative stress generated with oxidized low-density lipoprotein. Free Radic Biol Med 31(11): 1334–1340. https://doi.org/10.1016/s0891-5849(01)00649-9

Mehu M, Narasimhulu CA, Singla DK (2022) Inflammatory cells in atherosclerosis. Antioxidants (Basel) 11(2): 233. https://doi.org/10.3390/antiox11020233

Mikušová V, Mikuš P (2021) Advances in chitosan-based nanoparticles for drug delivery. Int J Molecular Sci 22(17): 9652. https://doi.org/10.3390/ijms22179652

Moshapa FT, Riches-Suman K, Palmer TM (2019) Therapeutic targeting of the proinflammatory IL-6-JAK/STAT signalling pathways responsible for vascular restenosis in type 2 diabetes mellitus. Cardiol Res Pract 2019: 9846312. https://doi.org/10.1155/2019/9846312

Moore KJ, Sheedy FJ, Fisher EA (2013) Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol 13: 709–721. https://doi.org/10.1038/nri3520

Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN (2020) The diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci 21(5): 1835. https://doi.org/10.3390/ijms21051835

Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H (2014) Atherosclerosis: Process, indicators, risk factors and new hopes. Int J Prev Med 5(8): 927–946. https://pmc.ncbi.nlm.nih.gov/articles/PMC4258672/

Rezagholizade-Shirvan A, Soltani M, Shokri S, Radfar R, Arab M, Shamloo E (2024) Bioactive compound encapsulation: Characteristics, applications in food systems, and implications for human health. Food Chem X 24: 101953. https://doi.org/10.1016/j.fochx.2024.101953

Rumahorbo CGP, Situmorang PC, Zagoto ERMP, Nisfa L, Hasanah U (2023) Effects of micro-colloidal Rhodomyrtus tomentosa on MMP9, GLUT-1, and IL-1β expression in Rattus norvegicus cervical cancer. J Pharm Pharmacogn Res 11(3): 537–546. https://doi.org/10.56499/jppres23.1618_11.3.537

Shah NA, Khan MR (2014) Antidiabetic effect of Sida cordata in alloxan induced diabetic rats. Biomed Res Int 2014: 671294. https://doi.org/10.1155/2014/671294

Situmorang PC, Ilyas S, Hutahaean S, Rosidah R (2021) Components and acute toxicity of nano herbal haramonting (Rhodomyrtus tomentosa). J Herbmed Pharmacol 10(1): 139–148. https://doi.org/10.34172/jhp.2021.15

Situmorang PC, Ilyas S, Siahaan DAS, Restuati M, Sari ER, Chairunisa C, Maliki MF (2022) Effect of Rhodomyrtus tomentosa Hassk. on HIF1α and VEGF expressions on hypertension placental. J Pharm Pharmacogn Res 10(6): 1076–1086. https://doi.org/10.56499/jppres22.1517_10.6.1076

Situmorang PC, Simanullang RH, Syahputra RA, Hutahaean MM, Sembiring H, Nisfa, Sari ER (2023) Histological analysis of TGFβ1 and VEGFR expression in cervical carcinoma treated with Rhodomyrtus tomentosa. Pharmacia 70(1): 217–223. https://doi.org/10.3897/pharmacia.70.e96811

Situmorang PC, Ilyas S, Syahputra RA, Sari RM, Nugraha AP, Ibrahim A (2024) Rhodomyrtus tomentosa as a new anticancer molecular strategy in breast histology via Her2, IL33, EGFR, and MUC1. Front Pharmacol 15: 1345645. https://doi.org/10.3389/fphar.2024.1345645

Simanullang RH, Situmorang PC, Herlina M, Noradina, Silalahi B, Manurung SS (2022) Histological changes of cervical tumors following Zanthoxylum acanthopodium DC treatment, and its impact on cytokine expression. Saudi J Biol Sci 29(4): 2706-2718. https://doi.org/10.1016/j.sjbs.2021.12.065

Srisuwan S, Tongtawe P, Srimanote P, Voravuthikunchai SP (2014) Rhodomyrtone modulates innate immune responses of THP-1 monocytes to assist in clearing methicillin-resistant Staphylococcus aureus. PloS One 9(10): e110321. https://doi.org/10.1371/journal.pone.0110321

Taouzinet L, Djaoudene O, Fatmi S, Bouiche C, Amrane-Abider M, Bougherra H, Rezgui F, Madani K (2023) Trends of nanoencapsulation strategy for natural compounds in the food industry. Processes 11(5): 1459. https://doi.org/10.3390/pr11051459

Uryga AK, Grootaert MOJ, Garrido AM, Oc S, Foote K, Chappell J, Finigan A, Rossiello F, d'Adda di Fagagna F, Aravani D, Jorgensen HF, Bennett MR (2021) Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury. Commun Biol 4: 611. https://doi.org/10.1038/s42003-021-02123-z

Vo TS, Ngo DH (2019) The health beneficial properties of Rhodomyrtus tomentosa as potential functional food. Biomolecules 9(2): 76. https://doi.org/10.3390/biom9020076

Wagner MA, Siddiqui MA (2012) The JAK-STAT pathway in hypertrophic stress signaling and genomic stress response. JAK-STAT 1(2): 131–141. https://doi.org/10.4161/jkst.20702

Waehre T, Damås JK, Yndestad A, Taskén K, Pedersen TM, Smith C, Halvorsen B, Frøland SS (2004) Effect of activated platelets on expression of cytokines in peripheral blood mononuclear cells - potential role of prostaglandin E2. Thromb Haemost 92(6): 1358–1367. https://doi.org/10.1160/TH04-03-0146

Yang X, Jia J, Yu Z, Duanmu Z, He H, Chen S, Qu C (2020) Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC Cardiovasc Disord 20: 133. https://doi.org/10.1186/s12872-020-01391-7

Zhang H, Dhalla NS (2024) The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease. Int J Mol Sci 25(2): 1082. https://doi.org/10.3390/ijms25021082

Zhou W, Ye SD, Wang W (2021) Elevated retinol binding protein 4 levels are associated with atherosclerosis in diabetic rats via JAK2/STAT3 signaling pathway. World J Diabetes 12(4): 466–479. https://doi.org/10.4239/wjd.v12.i4.466

Zhuge Y, Zhang J, Qian F, Wen Z, Niu C, Xu K, Ji H, Rong X, Chu M, Jia C (2020) Role of smooth muscle cells in cardiovascular disease. Int J Biol Sci 16(14): 2741–2751. https://doi.org/10.7150/ijbs.49871

© 2025 Journal of Pharmacy & Pharmacognosy Research

© 2013-2020 by the authors; licensee JPPRes, Antofagasta, Chile. This journal is an open-access journal distributed under the terms and conditions of the Creative Commons Attribution license-Non Commercial 4.0 international. The content on this site is intended for health professionals. If you are not a health professional, please talk to your doctor about any doubts or concerns regarding your health

Made with ♥ by AVAGAX Studio