The effect of aerobic exercise and bitter orange peel extract on the expression of JAK2/State3 genes in the myocardial tissue of obese rats

Subject Areas : Cellular & Molecular Exercise Biology and Sports Genetic

Shahrzad Haji Ali Akbar ¹ , Mohammad Ali Azarbayjani ² , Shahin Riyahi Malayeri ³ , Hoseyn Fatolahi ⁴

1 - Department of Exercise Physiology, CT.C., Islamic Azad University, Tehran, Iran.
2 - Department of Exercise Physiology, CT.C., Islamic Azad University, Tehran, Iran.
3 - Department of Exercise Physiology, ET.C., Islamic Azad University, Tehran, Iran.
4 - Department of exercise physiology, Pardis Branch, Islamic Azad University, Pardis.Iran

Received: 2025-04-14 Accepted : 2025-06-05 Published : 2025-07-11

Keywords: Aerobic Exercise, Bitter Orange Peel, JAK2/STAT3 Genes,

Abstract :

 

Myocardial tissue fibrosis and cardiac function impairment represent one of the complications of obesity. Evidence suggests that both regular physical activity and medicinal plants, individually, can prevent cardiac fibrosis by modulating cardiac fibrotic pathways.

Accordingly, the present study aimed to investigate the effect of aerobic exercise and bitter orange peel extract on the expression of JAK2/STAT3 genes in the myocardial tissue of obese rats.Thirty adult female Wistar rats from the animal facility of Islamic Azad University, Central Tehran Branch, were selected as subjects and randomly divided into five groups (six rats per group): (1) normal diet control, (2) high-fat diet control, (3) high-fat diet + aerobic exercise, (4) high-fat diet + ethanolic extract of bitter orange peel, and (5) high-fat diet + aerobic exercise + ethanolic extract of bitter orange peel. To induce obesity, 20% palm oil, 1.5% cholesterol, and 0.25% cholic acid were added to the standard diet. Subjects received this regimen for four weeks prior to and during the four-week intervention. The aerobic exercise program consisted of four weeks of treadmill running at a moderate intensity, five sessions per week. The ethanolic extract of bitter orange peel was administered orally at 100 mg/kg body weight for four weeks. Following euthanasia, myocardial tissue from the left ventricle was collected to assess JAK2 and STAT3 gene expression via RT-PCR.

Results showed that expression of JAK2 (P=0.001) and STAT3 (P=0.001) was significantly higher in the high-fat diet control group than the normal diet control group. Gene expression was significantly decreased in the aerobic exercise + high-fat diet group compared to the high-fat diet control group. Similarly, a significant reduction in gene expression was observed in the bitter orange peel extract + high-fat diet group. The greatest reduction was recorded in the combined aerobic exercise + bitter orange extract + high-fat diet group.

The findings of the present study suggest that the combination of aerobic exercise and ethanolic extract of bitter orange peel may exert protective effects on cardiac tissue in obesity induced by a high-fat diet. This is done through downregulation of the fibrotic genes JAK2 and STAT3.

References:

[1] Beckles, D.L., Mascareno, E., Siddiqui, M.A. (2006). Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy. Vascul Pharmacol, Dec;45(6):350-7.
[2] Eid, R.A., Alkhateeb, M.A., El-Kott, A.F., Eleawa, S.M., Zaki, M.S.A., Alaboodi, S.A., Salem Al-Shudiefat, A.A., Aldera, H., Alnamar, N.M., Alassiri, M., Khalil, M.A. (2019). A high-fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG II/TGF-1β/Smad3 pathway: The role of ROS and IL-6 trans-signaling. J Food Biochem, 43(8): e12952.
[3] Geng, Z., Fan, W.Y., Zhou, B., and et al. (2019). FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress. J Transl Med, 17: 107.
[4] Guo, B., Yu, Y., Wang, M., Li, R., He, X., Tang, S., Liu, Q., Mao, Y. (2024). Targeting the JAK2/STAT3 signaling pathway with natural plants and phytochemical ingredients: A novel therapeutic method for combatting cardiovascular diseases. Biomed Pharmacother, 172:116313.
[5] Gurzov, E.N., Stanley, W.J., Pappas, E.G., Thomas, H.E., Gough, D.J. (2016). The JAK/STAT pathway in obesity and diabetes. FEBS J., 283(16):3002-15.
[6] Han, H.Y., Lee, S.K., Choi, B.K., Lee, D.R., Lee, H.J., Kim, T.W. (2019). Preventive Effect of Citrus aurantium Peel Extract on High-Fat Diet-Induced Non-alcoholic Fatty Liver in Mice. Biol Pharm Bull, 42(2):255-260.
[7] Hu, X., Li, J., Fu, M., Zhao, X., Wang, W. (2021). The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther., 26;6(1):402.
[8] Jabri Karoui, I., Marzouk, B. (2013). Characterization of bioactive compounds in Tunisian bitter orange (Citrus aurantium L.) peel and juice and determination of their antioxidant activities. Biomed Res Int., 345415.
[9] Jang, Y.J., Kim, H.Y., Na, S.W., Hong, M.H., Yoon, J.J., Lee, H.S., Kang, D.G. (2024). The Cardioprotective Potential of Herbal Formulas in Myocardial Infarction-Induced Heart Failure through Inhibition of JAK/STAT3 Signaling and Improvement of Cardiac Function. Pharmaceuticals (Basel), 27;17(9):1132.
[10] Kachur, S., Lavie, C.J., de Schutter, A., Milani, R.V., Ventura, H.O. (2017). Obesity and Cardiovascular Diseases. Minerva Med., 108: 212–228.
[11] Kang W., Yawen, D., Han, X. (2023). Exercise and cardiac fibrosis. Current Opinion in Physiology, 31:100630
[12] Kerekes, D., Horváth, A., Kúsz, N., Borcsa, B.L., Szemerédi, N., Spengler, G., Csupor, D. (2022). Coumarins, furocoumarins and limonoids of Citrus trifoliata and their effects on human colon adenocarcinoma cell lines. Heliyon, 29;8(9): e10453.
[13] Kruszewska, J., Cudnoch-Jedrzejewska, A., Czarzasta, K. (2022). Remodeling and Fibrosis of the Cardiac Muscle in the Course of Obesity-Pathogenesis and Involvement of the Extracellular Matrix. Int J Mol Sci., 11;23(8):4195.
[14] Kwan, H.Y., Liu, B., Huang, C., Fatima, S., Su, T., Zhao, X., Ho, A.H.M., Han, Q., Hu, X., Gong, R.H., Chen, M., Wong, H.L.X., Bian, Z. (2019). Signal transducer and activator of transcription-3 drives the high-fat diet-associated prostate cancer growth. Cell Death Dis., 2;10(9):637.
[15] Ma, Y., Kuang, Y., Bo, W., Liang, Q., Zhu, W., Cai, M., Tian, Z. (2021). Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction. Int J Mol Sci., 15;22(22):12341.
[16] Mendoza, M.F., Kachur, S.M., Lavie, C.J. (2020). Hypertension in Obesity. Curr. Opin. Cardiol., 35: 389–396.
[17] Nikbin, S., Tajik, A., Allahyari, P., Matin, G., Hoseini Roote, S.S., Barati, E., Ayazi, M., Karimi, L., Dayani Yazdi F., Javadinejad, N., Azarbayjani, M.A. (2020). Aerobic exercise and eugenol supplementation ameliorated liver injury induced by chlorpyrifos via modulation acetylcholinesterase activation and antioxidant defense. Environmental toxicology, 35(7):783-93.
[18] O’Shea, J.J., and et al. (2015). The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med., 66:311–328.
[19] Od, E.k.P., Deenin, W., Malakul, W., Phoungpetchara, I., Tunsophon, S. (2020). Anti obesity effect of Carica papaya in high fat diet fed rats. Biomedical reports, 1;13(4):1-9.
[20] Sun, X.J., Mao, J.R. (2018). Role of Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in cardioprotection of exercise preconditioning. Eur Rev Med Pharmacol Sci., 22(15):4975-4986.
[21] Teixeira-Fonseca, J.L., Orts, D.J.B.Y., Silva, P.L.D., Conceição, M.R.L., Hermes, H., Prudencio, C.R., Roman-Campos, D. (2024). In Vivo Anti-Inflammatory Activity of D-Limonene in a Rat Model of Monocrotaline-Induced Pulmonary Hypertension: Implications to the Heart Function. Arq Bras Cardiol., 121(12): e20240195.
[22] Wang, T., Sun, X., Cui, H., Liu, K., Zhao, J. (2020). The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway. Mol Med Rep., 21(3):1097-1106.
[23] You, X., Jiang, X., Zhang, C., and et al. (2022). Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling. Aging (Albany NY), 14:1110–1127.
[24] Yu, X. (2023). Promising Therapeutic Treatments for Cardiac Fibrosis: Herbal Plants and Their Extracts. Cardiol Ther., 12(3):415-443.