Journal of Exercise & Organ Cross Talk
Journal of Eexercise & Organ Cross Talk

Long-term aerobic exercise with curcumin supplementation improves cardiac fibrosis via TGF-β1/TRAF6/CTGF signaling in brain tumor of rats

Document Type : Original Article

Authors

Neda Taherizadeh 1
Farshad Ghazalian 1
Hossein Shirvani 2
Mandana Gholami 1
Hossein Abednatanzi 1

1 Department of Physical Education and Sport Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.

2 Exercise Physiology Research Center, Lifestyle Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.

https://doi.org/10.22122/jeoct.2024.495703.1136
Abstract
The aim of the present study is to investigate the effect of aerobic exercise and nano-curcumin supplementation on cardiac TGF-β1/TRAF6 and CTGF pathways in rat with brain tumors. Forty male Wistar rats were divided into 5 groups (n=8 in each) of healthy control, brain tumor, tumor + aerobic exercise (AE), tumor + nanocurcumin (N-CUR) and tumor+AE+N-CUR. Glioblastoma was injected into the rats in the frontal cortex. Nano curcumin supplement at the dose of 80 mg/kg was gavage for 4 weeks, 5 days a week. The training groups performed aerobic exercises on the treadmill for 4 weeks, 3 days a week at a speed of 18 meters per minute, for 25-40 minutes. At the end, the rats were sacrificed and TGF-β1, TRAF6, CTGF were analyzed from the myocardium by Real-time PCR method. Compared to the healthy control group, Tumor group significantly increased TGF-β1 mRNA and TRAF6 mRNA in the myocardium (p<0.05). Also, compared to the healthy control group, all tumor groups showed a significant increase in CTGF mRNA expression (p<0.05). In contrast to the Tumor group, the Tumor+AE and Tumor+AE+N-CUR groups showed a significant decrease in TGF-β1 mRNA at myocardium (p=0.0010 and p=0.0002, respectively). It seems that aerobic exercise or exercise with nano-curcumin supplement has better protective effects on the heart of tumor rats with downregulation of TGF-β1. It is suggested that different doses and various exercise modalities should be investigated to control cardiac fibrosis from the TGF-β1/TRAF6 and CTGF pathways.

What is already known on this subject?

Sedentary lifestyle caused by old age or disease leads to the induction of cellular damage in heart tissue.

 

What this study adds?

Combination of exercise and Nano curcumin by controlling and reducing TGF-β can improve cardiac fibrosis in different cancer models and therefore have protective effects on heart tissue.

Keywords

Aerobic exercise
Nano-curcumin
TGF-β1
Cardiac fibrosis
Brain tumor

Subjects

Acknowledgements

None.

Funding

The funding for this research was provided by the author.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval The study was approved by the Ethics Committee of the Islamic Azad University, Tehran, Iran under protocol number IR.IAU.SRB.REC.1401.029.

Informed consent Not applicable

Author contributions

Conceptualization: N.T., H.A., M.Gh.; Methodology: H.Sh., H.A., F.Gh.; Software: H.A.; Validation: N.T., Formal analysis; Investigation: M.Gh., F.Gh.; Resources: H.Sh., H.A.; Data curation: N.T., H.A., M.Gh.; Writing - original draft: H.Sh.; Writing – review & editing: H.A.; Visualization: M.Gh.; Supervision: F.Gh. Project administration: H.A.; Funding acquisition: N.T.

Abrahams, S., Haylett, W. L., Johnson, G., Carr, J. A., & Bardien, S. (2019). Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: A review. Neuroscience, 406, 1-21. doi: https://doi.org/10.1016/j.neuroscience.2019.02.020
Ashrafizadeh, M., Zarrabi, A., Hashemi, F., Zabolian, A., Saleki, H., Bagherian, M.,…Ang, H. L. (2020). Polychemotherapy with curcumin and doxorubicin via biological nanoplatforms: enhancing antitumor activity. Pharmaceutics, 12(11), 1084. doi: https://doi.org/10.3390/pharmaceutics12111084
Ashrafizadeh, M., Zarrabi, A., Hushmandi, K., Zarrin, V., Moghadam, E. R., Hashemi, F.,…Hashemi, F. (2020). Toward regulatory effects of curcumin on transforming growth factor-beta across different diseases: review. Frontiers in Pharmacology, 11, 585413. doi: https://doi.org/10.3389/fphar.2020.585413
Batlle, E., & Massagué, J. (2019). Transforming growth factor-β signaling in immunity and cancer. Immunity, 50(4), 924-940. URL: https://www.cell.com/immunity/fulltext/S1074-7613(19)30141-4
Chai, Y.-s., Chen, Y.-q., Lin, S.-h., Xie, K., Wang, C.-j., Yang, Y.-z., & Xu, F. (2020). Curcumin regulates the differentiation of naïve CD4+ T cells and activates IL-10 immune modulation against acute lung injury in mice. Biomedicine & Pharmacotherapy, 125, 109946. doi: https://doi.org/10.1016/j.biopha.2020.109946  
Deshmukh, P. A., Bellary, S. R., Schwender, F. T., Kamalov, G., Magotra, M., de Jongh Curry, A. L.,…Weber, K. T. (2011). Spironolactone prevents the inducibility of ventricular tachyarrhythmia in rats with aldosteronism. Journal of cardiovascular pharmacology, 58(5), 487-491. doi: https://doi.org/10.1097/FJC.0b013e31822a78c1
Ding, Y.-f., Peng, Y.-r., Li, J., Shen, H., Shen, M.-q., & Fang, T.-h. (2013). Gualou Xiebai Decoction prevents myocardial fibrosis by blocking TGF-beta/Smad signalling. Journal of Pharmacy and Pharmacology, 65(9), 1373-1381. doi: https://doi.org/10.1111/jphp.12102
Farhood, B., Mortezaee, K., Goradel, N. H., Khanlarkhani, N., Salehi, E., Nashtaei, M. S.,…Sahebkar, A. (2019). Curcumin as an anti‐inflammatory agent: Implications to radiotherapy and chemotherapy. Journal of cellular physiology, 234(5), 5728-5740. doi: https://doi.org/10.1002/jcp.27442
Gabrielsen, A., Lawler, P. R., Yongzhong, W., Steinbrüchel, D., Blagoja, D., Paulsson-Berne, G.,…Hansson, G. K. (2007). Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. Journal of molecular and cellular cardiology, 42(4), 870-883. doi: https://doi.org/10.1016/j.yjmcc.2006.12.016
Gaetano, A. (2016). Relationship between physical inactivity and effects on individual health status. Journal of Physical Education and Sport, 16(4), 1069-1074. doi: https://doi.org/10.7752/jpes.2016.s2170
Giordano, A., & Tommonaro, G. (2019). Curcumin and cancer. Nutrients, 11(10), 2376. doi: https://doi.org/10.3390/nu11102376
Gomes-Santos, I. L., Fernandes, T., Couto, G. K., Ferreira-Filho, J. C. A., Salemi, V. M. C., Fernandes, F. B.,…de Oliveira, E. M. (2014). Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats. PLoS ONE, 9(5), e98012. doi: https://doi.org/10.1371/journal.pone.0098012
Gremeaux, V., Gayda, M., Lepers, R., Sosner, P., Juneau, M., & Nigam, A. (2012). Exercise and longevity. Maturitas, 73(4), 312-317. doi: https://doi.org/10.1016/j.maturitas.2012.09.012
Gu, J., Liu, X., Wang, Q.-x., Tan, H.-w., Guo, M., Jiang, W.-f., & Zhou, L. (2012). Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts. Experimental cell research, 318(16), 2105-2115. doi: https://doi.org/10.1016/j.yexcr.2012.06.015
Gui, T., Sun, Y., Shimokado, A., & Muragaki, Y. (2012). The roles of mitogen-activated protein kinase pathways in TGF-β-induced epithelial-mesenchymal transition. Journal of signal transduction, 2012. doi: https://doi.org/10.1155/2012/289243
Gusso, S., Pinto, T., Baldi, J. C., Derraik, J. G., Cutfield, W. S., Hornung, T., & Hofman, P. L. (2017). Exercise training improves but does not normalize left ventricular systolic and diastolic function in adolescents with type 1 diabetes. Diabetes care, 40(9), 1264-1272. doi: https://doi.org/10.2337/dc16-2347
Haque, S., & Morris, J. C. (2017). Transforming growth factor-β: A therapeutic target for cancer. Human vaccines & immunotherapeutics, 13(8), 1741-1750. doi: https://doi.org/10.1080/21645515.2017.1327107
Jun, J.-I., & Lau, L. F. (2011). Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nature reviews Drug discovery, 10(12), 945-963. doi: https://doi.org/10.1038/nrd3599
Katzmarzyk, P. T., Powell, K. E., Jakicic, J. M., Troiano, R. P., Piercy, K., Tennant, B., & Committee, P. A. G. A. (2019). Sedentary behavior and health: update from the 2018 physical activity guidelines advisory committee. Medicine and science in sports and exercise, 51(6), 1227. doi: https://doi.org/10.1249/MSS.0000000000001935
Khalil, H., Kanisicak, O., Prasad, V., Correll, R. N., Fu, X., Schips, T.,…Lee, S.-J. (2017). Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. The Journal of clinical investigation, 127(10), 3770-3783. doi: https://doi.org/10.1172/JCI94753.
Khan, R., & Sheppard, R. (2006). Fibrosis in heart disease: understanding the role of transforming growth factor‐β1 in cardiomyopathy, valvular disease and arrhythmia. Immunology, 118(1), 10-24. doi: https://doi.org/10.1111/j.1365-2567.2006.02336.x
Koitabashi, N., Arai, M., Kogure, S., Niwano, K., Watanabe, A., Aoki, Y.,…Takigawa, M. (2007). Increased connective tissue growth factor relative to brain natriuretic peptide as a determinant of myocardial fibrosis. Hypertension, 49(5), 1120-1127. doi: https://doi.org/10.1161/HYPERTENSIONAHA.106.077537
Kraus, W. E., Powell, K. E., Haskell, W. L., Janz, K. F., Campbell, W. W., Jakicic, J. M.,…Piercy, K. L. (2019). Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease. Medicine and science in sports and exercise, 51(6), 1270. doi: https://doi.org/10.1249/MSS.0000000000001939
Kwak, H.-B., Kim, J.-h., Joshi, K., Yeh, A., Martinez, D. A., & Lawler, J. M. (2011). Exercise training reduces fibrosis and matrix metalloproteinase dysregulation in the aging rat heart. The FASEB Journal, 25(3), 1106. doi: https://doi.org/10.1096/fj.10-172924
Landström, M. (2010). The TAK1–TRAF6 signalling pathway. The international journal of biochemistry & cell biology, 42(5), 585-589. doi: https://doi.org/10.1016/j.biocel.2009.12.023
Langer, C. J., & Mehta, M. P. (2005). Current management of brain metastases, with a focus on systemic options. Journal of Clinical Oncology, 23(25), 6207-6219. doi: https://doi.org/10.1200/JCO.2005.03.145
Lavie, C. J., Ozemek, C., Carbone, S., Katzmarzyk, P. T., & Blair, S. N. (2019). Sedentary behavior, exercise, and cardiovascular health. Circulation research, 124(5), 799-815. doi: https://doi.org/10.1161/CIRCRESAHA.118.31266
Leask, A. (2010). Potential therapeutic targets for cardiac fibrosis: TGFβ, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circulation research, 106(11), 1675-1680. doi: https://doi.org/10.1161/CIRCRESAHA.110.217737
Lee, I.-M., Shiroma, E. J., Lobelo, F., Puska, P., Blair, S. N., Katzmarzyk, P. T., & Group, L. P. A. S. W. (2012). Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. The lancet, 380(9838), 219-229.
Liu, J., Masurekar, M. R., Vatner, D. E., Jyothirmayi, G. N., Regan, T. J., Vatner, S. F.,…Malhotra, A. (2003). Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. American Journal of Physiology-Heart and Circulatory Physiology, 285(6), H2587-H2591. doi: https://doi.org/10.1152/ajpheart.00516.2003
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods, 25(4), 402-408. doi: https://doi.org/10.1006/meth.2001.1262
Ma, J., Sanchez-Duffhues, G., Goumans, M.-J., & Ten Dijke, P. (2020). TGF-β-induced endothelial to mesenchymal transition in disease and tissue engineering. Frontiers in cell and developmental biology, 8, 260. doi: https://doi.org/10.3389/fcell.2020.00260
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. International journal of molecular sciences, 22(22), 12341. doi: https://doi.org/10.3390/ijms222212341
Muñoz-Durango, N., Fuentes, C. A., Castillo, A. E., González-Gómez, L. M., Vecchiola, A., Fardella, C. E., & Kalergis, A. M. (2016). Role of the renin-angiotensin-aldosterone system beyond blood pressure regulation: molecular and cellular mechanisms involved in end-organ damage during arterial hypertension. International journal of molecular sciences, 17(7), 797. doi: https://doi.org/10.3390/ijms17070797
Newton, H. B. (2007). Symptom management and supportive care of the patient with brain metastases. Brain metastases, 53-73. doi: https://doi.org/10.1007/978-0-387-69222-7_4
Norton, G. R., Tsotetsi, J., Trifunovic, B., Hartford, C., Candy, G. P., & Woodiwiss, A. J. (1997). Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats. Circulation, 96(6), 1991-1998. doi: https://doi.org/10.1161/01.CIR.96.6.1991
Parichatikanond, W., Luangmonkong, T., Mangmool, S., & Kurose, H. (2020). Therapeutic targets for the treatment of cardiac fibrosis and cancer: focusing on TGF-β signaling. Frontiers in Cardiovascular Medicine, 7, 34. doi: https://doi.org/10.3389/fcvm.2020.00034
Pourbagher-Shahri, A. M., Farkhondeh, T., Ashrafizadeh, M., Talebi, M., & Samargahndian, S. (2021). Curcumin and cardiovascular diseases: focus on cellular targets and cascades. Biomedicine & Pharmacotherapy, 136, 111214. doi: https://doi.org/10.1016/j.biopha.2020.111214
Schmitt, E. E., McNair, B. D., Polson, S. M., Cook, R. F., & Bruns, D. R. (2022). Mechanisms of exercise-induced cardiac remodeling differ between young and aged hearts. Exercise and sport sciences reviews, 50(3), 137-144. doi: https://doi.org/10.1249/JES.0000000000000290
Suresh, P. S. (2020). Curcumin and Coagulopathy in the COVID19 Era. Indian journal of clinical Biochemistry, 35(4), 504-505. doi: https://doi.org/10.1007/s12291-020-00914-5
Swanson, L. W. (2018). Brain maps 4.0—Structure of the rat brain: An open access atlas with global nervous system nomenclature ontology and flatmaps. Journal of Comparative Neurology, 526(6), 935-943. doi: https://doi.org/10.1002/cne.24381
Thomas, D. P., McCormick, R. J., Zimmerman, S. D., Vadlamudi, R. K., & Gosselin, L. E. (1992). Aging-and training-induced alterations in collagen characteristics of rat left ventricle and papillary muscle. American Journal of Physiology-Heart and Circulatory Physiology, 263(3), H778-H783. doi: https://doi.org/10.1152/ajpheart.1992.263.3.H778
Vijayakurup, V., Thulasidasan, A. T., Shankar G, M., Retnakumari, A. P., Nandan, C. D., Somaraj, J.,…Liju, V. B. (2019). Chitosan Encapsulation Enhances the Bioavailability and Tissue Retention of Curcumin and Improves its Efficacy in Preventing B [a] P-induced Lung CarcinogenesisChitosan Nanocurcumin: A Potent Lung Cancer Chemopreventive. Cancer Prevention Research, 12(4), 225-236. doi: https://doi.org/10.1158/1940-6207.CAPR-18-0437
Xue, B., Xue, Y., Zhou, J., & Yang, Q. (2020). The Effect of Curcumin Nano-Suspension on Myocardial Fibrosis in Diabetic Rats. Nanoscience and Nanotechnology Letters, 12(10), 1215-1220. doi: https://doi.org/10.1166/nnl.2020.3225
Yin, J., Wang, L., Wang, Y., Shen, H., Wang, X., & Wu, L. (2019). Curcumin reverses oxaliplatin resistance in human colorectal cancer via regulation of TGF-β/Smad2/3 signaling pathway. OncoTargets and therapy, 12, 3893. URL: https://www.tandfonline.com/doi/full/10.2147/OTT.S199601#d1e694
Zhang, H., Wu, J., Dong, H., Khan, S. A., Chu, M.-L., & Tsuda, T. (2014). Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling. Clinical science, 126(4), 275-288. doi: https://doi.org/10.1042/CS20120636
 
Zhang, W., Chen, X. F., Huang, Y. J., Chen, Q. Q., Bao, Y. J., & Zhu, W. (2012). 2, 3, 4′, 5‐T etrahydroxystilbene‐2‐O‐β‐d‐glucoside inhibits angiotensin II‐induced cardiac fibroblast proliferation via suppression of the reactive oxygen species–extracellular signal‐regulated kinase 1/2 pathway. Clinical and Experimental Pharmacology and Physiology, 39(5), 429-437. doi: https://doi.org/10.1111/j.1440-1681.2012.05692.x
Zhao, J.-L., Zhang, T., Shao, X., Zhu, J.-J., & Guo, M.-Z. (2019). Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis. BMC complementary and alternative medicine, 19(1), 1-11. doi: https://doi.org/10.1186/s12906-019-2702-6
 
 
Journal of Exercise & Organ Cross Talk
Volume 4, Issue 3
Summer 2024
Pages 157-165

  • Receive Date 24 July 2024
  • Revise Date 15 September 2024
  • Accept Date 25 September 2024

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us