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

Exercise and Nano-curcumin supplementation mediates cross-talk between MAPK/ERK signaling in the regulation of inflammatory disease

Document Type : Original Article

Authors

Zahra Vafaeimastanabad 1
Nader Hamedchaman 2
Masoumeh Hosseini 1
Amir Maleki 2

1 Department of Physical Education and Sport Sciences, East Tehran Branch, Islamic Azad University, Tehran, Iran.

2 Department of Exercise Physiology, Faculty of Sports Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran.

https://doi.org/10.22122/jeoct.2024.468662.1116
Abstract
Impaired cell internal settings and excessive proliferation causes the occurrence of diverse ranges of syndrom and diseases. The pathological stress underlying these conditions triggers persistent flux through multiple intracellular signaling pathways amongst MAPK/ERK as master regulator. Regarding the anti-inflammatory effects of muscle contraction induced myokines and nano-curcumin supplementation, we aimed to investigate the effects of aerobic training and nano-curcumin supplementation on RAS and ERK gene expression in rat muscle tissue. In this experimental study, 32 male wistar rats (aged 4-6 weeks, 130-150 g) were randomly assigned into 4 groups, including Control (C), Moderate Intensity Continious Training (MICT), Nano-Curcumin Supplementation (NCS) and Moderate Intensity Continious Training + Nano-curcumin (MICT+NCS). The training groups implemented the MICT protocol consisted of running at a velocity of 18-20 m/min, 5 days a week and for a total time of 4 weeks. The Supplement groups received 80 mg/kg/day through oral gavage. Regarding the results of one-way ANOVA, 4 weeks of moderate intensity aerobic exercise and Nano-curcumin supplementation led to a significant difference in the RAS (P=0.001) and ERK (P=0.01) gene expression levels in muscle tissue of rats among the study groups. Also, the results of the Bonferronie test showed that implementation of 4 weeks of MICT along with nano-curcumin supplementation alleviated the RAS/ERK gene expression levels, meanwhile nano-curcumin more efficiently down-regulated the pathway; suggesting that nano-curcumin can be an effective ergogenic aid for improving anti-inflmmatory properties through RAS/ERK signaling pathway.

What is already known on this subject?

Most inflammatory perturbations come up with MAP/ERK dysregulation signaling as a hallmark of disease commencement. The existing knowledge encompasses several key findings as follows; It has been well understood that muscle contraction induces the secretion of diverse ranges of peptides such as myokines from skeletal muscle known as "exerkines" that cross-talk with various vital tissues in the body, like heart, liver, white and brown adipose tissue, and the nervous system, play a crucial role in inter-organ communication and act as dominant keyregulator in metabolic reactions for different purposes amongst inflammatory regulation. Additionally, previous research has demonstrated that exercise can boost liver health by influencing antioxidant systems, adjustment of liver enzymes, and facilitating metabolite excretion. Furthermore, the effects of trace elements, such as curcumin, on the modulation of inflammatory factors in various populations, including individuals with dyslipidemia, obesity, and T2M suffering from MetS, have not been well elucidated. This body of knowledge provides a foundation for understanding the complex interplay between exercise, circulatory trace-minerals, and the liver, and its implications for metabolic health and disease prevention.

 

What this study adds?

The novel finding of this study provides insights into the impact of exercise-induced myokines on the modulation of liver homeostasis; the anti-inflammatory effects of aerobic exercise have been proven, but short-term (≤4 weeks) responses of Ras/ERK gene expression levels to this training protocol could not efficiently be modulated; So, it contributes to understand that adaptation to mid (4-6 weeks) or long-term (≥6 weeks) more efficiently modulate this signaling pathway. Furthermore, in the attribute of fat-soluble properties of curcumin, the usage of curcumin in the format of Nano-curcumin for better ingestion/absorption, could manifest potential anti-inflammatory responses probably due to increasement of bile production. Finally, the insulin-synergize role of curcumin due to its role in the regulation of enzymes in the insulin signaling cascade, might assert anabolic adaptations in the body.

Keywords

Aerobic exercise
Nano-curcumin
RAS
ERK

Subjects

Acknowledgements

We hereby sincerely thank and appreciate all the people who have cooperated in this research.

Funding

This study was extracted from the Ph.D. thesis of the first author. No funding was received for this study.

Compliance with ethical standards

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

Ethical approval Compliance with ethical guidelines: This study followed the ethical standards and was approved by the Ethics Committee of Islamic Azad University [IR.IAU.SRB.REC.1400.055]

Informed consent Not applicable

Author contributions

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

Ababd, Z. V. M., Chaman, N. H., Hosseini, M., & Maleki, A. (2023). Aerobic Exercise and Nano-curcumin Supplementation Prevent cancer symptom development through MAPK/ERK pathway. https://doi.org/10.21203/rs.3.rs-3257588/v1
Aggarwal, B. B. (2010). Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annual review of nutrition, 30(1), 173-199. https://doi.org/10.1146/annurev.nutr.012809.104755
Asgharzadeh, F., Rouzbahani, R., & Khazaei, M. (2016). Chronic low-grade inflammation: Etiology and its effects. Journal of Isfahan Medical School, 34(379), 408-421.
Cao, A.-L., Tang, Q.-F., Zhou, W.-C., Qiu, Y.-Y., Hu, S.-J., & Yin, P.-H. (2015). Ras/ERK signaling pathway is involved in curcumin-induced cell cycle arrest and apoptosis in human gastric carcinoma AGS cells. Journal of Asian natural products research, 17(1), 56-63. https://doi.org/10.1080/10286020.2014.951923
Care, I. o. L. A. R. C. o., & Animals, U. o. L. (1986). Guide for the care and use of laboratory animals. US Department of Health and Human Services, Public Health Service, National Research Council (US) Institute for Laboratory;  https://doi.org/10.17226/5140
Casar, B., Pinto, A., & Crespo, P. (2009). ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task. Cell Cycle, 8(7), 1007-1013. https://doi.org/10.4161/cc.8.7.8078
Creer, A., Gallagher, P., Slivka, D., Jemiolo, B., Fink, W., & Trappe, S. (2005). Influence of muscle glycogen availability on ERK1/2 and Akt signaling after resistance exercise in human skeletal muscle. Journal of applied physiology, 99(3), 950-956. https://doi.org/10.1152/japplphysiol.00110.2005
Farsani, S. S. M., Sadeghizadeh, M., Gholampour, M. A., Safari, Z., & Najafi, F. (2020). Nanocurcumin as a novel stimulator of megakaryopoiesis that ameliorates chemotherapy-induced thrombocytopenia in mice. Life Sciences, 256, 117840. https://doi.org/10.1016/j.lfs.2020.117840
Fathi, R., Nasiri, K., Akbari, A., Ahmadi-KaniGolzar, F., & Farajtabar, Z. (2020). Exercise protects against ethanol-induced damage in rat heart and liver through the inhibition of apoptosis and activation of Nrf2/Keap-1/HO-1 pathway. Life Sciences, 256, 117958. https://doi.org/10.1016/j.lfs.2020.117958
Gao, J., Zhou, H., Lei, T., Zhou, L., Li, W., Li, X., & Yang, B. (2011). Curcumin inhibits renal cyst formation and enlargement in vitro by regulating intracellular signaling pathways. European journal of pharmacology, 654(1), 92-99. https://doi.org/10.1016/j.ejphar.2010.12.008
Guo, Y.-J., Pan, W.-W., Liu, S.-B., Shen, Z.-F., Xu, Y., & Hu, L.-L. (2020). ERK/MAPK signalling pathway and tumorigenesis. Experimental and therapeutic medicine, 19(3), 1997-2007. https://doi.org/10.3892/etm.2020.8454
Hong, L., Wang, Y., Chen, W., & Yang, S. (2018). MicroRNA‐508 suppresses epithelial‐mesenchymal transition, migration, and invasion of ovarian cancer cells through the MAPK1/ERK signaling pathway. Journal of cellular biochemistry, 119(9), 7431-7440.  https://doi.org/10.1002/jcb.27052
Hosseini, M., Hassanian, S. M., Mohammadzadeh, E., ShahidSales, S., Maftouh, M., Fayazbakhsh, H., Khazaei, M., & Avan, A. (2017). Therapeutic potential of curcumin in treatment of pancreatic cancer: current status and future perspectives. Journal of cellular biochemistry, 118(7), 1634-1638.  https://doi.org/10.1002/jcb.25897
Jiang, W., Zhu, J., Zhuang, X., Zhang, X., Luo, T., Esser, K. A., & Ren, H. (2015). Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal. J Biol Chem, 290(39), 23646-23655. https://doi.org/10.1074/jbc.M115.686519
Kramer, H. F., & Goodyear, L. J. (2007). Exercise, MAPK, and NF-κB signaling in skeletal muscle. Journal of applied physiology, 103(1), 388-395. https://doi.org/10.1152/japplphysiol.00085.2007
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. https://doi.org/10.1006/meth.2001.1262
Ma, Q. L., Harris‐White, M. E., Ubeda, O. J., Simmons, M., Beech, W., Lim, G. P., Teter, B., Frautschy, S. A., & Cole, G. M. (2007). Evidence of Aβ‐and transgene‐dependent defects in ERK‐CREB signaling in Alzheimer’s models. Journal of neurochemistry, 103(4), 1594-1607.  https://doi.org/10.1111/j.1471-4159.2007.04869.x
Maik-Rachline, G., Hacohen-Lev-Ran, A., & Seger, R. (2019). Nuclear ERK: mechanism of translocation, substrates, and role in cancer. International journal of molecular sciences, 20(5), 1194. https://doi.org/10.3390/ijms20051194
Melo-Lima, S., Lopes, M. C., & Mollinedo, F. (2015). ERK1/2 acts as a switch between necrotic and apoptotic cell death in ether phospholipid edelfosine-treated glioblastoma cells. Pharmacological Research, 95, 2-11. https://doi.org/10.1016/j.phrs.2015.02.007  
Mirdar Harijani, S., & Musavi, N. (2020). The effect of 12 weeks of submaximal swimming training on immunoreactivity of Ras and Raf-1 in lung epithelial cells of Wistar rats exposed to carcinogen NN. Research in Sport Medicine and Technology, 18(19), 113-126. https://doi.org/10.29252/jsmt.18.19.113
Moens, U., Kostenko, S., & Sveinbjørnsson, B. (2013). The role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes, 4(2), 101-133.  https://doi.org/10.3390/genes4020101
Moon, H., & Ro, S. W. (2021). MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers, 13(12), 3026.  https://doi.org/10.3390/cancers13123026
Moosavi, M., Owjfard, M., & Farokhi, M. (2018). Curcumin prevents 6-OHDA induced cell death and ERK disruption in human neuroblastoma cells. https://doi.org/10.22100/jkh.v13i3.1925
Mundekkad, D., & Cho, W. C. (2023). Applications of curcumin and its nanoforms in the treatment of cancer. Pharmaceutics, 15(9), 2223. https://doi.org/10.3390/pharmaceutics15092223
Nader, G. A., & Esser, K. A. (2001). Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. Journal of applied physiology, 90(5), 1936-1942. https://doi.org/10.1152/jappl.2001.90.5.1936
Nemati, J., Samadi, M., Hadidi, V., & Ghodrat, L. (2018). The effect of 8 weeks of resistance training on total and phosphorylated extracellular signal regulated kinases (ERK) in flexor hallucis longusmuscle of rats. Journal of Practical Studies of Biosciences in Sport, 6(12), 117-126.  https://doi.org/10.22077/jpsbs.2017.318.1129
Okamoto, M., Mizuuchi, D., Omura, K., Lee, M., Oharazawa, A., Yook, J. S., Inoue, K., & Soya, H. (2021). High-intensity intermittent training enhances spatial memory and hippocampal neurogenesis associated with BDNF signaling in rats. Cerebral Cortex, 31(9), 4386-4397. https://doi.org/10.1093/cercor/bhab093
Park, S. W., Nhieu, J., Persaud, S. D., Miller, M. C., Xia, Y., Lin, Y.-W., Lin, Y.-L., Kagechika, H., Mayo, K. H., & Wei, L.-N. (2019). A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1. Scientific reports, 9(1), 10929. https://doi.org/10.1038/s41598-019-47354-7
Rauf, A., Khalil, A. A., Awadallah, S., Khan, S. A., Abu‐Izneid, T., Kamran, M., Hemeg, H. A., Mubarak, M. S., Khalid, A., & Wilairatana, P. (2024). Reactive oxygen species in biological systems: Pathways, associated diseases, and potential inhibitors—A review. Food Science & Nutrition, 12(2), 675-693. https://doi.org/10.1002/fsn3.3784
Roberts, P. J., & Der, C. J. (2007). Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26(22), 3291-3310. https://doi.org/10.1038/sj.onc.1210422
Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023). Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: current status in clinical trials. Genes & diseases, 10(1), 76-88. https://doi.org/10.1016/j.gendis.2022.05.006
Sun, Y., Liu, W.-Z., Liu, T., Feng, X., Yang, N., & Zhou, H.-F. (2015). Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. Journal of Receptors and Signal Transduction, 35(6), 600-604. https://doi.org/10.3109/10799893.2015.1030412
Tajbakhsh, A., Hasanzadeh, M., Rezaee, M., Khedri, M., Khazaei, M., ShahidSales, S., Ferns, G. A., Hassanian, S. M., & Avan, A. (2018). Therapeutic potential of novel formulated forms of curcumin in the treatment of breast cancer by the targeting of cellular and physiological dysregulated pathways. Journal of cellular physiology, 233(3), 2183-2192. https://doi.org/10.1002/jcp.25961
Thompson, H., Maynard, E., Morales, E., & Scordilis, S. (2003). Exercise‐induced HSP27, HSP70 and MAPK responses in human skeletal muscle. Acta physiologica scandinavica, 178(1), 61-72.  https://doi.org/10.1046/j.1365-201X.2003.01112.x
Vijayakurup, V., Thulasidasan, A. T., Shankar G, M., Retnakumari, A. P., Nandan, C. D., Somaraj, J., Antony, J., Alex, V. V., Vinod, B. S., & 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 carcinogenesis. Cancer Prevention Research, 12 (4), 225-236. https://doi.org/10.1158/1940-6207.CAPR-18-0437
Wencker, D., Chandra, M., Nguyen, K., Miao, W., Garantziotis, S., Factor, S. M., Shirani, J., Armstrong, R. C., & Kitsis, R. N. (2003). A mechanistic role for cardiac myocyte apoptosis in heart failure. The Journal of clinical investigation, 111(10), 1497-1504. https://doi:10.1172/JCI200317664
Wretman, C., Lionikas, A., Widegren, U., Lännergren, J., Westerblad, H., & Henriksson, J. (2001). Effects of concentric and eccentric contractions on phosphorylation of MAPKerk1/2 and MAPKp38 in isolated rat skeletal muscle. The Journal of physiology, 535(1), 155-164. https://doi.org/10.1111/j.1469-7793.2001.00155.x
Xie, L., Jiang, Y., Ouyang, P., Chen, J., Doan, H., Herndon, B., Sylvester, J. E., Zhang, K., Molteni, A., & Reichle, M. (2007). Effects of dietary calorie restriction or exercise on the PI3K and ras signaling pathways in the skin of mice. Journal of biological chemistry, 282(38), 28025-28035. https://doi.org/10.1074/jbc.M604857200
Zhang, J., Yu, J., Xie, R., Chen, W., & Lv, Y. (2016). Combinatorial anticancer effects of curcumin and sorafenib towards thyroid cancer cells via PI3K/Akt and ERK pathways. Natural Product Research, 30(16), 1858-1861. https://doi.org/10.1080/14786419.2015.1074229
Zhang, Z., Yi, P., Tu, C., Zhan, J., Jiang, L., & Zhang, F. (2019). Curcumin inhibits ERK/c‐Jun expressions and phosphorylation against endometrial carcinoma. BioMed research international, 2019(1), 8912961. https://doi.org/10.1155/2019/8912961
 
 
Journal of Exercise & Organ Cross Talk
Volume 4, Issue 1
Winter 2024
Pages 22-30

  • Receive Date 16 January 2024
  • Revise Date 10 March 2024
  • Accept Date 27 March 2024

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us