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The Role of mTOR in Doxorubicin-Altered Cardiac Metabolism: A Promising Therapeutic Target of Natural Compounds

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Abstract

Doxorubicin (DOX) is commonly used for the treatment of various types of cancer, however can cause serious side effects, including cardiotoxicity. The mechanisms involved in DOX-induced cardiac damage are complex and not yet fully understood. One mechanism is the disruption of cardiac metabolism, which can impair cardiac function. The mammalian target of rapamycin (mTOR) is a key regulator of cardiac energy metabolism, and dysregulation of mTOR signaling has been implicated in DOX-induced cardiac dysfunction. Natural compounds (NCs) have been shown to improve cardiac function in vivo and in vitro models of DOX-induced cardiotoxicity. This review article explores the protective effects of NCs against DOX-induced cardiac injury, with a focus on their regulation of mTOR signaling pathways. Generally, the modulation of mTOR signaling by NCs represents a promising strategy for decreasing the cardiotoxic effects of DOX.

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Abbreviations

β-lap:

Beta-LAPachone

ADP:

Adenosine diphosphate

AMPK:

Adenosine monophosphate–activated protein kinase

AP:

Apigenin

API:

Apigenin

APS:

Astragalus polysaccharide

ASP:

Aspalathin

ATP:

Adenosine triphosphate

BAX:

BCL-2-associated X protein

BCL-2:

B-cell lymphoma 2

CRA:

Corosolic acid

CUR:

Curcumin

Deptor:

DEP domain-containing mTOR-interacting protein

DHM:

Dihydromyricetin

DHT:

Dihydrotanshinone I

DOX:

Doxorubicin

E2F1:

E2 promoter binding factor 1

ETC:

Electron transport chain

FA:

Ferulic acid

GL:

Glycyrrhizin

HMGB1:

High-mobility group box 1

LAMP1:

Lysosomal-associated membrane proteins-1

LC3:

Protein light chain 3

LKB1:

Liver kinase B1

LUTG:

Luteolin-7-O-glucoside

mLST8:

Mammalian lethal with SEC13 protein 8

mTOR:

Mammalian target of rapamycin

mTORC1:

MTOR complex 1

mTORC2:

MTOR complex 2

NAD+ :

Nicotinamide adenine dinucleotide

NCs:

Natural compounds

NEF:

Neferine

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

p-AKT:

Phosphorylated-AKT

p-mTOR:

Phosphorylated-mTOR

PCr:

Creatine phosphate

PI3K:

Phosphoinositide 3-kinases

PKC:

Protein kinase C

Rags:

Ras-related GTP binding proteins

Raptor:

Regulatory-associated protein of mTOR

Rictor:

Rapamycin-insensitive companion of mTOR

ROS:

Reactive oxygen species

RSV:

Resveratrol

SCU:

Scutellarin

Sin1:

Stress-activated map kinase-interacting protein 1

SIRT1:

Sirtuin 1

SP:

Spinacetin

t-AKT:

Total-AKT

t-mTOR:

Total-mTOR

Tan-IIA:

Tanshinone IIA

TFEB:

Transcription factor EB

TQ:

Thymoquinone

TSC2:

Tuberous sclerosis complex 2

ULK1:

Unc-51-like kinase 1

WWGPE:

Whole wheat grain polyphenolic extract

References

  1. Yarmohmmadi, F., Rahimi, N., Faghir-Ghanesefat, H., Javadian, N., Abdollahi, A., Pasalar, P., & Dehpour, A. R. (2017). Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat. European Journal of Pharmacology, 796, 39–44. https://doi.org/10.1016/j.ejphar.2016.12.022

    Article  CAS  PubMed  Google Scholar 

  2. Okpara, E. S., Adedara, I. A., Guo, X., Klos, M. L., Farombi, E. O., & Han, S. (2022). Molecular mechanisms associated with the chemoprotective role of protocatechuic acid and its potential benefits in the amelioration of doxorubicin-induced cardiotoxicity: A review. Toxicology Reports, 9, 1713–1724. https://doi.org/10.1016/j.toxrep.2022.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S., & Navik, U. (2021). Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 139, 111708. https://doi.org/10.1016/j.biopha.2021.111708

    Article  CAS  Google Scholar 

  4. Oxidative medicine and cellular longevity, 2022, 7176282. https://doi.org/10.1155/2022/7176282.

  5. Journal of molecular and cellular cardiology, 69, 4–16. https://doi.org/10.1016/j.yjmcc.2014.01.007.

  6. Szwed, A., Kim, E., & Jacinto, E. (2021). Regulation and metabolic functions of mTORC1 and mTORC2. Physiological Reviews, 101(3), 1371–1426. https://doi.org/10.1152/physrev.00026.2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jiao, Y., Li, Y., Zhang, J., Zhang, S., Zha, Y., & Wang, J. (2022). RRM2 alleviates doxorubicin-induced cardiotoxicity through the AKT/mTOR signaling pathway. Biomolecules, 12(2), 299. https://doi.org/10.3390/biom12020299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Molecular medicine reports, 23(4), 1–11. https://doi.org/10.3892/mmr.2021.11938.

  9. Johnson, R., Shabalala, S., Louw, J., Kappo, A. P., & Muller, C. J. F. (2017). Aspalathin reverts Doxorubicin-Induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signaling. Molecules (Basel Switzerland), 22(10), 1589. https://doi.org/10.3390/molecules22101589

    Article  CAS  PubMed  Google Scholar 

  10. Yarmohammadi, F., Rezaee, R., & Karimi, G. (2021). Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway. Phytotherapy Research, 35(3), 1163–1175. https://doi.org/10.1002/ptr.6882

    Article  CAS  PubMed  Google Scholar 

  11. Lv, X., Zhu, Y., Deng, Y., Zhang, S., Zhang, Q., Zhao, B., & Li, G. (2020). Glycyrrhizin improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway to prevent doxorubicin-induced cardiotoxicity. Toxicology, 441, 152508. https://doi.org/10.1016/j.tox.2020.152508

    Article  CAS  PubMed  Google Scholar 

  12. Phytomedicine: international journal of phytotherapy and phytopharmacology, 99, 154027. https://doi.org/10.1016/j.phymed.2022.154027.

  13. Manolis, A. S., Manolis, A. A., Manolis, T. A., Apostolaki, N. E., Apostolopoulos, E. J., Melita, H., & Katsiki, N. (2021). Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications. Medicinal Research Reviews, 41(1), 275–313. https://doi.org/10.1002/med.21732

    Article  CAS  PubMed  Google Scholar 

  14. Garcia-Ropero, A., Santos-Gallego, C. G., Zafar, M. U., & Badimon, J. J. (2019). Metabolism of the failing heart and the impact of SGLT2 inhibitors. Expert Opinion on drug Metabolism & Toxicology, 15(4), 275–285. https://doi.org/10.1080/17425255.2019.1588886

    Article  CAS  Google Scholar 

  15. Scientific Reports, 13(1), 8346. https://doi.org/10.21203/rs.3.rs-614231/v1.

  16. Carvalho, R. A., Sousa, R. P. B., Cadete, V. J. J., Lopaschuk, G. D., Palmeira, C. M. M., Bjork, J. A., & Wallace, K. B. (2010). Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. Toxicology, 270(2), 92–98. https://doi.org/10.1016/j.tox.2010.01.019

    Article  CAS  PubMed  Google Scholar 

  17. Journal of applied toxicology: JAT, 36(11), 1486–1495. https://doi.org/10.1002/jat.3307.

  18. γ‐mediated metabolic reprogramming in cardiomyocytes. The Journal of pathology, 247(3), 320–332. https://doi.org/10.1002/path.5192.

  19. Gorini, S., De Angelis, A., Berrino, L., Malara, N., Rosano, G., & Ferraro, E. (2018). Chemotherapeutic drugs and mitochondrial dysfunction: Focus on doxorubicin, trastuzumab, and sunitinib. Oxidative medicine and cellular longevity, 2018, 7582730. https://doi.org/10.1155/2018/7582730

  20. Nolfi-Donegan, D., Braganza, A., & Shiva, S. (2020). Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biology, 37, 101674. https://doi.org/10.1016/j.redox.2020.101674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Russo, M., Della Sala, A., Tocchetti, C. G., Porporato, P. E., & Ghigo, A. (2021). Metabolic aspects of anthracycline cardiotoxicity. Current Treatment Options in Oncology, 22(2), 18. https://doi.org/10.1007/s11864-020-00812-1

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shi, S., Chen, Y., Luo, Z., Nie, G., & Dai, Y. (2023). Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy. Cell Communication and Signaling: CCS, 21(1), 61. https://doi.org/10.1186/s12964-023-01077-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nature cancer, 1(3), 315–328. https://doi.org/10.1038/s43018-020-0039-1.

  24. Chen, Y., & Zhou, X. (2020). Research progress of mTOR inhibitors. European Journal of Medicinal Chemistry, 208, 112820. https://doi.org/10.1016/j.ejmech.2020.112820

    Article  CAS  PubMed  Google Scholar 

  25. Getz, L. J., Runte, C. S., Rainey, J. K., & Thomas, N. A. (2019). Tyrosine phosphorylation as a widespread regulatory mechanism in prokaryotes. Journal of Bacteriology, 201(19), e00205–e00219. https://doi.org/10.1128/JB.00205-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sciarretta, S., Forte, M., Frati, G., & Sadoshima, J. (2018). New insights into the role of mTOR signaling in the cardiovascular system. Circulation Research, 122, 489–505. https://doi.org/10.1161/CIRCRESAHA.117.311147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mao, Z., & Zhang, W. (2018). Role of mTOR in glucose and lipid metabolism. International Journal of Molecular Sciences, 19(7). https://doi.org/10.3390/ijms19072043

  28. Molecular cell, 39(2), 171–183. https://doi.org/10.1016/j.molcel.2010.06.022.

  29. Shi, F., & Collins, S. (2023). Regulation of mTOR signaling: Emerging role of cyclic nucleotide-dependent protein kinases and implications for cardiometabolic disease. International Journal of Molecular Sciences, 24(14). https://doi.org/10.3390/ijms241411497

  30. Kaldirim, M., Lang, A., Pfeiler, S., Fiegenbaum, P., Kelm, M., Bönner, F., & Gerdes, N. (2022). Modulation of mTOR signaling in cardiovascular disease to target acute and chronic inflammation. Frontiers in Cardiovascular Medicine, 9, 907348. https://doi.org/10.3389/fcvm.2022.907348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aging Cell, 19(4), e13126. https://doi.org/10.1111/acel.13126.

  32. Science (New York, N.Y.), 366(6464), 468–475. https://doi.org/10.1126/science.aay0166.

  33. Nature, 614(7948), 572–579. https://doi.org/10.1038/s41586-022-05652-7.

  34. Dang, T. T., & Back, S. H. (2021). Translation inhibitors activate autophagy master regulators TFEB and TFE3. International Journal of Molecular Sciences, 22(21), 12083. https://doi.org/10.3390/ijms222112083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deleyto-Seldas, N., & Efeyan, A. (2021). The mTOR–autophagy axis and the control of metabolism. Frontiers in Cell and Developmental Biology, 9, 655731. https://doi.org/10.3389/fcell.2021.655731

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sadria, M., & Layton, A. T. (2021). Interactions among mTORC, AMPK and SIRT: A computational model for cell energy balance and metabolism. Cell Communication and Signaling, 19(1), 1–17. https://doi.org/10.1101/2020.10.07.330308

    Article  Google Scholar 

  37. Bazer, F. W., Seo, H., Wu, G., & Johnson, G. A. (2020). Interferon tau: Influences on growth and development of the conceptus. Theriogenology, 150, 75–83. https://doi.org/10.1016/j.theriogenology.2020.01.069

    Article  CAS  PubMed  Google Scholar 

  38. Jacinto, E. (2019). Amplifying mTORC2 signals through AMPK during energetic stress. Science Signaling, 12(585), eaax5855. https://doi.org/10.1126/scisignal.aax5855

    Article  CAS  PubMed  Google Scholar 

  39. Fu, W., & Hall, M. N. (2020). Regulation of mTORC2 signaling. Genes, 11(9), 1045. https://doi.org/10.3390/genes11091045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nature Communications, 11(1), 575. https://doi.org/10.1038/s41467-020-14430-w.

  41. Journal of Diabetes Research, 2022. https://doi.org/10.1155/2022/1755563.

  42. Shi, B., Ma, M., Zheng, Y., Pan, Y., & Lin, X. (2019). mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury. Journal of Cellular Physiology, 234(8), 12562–12568. https://doi.org/10.1002/jcp.28125

    Article  CAS  PubMed  Google Scholar 

  43. Circulation research, 132(5), e148–e165. https://doi.org/10.1161/CIRCRESAHA.119.316388.

  44. Daneshgar, N., Rabinovitch, P. S., & Dai, D. F. (2021). TOR signaling pathway in cardiac aging and heart failure. Biomolecules, 11(2), 168. https://doi.org/10.3390/biom11020168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mohan, U. P., PB, T. P., Iqbal, S. T. A., & Arunachalam, S. (2021). Mechanisms of doxorubicin-mediated reproductive toxicity–a review. Reproductive Toxicology, 102, 80–89. https://doi.org/10.1016/j.reprotox.2021.04.003

    Article  CAS  PubMed  Google Scholar 

  46. Oncotarget, 8(3), 4837–4848. https://doi.org/10.18632/oncotarget.13596.

  47. β-LAPachone ameliorates doxorubicin-induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice. Basic & clinical pharmacology & toxicology, 126(4), 364–373. https://doi.org/10.1111/bcpt.13340.

  48. Biochemical Pharmacology, 180, 114188. https://doi.org/10.1016/j.bcp.2020.114188.

  49. Yu, W., Qin, X., Zhang, Y., Qiu, P., Wang, L., Zha, W., & Ren, J. (2020). Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner. Cardiovascular Diagnosis and Therapy, 10(4), 752. https://doi.org/10.21037/cdt-19-707

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wang, M., Firrman, J., Liu, L., & Yam, K. (2019). A review on flavonoid apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. BioMed Research International, 2019, 7010467. https://doi.org/10.1155/2019/7010467

  51. Thomas, S. D., Jha, N. K., Jha, S. K., Sadek, B., & Ojha, S. (2023). Pharmacological and molecular insight on the cardioprotective role of apigenin. Nutrients, 15(2), 385. https://doi.org/10.3390/nu15020385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yu, W., Sun, H., Zha, W., Cui, W., Xu, L., Min, Q., & Wu, J. (2017). Apigenin attenuates adriamycin-induced cardiomyocyte apoptosis via the PI3K/AKT/mTOR pathway. Evidence-based complementary and alternative medicine: eCAM, 2017, 2590676. https://doi.org/10.1155/2017/2590676

  53. Biomolecules, 11(3), 392. https://doi.org/10.3390/biom11030392.

  54. Fu, Y. S., Chen, T. H., Weng, L., Huang, L., Lai, D., & Weng, C. F. (2021). Pharmacological properties and underlying mechanisms of curcumin and prospects in medicinal potential. Biomedicine & Pharmacotherapy, 141, 111888. https://doi.org/10.1016/j.biopha.2021.111888

    Article  CAS  Google Scholar 

  55. Vafaeipour, Z., Razavi, B. M., & Hosseinzadeh, H. (2022). Effects of turmeric (Curcuma longa) and its constituent (curcumin) on the metabolic syndrome: An updated review. Journal of Integrative Medicine, 20(3), 193–203. https://doi.org/10.1039/D2FO02625B

    Article  PubMed  Google Scholar 

  56. Yarmohammadi, F., Hayes, A. W., & Karimi, G. (2021). Protective effects of curcumin on chemical and drug-induced cardiotoxicity: A review. Naunyn-Schmiedeberg’s Archives of Pharmacology, 394, 1341–1353. https://doi.org/10.1007/s00210-021-02072-8

    Article  CAS  PubMed  Google Scholar 

  57. Psychopharmacology, 240(5), 1179–1190. https://doi.org/10.1007/s00213-023-06357-z.

  58. Zhang, Q., & Wu, L. (2022). In vitro and in vivo cardioprotective effects of curcumin against doxorubicin-induced cardiotoxicity: A systematic review. Journal of oncology, 2022, 7277562. https://doi.org/10.1155/2022/7277562

  59. Yao, H., Zhou, L., Tang, L., Guan, Y., Chen, S., Zhang, Y., & Han, X. (2017). Protective effects of luteolin-7-O-glucoside against starvation-induced injury through upregulation of autophagy in H9c2 cells. Bioscience Trends, 11(5), 557–564. https://doi.org/10.5582/bst.2017.01111

    Article  CAS  PubMed  Google Scholar 

  60. Zang, Y., Igarashi, K., & Li, Y. (2016). Anti-diabetic effects of luteolin and luteolin-7-O-glucoside on KK-A y mice. Bioscience Biotechnology and Biochemistry, 80(8), 1580–1586. https://doi.org/10.1080/09168451.2015.1116928

    Article  CAS  PubMed  Google Scholar 

  61. Nutrients, 14(6), 1155. https://doi.org/10.3390/nu14061155.

  62. Biomolecules, 10(4), 502. https://doi.org/10.3390/biom10040502.

  63. Cardiovascular toxicology, 16(2), 101–110. https://doi.org/10.1007/s12012-015-9317-z.

  64. Biomedicine & Pharmacotherapy, 158, 114203. https://doi.org/10.1016/j.biopha.2022.114203.

  65. Asokan, S. M., Mariappan, R., Muthusamy, S., & Velmurugan, B. K. (2018). Pharmacological benefits of neferine-A comprehensive review. Life Sciences, 199, 60–70. https://doi.org/10.1016/j.lfs.2018.02.032

    Article  CAS  Google Scholar 

  66. Guolan, D., Lingli, W., Wenyi, H., Wei, Z., Baowei, C., & Sen, B. (2018). Anti-inflammatory effects of neferine on LPS-induced human endothelium via MAPK, and NF-κβ pathways. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 73(9), 541–544. https://doi.org/10.1691/ph.2018.8443

    Article  CAS  Google Scholar 

  67. Lohanathan, B. P., Rathinasamy, B., Huang, C. Y., & Viswanadha, V. P. (2022). Neferine attenuates doxorubicin-induced fibrosis and hypertrophy in H9c2 cells. Journal of Biochemical and Molecular Toxicology, 36(7), e23054. https://doi.org/10.1002/jbt.23054

    Article  CAS  PubMed  Google Scholar 

  68. Bharathi Priya, L., Baskaran, R., Huang, C. Y., & Vijaya Padma, V. (2018). Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts. Journal of Cellular Biochemistry, 119(2), 1441–1452. https://doi.org/10.1002/jcb.26305

    Article  CAS  PubMed  Google Scholar 

  69. Van Hung, P. (2016). Phenolic compounds of cereals and their antioxidant capacity. Critical Reviews in Food Science and Nutrition, 56(1), 25–35. https://doi.org/10.1080/10408398.2012.708909

    Article  CAS  PubMed  Google Scholar 

  70. Ma, D., Wang, C., Feng, J., & Xu, B. (2021). Wheat grain phenolics: A review on composition, bioactivity, and influencing factors. Journal of the Science of Food and Agriculture, 101(15), 6167–6185. https://doi.org/10.1002/jsfa.11428

    Article  CAS  PubMed  Google Scholar 

  71. Sahu, R., Dua, T. K., Das, S., De Feo, V., & Dewanjee, S. (2019). Wheat phenolics suppress doxorubicin-induced cardiotoxicity via inhibition of oxidative stress, MAP kinase activation, NF-κB pathway, PI3K/Akt/mTOR impairment, and cardiac apoptosis. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 125, 503–519. https://doi.org/10.1016/j.fct.2019.01.034

    Article  CAS  PubMed  Google Scholar 

  72. Zhao, J., Zhou, H., An, Y., Shen, K., & Yu, L. (2021). Biological effects of corosolic acid as an anti–inflammatory, anti–metabolic syndrome and anti–neoplasic natural compound. Oncology Letters, 21(2), 1. https://doi.org/10.3892/ol.2020.12345

    Article  ADS  CAS  Google Scholar 

  73. International Journal of Molecular Medicine, 45(5), 1425–1435. https://doi.org/10.3892/ijmm.2020.4531.

  74. Alkholifi, F. K., Devi, S., Yusufoglu, H. S., & Alam, A. (2023). The cardioprotective effect of corosolic acid in the diabetic rats: A possible mechanism of the PPAR-γ pathway. Molecules, 28(3), 929. https://doi.org/10.3390/molecules28030929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Che, Y., Wang, Z., Yuan, Y., Zhou, H., Wu, H., Wang, S., & Tang, Q. (2022). By restoring autophagic flux and improving mitochondrial function, corosolic acid protects against dox-induced cardiotoxicity. Cell Biology and Toxicology, 38(3), 451–467. https://doi.org/10.1007/s10565-021-09619-8

    Article  CAS  PubMed  Google Scholar 

  76. International Journal of Molecular Sciences, 23(23), 15180. https://doi.org/10.3390/ijms232315180.

  77. Wei, Y., Xu, M., Ren, Y., Lu, G., Xu, Y., Song, Y., & Ji, H. (2016). The cardioprotection of dihydrotanshinone I against myocardial ischemia–reperfusion injury via inhibition of arachidonic acid ω-hydroxylase. Canadian Journal of Physiology and Pharmacology, 94(12), 1267–1275. https://doi.org/10.1139/cjpp-2016-0036

    Article  CAS  PubMed  Google Scholar 

  78. κB inflammatory signaling axis: a novel therapeutic pathway of dihydrotanshinone I in doxorubicin-induced cardiotoxicity. Journal of experimental & clinical cancer research: CR, 39(1), 93. https://doi.org/10.1186/s13046-020-01595-x.

  79. Yarmohammadi, F., Karbasforooshan, H., Hayes, A. W., & Karimi, G. (2021). Inflammation suppression in doxorubicin-induced cardiotoxicity: Natural compounds as therapeutic options. Naunyn-Schmiedeberg’s Archives of Pharmacology, 394(10), 2003–2011. https://doi.org/10.1007/s00210-021-02132-z

    Article  CAS  PubMed  Google Scholar 

  80. Fang, Z., Zhang, M., Liu, J., Zhao, X., Zhang, Y., & Fang, L. (2021). Tanshinone IIA: A review of its anticancer effects. Frontiers in Pharmacology, 11, 611087. https://doi.org/10.3389/fphar.2020.611087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Guo, R., Li, L., Su, J., Li, S., Duncan, S. E., Liu, Z., & Fan, G. (2020). Pharmacological activity and mechanism of tanshinone IIA in related diseases. Drug Design Development and Therapy, 14, 4735–4748. https://doi.org/10.2147/DDDT.S266911

    Article  PubMed  PubMed Central  Google Scholar 

  82. Feng, J., Liu, L., Yao, F., Zhou, D., He, Y., & Wang, J. (2021). The protective effect of tanshinone IIa on endothelial cells: A generalist among clinical therapeutics. Expert Review of Clinical Pharmacology, 14(2), 239–248. https://doi.org/10.1080/17512433.2021.1878877

    Article  CAS  PubMed  Google Scholar 

  83. He, Z., Sun, C., Xu, Y., & Cheng, D. (2016). Reduction of atrial fibrillation by Tanshinone IIA in chronic heart failure. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 84, 1760–1767. https://doi.org/10.1016/j.biopha.2016.10.110

    Article  CAS  Google Scholar 

  84. Frontiers in Pharmacology, 14, 1165212. https://doi.org/10.3389/fphar.2023.1165212.

  85. Cancers, 11(7), 910. https://doi.org/10.3390/cancers11070910.

  86. Chaudhary, S. K., Sandasi, M., Makolo, F., van Heerden, F. R., & Viljoen, A. M. (2021). Aspalathin: A rare dietary dihydrochalcone from aspalathus linearis (rooibos tea). Phytochemistry Reviews, 1–32. https://doi.org/10.1007/s11101-021-09741-9

  87. Molecules, 24(9), 1713. https://doi.org/10.3390/molecules24091713.

  88. Li, C., Liu, Y., Zhang, Y., Li, J., & Lai, J. (2022). Astragalus polysaccharide: A review of its immunomodulatory effect. Archives of Pharmacal Research, 45(6), 367–389. https://doi.org/10.1007/s12272-022-01393-3

    Article  CAS  PubMed  Google Scholar 

  89. Zheng, Y., Ren, W., Zhang, L., Zhang, Y., Liu, D., & Liu, Y. (2020). A review of the pharmacological action of Astragalus polysaccharide. Frontiers in Pharmacology, 11, 349. https://doi.org/10.3389/fphar.2020.00349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu, D., Chen, L., Zhao, J., & Cui, K. (2018). Cardioprotection activity and mechanism of astragalus polysaccharide in vivo and in vitro. International Journal of Biological Macromolecules, 111, 947–952. https://doi.org/10.1016/j.ijbiomac.2018.01.048

    Article  CAS  PubMed  Google Scholar 

  91. Zhang, Y., Zhou, Q., Ding, X., Wang, H., & Tan, G. (2021). HILIC-MS-based metabolomics reveal that astragalus polysaccharide alleviates doxorubicin-induced cardiomyopathy by regulating sphingolipid and glycerophospholipid homeostasis. Journal of Pharmaceutical and Biomedical Analysis, 203, 114177. https://doi.org/10.1016/j.jpba.2021.114177

    Article  CAS  PubMed  Google Scholar 

  92. Zhang, H., Caprioli, G., Hussain, H., Le, N. P. K., Farag, M. A., & Xiao, J. (2021). A multifaceted review on dihydromyricetin resources, extraction, bioavailability, biotransformation, bioactivities, and food applications with future perspectives to maximize its value. eFood, 2(4), 164–184. https://doi.org/10.53365/efood.k/143518

    Article  Google Scholar 

  93. Frontiers in Pharmacology, 12, 3721. https://doi.org/10.3389/fphar.2021.794563.

  94. Wang, Y., Wang, J., Xiang, H., Ding, P., Wu, T., & Ji, G. (2022). Recent update on application of dihydromyricetin in metabolic related diseases. Biomedicine & Pharmacotherapy, 148, 112771. https://doi.org/10.1016/j.biopha.2022.112771

    Article  CAS  Google Scholar 

  95. Frontiers in pharmacology, 9, 1204. https://doi.org/10.3389/fphar.2018.01204.

  96. Wang, L., & Ma, Q. (2018). Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacology & Therapeutics, 190, 105–127. https://doi.org/10.1016/j.pharmthera.2018.05.006

    Article  CAS  Google Scholar 

  97. Huang, H., Geng, Q., Yao, H., Shen, Z., Wu, Z., Miao, X., & Shi, P. (2018). Protective effect of scutellarin on myocardial infarction induced by isoprenaline in rats. Iranian Journal of Basic Medical Sciences, 21(3), 267. https://doi.org/10.22038/ijbms.2018.26110.6415

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  98. Xu, L., Chen, R., Ma, X., Zhu, Y., Sun, G., & Sun, X. (2020). Scutellarin protects against myocardial ischemia-reperfusion injury by suppressing NLRP3 inflammasome activation. Phytomedicine, 68, 153169. https://doi.org/10.1016/j.phymed.2020.153169

    Article  CAS  PubMed  Google Scholar 

  99. Chemistry & biodiversity, 20(1), e202200450. https://doi.org/10.1002/cbdv.202200450.

  100. Toxicology in vitro: an international journal published in association with BIBRA, 82, 105366. https://doi.org/10.1016/j.tiv.2022.105366.

  101. Lu, Y., Feng, Y., Liu, D., Zhang, Z., Gao, K., Zhang, W., & Tang, H. (2018). Thymoquinone attenuates myocardial ischemia/reperfusion injury through activation of SIRT1 signaling. Cellular Physiology and Biochemistry, 47(3), 1193–1206. https://doi.org/10.1159/000490216

    Article  CAS  PubMed  Google Scholar 

  102. Tabassum, S., Rosli, N., Ichwan, S. J. A., & Mishra, P. (2021). Thymoquinone and its pharmacological perspective: A review. Pharmacological Research - Modern Chinese Medicine, 1, 100020. https://doi.org/10.1016/j.prmcm.2021.100020

    Article  Google Scholar 

  103. Gur, F. M., & Aktas, I. (2021). The ameliorative effects of thymoquinone and beta-aminoisobutyric acid on streptozotocin-induced diabetic cardiomyopathy. Tissue and Cell, 71, 101582. https://doi.org/10.1016/j.tice.2021.101582

    Article  CAS  PubMed  Google Scholar 

  104. Liu, D., & Zhao, L. (2022). Thymoquinone–induced autophagy mitigates doxorubicin–induced H9c2 cell apoptosis. Experimental and Therapeutic Medicine, 24(5), 694. https://doi.org/10.3892/etm.2022.11630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nagar, P. S., Rane, S., & Dwivedi, M. (2022). LC-MS/MS standardization and validation of glycyrrhizin from the roots of taverniera cuneifolia: A potential alternative source of glycyrrhiza glabra. Heliyon, 8(8), e10234. https://doi.org/10.1016/j.heliyon.2022.e10234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Thakur, V., Alcoreza, N., Delgado, M., Joddar, B., & Chattopadhyay, M. (2021). Cardioprotective effect of glycyrrhizin on myocardial remodeling in diabetic rats. Biomolecules, 11(4), 569. https://doi.org/10.3390/biom11040569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Translational stroke research, 11, 967–982. https://doi.org/10.1007/s12975-019-00772-1.

  108. Mano, Y., Abe, K., Takahashi, M., Higurashi, T., Kawano, Y., Miyazaki, S., & Maeda-Minami, A. (2023). Optimal administration of glycyrrhizin avoids pharmacokinetic interactions with high-dose methotrexate and exerts a hepatoprotective effect. Anticancer Research, 43(4), 1493–1501. https://doi.org/10.21873/anticanres.16298

    Article  CAS  PubMed  Google Scholar 

  109. Jäger, T., Mokos, A., Prasianakis, N. I., & Leyer, S. (2022). Pore-level multiphase simulations of realistic distillation membranes for water desalination. Membranes, 11(4), 569. https://doi.org/10.3390/biom11040569

    Article  CAS  Google Scholar 

  110. Naunyn-Schmiedeberg’s Archives of Pharmacology, 393, 979–989. https://doi.org/10.1007/s00210-019-01767-3.

  111. Frontiers in Immunology, 11, 1104. https://doi.org/10.3389/fimmu.2020.01104.

  112. κB and PI3K/Akt/mTOR pathways. Molecular immunology, 94, 7–17. https://doi.org/10.1016/j.molimm.2017.12.008.

  113. Oh, H., Choi, A., Seo, N., Lim, J. S., You, J. S., & Chung, Y. E. (2021). Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on post-contrast acute kidney injury. Scientific Reports, 11(1), 1–12. https://doi.org/10.1038/s41598-021-94928-5

    Article  CAS  Google Scholar 

  114. Malviya, V., Tawar, M., Burange, P., & Jodh, R. (2022). A brief review on resveratrol, 12(2), 157–162. https://doi.org/10.52711/2231-5659.2022.00027

  115. Dyck, G. J. B., Raj, P., Zieroth, S., Dyck, J. R. B., & Ezekowitz, J. A. (2019). The effects of resveratrol in patients with cardiovascular disease and heart failure: A narrative review. International Journal of Molecular Sciences, 20(4), 904. https://doi.org/10.3390/ijms20040904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Li, T., Tan, Y., Ouyang, S., He, J., & Liu, L. (2022). Resveratrol protects against myocardial ischemia-reperfusion injury via attenuating ferroptosis. Gene, 808, 145968. https://doi.org/10.1016/j.gene.2021.145968

    Article  CAS  PubMed  Google Scholar 

  117. Gu, J., Fan, Y. Q., Zhang, H. L., Pan, J. A., Yu, J. Y., Zhang, J. F., & Wang, C. Q. (2018). Resveratrol suppresses doxorubicin-induced cardiotoxicity by disrupting E2F1 mediated autophagy inhibition and apoptosis promotion. Biochemical Pharmacology, 150, 202–213. https://doi.org/10.1016/j.bcp.2018.02.025

    Article  CAS  PubMed  Google Scholar 

  118. Gu, J., Hu, W., Song, Z. P., Chen, Y. G., Zhang, D. D., & Wang, C. Q. (2016). Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity. International Immunopharmacology, 32, 1–7. https://doi.org/10.1016/j.intimp.2016.01.002

    Article  CAS  PubMed  Google Scholar 

  119. Lei, Y., & Klionsky, D. J. (2023). Transcriptional regulation of autophagy and its implications in human disease. Cell Death & Differentiation, 1–14. https://doi.org/10.1038/s41418-023-01162-9

  120. Rahman, M. A., Cho, Y., Nam, G., & Rhim, H. (2021). Antioxidant compound, oxyresveratrol, inhibits APP production through the AMPK/ULK1/mTOR-mediated autophagy pathway in mouse cortical astrocytes. Antioxidants, 10(3), 408. https://doi.org/10.3390/antiox10030408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gomes, C. L., de Albuquerque Wanderley Sales, V., Gomes de Melo, C., Ferreira da Silva, R. M., Nishimura, V., Rolim, R. H., L. A., & Rolim Neto, P. J. (2021). Beta-lapachone: Natural occurrence, physicochemical properties, biological activities, toxicity and synthesis. Phytochemistry, 186, 112713. https://doi.org/10.1016/j.phytochem.2021.112713

    Article  CAS  PubMed  Google Scholar 

  122. β-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology, 392, 633–640. https://doi.org/10.1007/s00210-019-01619-0.

  123. Tabrizi, F. B., Yarmohammadi, F., Hayes, A. W., & Karimi, G. (2022). The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin-induced cardiotoxicity: A review. Journal of Biochemical and Molecular Toxicology, 36(1), e22946. https://doi.org/10.1002/jbt.22946

    Article  CAS  PubMed  Google Scholar 

  124. Chemico-biological interactions, 317, 108972. https://doi.org/10.1016/j.cbi.2020.108972.

  125. Human Gene Therapy, 33(11–12), 598–613. https://doi.org/10.1089/hum.2021.176.

  126. Frontiers in Pharmacology, 13, 870699. https://doi.org/10.3389/fphar.2022.870699.

  127. Liu, D., & Zhao, L. (2022). Spinacetin alleviates doxorubicin-induced cardiotoxicity by initiating protective autophagy through SIRT3/AMPK/mTOR pathways. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 101, 154098. https://doi.org/10.1016/j.phymed.2022.154098

    Article  CAS  PubMed  Google Scholar 

  128. Frontiers in Pharmacology, 9, 824. https://doi.org/10.3389/fphar.2018.00824.

  129. Murcia, M. A., Jiménez-Monreal, A. M., Gonzalez, J., & Martínez-Tomé, M. (2020). Chapter 11 - Spinach. In A. K. B. T.-N. C. and A. P. of F. and V. Jaiswal (Ed.), (pp. 181–195). Academic Press. https://doi.org/10.1016/B978-0-12-812780-3.00011-8

  130. Zhang, T., Liu, J., Tong, Q., & Lin, L. (2020). SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. International Journal of Molecular Sciences, 21(2), 372. https://doi.org/10.3390/ijms21020372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Authors are grateful to the Kermanshah University of Medical Sciences Office of Vice Chancellor for Research, Kermanshah, Iran.

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  1. Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Fatemeh Yarmohammadi, Mahvash Hesari & Dareuosh Shackebaei

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F.Y. and M.H. wrote the main manuscript text. F.Y. prepared figures. D.SH. edited the main manuscript text. All authors reviewed the manuscript.

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Correspondence to Dareuosh Shackebaei.

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Yarmohammadi, F., Hesari, M. & Shackebaei, D. The Role of mTOR in Doxorubicin-Altered Cardiac Metabolism: A Promising Therapeutic Target of Natural Compounds. Cardiovasc Toxicol 24, 146–157 (2024). https://doi.org/10.1007/s12012-023-09820-7

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