Volume 29, Issue 4 (December 2025)                   Physiol Pharmacol 2025, 29(4): 350-374 | Back to browse issues page


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Sheibani M, Shayan M, Mohammadgholi-Beiki A, Sharifi A, Jafari-Sabet M, Sharifi A M. Applications of phytomedicines in cardiovascular regeneration therapy: pre-clinical and clinical studies. Physiol Pharmacol 2025; 29 (4) :350-374
URL: http://ppj.phypha.ir/article-1-2339-en.html
Abstract:   (2634 Views)
Cardiovascular diseases (CVDs) are the leading cause of death in human societies. Several medicinal and interventional therapeutic approaches are approved for the treatment of CVDs, one of which is phytomedicine. Phytomedicine is described as the exploitation of the therapeutic properties of herbal medicines. The cardioprotective effects of phytochemicals are due to their anti-oxidative, anti-hypercholesterolemia, anti-inflammatory, antiangiogenic, and anti ischemic activities, reducing the risk factors of developing CVDs. Regenerative medicine (RM) is a well-established f ield that aims to replace, repair, and regenerate diseased and injured human cells, tissues, or organs. Stem cells’ (SC) potential to differentiate into various cell types and their self-renewal capabilities have made them an excellent tool for applying RM in CVD. The intersection of phytomedicines and regenerative medicine can be categorized into two main areas. Phytochemicals have been shown to significantly enhance the proliferation and differentiation of mesenchymal stem cells (MSCs). For example, certain plant extracts promote osteogenic (bone-forming) and chondrogenic (cartilage-forming) differentiation of MSCs, thereby enhancing stem cell function. Additionally, plant derived compounds can mitigate the side effects associated with conventional therapies while offering effective treatment options for tissue regeneration (natural alternatives to traditional therapeutics). This paper reviews current evidence and studies on the beneficial properties of phytomedicines in cardiac RM, both in animal models and in humans. In summary, all of the mentioned studies suggestthat the use of phytomedicine may be directly or indirectly involved in cardiogenesis and angiogenesis by stimulating endogenous SCs and their secretory activity, modulating cytokine release, signal transduction, and elevating the levels of several cardiac regeneration factors. On the other hand, various mechanisms through which these herbal medicines act, such as reducing oxidative stress, controlling inflammation, and promoting angiogenesis, underscore their potential as viable alternatives or adjuncts to conventional therapies for cardiovascular diseases. The integration of phytomedicine into clinical practice could lead to enhanced overall therapeutic efficacy, more effective and personalized treatment, fewer cardiovascular risks and better health outcomes. Further research is required to elucidate the specific molecular pathways through which phytomedicines exert their beneficial effects on cardiac tissue. Understanding these mechanisms will help in developing targeted therapies.
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Type of Manuscript: Review | Subject: Cardiovascular Physiology/Pharmacology

References
1. Alaribe F N, Motaung K S C M. Medicinal plants in tissue engineering and regenerative medicine in the African continent. Tissue Engineering Part A 2019; 25: 827-829. [DOI:10.1089/ten.tea.2019.0060]
2. Avagimyan A, Mkrtchyan L, Abrahomovich O, Sheibani M, Guevorkyan A, Sarrafzadegan N, et al. AC-Mode of chemotherapy as a trigger of cardiac syndrome X: a case study. Current Problems in Cardiology 2022; 47: 100994. [DOI:10.1016/j.cpcardiol.2021.100994]
3. Bagheri G, Ayatollahi S A, Ramírez-Alarcón K, Salehi B, Mohammadi R, Rahmani A, et al. Phytochemical screening of Alstonia venenata leaf and bark extracts and their antimicrobial activities. Cellular and Molecular Biology 2020; 66: 224-231. [DOI:10.14715/cmb/2019.66.1.3]
4. Baur J A, Sinclair D A. Therapeutic potential of resveratrol: the in vivo evidence. Nature reviews Drug discovery 2006; 5: 493-506. [DOI:10.1038/nrd2060]
5. Bergmann O, Bhardwaj R D, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98-102. [DOI:10.1126/science.1164680]
6. Bertelli A A, Das D K. Grapes, wines, resveratrol, and heart health. Journal of Cardiovascular Pharmacology 2009; 54: 468-476. [DOI:10.1097/FJC.0b013e3181bfaff3]
7. Bortolotti F, Ruozi G, Falcione A, Doimo S, Dal Ferro M, Lesizza P, et al. In vivo functional selection identifies cardiotrophin-1 as a cardiac engraftment factor for mesenchymal stromal cells. Circulation 2017; 136: 1509-1524. [DOI:10.1161/CIRCULATIONAHA.117.029003]
8. Brønnum H, Eskildsen T, Andersen D C, Schneider M, Sheikh S P. IL-1β suppresses TGF-β-mediated myofibroblast differentiation in cardiac fibroblasts. Growth Factors 2013; 31: 81-89. [DOI:10.3109/08977194.2013.787994]
9. Bu L, Dai O, Zhou F, Liu F, Chen J-F, Peng C, Xiong L. Traditional Chinese medicine formulas, extracts, and compounds promote angiogenesis. Biomedicine & Pharmacotherapy 2020; 132: 110855. [DOI:10.1016/j.biopha.2020.110855]
10. Cambier L, Plate M, Sucov H M, Pashmforoush M. Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3. Development 2014; 141: 2959-2971. [DOI:10.1242/dev.103416]
11. Carresi C, Musolino V, Gliozzi M, Maiuolo J, Mollace R, Nucera S, et al. Anti-oxidant effect of bergamot polyphenolic fraction counteracts doxorubicin-induced cardiomyopathy: Role of autophagy and c-kitposCD45negCD31neg cardiac stem cell activation. Journal of Molecular and Cellular Cardiology 2018; 119: 10-18. [DOI:10.1016/j.yjmcc.2018.04.007]
12. Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, et al. The potential properties of natural compounds in cardiac stem cell activation: their role in myocardial regeneration. Nutrients 2021a; 13: 275. [DOI:10.3390/nu13010275]
13. Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, et al. The potential properties of natural compounds in cardiac stem cell activation: their role in myocardial regeneration. Nutrients 2021b; 13. [DOI:10.3390/nu13010275]
14. Chan L, Yue P Y, Wong Y, Wong R N. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2. Biochemical Pharmacology 2013; 86: 392-400. [DOI:10.1016/j.bcp.2013.05.006]
15. Chan L S, Yue P Y, Mak N K, Wong R N. Role of microRNA-214 in ginsenoside-Rg1-induced angiogenesis. uropean Journal of Pharmaceutical Sciences 2009a; 38: 370-377. [DOI:10.1016/j.ejps.2009.08.008]
16. Chan S S-K, Chen J-H, Hwang S-M, Wang I-J, Li H-J, Lee R T, Hsieh P C. Salvianolic acid B-vitamin C synergy in cardiac differentiation from embryonic stem cells. Biochemical and Biophysical Research Communications 2009b; 387: 723-728. [DOI:10.1016/j.bbrc.2009.07.122]
17. Chandrasekara A, Shahidi F. Herbal beverages: Bioactive compounds and their role in disease risk reduction - A review. Journal of Traditional and Complementary Medicine 2018; 8: 451-458. [DOI:10.1016/j.jtcme.2017.08.006]
18. Chang Chien G C, Stogicza A. Chapter 17 - Regenerative Medicine. In: Pangarkar S, Pham QG and Eapen BC, editors. Pain Care Essentials and Innovations: Elsevier, 2021: 245-253. [DOI:10.1016/B978-0-323-72216-2.00017-X]
19. Chen J, Venkat P, Zacharek A, Chopp M. Neurorestorative therapy for stroke. Frontiers in Human Neuroscience 2014; 8: 382. [DOI:10.3389/fnhum.2014.00382]
20. Chen L, Tredget E E, Wu P Y, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PloS One 2008; 3: e1886. [DOI:10.1371/journal.pone.0001886]
21. Cheng L, Chen H, Yao X, Qi G, Liu H, Lee K, et al. A plant-derived remedy for repair of infarcted heart. PLoS One 2009; 4: e4461. [DOI:10.1371/journal.pone.0004461]
22. Choi W-Y, Poss K D. Chapter eleven - Cardiac Regeneration. In: Bruneau BG, editor. Current Topics in Developmental Biology. Vol 100: Academic Press, 2012: 319-344. [DOI:10.1016/B978-0-12-387786-4.00010-5]
23. Cochain C, Channon K M, Silvestre J-S. Angiogenesis in the infarcted myocardium. Antioxidants & Redox Signaling 2013; 18: 1100-1113. [DOI:10.1089/ars.2012.4849]
24. Cronier L, Bastide B, Defamie N, Niger C, Pointis G, Gasc J, Malassine A. lnvolvement of gap junctional communication and connexin expression in trophoblast differentiation of the human placenta. Histology and Histopathology 2001; 16: 285-295.
25. Cudmore M J, Hewett P W, Ahmad S, Wang K-Q, Cai M, Al-Ani B, et al. The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. Nature Communications 2012; 3: 1-12. [DOI:10.1038/ncomms1977]
26. El-Sabban M E, Abi-Mosleh L F, Talhouk R S. Developmental regulation of gap junctions and their role in mammary epithelial cell differentiation. Journal of Mammary Gland Biology and Neoplasia 2003; 8: 463-473. [DOI:10.1023/B:JOMG.0000017432.04930.76]
27. Farboud S P, Fathi E, Valipour B, Farahzadi R. Toward the latest advancements in cardiac regeneration using induced pluripotent stem cells (iPSCs) technology: approaches and challenges. Journal of Translational Medicine 2024; 22: 783. [DOI:10.1186/s12967-024-05499-8]
28. Farid A, Sheibani M, Shojaii A, Noori M, Motevalian M. Evaluation of anti-inflammatory effects of leaf and seed extracts of Plantago major on acetic acid-induced ulcerative colitis in rats. Journal of Ethnopharmacology 2022; 298: 115595. [DOI:10.1016/j.jep.2022.115595]
29. Feng-qin X, Li-zhi L, Hao X, Li-fang Y, Ke-ji C, Nian-fang S. Effect of Xiongshao Capsule on the function of vascular endothelium of patients with cervical atherosclerosis. Chinese Journal of Integrative Medicine 2004; 10: 14-18. [DOI:10.1007/BF02836551]
30. Foulquier S, Daskalopoulos E P, Lluri G, Hermans K C M, Deb A, Blankesteijn W M. WNT Signaling in Cardiac and Vascular Disease. Pharmacological Reviews 2018; 70: 68-141. [DOI:10.1124/pr.117.013896]
31. Furth M E, Atala A. Chapter 6 - Tissue Engineering: Future Perspectives. In: Lanza R, Langer R and Vacanti J, editors. Principles of Tissue Engineering (Fourth Edition). Boston: Academic Press, 2014: 83-123. [DOI:10.1016/B978-0-12-398358-9.00006-9]
32. Gao X-F, Shi H-M, Sun T, Ao H. Effects of Radix et Rhizoma Rhodiolae Kirilowii on expressions of von Willebrand factor, hypoxia-inducible factor 1 and vascular endothelial growth factor in myocardium of rats with acute myocardial infarction. Journal of Chinese Integrative Medicine 2009; 7: 434-440. [DOI:10.3736/jcim20090507]
33. Gomez J M Q, Mora R M S, Diaz A C, De Castro M D L. Use of olive leaf extracts in a pharmaceutical composition for inducing angiogenesis and vasculogenesis. 2012.
34. Gorbunov N, Petrovski G, Gurusamy N, Ray D, Kim D H, Das D K. Regeneration of infarcted myocardium with resveratrol-modified cardiac stem cells. Journal of Cellular and Molecular Medicine 2012; 16: 174-184. [DOI:10.1111/j.1582-4934.2011.01281.x]
35. Grego-Bessa J, Luna-Zurita L, del Monte G, Bolós V, Melgar P, Arandilla A, et al. Notch signaling is essential for ventricular chamber development. Developmental Cell 2007; 12: 415-429. [DOI:10.1016/j.devcel.2006.12.011]
36. Gu W, Hong X, Le Bras A, Nowak W N, Bhaloo S I, Deng J, et al. Smooth muscle cells differentiated from mesenchymal stem cells are regulated by microRNAs and suitable for vascular tissue grafts. Journal of Biological Chemistry 2018; 293: 8089-8102. [DOI:10.1074/jbc.RA118.001739]
37. Guo B B, Bellingham S A, Hill A F. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. Journal of Biological Chemistry 2015; 290: 3455-3467. [DOI:10.1074/jbc.M114.605253]
38. Guo B Q, Xu J B, Xiao M, Ding M, Duan L J. Puerarin reduces ischemia/reperfusion-induced myocardial injury in diabetic rats via upregulation of vascular endothelial growth factor A/angiotensin-1 and suppression of apoptosis. Molecular Medicine Reports 2018; 17: 7421-7427. [DOI:10.3892/mmr.2018.8754]
39. Guo J, Jie W, Kuang D, Ni J, Chen D, Ao Q, Wang G. Ischaemia/reperfusion induced cardiac stem cell homing to the injured myocardium by stimulating stem cell factor expression via NF-κB pathway. International Journal of Experimental Pathology 2009; 90: 355-364. [DOI:10.1111/j.1365-2613.2009.00659.x]
40. Gurusamy N, Ray D, Lekli I, Das D K. Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. Journal of Cellular and Molecular Medicine 2010; 14: 2235-2239. [DOI:10.1111/j.1582-4934.2010.01140.x]
41. He F, Yu C, Liu T, Jia H. Ginsenoside Rg1 as an effective regulator of mesenchymal stem cells. Frontiers in Pharmacology 2020; 10: 1565. [DOI:10.3389/fphar.2019.01565]
42. Hennings A, Hannemann A, Rettig R, Dörr M, Nauck M, Völzke H, et al. Circulating angiopoietin-2 and its soluble receptor Tie-2 concentrations are related to renal function in two population-based cohorts. PLoS One 2016; 11: e0166492. [DOI:10.1371/journal.pone.0166492]
43. Huang F, Liu Y, Yang X, Che D, Qiu K, Hammock B D, et al. Shexiang Baoxin pills promotes angiogenesis in myocardial infarction rats via up-regulation of 20-HETE-mediated endothelial progenitor cells mobilization. Atherosclerosis 2017; 263: 184-191. [DOI:10.1016/j.atherosclerosis.2017.06.012]
44. Huang J, Li L S, Yang D L, Gong Q H, Deng J, Huang X N. Inhibitory efect of Ginsenoside Rg1 on vascular smooth muscle Cell Proliferation Induced by PDGF-BB Is Involved in Nitric Oxide Formation. Evidence-Based Complementary and Alternative Medicine 2012; 2012: 314395. [DOI:10.1155/2012/314395]
45. Jin M-s, Shi S, Zhang Y, Yan Y, Sun X-d, Liu W, Liu H-w. Icariin-mediated differentiation of mouse adipose-derived stem cells into cardiomyocytes. Molecular and Cellular Biochemistry 2010; 344: 1-9. [DOI:10.1007/s11010-010-0523-5]
46. Kahn J, Byk T, Jansson-Sjostrand L, Petit I, Shivtiel S, Nagler A, et al. Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation. Blood 2004; 103: 2942-2949. [DOI:10.1182/blood-2003-07-2607]
47. Kanelidis A J, Premer C, Lopez J, Balkan W, Hare J M. Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction: a meta-analysis of preclinical studies and clinical trials. Circulation Research 2017; 120: 1139-1150. [DOI:10.1161/CIRCRESAHA.116.309819]
48. Karin M, Lin A. NF-κB at the crossroads of life and death. Nature Immunology 2002; 3: 221-227. [DOI:10.1038/ni0302-221]
49. Khalilzadeh M, Shayan M, Jourian S, Rahimi M, Sheibani M, Dehpour A R. A comprehensive insight into the anti-inflammatory properties of dapsone. Naunyn Schmiedebergs Arch Pharmacol 2022; 395: 1509-1523. [DOI:10.1007/s00210-022-02297-1]
50. Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez L A, Christofidou-Solomidou M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 2001; 19: 453-466. [DOI:10.1634/stemcells.19-5-453]
51. Kim Y Y, Ku S-Y, Rosenwaks Z, Liu H C, Oh S K, Moon S Y, Choi Y M. Red ginseng extract facilitates the early differentiation of human embryonic stem cells into mesendoderm lineage. Evidence-Based Complementary and Alternative Medicine 2010; 2011. [DOI:10.1155/2011/167376]
52. Kinder D H, Knecht K T. Lupine (Lupinus caudatus L., Lupinus albus L.) seeds: History of use, use as an antihyperglycemic medicinal, and use as a food. Nuts and Seeds in Health and Disease Prevention: Elsevier, 2011: 711-716. [DOI:10.1016/B978-0-12-375688-6.10084-2]
53. Kinnaird T, Stabile E, Burnett M, Shou M, Lee C, Barr S, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004; 109: 1543-1549. [DOI:10.1161/01.CIR.0000124062.31102.57]
54. Kopan R, Ilagan M X G. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137: 216-233. [DOI:10.1016/j.cell.2009.03.045]
55. Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf D J, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. Journal of Molecular Histology 2004; 35: 233-245. [DOI:10.1023/B:HIJO.0000032355.66152.b8]
56. Kumar G, Dey S K, Kundu S. Herbs and their bioactive ingredients in cardio-protection: Underlying molecular mechanisms and evidences from clinical studies. Phytomedicine 2021; 92: 153753. [DOI:10.1016/j.phymed.2021.153753]
57. Lee J A, An J, Kang T M, De D, Kim K K. Discovery of natural compounds promoting cardiomyocyte differentiation. Stem Cells and Development 2019; 28: 13-27. [DOI:10.1089/scd.2018.0153]
58. Leybaert L, Lampe P D, Dhein S, Kwak B R, Ferdinandy P, Beyer E C, et al. Connexins in cardiovascular and neurovascular health and disease: pharmacological implications. Pharmacological Reviews 2017; 69: 396-478. [DOI:10.1124/pr.115.012062]
59. LI C-s, QU Z-q, WANG S-s, HAO X-w, ZHANG X-q, Jing G, Fei H. Effects of Suxiao Jiuxin Pill () on oxidative stress and inflammatory response in rats with experimental atherosclerosis. Journal of Traditional Chinese Medicine 2011; 31: 107-111. [DOI:10.1016/S0254-6272(11)60022-8]
60. Li J, Fan W, Ao H. Effect of rhodiola on expressions of Flt-1, KDR and Tie-2 in rats with ischemic myocardium. Chinese Journal of Integrated Traditional and Western Medicine 2005; 25: 445-448.
61. Li Y-J, Duan C-L, Liu J-X. Salvianolic acid A promotes the acceleration of neovascularization in the ischemic rat myocardium and the functions of endothelial progenitor cells. Journal of Ethnopharmacology 2014; 151: 218-227. [DOI:10.1016/j.jep.2013.10.019]
62. Li Z, Zhang S, Cao L, Li W, Ye Y C, Shi Z X, et al. Tanshinone IIA and Astragaloside IV promote the angiogenesis of mesenchymal stem cell-derived endothelial cell-like cells via upregulation of Cx37, Cx40 and Cx43. Experimental and Therapeutic Medicine 2018; 15: 1847-1854. [DOI:10.3892/etm.2018.6428]
63. Lin C M, Chiu J H, Wu I H, Wang B W, Pan C M, Chen Y H. Ferulic acid augments angiogenesis via VEGF, PDGF and HIF-1 alpha. Journal of Nutritional Biochemistry 2010; 21: 627-633. [DOI:10.1016/j.jnutbio.2009.04.001]
64. Liu J, Zhu P, Song P, Xiong W, Chen H, Peng W, et al. Pretreatment of adipose derived stem cells with curcumin facilitates myocardial recovery via antiapoptosis and angiogenesis. Stem Cells International 2015:2015:638153. [DOI:10.1155/2015/638153]
65. Lu Z, Zhang Y, Zhuang P, Zhang J, Zhou H, Zhang M, et al. Protective effect of Suxiao jiuxin pill, a traditional Chinese medicine, against acute myocardial ischemia in dogs. BMC Complementary and Alternative Medicine 2015; 15: 1-10. [DOI:10.1186/s12906-015-0908-9]
66. MacDonald B T, Tamai K, He X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Developmental cell 2009; 17: 9-26. [DOI:10.1016/j.devcel.2009.06.016]
67. Mahmud S, Alam S, Emon N U, Boby U H, Kamruzzaman, Ahmed F, et al. Opportunities and challenges in stem cell therapy in cardiovascular diseases: Position standing in 2022. Saudi Pharmaceutical Journal 2022; 30: 1360-1371. [DOI:10.1016/j.jsps.2022.06.017]
68. Marquez-Curtis L A, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. BioMed Research International 2013:2013:561098. [DOI:10.1155/2013/561098]
69. Mazzanti G. Pharmacological considerations on herbal medicine use. Annali Dell’istituto Superiore di Sanita 2005; 41: 23-26.
70. Miao C, Lei M, Hu W, Han S, Wang Q. A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem cell Research & Therapy 2017; 8: 1-6. [DOI:10.1186/s13287-017-0697-9]
71. Mohammad Jafari R, Sheibani M, Nezamoleslami S, Shayesteh S, Jand Y, Dehpour A R. Drug repositioning: a review. Journal of Iranian Medical Council 2018; 1: 7-10.
72. Mujoo K, Nikonoff L E, Sharin V G, Bryan N S, Kots A Y, Murad F. Curcumin induces differentiation of embryonic stem cells through possible modulation of nitric oxide-cyclic GMP pathway. Protein & Cell 2012; 3: 535-544. [DOI:10.1007/s13238-012-2053-2]
73. Müller A, Linke W, Klaus W. Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes. Planta medica 1999; 65: 335-339. [DOI:10.1055/s-1999-13997]
74. Nadal-Ginard B, Ellison G M, Torella D. The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult. Stem Cell Research 2014; 13: 615-630. [DOI:10.1016/j.scr.2014.04.008]
75. Nagalingam A. Drug delivery aspects of herbal medicines. Japanese Kampo Medicines for the Treatment of Common Diseases: Focus on Inflammation. 2017; 17: 143. [DOI:10.1016/B978-0-12-809398-6.00015-9]
76. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005; 112: 1128-1135. [DOI:10.1161/CIRCULATIONAHA.104.500447]
77. Nikonov G, Yagudaev M. Structure of ursinoic acid and ursinin. Chemistry of Natural Compounds 1970; 6: 429-432. [DOI:10.1007/BF00564241]
78. Ntege E H, Sunami H, Shimizu Y. Advances in regenerative therapy: A review of the literature and future directions. Regenerative Therapy 2020; 14: 136-153. [DOI:10.1016/j.reth.2020.01.004]
79. Nussbaum J, Minami E, Laflamme M A, Virag J A, Ware C B, Masino A, et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. The FASEB Journal 2007; 21: 1345-1357. [DOI:10.1096/fj.06-6769com]
80. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson S M, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-705. [DOI:10.1038/35070587]
81. Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornhäuser M, Werner C. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004; 22: 377-384. [DOI:10.1634/stemcells.22-3-377]
82. Pahlavan S, Tousi M S, Ayyari M, Alirezalu A, Ansari H, Saric T, Baharvand H. Effects of hawthorn (Crataegus pentagyna) leaf extract on electrophysiologic properties of cardiomyocytes derived from human cardiac arrhythmia-specific induced pluripotent stem cells. The FASEB Journal 2018; 32: 1440-1451. [DOI:10.1096/fj.201700494RR]
83. Pahnke A, Conant G, Huyer L D, Zhao Y, Feric N, Radisic M. The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective. Biochemical and Biophysical Research Communications 2016; 473: 698-703. [DOI:10.1016/j.bbrc.2015.11.060]
84. Pandur P, Läsche M, Eisenberg L M, Kühl M. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 2002; 418: 636-641. [DOI:10.1038/nature00921]
85. Pang J K S, Phua Q H, Soh B-S. Applications of miRNAs in cardiac development, disease progression and regeneration. Stem Cell Research & Therapy 2019; 10: 336. [DOI:10.1186/s13287-019-1451-2]
86. Parsons-Wingerter P, Elliott K E, Clark J I, Farr A G. Fibroblast growth factor-2 selectively stimulates angiogenesis of small vessels in arterial tree. Arteriosclerosis, Thrombosis, and Vascular Biology 2000; 20: 1250-1256. [DOI:10.1161/01.ATV.20.5.1250]
87. Pugh C W, Ratcliffe P J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Medicine 2003; 9: 677-684. [DOI:10.1038/nm0603-677]
88. Qin C, Liu S, Zhou S, Xia X, Hu J, Yu Y, Ma D. Tanshinone IIA promotes vascular normalization and boosts Sorafenib’s anti-hepatoma activity via modulating the PI3K-AKT pathway. Frontiers in Pharmacology 2023; 14: 1189532. [DOI:10.3389/fphar.2023.1189532]
89. Qu H, Feng Z, Li Z, Li C, Tang M, Zhou Z, et al. Induction of substantial myocardial regeneration by an active fraction of the Chinese herb Rosa laevigata Michx. BMC Complementary and Alternative Medicine 2015a; 15: 1-11. [DOI:10.1186/s12906-015-0795-0]
90. Qu H, Feng Z, Li Z, Li C, Tang M, Zhou Z, et al. Induction of substantial myocardial regeneration by an active fraction of the Chinese herb Rosa laevigata Michx. BMC Complementary and Alternative Medicine 2015b; 15: 359. [DOI:10.1186/s12906-015-0795-0]
91. Rastogi S, Pandey M M, Rawat A K. Traditional herbs: a remedy for cardiovascular disorders. Phytomedicine 2016; 23: 1082-9. [DOI:10.1016/j.phymed.2015.10.012]
92. Ren C, Yao Y, Han R, Huang Q, Li H, Wang B, et al. Cerebral ischemia induces angiogenesis in the peri-infarct regions via Notch1 signaling activation. Experimental Neurology 2018; 304: 30-40. [DOI:10.1016/j.expneurol.2018.02.013]
93. Roca C, Adams R H. Regulation of vascular morphogenesis by Notch signaling. Genes & Aevelopment 2007; 21: 2511-2524. [DOI:10.1101/gad.1589207]
94. Rosenstrauch D, Poglajen G, Zidar N, Gregoric I D. Stem cell therapy for ischemic heart failure. Texas Heart Institute Journal 2005; 32: 339.
95. Ruan X-f, Ju C-w, Shen Y, Liu Y-t, Kim I-m, Yu H, et al. Suxiao Jiuxin pill promotes exosome secretion from mouse cardiac mesenchymal stem cells in vitro. Acta Pharmacologica Sinica 2018; 39: 569-578. [DOI:10.1038/aps.2018.19]
96. Sajid M, Cameotra S S, Khan M S A, Ahmad I. Nanoparticle-based delivery of phytomedicines: challenges and opportunities. New Look to phytomedicine: Elsevier, 2019: 597-623. [DOI:10.1016/B978-0-12-814619-4.00024-0]
97. Sasaki T, Oh K-B, Matsuoka H, Saito M. Effect of Panax ginseng components on the differentiation of mouse embryonic stem cells into cardiac-like cells. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan 2008; 128: 461-467. [DOI:10.1248/yakushi.128.461]
98. Saxena A, Chen W, Su Y, Rai V, Uche O U, Li N, Frangogiannis N G. IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. The Journal of Immunology 2013; 191: 4838-4848. [DOI:10.4049/jimmunol.1300725]
99. Scioli M G, Terriaca S, Fiorelli E, Storti G, Fabbri G, Cervelli V, Orlandi A. Extracellular vesicles and cancer stem cells in tumor progression: new therapeutic perspectives. International Journal of Molecular Sciences 2021; 22: 10572. [DOI:10.3390/ijms221910572]
100. Segers V F, Lee R T. Stem-cell therapy for cardiac disease. Nature 2008; 451: 937-942. [DOI:10.1038/nature06800]
101. Senyo S E, Steinhauser M L, Pizzimenti C L, Yang V K, Cai L, Wang M, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 2013; 493: 433-436. [DOI:10.1038/nature11682]
102. Shaito A, Thuan D T B, Phu H T, Nguyen T H D, Hasan H, Halabi S, et al. Herbal medicine for cardiovascular diseases: efficacy, mechanisms, and safety. Frontiers in Pharmacology 2020; 11. [DOI:10.3389/fphar.2020.00422]
103. Sharma R A, Gescher A J, Steward W P. Curcumin: The story so far. European Journal of Cancer 2005; 41: 1955-1968. [DOI:10.1016/j.ejca.2005.05.009]
104. Sheibani M, Nayernouri T, Dehpour A R. Herbal medicines and other traditional remedies in Iran - a tragedy unfolds. Archives of Iranian Medicine 2018; 21: 312-314.
105. Sheibani M, Nezamoleslami S, Mousavi S E, Faghir-Ghanesefat H, Yousefi-Manesh H, Rezayat S M, Dehpour A. Protective effects of spermidine against cirrhotic cardiomyopathy in bile duct-ligated rats. Journal of Cardiovascular Pharmacology 2020; 76: 286-295. [DOI:10.1097/FJC.0000000000000872]
106. Shen W, Fan W, Shi H. Effects of shexiang baoxin pill on angiogenesis in atherosclerosis plaque and ischemic myocardium. Chinese Journal of Integrated Traditional and Western Medicine 2010; 30: 1284-1287.
107. Shen X, Pan B, Zhou H, Liu L, Lv T, Zhu J, et al. Differentiation of mesenchymal stem cells into cardiomyocytes is regulated by miRNA-1-2 via WNT signaling pathway. Journal of Biomedical Science 2017; 24: 29. [DOI:10.1186/s12929-017-0337-9]
108. Shi W-L, Zhao J, Yuan R, Lu Y, Xin Q-Q, Liu Y, et al. Combination of ligusticum chuanxiong and radix paeonia promotes angiogenesis in ischemic myocardium through notch signalling and mobilization of stem cells. Evidence-Based Complementary and Alternative Medicine 2019; 2019. [DOI:10.1155/2019/7912402]
109. Shi X, Li W, Liu H, Yin D, Zhao J. The ROS/NF-κB/NR4A2 pathway is involved in H(2)O(2) induced apoptosis of resident cardiac stem cells via autophagy. Oncotarget 2017; 8: 77634-77648. [DOI:10.18632/oncotarget.20747]
110. Shohet R V, Garcia J A. Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia. Journal of Molecular Medicine 2007; 85: 1309-1315. [DOI:10.1007/s00109-007-0279-x]
111. Simon A M, McWhorter A R. Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin37 or connexin40. Journal of Cell Science 2003; 116: 2223-2236. [DOI:10.1242/jcs.00429]
112. Song Y S, Joo H W, Park I H, Shen G Y, Lee Y, Shin J H, et al. Bone marrow mesenchymal stem cell-derived vascular endothelial growth factor attenuates cardiac apoptosis via regulation of cardiac miRNA-23a and miRNA-92a in a rat model of myocardial infarction. PLoS One 2017; 12: e0179972. [DOI:10.1371/journal.pone.0179972]
113. Stamm C, Kleine H-D, Choi Y-H, Dunkelmann S, Lauffs J-A, Lorenzen B, et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. The Journal of Thoracic and Cardiovascular Surgery 2007; 133: 717-725. e5. [DOI:10.1016/j.jtcvs.2006.08.077]
114. Strauer B E, Brehm M, Zeus T, Köstering M, Hernandez A, Sorg R d V, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106: 1913-1918. [DOI:10.1161/01.CIR.0000034046.87607.1C]
115. Su F, Zhang W, Liu J. Membrane estrogen receptor alpha is an important modulator of bone marrow C-Kit+ cells mediated cardiac repair after myocardial infarction. International Journal of Clinical and Experimental Pathology 2015; 8: 4284.
116. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663-676. [DOI:10.1016/j.cell.2006.07.024]
117. Talkhabi M, Aghdami N, Baharvand H. Human cardiomyocyte generation from pluripotent stem cells: A state-of-art. Life Sciences 2016; 145: 98-113. [DOI:10.1016/j.lfs.2015.12.023]
118. Tang Y L, Zhu W, Cheng M, Chen L, Zhang J, Sun T, et al. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circulation Research 2009; 104: 1209-1216. [DOI:10.1161/CIRCRESAHA.109.197723]
119. Taylor C J, Roalfe A K, Iles R, Hobbs F R. Ten-year prognosis of heart failure in the community: follow-up data from the Echocardiographic Heart of England Screening (ECHOES) study. European Journal of Heart Failure 2012; 14: 176-184. [DOI:10.1093/eurjhf/hfr170]
120. Terriaca S, Fiorelli E, Scioli M G, Fabbri G, Storti G, Cervelli V, Orlandi A. Endothelial progenitor cell-derived extracellular vesicles: potential therapeutic application in tissue repair and regeneration. International Journal of Molecular Sciences 2021; 22: 6375. [DOI:10.3390/ijms22126375]
121. Tong Y, Xu W, Han H, Chen Y, Yang J, Qiao H, et al. Tanshinone IIA increases recruitment of bone marrow mesenchymal stem cells to infarct region via up-regulating stromal cell-derived factor-1/CXC chemokine receptor 4 axis in a myocardial ischemia model. Phytomedicine 2011; 18: 443-450. [DOI:10.1016/j.phymed.2010.10.009]
122. Ude C C, Miskon A, Idrus R B H, Abu Bakar M B. Application of stem cells in tissue engineering for defense medicine. Military Medical Research 2018; 5: 7. [DOI:10.1186/s40779-018-0154-9]
123. Walker R, Janda E, Mollace V. Chapter 84 - The use of bergamot-derived polyphenol fraction in cardiometabolic risk prevention and its possible mechanisms of action. In: Watson RR, Preedy VR and Zibadi S, editors. Polyphenols in Human Health and Disease. San Diego: Academic Press, 2014: 1087-1105. [DOI:10.1016/B978-0-12-398456-2.00084-0]
124. Wang L, Zhang Y-G, Wang X-M, Ma L-F, Zhang Y-M. Naringin protects human adipose-derived mesenchymal stem cells against hydrogen peroxide-induced inhibition of osteogenic differentiation. Chemico-Biological Interactions 2015a; 242: 255-261. [DOI:10.1016/j.cbi.2015.10.010]
125. Wang S, Chen J, Fu Y, Chen X. Promotion of Astragaloside IV for EA-hy926 Cell Proliferation and Angiogenic Activity via ERK½ Pathway. Journal of Nanoscience and Nanotechnology 2015b; 15: 4239-4244. [DOI:10.1166/jnn.2015.9785]
126. Wang T, Chen X, Wang K, Ju J, Yu X, Yu W, et al. Cardiac regeneration: Pre-existing cardiomyocyte as the hub of novel signaling pathway. Genes & Diseases 2024; 11: 747-759. [DOI:10.1016/j.gendis.2023.01.031]
127. Wang X, Gu H, Huang W, Peng J, Li Y, Yang L, et al. Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes 2016; 65: 3111-3128. [DOI:10.2337/db15-1563]
128. Wang X, Zhang Y, Yang Y, Zhang W, Luo L, Han F, et al. Curcumin pretreatment protects against hypoxia/reoxgenation injury via improvement of mitochondrial function, destabilization of HIF-1α and activation of Epac1-Akt pathway in rat bone marrow mesenchymal stem cells. Biomedicine & Pharmacotherapy 2019; 109: 1268-1275. [DOI:10.1016/j.biopha.2018.11.005]
129. Wen J, Zhang J Q, Huang W, Wang Y. SDF-1α and CXCR4 as therapeutic targets in cardiovascular disease. American Journal of Cardiovascular Disease 2012; 2: 20-28.
130. Wo Y b, Zhu D y, Hu Y, Wang Z Q, Liu J, Lou Y J. Reactive oxygen species involved in prenylflavonoids, icariin and icaritin, initiating cardiac differentiation of mouse embryonic stem cells. Journal of Cellular Biochemistry 2008; 103: 1536-1550. [DOI:10.1002/jcb.21541]
131. Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends in Biochemical Sciences 2010; 35: 161-8. [DOI:10.1016/j.tibs.2009.10.002]
132. Xie J, Wang H, Song T, Wang Z, Li F, Ma J, et al. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4. Protoplasma 2013; 250: 521-530. [DOI:10.1007/s00709-012-0435-1]
133. Yang M, Chen G, Chen C, Zhang Y, Yan C. Effect of Ginsenoside Rg1 in promoting myocardial regeneration after myocardial infarction in rats. Chinese Heart Journal 2008; 20: 697-707.
134. Yousefi-Manesh H, Dehpour A R, Nabavi S M, Khayatkashani M, Asgardoon M H, Derakhshan M H, et al. Therapeutic effects of hydroalcoholic extracts from the ancient apple mela rosa dei monti sibillini in transient global ischemia in rats. Pharmaceuticals 2021; 14: 1106. [DOI:10.3390/ph14111106]
135. Yu J-M, Zhang X-B, Jiang W, Wang H-D, Zhang Y-N. Astragalosides promote angiogenesis via vascular endothelial growth factor and basic fibroblast growth factor in a rat model of myocardial infarction. Molecular Medicine Reports 2015; 12: 6718-6726. [DOI:10.3892/mmr.2015.4307]
136. Yuan R, Shi W-L, Xin Q-Q, Chen K-J, Cong W-H. Holistic regulation of angiogenesis with Chinese herbal medicines as a new option for coronary artery disease. Evidence-Based Complementary and Alternative Medicine 2018; 2018. [DOI:10.1155/2018/3725962]
137. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Research & Therapy 2019; 10: 68. [DOI:10.1186/s13287-019-1165-5]
138. Zhang D, Fan G-C, Zhou X, Zhao T, Pasha Z, Xu M, et al. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology 2008; 44: 281-292. [DOI:10.1016/j.yjmcc.2007.11.010]
139. Zhang L, Wang Y, Yu L, Liu L, Qu H, Gao X, et al. QI-SHEN-YI-QI accelerates angiogenesis after myocardial infarction in rats. International Journal of Cardiology 2010; 143: 105-109. [DOI:10.1016/j.ijcard.2008.11.210]
140. Zhang Q, Chen Z-W, Zhao Y-H, Liu B-W, Liu N-W, Ke C-C, Tan H-M. Bone marrow stromal cells combined with sodium ferulate and n-butylidenephthalide promote the effect of therapeutic angiogenesis via advancing astrocyte-derived trophic factors after ischemic stroke. Cell Transplantation 2017; 26: 229-242. [DOI:10.3727/096368916X693536]
141. Zhang S, Chen S, Shen Y, Yang D, Liu X, Sun-Chi A C, Xu H. Puerarin induces angiogenesis in myocardium of rat with myocardial infarction. Biological and Pharmaceutical Bulletin 2006; 29: 945-950. [DOI:10.1248/bpb.29.945]
142. Zhang S, Qi Y, Xu Y, Han X, Peng J, Liu K, Sun C. Protective effect of flavonoid-rich extract from Rosa laevigata Michx on cerebral ischemia-reperfusion injury through suppression of apoptosis and inflammation. Neurochemistry International 2013; 63: 522-532. [DOI:10.1016/j.neuint.2013.08.008]
143. ZHU D y, LOU Y j. Icariin-mediated expression of cardiac genes and modulation of nitric oxide signaling pathway during differentiation of mouse embryonic stem cells into cardiomyocytes in vitro. Acta Pharmacologica Sinica 2006; 27: 311-320. [DOI:10.1111/j.1745-7254.2006.00275.x]
144. ZHU D y, LOU Y j. Inducible effects of icariin, icaritin, and desmethylicaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro. Acta Pharmacologica Sinica 2005; 26: 477-485. [DOI:10.1111/j.1745-7254.2005.00076.x]
145. Zhu H, Chen Z, Ma Z, Tan H, Xiao C, Tang X, et al. Tanshinone IIA protects endothelial cells from H2O2-induced injuries via PXR activation. Biomol Ther (Seoul) 2017; 25: 599-608. [DOI:10.4062/biomolther.2016.179]

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