Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Analysis of common and characteristic actions of Panax ginseng and Panax notoginseng in wound healing based on network pharmacology and meta-analysis

  • Zhen Wang (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Xueheng Xie (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Mengchen Wang (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Meng Ding (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Shengliang Gu (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Xiaoyan Xing (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College) ;
  • Xiaobo Sun (Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College)
  • Received : 2022.06.17
  • Accepted : 2023.02.22
  • Published : 2023.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

In recent years, an increasing number of reports have explored the wound healing mechanism of these two traditional Chinese herbal medicines- Panax ginseng and Panax notoginseng, but there is no systematic research on the related core functions and different mechanisms in the treatment of wound healing up to now. Based on network pharmacology and meta-analysis, the present work aimed to comprehensively review the commonality and diversity of P. ginseng and P. notoginseng in wound healing. In this study, a wound healing-related "ingredients-targets" network of two herbs was constructed. Thereafter, meta-analysis of the multiple target lists by Metascape showed that these two medicines significantly regulated blood vessel development, responses to cytokines and growth factors and oxygen levels, cell death, cell proliferation and differentiation, and cell adhesion. To better understand the discrepancy between these two herbs, it was found that common signaling pathways including Rap1, PI3K/AKT, MAPK, HIF-1 and Focal adhesion regulated the functions listed above. In parallel, the different pathways including renin-angiotensin system, RNA transport and circadian rhythm, autophagy, and the different metabolic pathways may also explained the discrepancies in the regulation of the above-mentioned functions, consistent with the Traditional Chinese Medicine theory about the effects of P. ginseng and P. notoginseng.

Keywords

Acknowledgement

The present work was funded by Major Program of the National Natural Science Foundation of China (No. 81891012, No. U1812403-5-3), and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2022-RC360-01; No. 2022-I2M-1-018; No. 2021-I2M-1-031).

References

  1. Willyard C. Unlocking the secrets of scar-free skin healing. Nature 2018;563:S86-8.  https://doi.org/10.1038/d41586-018-07430-w
  2. Ronkina N, Gaestel M. MAPK-Activated Protein Kinases: Servant or Partner? Annu Rev Biochem. 2022 Jun 21;91:505-40.  https://doi.org/10.1146/annurev-biochem-081720-114505
  3. den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Translational Research : The Journal of Laboratory and Clinical Medicine 2019;204:39-50.  https://doi.org/10.1016/j.trsl.2018.10.001
  4. Zhu J, Zhou H, Gerhard EM, Zhang S, Parra Rodriguez FI, Pan T, et al. Smart bioadhesives for wound healing and closure. Bioactive Materials 2023;19:360-75. 
  5. Muniandy K, Gothai S, Tan WS, Kumar SS, Mohd Esa N, Chandramohan G, et al. In Vitro wound healing potential of stem extract of Alternanthera sessilis. Evidence-based complementary and alternative medicine, vol. 2018;2018, 3142073. 
  6. Leise BS. Topical wound medications, vol. 34. The Veterinary clinics of North America Equine practice; 2018. p. 485-98. 
  7. Desmet CM, Preat V, Gallez B. Nanomedicines and gene therapy for the delivery of growth factors to improve perfusion and oxygenation in wound healing. Adv Drug Deliv Rev 2018;129:262-84.  https://doi.org/10.1016/j.addr.2018.02.001
  8. Jia D, Jiang H, Weng X, Wu J, Bai P, Yang W, et al. Interleukin-35 promotes macrophage survival and improves wound healing after myocardial infarction in mice. Circulation Research 2019;124:1323-36.  https://doi.org/10.1161/CIRCRESAHA.118.314569
  9. Li KC, Wang CH, Zou JJ, Qu C, Wang XL, Tian XS, et al. Loss of Atg7 in endothelial cells enhanced cutaneous wound healing in a mouse model. The Journal of Surgical Research 2020;249:145-55.  https://doi.org/10.1016/j.jss.2019.12.004
  10. Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev 2019;146:97-125.  https://doi.org/10.1016/j.addr.2018.09.010
  11. Yang BR, Yuen SC, Fan GY, Cong WH, Leung SW, Lee SM. Identification of certain Panax species to be potential substitutes for Panax notoginseng in hemostatic treatments. Pharmacol Res 2018;134:1-15.  https://doi.org/10.1016/j.phrs.2018.05.005
  12. Dong TT, Cui XM, Song ZH, Zhao KJ, Ji ZN, Lo CK, et al. Chemical assessment of roots of Panax notoginseng in China: regional and seasonal variations in its active constituents. Journal of Agricultural and Food Chemistry 2003;51:4617-23.  https://doi.org/10.1021/jf034229k
  13. Men SY, Huo QL, Shi L, Yan Y, Yang CC, Yu W, et al. Panax notoginseng saponins promotes cutaneous wound healing and suppresses scar formation in mice. Journal of Cosmetic Dermatology 2020;19:529-34.  https://doi.org/10.1111/jocd.13042
  14. Riaz M, Rahman NU, Zia-Ul-Haq M, Jaffar HZE, Manea R. Ginseng: a dietary supplement as immune-modulator in various diseases. Trends in Food Science & Technology 2019;83:12-30.  https://doi.org/10.1016/j.tifs.2018.11.008
  15. Park KS, Park DH. The effect of Korean Red Ginseng on full-thickness skin wound healing in rats. J Ginseng Res 2019;43:226-35.  https://doi.org/10.1016/j.jgr.2017.12.006
  16. Hopkins ALJNb. Network Pharmacology 2007;25:1110-1.  https://doi.org/10.1038/nbt1007-1110
  17. Shao L, Zhang BJCjonm. Traditional Chinese medicine network pharmacology. Theory, Methodology and Application 2013;11:110-20.  https://doi.org/10.1016/S1875-5364(13)60037-0
  18. Zhang G-b, Li Q-y, Chen Q-l, Su S-bJE-BC, Medicine A. Network pharmacology: a new approach for Chinese herbal medicine research, vol. 2013;2013. 
  19. Li H, Zhao L, Zhang B, Jiang Y, Wang X, Guo Y, et al. A network pharmacology approach to determine active compounds and action mechanisms of ge-gen-qin-lian decoction for treatment of type 2 diabetes. 2014. 2014. 
  20. Xiong Y, Hu Y, Chen L, Zhang Z, Zhang Y, Niu M, et al. Unveiling active constituents and potential targets related to the hematinic effect of steamed Panax notoginseng using network pharmacology coupled with multivariate data analysesvol. 9; 2019. p. 1514. 
  21. Piao C-L, Luo J-L, Jin D, Tang C, Wang L, Lian F-M, et al. Utilizing network pharmacology to explore the underlying mechanism of Radix Salviae in diabetic retinopathy. 2019. p. 1-12. 14.  https://doi.org/10.1186/s13020-018-0223-8
  22. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nature Communications 2019;10:1523. 
  23. Xu H-Y, Zhang Y-Q, Liu Z-M, Chen T, Lv C-Y, Tang S-H, et al. ETCM: An Encyclopaedia of Traditional Chinese Medicine 2019;47:D976-82.  https://doi.org/10.1093/nar/gky987
  24. Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. 2014. p. 1-6. 6.  https://doi.org/10.1186/1758-2946-6-1
  25. Liu Z, Guo F, Wang Y, Li C, Zhang X, Li H, et al. BATMAN-TCM: a Bioinformatics analysis Tool for molecular mechANism of traditional Chinese medicine. Scientific Reports 2016;6:21146. 
  26. Ballesteros JL, Tacchini M, Spagnoletti A, Grandini A, Paganetto G, Neri LM, et al. Rediscovering medicinal amazonian aromatic plants: piper carpunya (piperaceae) essential oil as paradigmatic study. Evid Based Complement Alternat Med 2019;2019:6194640. 
  27. Muniandy K, Gothai S, Tan WS, Kumar SS, Mohd Esa N, Chandramohan G, et al. In Vitro wound healing potential of stem extract of Alternanthera sessilis. Evid Based Complement Alternat Med 2018;2018:3142073. 
  28. Babu S, Jayaraman S. An update on β-sitosterol: a potential herbal nutraceutical for diabetic management. Biomed Pharmacother 2020;131:110702. 
  29. Eming SA, Brachvogel B, Odorisio T, Koch MJPih, cytochemistry. Regulation of angiogenesis: wound healing as a model. 2007. p. 115-70. 42. 
  30. Sheng L, Zhang Z, Zhang Y, Wang E, Ma B, Xu Q, et al. A novel "hot spring"- mimetic hydrogel with excellent angiogenic properties for chronic wound healing. 2021. p. 264. 120414. 
  31. Huang L, Cai HA, Zhang MS, Liao RY, Huang X, Hu FD. Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis. Journal of Pharmacological Sciences 2021;147:271-83.  https://doi.org/10.1016/j.jphs.2021.07.008
  32. Zhang X, Kang X, Jin L, Bai J, Liu W, Wang Z. Stimulation of wound healing using bioinspired hydrogels with basic fibroblast growth factor (bFGF). International Journal of Nanomedicine 2018;13:3897-906.  https://doi.org/10.2147/IJN.S168998
  33. Kopecki Z, Luchetti MM, Adams DH, Strudwick X, Mantamadiotis T, Stoppacciaro A, et al. Collagen loss and impaired wound healing is associated with c-Myb deficiency. The Journal of Pathology 2007;211:351-61.  https://doi.org/10.1002/path.2113
  34. Zhang L, Hu Q, Jin H, Yang Y, Yang Y, Yang R, et al. Effects of ginsenoside Rb1 on second-degree burn wound healing and FGF-2/PDGF-BB/PDGFR-β pathway modulation. Chinese Medicine 2021;16:45. 
  35. Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). International Journal of Molecular Medicine 2017;40:271-80.  https://doi.org/10.3892/ijmm.2017.3036
  36. Griffiths HR, Gao D, Pararasa C. Redox regulation in metabolic programming and inflammation. Redox Biology 2017;12:50-7.  https://doi.org/10.1016/j.redox.2017.01.023
  37. Agrawal S, Maity S, AlRaawi Z, Al-Ameer M, Kumar TKS. Targeting drugs against fibroblast growth factor(s)-induced cell signaling. Current Drug Targets 2021;22:214-40.  https://doi.org/10.2174/1389450121999201012201926
  38. Li WP, Ma K, Jiang XY, Yang R, Lu PH, Nie BM, et al. Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells. Neural Regeneration Research 2018;13:1927-36.  https://doi.org/10.4103/1673-5374.239439
  39. Gahmberg CG, Gronholm M. How integrin phosphorylations regulate cell € adhesion and signaling. Trends in Biochemical Sciences 2022;47:265-78.  https://doi.org/10.1016/j.tibs.2021.11.003
  40. Cao G, Xiang C, Zhou R, Zhang Y, Xu H, Yang H, et al. Notoginsenoside R1 facilitated wound healing in high-fat diet/streptozotocin-induced diabetic rats. Oxidative Medicine and Cellular Longevity 2022;2022:2476493. 
  41. Rong F, Wang T, Zhou Q, Peng H, Yang J, Fan Q, et al. Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications. Bioactive Materials 2023;19:198-216.  https://doi.org/10.1016/j.bioactmat.2022.03.043
  42. Novakovic M, Rout A, Kingsley T, Kirchoff R, Singh A, Verma V, et al. Role of gut microbiota in cardiovascular diseases. World Journal of Cardiology 2020;12:110-22.  https://doi.org/10.4330/wjc.v12.i4.110
  43. Jang KJ, Choi SH, Yu GJ, Hong SH, Chung YH, Kim CH, et al. Anti-inflammatory potential of total saponins derived from the roots of Panax ginseng in lipopolysaccharide-activated RAW 264.7 macrophages. 2016. p. 1109-15. 11. 
  44. Tandara AA, Tajwjos Mustoe. Oxygen in wound healing-more than a nutrient. 2004. p. 294-300. 28.  https://doi.org/10.1007/s00268-003-7400-2
  45. Schmidt A, Liebelt G, Niessner F, von Woedtke T, Bekeschus SJRb. Gas plasma-spurred wound healing is accompanied by regulation of focal adhesion, matrix remodeling, and tissue oxygenation. 2021, 101809. 38. 
  46. Liu Y, Yang X, Liu Y, Jiang T, Ren S, Chen J, et al. NRF2 signalling pathway: new insights and progress in the field of wound healing. J Cell Mol Med 2021;25:5857-68.  https://doi.org/10.1111/jcmm.16597
  47. Kimmel HM, Grant A, Ditata J. The presence of oxygen in wound healing. Wounds : A Compendium of Clinical Research and Practice 2016;28:264-70. 
  48. Zhang EY, Gao B, Shi HL, Huang LF, Yang L, Wu XJ, et al. 20(S)-Protopanaxadiol enhances angiogenesis via HIF-1a-mediated VEGF secretion by activating p70S6 kinase and benefits wound healing in genetically diabetic mice. Experimental & Molecular Medicine 2017;49:e387. 
  49. Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, Bobryshev YV. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2. Immunobiology 2018;223:101-11.  https://doi.org/10.1016/j.imbio.2017.10.005
  50. Yan X, Zhang H, Fan Q, Hu J, Tao R, Chen Q, et al. Dectin-2 deficiency modulates Th1 differentiation and improves wound healing after myocardial infarction. 2017. p. 1116-29. 120.  https://doi.org/10.1161/CIRCRESAHA.116.310260
  51. Kang B, Kim CY, Hwang J, Sun S, Yang H, Suh HJ, et al. Red ginseng extract regulates differentiation of monocytes to macrophage and inflammatory signalings in human monocytes. Food Science and Biotechnology 2019;28:1819-28.  https://doi.org/10.1007/s10068-019-00611-x
  52. Brockmann L, Giannou AD, Gagliani N, Huber S. Regulation of T(H)17 cells and associated cytokines in wound healing, tissue regeneration, and carcinogenesis. Int J Mol Sci 2017;18. 
  53. Zhao Y, Sun X, Yu X, Gao R, Yin LJB. Pharmacotherapy. Saponins from Panax notoginseng leaves improve the symptoms of aplastic anemia and aberrant immunity in mice. 2018. p. 959-65. 102.  https://doi.org/10.1016/j.biopha.2018.03.175
  54. Eble JA, Niland S. The extracellular matrix of blood vessels. Current Pharmaceutical Design 2009;15:1385-400.  https://doi.org/10.2174/138161209787846757
  55. Chen T-Y, Wen T-K, Dai N-T, Hsu S-hJB. Cryogel/hydrogel biomaterials and acupuncture combined to promote diabetic skin wound healing through immunomodulation. 2021, 120608. 269. 
  56. Irfan M, Kwak YS, Han CK, Hyun SH, Rhee MH. Adaptogenic effects of Panax ginseng on modulation of cardiovascular functions. J Ginseng Res 2020;44:538-43.  https://doi.org/10.1016/j.jgr.2020.03.001
  57. Kanehisa M, Goto SJNar. KEGG: Kyoto Encyclopedia of Genes and Genomes 2000;28:27-30.  https://doi.org/10.1093/nar/28.1.27
  58. Wilson CW, Ye W. Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling. Cell Adhesion & Migration 2014;8:76-83.  https://doi.org/10.4161/cam.28115
  59. Li Y, Sun R, Zou J, Ying Y, Luo Z. Dual roles of the AMP-activated protein kinase pathway in angiogenesis. Cells 2019;8. 
  60. Luo X, Zheng E, Wei L, Zeng H, Qin H, Zhang X, et al. The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis. Cell Death Dis 2021;12:328. 
  61. Ding Q, Zhu W, Diao Y, Xu G, Wang L, Qu S, et al. Elucidation of the mechanism of action of ginseng against acute lung injury/acute respiratory distress syndrome by a network pharmacology-based strategy. Front Pharmacol 2020;11:611794. 
  62. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010;1802:396-405.  https://doi.org/10.1016/j.bbadis.2009.12.009
  63. Ramirez MP, Anderson MJM, Kelly MD, Sundby LJ, Hagerty AR, Wenthe SJ, et al. Dystrophin missense mutations alter focal adhesion tension and mechanotransduction. Proc Natl Acad Sci U S A 2022;119:e2205536119. 
  64. Andrikopoulou E, Zhang X, Sebastian R, Marti G, Liu L, Milner S M, et al. Current Insights into the role of HIF-1 in cutaneous wound healing. 2011. p. 218-35. 11.  https://doi.org/10.2174/156652411795243414
  65. Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, et al. The role of hypoxia-inducible factor in wound healing. 2014. p. 390-9. 3.  https://doi.org/10.1089/wound.2013.0520
  66. Gambari L, Lisignoli G, Cattini L, Manferdini C, Facchini A, Grassi F. Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor cells via NRF2-dependent mechanism. Pharmacol Res 2014;87:99-112.  https://doi.org/10.1016/j.phrs.2014.06.014
  67. Hu K, Olsen BRJTJoci. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. 2016. p. 509-26. 126.  https://doi.org/10.1172/JCI82585
  68. Wang K, Gheblawi M, Nikhanj A, Munan M, MacIntyre E, O'Neil C, et al. Dysregulation of ACE (Angiotensin-Converting enzyme)-2 and renin-angiotensin peptides in SARS-CoV-2 mediated mortality and end-organ injuries. Hypertension (Dallas, Tex 1979;79:365-78. 2022.  https://doi.org/10.1161/HYPERTENSIONAHA.121.18295
  69. Salas-Oropeza J, Jimenez-Estrada M, Perez-Torres A, Castell-Rodriguez AE, Becerril-Millan R, Rodriguez-Monroy MA, et al. Wound healing activity of α-pinene and α-phellandrene. Molecules 2021;26. 
  70. Zinder R, Cooley R, Vlad LG, Molnar JA. Vitamin A and wound healing. Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition 2019;34:839-49.  https://doi.org/10.1002/ncp.10420
  71. Spiller S, Wippold T, Bellmann-Sickert K, Franz S, Saalbach A, Anderegg U, et al. Protease-triggered release of stabilized CXCL12 from coated scaffolds in an ex vivo wound model. Pharmaceutics 2021;13. 
  72. Hsu C-C, Zhang X, Wang G, Zhang W, Cai Z, Pan B-S, et al. Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK. 2021. p. 3803-19. 81.  https://doi.org/10.1016/j.molcel.2021.08.025
  73. Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol 2013;3:365-401.  https://doi.org/10.1002/cphy.c120006
  74. Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): a multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther 2022;233:108024. 
  75. Ramos-Lopez O, Samblas M, Milagro FI, Riezu-Boj JI, Crujeiras AB, Martinez JA, et al. Circadian gene methylation profiles are associated with obesity, metabolic disturbances and carbohydrate intake. Chronobiol Int 2018;35:969-81.  https://doi.org/10.1080/07420528.2018.1446021
  76. Deng P, Jin W, Liu Z, Gao M, Zhou J. Novel multifunctional adenine-modified chitosan dressings for promoting wound healing. Carbohydrate Polymers 2021;260:117767. 
  77. Tandon S, Singh B, Kapoor S, Mangal S. Comparison of effect of pH modulation on wound healing with topical application of citric acid versus superoxide ions. In: Nigerian journal of surgery : official publication of the Nigerian Surgical Research Society; 2020. p. 122-6. 26. 
  78. Ozay Y, Guzel S, Yumrutas O, Pehlivanoglu B, Erdogdu IH, Yildirim Z, et al. Wound healing effect of kaempferol in diabetic and nondiabetic rats. The Journal of Surgical Research 2019;233:284-96.  https://doi.org/10.1016/j.jss.2018.08.009
  79. Chaniad P, Tewtrakul S, Sudsai T, Langyanai S, Kaewdana K. Anti-inflammatory, wound healing and antioxidant potential of compounds from Dioscorea bulbifera L. bulbils. PLoS One. 2020;15:e0243632. 
  80. Poljsak N, Kreft S, Kocevar Glavac N. Vegetable butters and oils in skin wound healing: scientific evidence for new opportunities in dermatology. Phytotherapy Research : PTR 2020;34:254-69.  https://doi.org/10.1002/ptr.6524
  81. Gai Y, Li L, Ma H, Riely BK, Liu B, Li HJA, et al. Critical role of MetR/MetB/MetC/MetX in cysteine and methionine metabolism, fungal development, and virulence of Alternaria alternata. 2020. p. e01911-20. 87.  https://doi.org/10.1128/AEM.01911-20
  82. Qi YS, Xie JB, Xie P, Duan Y, Ling YQ, Gu YL, et al. Uncovering the anti-NSCLC effects and mechanisms of gypenosides by metabolomics and network pharmacology analysis. Journal of Ethnopharmacology 2021;281:114506. 
  83. Holeꠙcek M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutrition & Metabolism 2018;15:33. 
  84. Zhenyukh O, Gonzalez-Amor M, Rodrigues-Diez RR, Esteban V, Ruiz-Ortega M, Salaices M, et al. Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation. J Cell Mol Med 2018;22:4948-62.  https://doi.org/10.1111/jcmm.13759
  85. Neinast M, Murashige D, Zjarop Arany. Branched chain amino acids. 2019. p. 139-64. 81.  https://doi.org/10.1146/annurev-physiol-020518-114455
  86. Liang L, Hui K, Hu C, Wen Y, Yang S, Zhu P, et al. Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells. J Exp Clin Cancer Res 2019;38:71. 
  87. Ma R, Li X, Tewari N, Liu Y, Bhawal UK, Zeng X. microRNA-21 ameliorates the impairment of autophagy in palatal wound healing. Journal of Physiology and Pharmacology : An Official Journal of the Polish Physiological Society 2020:71. 
  88. Qiang L, Yang S, Cui YH, He YY. Keratinocyte autophagy enables the activation of keratinocytes and fibroblastsand facilitates wound healing. Autophagy 2021;17:2128-43.  https://doi.org/10.1080/15548627.2020.1816342
  89. Parikh M, Kura B, O'Hara KA, Dibrov E, Netticadan T, Slezak J, et al. Cardioprotective effects of dietary flaxseed post-infarction are associated with changes in MicroRNA expression. Biomolecules 2020;10. 
  90. Dunn LL, Kong SMY, Tumanov S, Chen W, Cantley J, Ayer A, et al. Hmox1 (heme oxygenase-1) protects against ischemia-mediated injury via stabilization of HIF-1α (Hypoxia-Inducible factor-1α). Arteriosclerosis, Thrombosis, and Vascular Biology 2021;41:317-30.  https://doi.org/10.1161/ATVBAHA.120.315393
  91. Michels AA, Robitaille AM, Buczynski-Ruchonnet D, Hodroj W, Reina JH, Hall MN, et al. mTORC1 directly phosphorylates and regulates human MAF1. Molecular and Cellular Biology 2010;30:3749-57.  https://doi.org/10.1128/MCB.00319-10
  92. Li X-T, Chen R, Jin L-M, Chen H-YJTAjoCm. Regulation on energy metabolism and protection on mitochondria of Panax ginseng polysaccharide. 2009. p. 1139-52. 37.  https://doi.org/10.1142/S0192415X09007454
  93. Leong PK, Wong HS, Chen J, Ko KMJE-BC, Medicine A. Yang/Qi invigoration: an herbal therapy for chronic fatigue syndrome with yang deficiency?. 2015. 2015. 
  94. Sylakowski K, Wells A. ECM-regulation of autophagy: the yin and the yang of autophagy during wound healing. Matrix Biology : Journal of the International Society for Matrix Biology 2021;100-101:197-206.  https://doi.org/10.1016/j.matbio.2020.12.006
  95. Xu Y, Jiang H, Li L, Chen F, Liu Y, Zhou M, et al. Branched-chain amino acid catabolism promotes thrombosis risk by enhancing tropomodulin-3 propionylation in platelets. Circulation 2020;142:49-64.  https://doi.org/10.1161/CIRCULATIONAHA.119.043581
  96. Holmes VA. Changes in haemostasis during normal pregnancy: does homocysteine play a role in maintaining homeostasis? The Proceedings of the Nutrition Society 2003;62:479-93.  https://doi.org/10.1079/PNS2003251
  97. Chatree S, Thongmaen N, Tantivejkul K, Sitticharoon C, Vucenik IJM. Role of inositols and inositol phosphates in energy metabolism. 2020. p. 5079. 25.  https://doi.org/10.3390/molecules25215079
  98. Lyu X, Yan K, Chen W, Wang Y, Zhu H, Pan H, et al. The characterization of metabolites alterations in white adipose tissue of diabetic GK Rats after ileal transposition surgery by an untargeted metabolomics approach. 2021. p. 275-84. 10.  https://doi.org/10.1080/21623945.2021.1926139
  99. Suzuki R, Sato Y, Fukaya M, Suzuki D, Yoshizawa F, Sato Y. Energy metabolism profile of the effects of amino acid treatment on hepatocytes: phenylalanine and phenylpyruvate inhibit glycolysis of hepatocytes. Nutrition (Burbank, Los Angeles County, Calif) 2021;82:111042. 
  100. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. 2012. p. 582-7. 109. https://doi.org/10.1073/pnas.1106750109