CNRClinical Neuroscience Research3083-48992981-8133Bio-Byword Scientific Publishing Pty. Ltd.10.26689/cnr.v2i1.6512ArticleApplication of Network Pharmacology to Explore the Anti-Aging Molecular Mechanism of Radix notoginsenghttps://artdesignp.com/journal/CNR/2/1/10.26689/cnr.v2i1.6512ZhangJunyang,YuQinglin,ZhaoTong,DingXueru,LiNa2024212024-03-29Objective: To study the anti-aging effects of Radix Notoginseng and to explore its molecular network mechanism. Methods: Aging and Radix notoginseng gene targets were searched and downloaded from the Genecards website, then Venn intersection analysis was performed to find common genes for diseases and drugs to explore candidate targets for Radix notoginseng in the treatment of aging. Bioinformatics was then used to analyze the biological processes, cellular components, molecular functions, and KEGG signaling pathways of the shared target network. Protein molecular network construction was carried out to find the core molecular network genes of the drug Radix notoginseng for the treatment of aging. A final PubMed literature comparison was performed to assess the value of the potential role of core network genes. Results: The keywords “Aging” and “Radix notoginseng” were queried in Genecards and 25,000 aging-related targets were obtained, 17 for Radix notoginseng. GO and KEGG analysis of the intersecting genes obtained from the Venn intersection analysis then showed that the BP with the highest potential to be associated with disease and drugs is positive regulation of protein phosphorylation, CC is macromolecular complex and MF is identical protein binding. The KEGG with the higher correlation is lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, and proteoglycans in cancer. A total of 10 hub genes were identified in the PPI network construction, including EGFR, MMP9, TNF, VEGFA, RHOA, CDKN1A, CASP3, CCND1, AKT1, and IL1B. Among these, it found that a large number of MMP9 and TNF genes were reported in the literature, with the remaining hub genes less frequently reported in the literature. Conclusion: This study uses bioinformatics and network pharmacology to explain the core network mechanisms of the drug Radix notoginseng in the treatment of aging using the latest databases. The results show that hub genes such as CDKN1A, EGFR, and AKT1 are involved in the core biological processes of aging. The results of the study provide an important reference for resolving the core molecular network mechanism of anti-aging properties and provide a validation basis for future experimental validation.

da Costa JP, Vitorino R, Silva GM, et al., 2016, A Synopsis on Aging: Theories, Mechanisms, and Future Prospects. Ageing Research Reviews, 2016(29): 90–112.

Zhao H, Han Z, Li G, et al., 2017, Therapeutic Potential and Cellular Mechanisms of Panax Notoginseng on Prevention of Aging and Cell Senescence-Associated Diseases. Aging and Disease, 8(6): 721–739.

Khaltourina D, Matveyev Y, Alekseev A, et al., 2020, Aging Fits the Disease Criteria of the International Classification of Diseases. Mechanisms of Ageing and Development, 2020(189): 111230.

Wang Z, Lyons B, Truscott RJ, et al., 2014, Human Protein Aging: Modification and Crosslinking through Dehydroalanine and Dehydrobutyrine Intermediates. Aging Cell, 13(2): 226–234.

Dizdaroglu M, Jaruga P, 2012, Mechanisms of Free Radical-Induced Damage to DNA. Free Radical Biology & Medicine, 46(4): 382–419.

Mikhelson, V, Gamaley I, 2012, Telomere Shortening is a Sole Mechanism of Aging in Mammals. Current Aging Science, 5(3): 203–208.

Unnikrishnan A, Freeman WM, Jackson J, et al., 2019, The Role of DNA Methylation in Epigenetics of Aging. Pharmacology & Therapeutics, 2019(195): 172–185.

Hou Y, Dan X, Babbar M, et al., 2019, Aging as a Risk Factor for Neurodegenerative Disease. Nature Reviews (Neurology), 15(10): 565–581.

Kritsilis M, Rizou VS, Koutsoudaki PN, et al., 2018, Aging, Cellular Senescence and Neurodegenerative Disease. International Journal of Molecular Sciences, 19(10): 2937.

Liu RM, 2022, Aging, Cellular Senescence, and Alzheimer’s Disease. International Journal of Molecular Sciences, 23(4): 1989.

Palmer AK, Gustafson B, Kirkland JL, et al., 2019, Cellular Senescence: At the Nexus between Aging and Diabetes. Diabetologia, 62(10): 1835–1841.

Costantino S, Paneni F, Cosentino F, et al., 2016, Aging, Metabolism and Cardiovascular Disease. The Journal of Physiology, 594(8): 2061–2073.

Kowald A, Passos JF, Kirkwood TBL, 2020, On the Evolution of Cellular Senescence. Aging Cell, 19(12): e13270.

Guarente L, 2014, Aging Research: Where do We Stand and Where are We Going. Cell, 159(1): 15–19.

Liu H, Lu X, Hu Y, et al., 2020, Chemical Constituents of Panax ginseng and Panax notoginseng Explain why they Differ in Therapeutic Efficacy. Pharmacological Research, 2020(161): 105263.

Chen X, Zhang J, Fang Y, et al., 2008, Ginsenoside Rg1 Delays Tert-Butyl Hydroperoxide-Induced Premature Senescence in Human WI-38 Diploid Fibroblast Cells. The Journals of Gerontology (Biological sciences and medical sciences), 63(3): 253–264.

Shi AW, Gu N, Liu XM, et al., 2011, Ginsenoside Rg1 Enhances Endothelial Progenitor Cell Angiogenic Potency and Prevents Senescence in Vitro. The Journal of International Medical Research, 39(4): 1306–1318.

Maria J, Ingrid Z, 2017, Effects of Bioactive Compounds on Senescence and Components of Senescence Associated Secretory Phenotypes in Vitro. Food and Function, 8(7): 2394–2418.

Zhang Y, Cai W, Han G, et al., 2020, Panax notoginseng Saponins Prevent Senescence and Inhibit Apoptosis by Regulating the PI3K?AKT?mTOR Pathway in Osteoarthritic Chondrocytes. International Journal of Molecular Medicine 45(4): 1225–1236.

Xu Y, Tan HY, Li S, et al., 2018, Panax notoginseng for Inflammation-Related Chronic Diseases: A Review on the Modulations of Multiple Pathways. The American Journal of Chinese Medicine, 46(5): 971–996.

Huang YD, Cheng JX, Shi Y, et al., 2022, Panax notoginseng: A Review on Chemical Components, Chromatographic Analysis, P. notoginseng Extracts, and Pharmacology in Recent Five Years. China Journal of Chinese Materia Medica, 47(10): 2584–2596.

Nogales C, Mamdouh ZM, List M, et al., 2022, Network Pharmacology: Curing Causal Mechanisms instead of Treating Symptoms. Trends in Pharmacological Sciences, 43(2): 136–150.

Zhang R, Zhu X, Bai H, et al., 2019, Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment. Frontiers in Pharmacology, 2019(10): 123.

Wang YN, Wu W, Chen HC, et al., 2010, Genistein Protects against UVB-induced Senescence-like Characteristics in Human Dermal Fibroblast by p66Shc Down-Regulation. Journal of Dermatological Science, 58(1): 19–27.

Black CN, Bot M, Révész D, et al., 2017, The Association between Three Major Physiological Stress Systems and Oxidative DNA and Lipid Damage. Psychoneuroendocrinology, 2017(80): 56–66.

Lin J, Kumari S, Kim C, et al., 2016, RIPK1 Counteracts ZBP1-mediated Necroptosis to Inhibit Inflammation. Nature, 540(7631): 124–128.

Saretzki G, Zglinicki TV, 2002, Replicative Aging, Telomeres, and Oxidative Stress. Annals of the New York Academy of Sciences, 2002(959): 24–29.

Yousefzadeh M, Henpita C, Vyas R, et al., 2021, DNA Damage: How and Why We Age? Elife, 2021(10): e62852.

Lin J, Epel E, 2022, Stress and Telomere Shortening: Insights from Cellular Mechanisms. Ageing Research Reviews, 2022(73): 101507.

Murphy MP, 2009, How Mitochondria Produce Reactive Oxygen Species. The Biochemical Journal, 417(1): 1–13.

Jauhari A, Baranov SV, Suofu Y, et al., 2020, Melatonin Inhibits Cytosolic Mitochondrial DNA-induced Neuroinflammatory Signaling in Accelerated Aging and Neurodegeneration. The Journal of Clinical Investigation, 130(6): 3124–3136.

Kauppila TES, Kauppila JHK, Larsson NG, 2017, Mammalian Mitochondria and Aging: An Update. Cell Metabolism, 25(1): 57–71.

Zhang D, Liu Y, Zhu Y, et al., 2022, A Non-Canonical cGAS-STING-PERK Pathway Facilitates the Translational Program Critical for Senescence and Organ Fibrosis. Nature Cell Biology, 24(5): 766–782.

Perdomo G, Henry HD, 2009, Apolipoprotein D in Lipid Metabolism and its Functional Implication in Atherosclerosis and Aging. Aging (Albany NY), 1(1): 17–27.

Bai R, Zhang T, Gao Y, et al., 2022, Rab31, a Receptor of Advanced Glycation End Products (RAGE) Interacting Protein, Inhibits AGE-induced Pancreatic Beta-cell Apoptosis through the pAKT/BCL2 Pathway. Endocrine Journal, 69(8): 1015–1026.

Nautiyal J, Kanwar SS, Majumdar AP, et al., 2010, EGFR(s) in Aging and Carcinogenesis of the Gastrointestinal Tract. Current Protein & Peptide Science 11(6): 436–450.

Chahal HS, Drake WM, 2007, The Endocrine System and Aging. The Journal of Pathology, 211(2): 173–180.

Stein GH, Drullinger LF, Soulard A, et al., 1999, Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts. Molecular and Cellular Biology, 19(3): 2109–2117.

Passos JF, Nelson G, Wang C, et al., 2010, Feedback between p21 and Reactive Oxygen Production is Necessary for Cell Senescence. Molecular Systems Biology, 2010(6): 347.

Majumdar AP, Du J, 2006, Phosphatidylinositol 3-kinase/Akt Signaling Stimulates Colonic Mucosal Cell Survival during Aging. American Journal of Physiology (Gastrointestinal and Liver Physiology), 290(1): 49–55.

Schmelz EM, Levi E, Du J, et al., 2004, Age-related Loss of EGF-receptor Related Protein (ERRP) in the Aging Colon is a Potential Risk Factor for Colon Cancer. Mechanisms of Aging and Development, 125(12): 917–922.

Nygaard M, Soerensen M, Flachsbart F, et al., 2013, AKT1 Fails to Replicate as a Longevity-Associated Gene in Danish and German Nonagenarians and Centenarians. European Journal of Human Genetics, 21(5): 574–577.

Bao J, Liu B, Wu C, 2020, Progress of Anti-aging Drugs Targeting Autophagy. Advances in Experimental Medicine and Biology, 2020(1207): 681–688.

Zhao X, Wang T, Cai B, et al., 2019, MicroRNA-495 Enhances Chondrocyte Apoptosis, Senescence and Promotes the Progression of Osteoarthritis by Targeting AKT1. American Journal of Translational Research, 11(4): 2232–2244.

Pawlikowska L, Hu D, Huntsman S, et al., 2009, Association of Common Genetic Variation in the Insulin/IGF1 Signaling Pathway with Human Longevity. Aging Cell, 8(4): 460–472.

Li N, Luo H, Liu X, et al., 2016, Association Study of Polymorphisms in FOXO3, AKT1 and IGF-2R Genes with Human Longevity in a Han Chinese Population. Oncotarget, 7(1): 23–32.