Exploring the roles of Polygonati Rhizoma in delaying skin aging using network pharmacology and molecular docking

Exploring the roles of Polygonati Rhizoma in delaying skin aging using network pharmacology and molecular docking | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring the roles of Polygonati Rhizoma in delaying skin aging using network pharmacology and molecular docking Xilong Wang, Qinzhen Lei, Xiaoyan Luo, Xinyuan Duo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6511835/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Polygonati Rhizoma has been reported to exhibit the ability to retard skin aging. However, the precise molecular mechanisms underlying remain largely elusive. In this study, we screened 9 active compounds in Polygonati Rhizoma using the TCMSP and SwissADME databases. Subsequently, 285 potential targets were identified via Swiss Target Prediction Database. Concurrently, 800 genes related to skin aging were retrieved from GeneCards, OMIM, and TTD databases. By intersecting these datasets with the potential targets of Polygonati Rhizoma , we pinpointed 17 overlapping genes. These genes were further subjected to GO function annotation and KEGG pathway analysis using DAVID database. A compound-target-pathway network was then constructed using Cytoscape software, highlighting two compounds (4',5-dihydroxyflavone and baicalein) and six targets (MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1). Molecular docking revealed that the binding energy between 4',5-dihydroxyflavone and baicalein with the six targets was less than -5 kcal/mol, particularly for MMP9, PTGS2, and CYP1B1, indicating a stable interaction. Finally, Polygonati Rhizoma flavonoids were isolated, and their antioxidant capacity was evaluated in vitro, confirming significant antioxidant activity. Collectively, our findings provide a systematic foundation for elucidating the molecular mechanisms underlying the anti-aging effects of Polygonati Rhizoma and offer valuable insights into the development of anti-skin aging cosmetics. Polygonati Rhizoma 4' 5-dihydroxyflavone baicalein anti-skin aging Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Polygonati Rhizoma , a traditional Chinese medicine with dual properties as both food and medicine, has been utilized for over two millennia. Its earliest documentation can be traced back to the “Ming Yi Bie Lu”. This herb is renowned for its diverse pharmacological activities, including replenishing Qi, nourishing Yin, moistening the lungs, fortifying the spleen, tonifying the kidneys, and enhancing immune function(Hu et al., 2022, Wang et al., 2023). Recently, pharmacological studies have demonstrated that Polygonati Rhizoma exhibits efficacy in delaying aging, improving immunity, alleviating fatigue, lowering blood glucose levels, exhibiting anti-tumor effects, protecting the cardiovascular system, enhancing memory, and potentially combating COVID-19(Li et al., 2018, Zhao et al., 2018, Mu et al., 2021). These beneficial effects are primarily attributed to its various bioactive ingredients such as alkaloids, flavonoids, steroidal saponins, lignans, amino acids, and polysaccharides(Zhao and Li, 2015, Cui et al., 2018). Among them, polysaccharides are considered one of the most significant active ingredients, possessing potent biological activities such as antioxidant, anti-aging, anti-fatigue, immune-enhancing, antibacterial, anti-inflammatory, lipid-lowering, anti-atherosclerotic, anti-osteoporotic, hepatoprotective, antidiabetic, anticancer properties, and potential preventive effects against Alzheimer's disease(Zhu et al., 2014, Cui et al., 2018, Liu et al., 2024). Similarly, the flavonoids found in Polygonati Rhizoma exhibit various beneficial effects, including anticancer, antioxidant, anti-atherosclerotic, antibacterial, hypoglycemic, and antihyperlipidemic activities(Shu et al., 2009, Yang et al., 2015, Sharma et al., 2018, Huang et al., 2020, Sharma et al., 2020). Consequently, Polygonati Rhizoma holds considerable promise for applications in functional foods and pharmaceuticals as a natural phytomedicine. Human aging is a multifaceted and dynamic physiological process characterized by a progressive decline in physiological function and an increased vulnerability to diseases, affecting all tissues and organs(Hayflick, 2000). The skin, as the body's largest organ, serves as a critical barrier that separates internal structures from the external environment, preventing water loss and microbial invasion(Blanpain and Fuchs, 2006). Being the outermost organ, the skin is continually exposed to both intrinsic and extrinsic stimuli, leading to visible signs of aging such as wrinkles, laxity, pigmentation, and roughness as individuals age(Khavkin and Ellis, 2011). In addition to its protective role, the skin also has an important cosmetic function. A youthful and attractive appearance has a positive impact on social behaviors and reproductive success, leading many people to spend considerable resources on cosmetics and pharmaceuticals aimed at delaying or reversing skin aging(Blanpain and Fuchs, 2006, Kazanci et al., 2016). It has been reported that the global anti-aging market exceeds 60 billion dollars(Scott et al., 2021). Historically, middle-aged and older adults were the primary consumers of anti-aging products. However, recent trends suggest a growing interest among younger individuals in preventive measures(Mandelblatt and Antoni, 2025). In recent years, the remarkable advancement in science and technology has significantly enhanced the quality of life, leading to an increased focus on health and wellness. Concurrently, concerns have emerged regarding the toxicity and side effects associated with synthetic drugs. As a result, there is a growing inclination towards natural and safe alternatives. Traditional Chinese herbs have garnered significant attention due to their efficacy, minimal side effects, and non-allergenic properties. Consumers are increasingly favoring cosmetic products that contain purely natural ingredients. Polygonati Rhizoma , a traditional Chinese medicinal herb with a long history of use, has been shown in previous studies to possess antioxidant, antimicrobial, whitening, and moisturizing properties(Xiaowei et al., 2019, Ma et al., 2021, Wang et al., 2022). In this study, we employed network pharmacology and molecular docking methods to investigate the potential roles of Polygonati Rhizoma in anti-skin aging. 2. Materials and methods 2.1 Acquisition of active ingredients and potential targets of Polygonati Rhizoma The chemical constituents of Polygonati Rhizoma were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database (https://www.tcmsp-e.com/tcmsp.php), filtered based on oral bioavailability (OB) ≥ 30% and drug likeness (DL) ≥ 0.1(Xu and Stevenson, 2000, Wang et al., 2021). The canonical simplified molecular-input line-entry system (SMILES) representations of these compounds were subsequently obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) or the NovoPro webpage tool (https://www.novopro.cn/tools/mol2smiles.html). These SMILES were then analyzed using SwissADME (http://www.swissadme.ch/) for pharmacokinetic evaluation, with active ingredients being selected based on gastrointestinal absorption marked as "yes" and at least two "yes" responses in the drug likeness subcategories(Daina et al., 2017). Finally, the SMILES were input into the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) to identify potential targets with a probability greater than 0.1(Gfeller et al., 2014). 2.2 Identification of Skin Aging-Related Targets Three databases, namely GeneCards (https://www.genecards.org/), OMIM (https://www.omim.org/), and TTD (https://db.idrblab.net/ttd/), were utilized to search potential targets associated with skin aging. The search term "skin aging" was employed across all three databases to compile a comprehensive list of targets. Subsequently, the resulting datasets were integrated, duplicates were removed, and the final consolidated subset was validated as comprising skin aging-related targets. 2.3 Intersection of targets for skin aging and polygonati rhizoma The targets associated with skin aging were integrated with those of Polygonati Rhizoma . Subsequently, the Venny 2.1 platform (https://bioinfogp.cnb.csic.es/tools/venny/index.html) was utilized to map and identify overlapping targets. These intersecting targets will serve as the foundation for subsequent analyses. 2.4 Enrichment analysis of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathways To elucidate the molecular mechanisms underlying the anti-skin aging effects of Polygonati Rhizoma , we conducted enrichment analysis on the GO functions and KEGG pathways associated with the common targets identified for delaying skin aging. This analysis was performed using the DAVID bioinformatics tool (https://david.ncifcrf.gov/). GO terms and KEGG pathways with a p value ≤ 0.05 were considered statistically significant. For further interpretation, the top 10 GO terms in each of the cellular component (CC), molecular function (MF), and biological process (BP) categories, as well as the top 20 KEGG pathways, were visualized using the Wei Shen Xin mapping platform (https://www.bioinformatics.com.cn/)(Tang et al., 2023). 2.5 Construction and analysis of network The compound-target-pathway (C-T-P) network was constructed utilizing Cytoscape software (version 3.10.3), with all parameters set to their default values. Within this network, nodes represent compounds, targets, and pathways, while edges denote the interactions between these nodes. Topological properties, including degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC), were comprehensively evaluated using the Centiscape 2.2 plugin to identify key components and critical targets. 2.6 Molecular docking The two-dimensional structures of the ligand molecules in SDF format were obtained from the PubChem database. Subsequently, Chem3D software (version 15.0) was employed to minimize the energy and convert the files into PDB format. For the protein receptor, its accession number (Reviewed, Human) was obtained from the UniProt database (https://www.uniprot.org/), after which the three-dimensional structure was downloaded in PDB format from the Protein Data Bank (https://www.rcsb.org/). Finally, PyMOL software (version 3.1.3.1) was utilized to eliminate extraneous ligands and water molecules prior to conducting the docking experiment. Molecular docking simulations were conducted utilizing AutoDock software (version 1.5.7)(Morris et al., 2009). The binding affinities between the active compounds and target proteins were evaluated, and the conformations of the ligand-receptor complexes exhibiting the lowest binding energies were visualized using PyMOL software. 2.7 Extraction of flavonoids from Polygonati Rhizoma The fresh rhizome of Polygonati Rhizoma was thoroughly cleaned and sliced after removing the fibrous roots. It was then dried at 50°C, pulverized, and sieved through a 60-mesh screen. Accurately weigh 1.00 g of the resulting powder and add 70% ethanol at a solid-liquid ratio of 1:20 (g/mL). Perform ultrasonic extraction at 60°C with a frequency of 40 kHz and power of 250 W for 50 minutes. After extraction, centrifuge the mixture at 4000 r/min for 5 minutes and collect the supernatant. The content of flavonoids in the supernatant was determined according to the method described in the literature(Chen et al., 2019). 2.8 Evaluation of the free radical scavenging capacity of flavonoids from Polygonati Rhizoma Evaluation of free radical scavenging capacity of the flavonoids was conducted using DPPH and hydroxyl radical scavenging assays, following established protocols with minor modifications(Tao et al., 2022). Specifically, for the DPPH radical scavenging assay, 2.0 mL of flavonoid solutions at various concentrations (0, 2, 4, 8, 12, 16, and 20 μg/mL) were mixed with 2.0 mL of a 0.1 mM ethanolic DPPH solution. Deionized water was used as the blank control, while DPPH alone served as the background control. Absorbance (A) was measured at 517 nm after incubation in the dark for 20 minutes. For the hydroxyl radical scavenging assay, 1.0 mL of 6 mM ferrous sulfate solution and 1.0 mL of 6 mM salicylate alcohol solution were thoroughly mixed in a 10 mL cuvette, followed by the addition of 1.0 mL of 6 mM hydrogen peroxide solution and 1.0 mL of flavonoid solutions at varying concentrations. Deionized water was substituted for the flavonoid solution to serve as the blank control, and deionized water was substituted for the hydrogen peroxide solution to serve as the background control. Absorbance (A) was measured at 510 nm in a constant temperature water bath at 37°C for 30 minutes. In both assays, ascorbic acid at the same concentration was utilized as a positive control, and the clearance rate was calculated as follows. Clearance (%) = (1 – (A sample – A back ))/A empty 3. Results 3.1 Active ingredients of Polygonati Rhizoma Thirty-eight chemical constituents of Polygonati Rhizoma were retrieved from the TCMSP database. Following the application of screening criteria (OB ≥ 30% and DL ≥ 0.18), twelve active components of Polygonati Rhizoma were identified. These compounds were further evaluated using pharmacokinetic parameters via the SwissADME web tool. Ultimately, nine compounds were confirmed as potential active ingredients. The detailed information regarding these compounds were presented in Table 1, and their structure were illustrated in Figure 1. Table 1 Detailed information of screened ingredients from Polygonati Rhizoma Molecule ID Molecule Name OB (%) DL MOL000546 diosgenin 80.88 0.81 MOL004941 (2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-one 71.12 0.18 MOL002959 3'-Methoxydaidzein 48.57 0.24 MOL006331 4',5-Dihydroxyflavone 48.55 0.19 MOL009760 sibiricoside A_qt 35.26 0.86 MOL003889 methylprotodioscin_qt 35.12 0.86 MOL009766 zhonghualiaoine 1 34.72 0.78 MOL002714 baicalein 33.52 0.21 MOL001792 DFV 32.76 0.18 3.2 Common targets of Polygonati Rhizoma and skin aging A comprehensive screening of the Swiss Target Prediction database identified 285 potential targets associated with Polygonati Rhizoma . Concurrently, using "skin aging" as the search term, we retrieved 679 relevant targets from the GeneCards database, 131 from the OMIM database, and 2 from the TDD database. After consolidating and de-duplicating these targets, a total of 800 unique targets related to skin aging were obtained. By intersecting the targets of Polygonati Rhizoma with those related to skin aging, we identified 17 overlapping targets (Figure 2), which were designated as potential targets for further investigation. 3.3 GO enrichment analysis Through GO enrichment analysis of 17 target genes common to Polygonati Rhizoma and skin aging, a total of 94 GO terms were identified, comprising 56 biological processes (BP), 15 cellular components (CC), and 23 molecular functions (MF). Based on the p values and the number of enriched genes, the top 10 enriched BPs, CCs, and MFs were selected for visualization, as illustrated in Figure 3. The enriched BPs primarily encompassed signal transduction, positive and negative regulation of transcription by RNA polymerase II, among others. The CCs were predominantly associated with the nucleus, cytosol, and cytoplasm, while the MFs were largely related to protein binding, zinc ion binding, and metal ion binding. 3.4 KEGG pathway enrichment analysis KEGG pathway analysis of the intersecting genes identified a total of 37 enriched pathways. Based on p values and the number of enriched genes, the top 20 pathways were categorized into four major groups: Environmental Information Processing, Cellular Processes, Organismal Systems, and Human Diseases (Figure 4). Key biological pathways included those related to cancer, TNF signaling, IL-17 signaling, lipid metabolism and atherosclerosis, as well as MicroRNAs in cancer. 3.5 Construction and analysis of C-T-P network The C-T-P network was constructed using Cytoscape_v3.10.3 software, consisting of 52 nodes and 133 edges (Figure 5). The Centiscape2.2 plugin was employed to analyze the network based on degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC). Nodes with values less than the predefined threshold were filtered out, leading to two active components and six target proteins within the network (Table 2). The identified active components were MOL006331 (4',5-Dihydroxyflavone) and MOL002714 (baicalein). The six target proteins were MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1. Table 2 Key components, targets, and networks in the compounds-targets-pathways network. Node name CC BC DC MOL006331 0.0079 270.36 8 MOL002714 0.0080 217.96 8 MAPK1 0.0105 716.46 25 MAPK10 0.0093 430.59 20 MMP9 0.0085 334.32 14 PTGS2 0.0087 296.19 12 PDGFRB 0.0079 173.01 10 CYP1B1 0.0075 103.20 6 Pathways in cancer 0.0093 221.27 9 3.6 Molecular docking results Two key components (4',5-dihydroxyflavone and baicalein) and six target proteins (MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1) were selected for molecular docking analysis. The results demonstrated that the binding energy between each receptor protein and the key components was negative (as shown in Table 3), indicating favorable interactions between the receptors and ligands. Among these receptors, MMP9, PTGS2, and CYP1B1 exhibited notably lower binding energy values with the ligands. The interactions between these three receptors and their respective ligands are presented in Figure 6. The findings reveal that hydrogen bonds were formed between all three proteins and their ligands. Specifically, MMP9 formed four and six hydrogen bonds with its ligand, PTGS2 formed one and nine hydrogen bonds, and CYP1B1 formed five and two hydrogen bonds, respectively. Table 3 The binding energy of key components and target receptors. Protein name Gene name Uniprot ID PDB ID Binding Energy (kcal/mol) in Complex with Ligands 4',5-Dihydroxyflavone baicalein Mitogen-activated protein kinase 1 MAPK1 P28482 1PME -6.55 -6.76 Mitogen-activated protein kinase 10 MAPK10 P53779 4KKG -6.94 -6.66 Matrix metalloproteinase-9 MMP9 P14780 1ITV 7.63 -7.78 Prostaglandin G/H synthase 2 PTGS2 P35354 5F19 -7.66 -7.18 Platelet-derived growth factor receptor beta PDGFRB P09619 2L6W -7.08 -6.53 Cytochrome P450 1B1 CYP1B1 Q16678 3PM0 -7.52 -7.18 3.7 Experimental verification Since both key active ingredients identified through network pharmacology and molecular docking belong to the flavonoids, we extracted Polygonati Rhizoma flavonoids and evaluate their capacity to scavenge free radicals. As shown in Figure 7, Polygonati Rhizoma flavonoids demonstrated significantly higher efficacy than ascorbic acid in scavenging DPPH and hydroxyl radicals. The IC50 values for the flavonoids were 1.06 ± 0.01 µg/mL and 4.59 ± 0.03 µg/mL, respectively. In contrast, the IC50 values for ascorbic acid were 2.67 ± 0.02 µg/mL and 13.83 ± 0.06 µg/mL, respectively. This indicates that Polygonati Rhizoma possess potent antioxidant properties and may serve as a promising candidate for skin anti-aging agents. 4. Discussion In recent years, phytomedicines have attracted considerable attention in pharmaceuticals and functional foods due to their natural origin and minimal side effects. As a traditional herbal plant, using of Polygonati Rhizoma in cosmetic is an attractive strategy to against skin aging. It has been reported that Polygonati Rhizoma was effective in moisturizing and whitening the skin(Liu et al., 2017). These effects were primarily attributed to its active ingredients, such as polysaccharides and flavonoids. Specifically, Polygonati Rhizoma polysaccharides contain a large number of alcoholic hydroxyl groups that act as hydrogen donors, neutralizing reactive hydroxyl radicals in the body and thereby exerting an antioxidant effect(Yang et al., 2017). Additionally, the polysaccharides possess numerous hydrophilic groups capable of forming hydrogen bonds with water molecules, creating a hydration film on the skin surface and thus enhancing skin moisturization(Xiaowei et al., 2019). Furthermore, Polygonati Rhizoma polysaccharides can inhibit tyrosinase activity, reducing melanin production and contributing to skin whitening(Zhen et al., 2011). Besides polysaccharides, flavonoids also exhibit various anti-skin aging properties, including antioxidation, promotion of cell renewal, protection against UV damage, moisturization, and reduction of pigmentation(Xiao et al., 2011, Agati et al., 2012). To date, over 30 theories have been proposed to elucidate the molecular mechanisms underlying skin aging(Heng et al., 2017). Among these, reactive oxygen species (ROS) were recognized as playing a pivotal role by inducing the expression of metalloproteinases, which can destroy the integrity of the extracellular matrix and thereby contribute to wrinkle formation(Kammeyer and Luiten, 2015). Furthermore, ROS also capable of triggering inflammatory responses(Chung et al., 2001). Notably, our study has identified three key targets (MMP9, PTGS2, and CYP1B1) for anti-skin aging treatment using Polygonati Rhizoma . MMP9 is a metalloproteinase implicated in the degradation of the extracellular matrix, leading to the development of skin wrinkles(Inomata et al., 2003). PTGS2, a cyclooxygenase enzyme, plays a crucial role in inflammation-associated pathological processes(Martín-Vázquez et al., 2023). CYP1B1, a member of the cytochrome P450 superfamily with monooxygenase activity, is associated with mitochondrial dysfunction and ROS production, both of which are critical factors contributing to skin aging(Lu et al., 2021). Collectively, our findings may offer promising therapeutic targets for combating skin aging. Two small flavonoid compounds (4',5-dihydroxyflavone and baicalein) from Polygonati Rhizoma were screened for their potential to delay skin aging. Molecular docking analysis revealed that the binding energy of these compounds to skin aging targets were lower than -5 kcal/mol, indicating strong binding affinities(Zhou et al., 2016). Meanwhile, 4',5-dihydroxyflavone has been characterized as a collagenase inhibitor, thereby exhibiting anti-degradative properties(Nitulescu et al., 2022). Baicalein suppresses the expression of matrix metalloproteinase-1 and displays robust antioxidant effects against H 2 O 2 -induced oxidative stress in HaCaT keratinocytes(Kim et al., 2012, Huang et al., 2019). In vitro experiments further confirmed that Polygonati Rhizoma flavonoids possess potent antioxidant capacities. Collectively, 4',5-dihydroxyflavone and baicalein are promising candidates as active ingredients in anti-aging cosmetics. In conclusion, this study demonstrated that 4',5-dihydroxyflavone and baicalein in Polygonati Rhizoma can target MMP9, PTGS2, and CYP1B1, which are key proteins associated with skin aging, thereby contributing to the delay of skin aging. This research not only provide a foundation for a fully understanding of the molecular mechanisms underlying the anti-aging effects of Polygonati Rhizoma but also offers valuable insights into the development of novel anti-aging cosmetics. Declarations Author contributions Wang Xilong was responsible for the conception and supervision of the study. Lei Qinzhen and Luo Xiaoyan contributed to the analysis of network pharmacology and molecular docking, respectively. Duo Xinyuan conducted the validation of the in vitro experiments. Acknowledgements This work was supported by grants from the Natural Science Foundation of Gansu Province (Grant No.23JRRM742), Longdong University Doctoral Science Foundation (Grant No. XYBYZK2216), and College Teachers' Innovation Fund of Gansu Provincial Education Department (Grant No. 2023B-209). Conflict of interest The authors declare that they have no conflict of interest. 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Journal of chemical information and computer sciences 40: 1177-1187 Yang J-x, Wu S, Huang X-l, Hu X-q, Zhang Y (2015) Hypolipidemic Activity and Antiatherosclerotic Effect of Polysaccharide of Polygonatum sibiricumin Rabbit Model and Related Cellular Mechanisms. Evidence-Based Complementary and Alternative Medicine 2015: 1-6 Yang R-F, Geng L-L, Lu H-Q, Fan X-D (2017) Ultrasound-synergized electrostatic field extraction of total flavonoids from Hemerocallis citrina baroni. Ultrasonics Sonochemistry 34: 571-579 Zhao P, Zhao C, Li X, Gao Q, Huang L, Xiao P, Gao W (2018) The genus Polygonatum : A review of ethnopharmacology, phytochemistry and pharmacology. Journal of Ethnopharmacology 214: 274-291 Zhao X, Li J (2015) Chemical constituents of the genus Polygonatum and their role in medicinal treatment. Natural product communications 10: 683-691 Zhen X, Mingyu Z, Yong C (2011) Progress on Study of Chinese Herbs in Anti-aging and Anti-freckle. Asia-Pacific Traditional Medicine 7: 160-162 Zhou W, Wang J, Wu Z, Huang C, Lu A, Wang Y (2016) Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases. Scientific reports 6: 36985-37002 Zhu X, Li Q, Lu F, Wang H, Yan S, Wang Q, Zhu W (2014) Antiatherosclerotic Potential of Rhizoma Polygonati Polysaccharide in Hyperlipidemia-induced Atherosclerotic Hamsters. Drug Research 65: 479-483 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6511835","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":446864688,"identity":"3985e54d-306f-4e71-aa26-17a9a5e68e5f","order_by":0,"name":"Xilong Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYPACCRkgwfgYzGZmbiBKCw9IrTEDgwGQYiRKCwNIC5s0WAsDAS0Gx88efsHYZsHDL91+rbqg4k80fztQy4+Kbbi1nMlLs2A4I8EjOedM2e0ZZwxyZxxmbGDsOXMbpxazAzlmBgwVEjwGN3LSbvO2GeQ2ALUwM7bh0XL+DVCLAURLMUjLfIJabuQYP4DYkn6MGaRlAyEt9jfemDGA/TIjh1ma54xx7kagloP4/CLZn2P8gbGtTo5fIv3hZ54Kudx55w8ffPCjArcWBlB0/AHTPAZwoQP41AMB8wcIzf6AgMJRMApGwSgYqQAAzsRTiViDTg4AAAAASUVORK5CYII=","orcid":"","institution":"Longdong University","correspondingAuthor":true,"prefix":"","firstName":"Xilong","middleName":"","lastName":"Wang","suffix":""},{"id":446864689,"identity":"5e536aab-ff4d-437c-856d-f58e169c20a9","order_by":1,"name":"Qinzhen Lei","email":"","orcid":"","institution":"Longdong University","correspondingAuthor":false,"prefix":"","firstName":"Qinzhen","middleName":"","lastName":"Lei","suffix":""},{"id":446864690,"identity":"3fd93e56-318c-41c4-858b-45253c5be080","order_by":2,"name":"Xiaoyan Luo","email":"","orcid":"","institution":"Longdong University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Luo","suffix":""},{"id":446864691,"identity":"96de9fc0-1880-4e6d-b01c-801e328a28e8","order_by":3,"name":"Xinyuan Duo","email":"","orcid":"","institution":"Longdong University","correspondingAuthor":false,"prefix":"","firstName":"Xinyuan","middleName":"","lastName":"Duo","suffix":""}],"badges":[],"createdAt":"2025-04-23 10:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6511835/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6511835/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81526054,"identity":"9f2be63f-fcd0-4b84-83c0-c33b00a63320","added_by":"auto","created_at":"2025-04-28 08:48:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":195853,"visible":true,"origin":"","legend":"\u003cp\u003eStructure of screened active ingredients from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/ed700422eae893ee8bb42bc7.png"},{"id":81526820,"identity":"8cc34ada-4a4c-4153-a022-4e130c482cc1","added_by":"auto","created_at":"2025-04-28 08:56:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":139338,"visible":true,"origin":"","legend":"\u003cp\u003eVenn diagram of overlapping targets between \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e and skin aging\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/a5d6ff3cca08544708370606.png"},{"id":81526057,"identity":"d54b5c6e-ccdf-4ce8-9922-b02b1694f718","added_by":"auto","created_at":"2025-04-28 08:48:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":264866,"visible":true,"origin":"","legend":"\u003cp\u003eGO enrichment analysis of shared genes between \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e and skin aging.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/431a59a378a6a0baa6a727f5.png"},{"id":81526058,"identity":"be2dd1dc-34db-4d20-98c9-47350ffcbf50","added_by":"auto","created_at":"2025-04-28 08:48:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":169228,"visible":true,"origin":"","legend":"\u003cp\u003eClassified KEGG pathways of intersecting genes in \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e and skin aging.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/006fceb5eae17dbb52336acc.png"},{"id":81526821,"identity":"d58276c7-1cbd-4f38-b8f0-2bcea1b3c793","added_by":"auto","created_at":"2025-04-28 08:56:10","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":604968,"visible":true,"origin":"","legend":"\u003cp\u003eCompound-target-pathway network for the anti-skin aging of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e. Yellow circles represent chemical components, cyan diamonds represent targets, and blue V-shapes represent pathways.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/4f752ca8699f6b687ae10ae3.png"},{"id":81526060,"identity":"68f7747d-fc5e-4a1a-bd00-6e7e79e1287b","added_by":"auto","created_at":"2025-04-28 08:48:10","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":640990,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular docking results of MMP9, PTGS2, and CYP1B1 with two key components. The dark blue color denotes the protein receptor, while cyan indicates the ligand. The red line symbolizes the hydrogen bond formed between the receptor and the ligand. Lime green highlights the amino acid residues involved in the formation of the hydrogen bond, and the numbers specify the length (Å) of the hydrogen bond.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/45407854124c7f035c80603a.png"},{"id":81526819,"identity":"02046296-58c0-4623-908c-e5f8046daa01","added_by":"auto","created_at":"2025-04-28 08:56:09","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":87737,"visible":true,"origin":"","legend":"\u003cp\u003eFree radical scavenging assay of the flavonoids from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e. (A) DPPH free radical scavenging assay. (B) Hydroxyl radical scavenging assay. * indicates p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/e10fd478ad017cb906eddf33.png"},{"id":82590412,"identity":"1618f149-23d0-4f61-9513-cdbeecb0f5b3","added_by":"auto","created_at":"2025-05-13 07:54:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2588397,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6511835/v1/f400f135-a94b-4f42-aa7e-b65da2e52cbd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the roles of Polygonati Rhizoma in delaying skin aging using network pharmacology and molecular docking","fulltext":[{"header":"1.\tIntroduction","content":"\u003cp\u003e\u003cem\u003ePolygonati Rhizoma\u003c/em\u003e, a traditional Chinese medicine with dual properties as both food and medicine, has been utilized for over two millennia. Its earliest documentation can be traced back to the “Ming Yi Bie Lu”. This herb is renowned for its diverse pharmacological activities, including replenishing Qi, nourishing Yin, moistening the lungs, fortifying the spleen, tonifying the kidneys, and enhancing immune function(Hu et al., 2022, Wang et al., 2023). Recently, pharmacological studies have demonstrated that \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e exhibits efficacy in delaying aging, improving immunity, alleviating fatigue, lowering blood glucose levels, exhibiting anti-tumor effects, protecting the cardiovascular system, enhancing memory, and potentially combating COVID-19(Li et al., 2018, Zhao et al., 2018, Mu et al., 2021). These beneficial effects are primarily attributed to its various bioactive ingredients such as alkaloids, flavonoids, steroidal saponins, lignans, amino acids, and polysaccharides(Zhao and Li, 2015, Cui et al., 2018). Among them, polysaccharides are considered one of the most significant active ingredients, possessing potent biological activities such as antioxidant, anti-aging, anti-fatigue, immune-enhancing, antibacterial, anti-inflammatory, lipid-lowering, anti-atherosclerotic, anti-osteoporotic, hepatoprotective, antidiabetic, anticancer properties, and potential preventive effects against Alzheimer's disease(Zhu et al., 2014, Cui et al., 2018, Liu et al., 2024). Similarly, the flavonoids found in \u003cem\u003ePolygonati Rhizoma \u003c/em\u003eexhibit various beneficial effects, including anticancer, antioxidant, anti-atherosclerotic, antibacterial, hypoglycemic, and antihyperlipidemic activities(Shu et al., 2009, Yang et al., 2015, Sharma et al., 2018, Huang et al., 2020, Sharma et al., 2020). Consequently, \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e holds considerable promise for applications in functional foods and pharmaceuticals as a natural phytomedicine.\u003c/p\u003e\n\u003cp\u003eHuman aging is a multifaceted and dynamic physiological process characterized by a progressive decline in physiological function and an increased vulnerability to diseases, affecting all tissues and organs(Hayflick, 2000). The skin, as the body's largest organ, serves as a critical barrier that separates internal structures from the external environment, preventing water loss and microbial invasion(Blanpain and Fuchs, 2006). Being the outermost organ, the skin is continually exposed to both intrinsic and extrinsic stimuli, leading to visible signs of aging such as wrinkles, laxity, pigmentation, and roughness as individuals age(Khavkin and Ellis, 2011). In addition to its protective role, the skin also has an important cosmetic function. A youthful and attractive appearance has a positive impact on social behaviors and reproductive success, leading many people to spend considerable resources on cosmetics and pharmaceuticals aimed at delaying or reversing skin aging(Blanpain and Fuchs, 2006, Kazanci et al., 2016). It has been reported that the global anti-aging market exceeds 60 billion dollars(Scott et al., 2021). Historically, middle-aged and older adults were the primary consumers of anti-aging products. However, recent trends suggest a growing interest among younger individuals in preventive measures(Mandelblatt and Antoni, 2025).\u003c/p\u003e\n\u003cp\u003eIn recent years, the remarkable advancement in science and technology has significantly enhanced the quality of life, leading to an increased focus on health and wellness. Concurrently, concerns have emerged regarding the toxicity and side effects associated with synthetic drugs. As a result, there is a growing inclination towards natural and safe alternatives. Traditional Chinese herbs have garnered significant attention due to their efficacy, minimal side effects, and non-allergenic properties. Consumers are increasingly favoring cosmetic products that contain purely natural ingredients. \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e, a traditional Chinese medicinal herb with a long history of use, has been shown in previous studies to possess antioxidant, antimicrobial, whitening, and moisturizing properties(Xiaowei et al., 2019, Ma et al., 2021, Wang et al., 2022). In this study, we employed network pharmacology and molecular docking methods to investigate the potential roles of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e in anti-skin aging.\u003c/p\u003e"},{"header":"2.\tMaterials and methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Acquisition of active ingredients and potential targets of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe chemical constituents of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database (https://www.tcmsp-e.com/tcmsp.php), filtered based on oral bioavailability (OB) ≥ 30% and drug likeness (DL) ≥ 0.1(Xu and Stevenson, 2000, Wang et al., 2021). The canonical simplified molecular-input line-entry system (SMILES) representations of these compounds were subsequently obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) or the NovoPro webpage tool (https://www.novopro.cn/tools/mol2smiles.html). These SMILES were then analyzed using SwissADME (http://www.swissadme.ch/) for pharmacokinetic evaluation, with active ingredients being selected based on gastrointestinal absorption marked as \"yes\" and at least two \"yes\" responses in the drug likeness subcategories(Daina et al., 2017). Finally, the SMILES were input into the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) to identify potential targets with a probability greater than 0.1(Gfeller et al., 2014). \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Identification of Skin Aging-Related Targets\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree databases, namely GeneCards (https://www.genecards.org/), OMIM (https://www.omim.org/), and TTD (https://db.idrblab.net/ttd/), were utilized to search potential targets associated with skin aging. The search term \"skin aging\" was employed across all three databases to compile a comprehensive list of targets. Subsequently, the resulting datasets were integrated, duplicates were removed, and the final consolidated subset was validated as comprising skin aging-related targets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Intersection of targets for skin aging and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003epolygonati rhizoma\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe targets associated with skin aging were integrated with those of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e. Subsequently, the Venny 2.1 platform (https://bioinfogp.cnb.csic.es/tools/venny/index.html) was utilized to map and identify overlapping targets. These intersecting targets will serve as the foundation for subsequent analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Enrichment analysis of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathways \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo elucidate the molecular mechanisms underlying the anti-skin aging effects of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e, we conducted enrichment analysis on the GO functions and KEGG pathways associated with the common targets identified for delaying skin aging. This analysis was performed using the DAVID bioinformatics tool (https://david.ncifcrf.gov/). GO terms and KEGG pathways with a p value ≤ 0.05 were considered statistically significant. For further interpretation, the top 10 GO terms in each of the cellular component (CC), molecular function (MF), and biological process (BP) categories, as well as the top 20 KEGG pathways, were visualized using the Wei Shen Xin mapping platform (https://www.bioinformatics.com.cn/)(Tang et al., 2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Construction and analysis of network\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe compound-target-pathway (C-T-P) network was constructed utilizing Cytoscape software (version 3.10.3), with all parameters set to their default values. Within this network, nodes represent compounds, targets, and pathways, while edges denote the interactions between these nodes. Topological properties, including degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC), were comprehensively evaluated using the Centiscape 2.2 plugin to identify key components and critical targets.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6 Molecular docking\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe two-dimensional structures of the ligand molecules in SDF format were obtained from the PubChem database. Subsequently, Chem3D software (version 15.0) was employed to minimize the energy and convert the files into PDB format. For the protein receptor, its accession number (Reviewed, Human) was obtained from the UniProt database (https://www.uniprot.org/), after which the three-dimensional structure was downloaded in PDB format from the Protein Data Bank (https://www.rcsb.org/). Finally, PyMOL software (version 3.1.3.1) was utilized to eliminate extraneous ligands and water molecules prior to conducting the docking experiment. Molecular docking simulations were conducted utilizing AutoDock software (version 1.5.7)(Morris et al., 2009). The binding affinities between the active compounds and target proteins were evaluated, and the conformations of the ligand-receptor complexes exhibiting the lowest binding energies were visualized using PyMOL software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7 Extraction of flavonoids from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe fresh rhizome of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e was thoroughly cleaned and sliced after removing the fibrous roots. It was then dried at 50°C, pulverized, and sieved through a 60-mesh screen. Accurately weigh 1.00 g of the resulting powder and add 70% ethanol at a solid-liquid ratio of 1:20 (g/mL). Perform ultrasonic extraction at 60°C with a frequency of 40 kHz and power of 250 W for 50 minutes. After extraction, centrifuge the mixture at 4000 r/min for 5 minutes and collect the supernatant. The content of flavonoids in the supernatant was determined according to the method described in the literature(Chen et al., 2019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.8 Evaluation of the free radical scavenging capacity of flavonoids from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvaluation of free radical scavenging capacity of the flavonoids was conducted using DPPH and hydroxyl radical scavenging assays, following established protocols with minor modifications(Tao et al., 2022). Specifically, for the DPPH radical scavenging assay, 2.0 mL of flavonoid solutions at various concentrations (0, 2, 4, 8, 12, 16, and 20 μg/mL) were mixed with 2.0 mL of a 0.1 mM ethanolic DPPH solution. Deionized water was used as the blank control, while DPPH alone served as the background control. Absorbance (A) was measured at 517 nm after incubation in the dark for 20 minutes. For the hydroxyl radical scavenging assay, 1.0 mL of 6 mM ferrous sulfate solution and 1.0 mL of 6 mM salicylate alcohol solution were thoroughly mixed in a 10 mL cuvette, followed by the addition of 1.0 mL of 6 mM hydrogen peroxide solution and 1.0 mL of flavonoid solutions at varying concentrations. Deionized water was substituted for the flavonoid solution to serve as the blank control, and deionized water was substituted for the hydrogen peroxide solution to serve as the background control. Absorbance (A) was measured at 510 nm in a constant temperature water bath at 37°C for 30 minutes. In both assays, ascorbic acid at the same concentration was utilized as a positive control, and the clearance rate was calculated as follows.\u003c/p\u003e\n\u003cp\u003eClearance (%) = (1 – (A \u003csub\u003esample\u003c/sub\u003e – A \u003csub\u003eback\u003c/sub\u003e))/A \u003csub\u003eempty\u003c/sub\u003e\u003c/p\u003e"},{"header":"3.\tResults","content":"\u003cp\u003e\u003cstrong\u003e3.1 Active ingredients of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirty-eight chemical constituents of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e were retrieved from the TCMSP database. Following the application of screening criteria (OB \u0026ge; 30% and DL \u0026ge; 0.18), twelve active components of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e were identified. These compounds were further evaluated using pharmacokinetic parameters via the SwissADME web tool. Ultimately, nine compounds were confirmed as potential active ingredients. The detailed information regarding these compounds were presented in Table 1, and their structure were illustrated in Figure 1.\u003c/p\u003e\n\u003cp\u003eTable 1 Detailed information of screened ingredients from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecule ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecule Name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOB (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL000546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003ediosgenin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e80.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL004941\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003e(2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-one\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e71.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL002959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003e3\u0026apos;-Methoxydaidzein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e48.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL006331\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003e4\u0026apos;,5-Dihydroxyflavone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e48.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL009760\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003esibiricoside A_qt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL003889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003emethylprotodioscin_qt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL009766\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003ezhonghualiaoine 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e34.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL002714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003ebaicalein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eMOL001792\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 312px;\"\u003e\n \u003cp\u003eDFV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e32.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e3.2 Common targets of \u003cem\u003ePolygonati Rhizoma\u0026nbsp;\u003c/em\u003eand skin aging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive screening of the Swiss Target Prediction database identified 285 potential targets associated with \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e. Concurrently, using \u0026quot;skin aging\u0026quot; as the search term, we retrieved 679 relevant targets from the GeneCards database, 131 from the OMIM database, and 2 from the TDD database. After consolidating and de-duplicating these targets, a total of 800 unique targets related to skin aging were obtained. By intersecting the targets of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e with those related to skin aging, we identified 17 overlapping targets (Figure 2), which were designated as potential targets for further investigation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 GO enrichment analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThrough GO enrichment analysis of 17 target genes common to \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e and skin aging, a total of 94 GO terms were identified, comprising 56 biological processes (BP), 15 cellular components (CC), and 23 molecular functions (MF). Based on the p values and the number of enriched genes, the top 10 enriched BPs, CCs, and MFs were selected for visualization, as illustrated in Figure 3. The enriched BPs primarily encompassed signal transduction, positive and negative regulation of transcription by RNA polymerase II, among others. The CCs were predominantly associated with the nucleus, cytosol, and cytoplasm, while the MFs were largely related to protein binding, zinc ion binding, and metal ion binding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 KEGG pathway enrichment analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKEGG pathway analysis of the intersecting genes identified a total of 37 enriched pathways. Based on p values and the number of enriched genes, the top 20 pathways were categorized into four major groups: Environmental Information Processing, Cellular Processes, Organismal Systems, and Human Diseases (Figure 4). Key biological pathways included those related to cancer, TNF signaling, IL-17 signaling, lipid metabolism and atherosclerosis, as well as MicroRNAs in cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Construction and analysis of C-T-P network\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe C-T-P network was constructed using Cytoscape_v3.10.3 software, consisting of 52 nodes and 133 edges (Figure 5). The Centiscape2.2 plugin was employed to analyze the network based on degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC). Nodes with values less than the predefined threshold were filtered out, leading to two active components and six target proteins within the network (Table 2). The identified active components were MOL006331 (4\u0026apos;,5-Dihydroxyflavone) and MOL002714 (baicalein). The six target proteins were MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1.\u003c/p\u003e\n\u003cp\u003eTable 2 Key components, targets, and networks in the compounds-targets-pathways network.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Node name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eMOL006331\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e270.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eMOL002714\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e217.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eMAPK1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e716.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eMAPK10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e430.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eMMP9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e334.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003ePTGS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e296.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003ePDGFRB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e173.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eCYP1B1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e103.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003ePathways in cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e0.0093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e221.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 Molecular docking results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo key components (4\u0026apos;,5-dihydroxyflavone and baicalein) and six target proteins (MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1) were selected for molecular docking analysis. The results demonstrated that the binding energy between each receptor protein and the key components was negative (as shown in Table 3), indicating favorable interactions between the receptors and ligands. Among these receptors, MMP9, PTGS2, and CYP1B1 exhibited notably lower binding energy values with the ligands. The interactions between these three receptors and their respective ligands are presented in Figure 6. The findings reveal that hydrogen bonds were formed between all three proteins and their ligands. Specifically, MMP9 formed four and six hydrogen bonds with its ligand, PTGS2 formed one and nine hydrogen bonds, and CYP1B1 formed five and two hydrogen bonds, respectively.\u003c/p\u003e\n\u003cp\u003eTable 3 The binding energy of key components and target receptors.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"555\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 139px;\"\u003e\n \u003cp\u003eProtein name\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 78px;\"\u003e\n \u003cp\u003eGene name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003eUniprot ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 66px;\"\u003e\n \u003cp\u003ePDB ID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003eBinding Energy (kcal/mol) in Complex with Ligands\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4\u0026apos;,5-Dihydroxyflavone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003ebaicalein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eMitogen-activated protein kinase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eMAPK1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eP28482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1PME\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-6.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-6.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eMitogen-activated protein kinase 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eMAPK10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eP53779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4KKG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-6.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-6.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eMatrix metalloproteinase-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eMMP9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eP14780\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e1ITV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-7.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eProstaglandin G/H synthase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003ePTGS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eP35354\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5F19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-7.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-7.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003ePlatelet-derived growth factor receptor beta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003ePDGFRB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eP09619\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e2L6W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-7.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-6.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eCytochrome P450 1B1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eCYP1B1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eQ16678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3PM0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-7.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-7.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e3.7 Experimental verification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince both key active ingredients identified through network pharmacology and molecular docking belong to the flavonoids, we extracted \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e flavonoids and evaluate their capacity to scavenge free radicals. As shown in Figure 7, \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e flavonoids demonstrated significantly higher efficacy than ascorbic acid in scavenging DPPH and hydroxyl radicals. The IC50 values for the flavonoids were 1.06 \u0026plusmn; 0.01 \u0026micro;g/mL and 4.59 \u0026plusmn; 0.03 \u0026micro;g/mL, respectively. In contrast, the IC50 values for ascorbic acid were 2.67 \u0026plusmn; 0.02 \u0026micro;g/mL and 13.83 \u0026plusmn; 0.06 \u0026micro;g/mL, respectively. This indicates that \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e possess potent antioxidant properties and may serve as a promising candidate for skin anti-aging agents.\u003c/p\u003e"},{"header":"4.\tDiscussion ","content":"\u003cp\u003eIn recent years, phytomedicines have attracted considerable attention in pharmaceuticals and functional foods due to their natural origin and minimal side effects. As a traditional herbal plant, using of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e in cosmetic is an attractive strategy to against skin aging. It has been reported that \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e was effective in moisturizing and whitening the skin(Liu et al., 2017). These effects were primarily attributed to its active ingredients, such as polysaccharides and flavonoids. Specifically, \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e polysaccharides contain a large number of alcoholic hydroxyl groups that act as hydrogen donors, neutralizing reactive hydroxyl radicals in the body and thereby exerting an antioxidant effect(Yang et al., 2017). Additionally, the polysaccharides possess numerous hydrophilic groups capable of forming hydrogen bonds with water molecules, creating a hydration film on the skin surface and thus enhancing skin moisturization(Xiaowei et al., 2019). Furthermore, \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e polysaccharides can inhibit tyrosinase activity, reducing melanin production and contributing to skin whitening(Zhen et al., 2011). Besides polysaccharides, flavonoids also exhibit various anti-skin aging properties, including antioxidation, promotion of cell renewal, protection against UV damage, moisturization, and reduction of pigmentation(Xiao et al., 2011, Agati et al., 2012).\u003c/p\u003e\n\u003cp\u003eTo date, over 30 theories have been proposed to elucidate the molecular mechanisms underlying skin aging(Heng et al., 2017). Among these, reactive oxygen species (ROS) were recognized as playing a pivotal role by inducing the expression of metalloproteinases, which can destroy the integrity of the extracellular matrix and thereby contribute to wrinkle formation(Kammeyer and Luiten, 2015). Furthermore, ROS also capable of triggering inflammatory responses(Chung et al., 2001). Notably, our study has identified three key targets (MMP9, PTGS2, and CYP1B1) for anti-skin aging treatment using \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e. MMP9 is a metalloproteinase implicated in the degradation of the extracellular matrix, leading to the development of skin wrinkles(Inomata et al., 2003). PTGS2, a cyclooxygenase enzyme, plays a crucial role in inflammation-associated pathological processes(Martín-Vázquez et al., 2023). CYP1B1, a member of the cytochrome P450 superfamily with monooxygenase activity, is associated with mitochondrial dysfunction and ROS production, both of which are critical factors contributing to skin aging(Lu et al., 2021). Collectively, our findings may offer promising therapeutic targets for combating skin aging.\u003c/p\u003e\n\u003cp\u003eTwo small flavonoid compounds (4',5-dihydroxyflavone and baicalein) from \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e were screened for their potential to delay skin aging. Molecular docking analysis revealed that the binding energy of these compounds to skin aging targets were lower than -5 kcal/mol, indicating strong binding affinities(Zhou et al., 2016). Meanwhile, 4',5-dihydroxyflavone has been characterized as a collagenase inhibitor, thereby exhibiting anti-degradative properties(Nitulescu et al., 2022). Baicalein suppresses the expression of matrix metalloproteinase-1 and displays robust antioxidant effects against H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e-induced oxidative stress in HaCaT keratinocytes(Kim et al., 2012, Huang et al., 2019). In vitro experiments further confirmed that\u003cem\u003e Polygonati Rhizoma\u003c/em\u003e flavonoids possess potent antioxidant capacities. Collectively, 4',5-dihydroxyflavone and baicalein are promising candidates as active ingredients in anti-aging cosmetics.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study demonstrated that 4',5-dihydroxyflavone and baicalein in \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e can target MMP9, PTGS2, and CYP1B1, which are key proteins associated with skin aging, thereby contributing to the delay of skin aging. This research not only provide a foundation for a fully understanding of the molecular mechanisms underlying the anti-aging effects of \u003cem\u003ePolygonati Rhizoma \u003c/em\u003ebut also offers valuable insights into the development of novel anti-aging cosmetics.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWang Xilong was responsible for the conception and supervision of the study. Lei Qinzhen and Luo Xiaoyan contributed to the analysis of network pharmacology and molecular docking, respectively. Duo Xinyuan conducted the validation of the in vitro experiments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the Natural Science Foundation of Gansu Province (Grant No.23JRRM742), Longdong University Doctoral Science Foundation (Grant No. XYBYZK2216), and College Teachers' Innovation Fund of Gansu Provincial Education Department (Grant No. 2023B-209).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":" References","content":"\u003col\u003e\n \u003cli\u003eAgati G, Azzarello E, Pollastri S, Tattini M (2012) Flavonoids as antioxidants in plants: Location and functional significance. 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Ultrasonics Sonochemistry 34: 571-579\u003c/li\u003e\n \u003cli\u003eZhao P, Zhao C, Li X, Gao Q, Huang L, Xiao P, Gao W (2018) The genus Polygonatum : A review of ethnopharmacology, phytochemistry and pharmacology. Journal of Ethnopharmacology 214: 274-291\u003c/li\u003e\n \u003cli\u003eZhao X, Li J (2015) Chemical constituents of the genus Polygonatum and their role in medicinal treatment. Natural product communications 10: 683-691\u003c/li\u003e\n \u003cli\u003eZhen X, Mingyu Z, Yong C (2011) Progress on Study of Chinese Herbs in Anti-aging and Anti-freckle. Asia-Pacific Traditional Medicine 7: 160-162\u003c/li\u003e\n \u003cli\u003eZhou W, Wang J, Wu Z, Huang C, Lu A, Wang Y (2016) Systems pharmacology exploration of botanic drug pairs reveals the mechanism for treating different diseases. Scientific reports 6: 36985-37002\u003c/li\u003e\n \u003cli\u003eZhu X, Li Q, Lu F, Wang H, Yan S, Wang Q, Zhu W (2014) Antiatherosclerotic Potential of Rhizoma Polygonati Polysaccharide in Hyperlipidemia-induced Atherosclerotic Hamsters. Drug Research 65: 479-483\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Polygonati Rhizoma, 4',5-dihydroxyflavone, baicalein, anti-skin aging","lastPublishedDoi":"10.21203/rs.3.rs-6511835/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6511835/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003ePolygonati Rhizoma\u003c/em\u003ehas been reported to exhibit the ability to retard skin aging. However, the precise molecular mechanisms underlying remain largely elusive. In this study, we screened 9 active compounds in \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e using the TCMSP and SwissADME databases. Subsequently, 285 potential targets were identified via Swiss Target Prediction Database. Concurrently, 800 genes related to skin aging were retrieved from GeneCards, OMIM, and TTD databases. By intersecting these datasets with the potential targets of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e, we pinpointed 17 overlapping genes. These genes were further subjected to GO function annotation and KEGG pathway analysis using DAVID database. A compound-target-pathway network was then constructed using Cytoscape software, highlighting two compounds (4',5-dihydroxyflavone and baicalein) and six targets (MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1). Molecular docking revealed that the binding energy between 4',5-dihydroxyflavone and baicalein with the six targets was less than -5 kcal/mol, particularly for MMP9, PTGS2, and CYP1B1, indicating a stable interaction. Finally, \u003cem\u003ePolygonati Rhizoma \u003c/em\u003eflavonoids were isolated, and their antioxidant capacity was evaluated in vitro, confirming significant antioxidant activity. Collectively, our findings provide a systematic foundation for elucidating the molecular mechanisms underlying the anti-aging effects of \u003cem\u003ePolygonati Rhizoma\u003c/em\u003e and offer valuable insights into the development of anti-skin aging cosmetics.\u003c/p\u003e","manuscriptTitle":"Exploring the roles of Polygonati Rhizoma in delaying skin aging using network pharmacology and molecular docking","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-28 08:48:05","doi":"10.21203/rs.3.rs-6511835/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"94666b4b-08dd-414c-817a-9d71e5bd1082","owner":[],"postedDate":"April 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-18T01:45:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-28 08:48:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6511835","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6511835","identity":"rs-6511835","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}