Betulinic Acid-Enriched Dillenia indica L. Bark Extract Attenuates UVB-Induced Skin Aging via KEAP1-Mediated Antioxidant Pathways
Abstract
1. Introduction
2. Materials and Methods
2.1. Molecular Docking and Molecular Dynamics Simulations
2.2. Preparation of Sample
2.3. Experimental Design and Statistical Optimization via RSM
2.4. Predictive Modeling of Extraction Outcomes Using ANN
2.5. Determination of TPC and TFC
2.6. Structural Characterization of Extract Constituents via ESI-MS/MS
2.7. In Vitro Simulated Digestion
2.8. Elastase Inhibition Assay
2.9. Cell-Free Antioxidant Assays
2.10. UVB-Induced ROS Measurement and Western Blot Analysis
2.11. HO-1 Protein Quantification Using Enzyme-Linked Immunosorbent Assay (ELISA)
2.12. Statistical Analysis
3. Results
3.1. Molecular Docking of BA with KEAP1
3.2. Structural Dynamics of KEAP1 Complexes via MD Simulation
3.3. Extraction Behavior and RSM-Based Optimization of Phenolic and Flavonoid Compounds from Dillenia indica L. Bark
3.4. Predictive Modeling Using ANN
3.5. Comparative Analysis of RSM and ANN Models
3.6. ESI-MS/MS-Based Metabolite Profiling of ODB
3.7. Identification and Significance of BA
3.8. Effect of Simulated Digestion on Antioxidant and Elastase Inhibitory Activities of ODB
3.9. Antioxidant Mechanism Through Nrf2 Activation and ROS Suppression
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ANN | Artificial Neural Network |
ABTS | 2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) |
CUPRAC | Cupric Ion Reducing Antioxidant Capacity |
DCF-DA | 2′,7′-Dichlorofluorescin diacetate |
DPPH | 2,2-Diphenyl-1-picrylhydrazyl |
EGCG | Epigallocatechin gallate |
ELISA | Enzyme-Linked Immunosorbent Assay |
ESI-MS/MS | Electrospray Ionization Tandem Mass Spectrometry |
FRAP | Ferric Reducing Antioxidant Power |
HO-1 | Heme Oxygenase-1 |
HRP | Horseradish Peroxidase |
KEAP1 | Kelch-like ECH-Associated Protein 1 |
MD | Molecular Dynamics |
ODB | Optimized Dillenia indica L. Bark extract |
p-Nrf2 | Phosphorylated Nuclear factor erythroid 2–related factor 2 |
Rg | Radius of gyration |
RMSD | Root Mean Square Deviation |
RMSF | Root Mean Square Fluctuation |
ROS | Reactive Oxygen Species |
RSM | Response Surface Methodology |
SASA | Solvent-Accessible Surface Area |
SGF | Simulated Gastric Fluid |
SIF | Simulated Intestinal Fluid |
SSF | Simulated Salivary Fluid |
TFC | Total Flavonoid Content |
TPC | Total Phenolic Content |
UVB | Ultraviolet B |
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Run | Independent Variables | Response | |||||||
---|---|---|---|---|---|---|---|---|---|
Temp (°C) (X1) | Time (min) (X2) | EC (%) (X3) | TPC (mg GAE/g) (Y1) | TFC (mg CE/g) (Y2) | |||||
RSM (pred) | ANN (pred) | Experimental | RSM (pred) | ANN (pred) | Experimental | ||||
1 | 45 | 45 | 95 | 76.59 | 77.15 | 77.15 ± 0.85 | 63.53 | 65.56 | 63.62 ± 1.05 |
2 | 60 | 30 | 80 | 76.19 | 75.57 | 75.57 ± 0.47 | 60.11 | 62.20 | 60.25 ± 0.22 |
3 | 20 | 45 | 60 | 76.05 | 75.34 | 76.62 ± 3.09 | 65.63 | 64.00 | 65.99 ± 1.01 |
4 | 60 | 30 | 40 | 78.25 | 79.38 | 79.38 ± 0.79 | 62.02 | 62.81 | 62.31 ± 0.25 |
5 | 30 | 60 | 40 | 76.00 | 77.11 | 76.82 ± 1.88 | 60.36 | 61.27 | 60.16 ± 0.19 |
6 | 30 | 60 | 80 | 79.16 | 78.23 | 78.23 ± 0.86 | 65.83 | 65.38 | 65.47 ± 0.49 |
7 | 60 | 60 | 80 | 78.32 | 79.13 | 79.13 ± 2.01 | 63.80 | 62.27 | 63.82 ± 1.00 |
8 | 45 | 45 | 60 | 81.92 | 81.98 | 81.77 ± 4.34 | 73.59 | 73.02 | 73.01 ± 0.56 |
9 | 45 | 45 | 60 | 81.92 | 81.98 | 81.53 ± 4.52 | 73.59 | 73.02 | 73.57 ± 1.01 |
10 | 60 | 60 | 40 | 75.56 | 75.82 | 75.82 ± 2.20 | 67.06 | 67.94 | 67.01 ± 0.19 |
11 | 45 | 20 | 60 | 76.28 | 76.47 | 76.48 ± 1.83 | 63.79 | 63.15 | 63.55 ± 1.06 |
12 | 30 | 30 | 40 | 75.42 | 74.81 | 74.81 ± 1.50 | 61.37 | 62.31 | 61.30 ± 0.15 |
13 | 70 | 45 | 60 | 77.71 | 76.99 | 76.86 ± 1.74 | 64.48 | 63.51 | 64.23 ± 0.39 |
14 | 45 | 45 | 60 | 81.92 | 81.98 | 82.68 ± 0.41 | 73.59 | 73.02 | 73.47 ± 0.94 |
15 | 45 | 45 | 60 | 81.92 | 81.98 | 81.49 ± 1.66 | 73.59 | 73.02 | 73.74 ± 1.02 |
16 | 45 | 45 | 60 | 81.92 | 81.98 | 82.48 ± 0.42 | 73.59 | 73.02 | 73.52 ± 1.00 |
17 | 45 | 45 | 25 | 75.63 | 74.81 | 74.80 ± 0.18 | 60.40 | 61.28 | 60.40 ± 0.09 |
18 | 30 | 30 | 80 | 73.76 | 73.69 | 73.69 ± 2.11 | 68.20 | 69.01 | 68.20 ± 1.09 |
19 | 45 | 45 | 60 | 81.92 | 81.98 | 81.61 ± 0.57 | 73.59 | 73.02 | 73.47 ± 0.99 |
20 | 45 | 70 | 60 | 78.53 | 78.05 | 78.05 ± 1.39 | 66.01 | 66.49 | 66.35 ± 0.49 |
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Song, B.-R.; Kim, S.; Lee, S.-H. Betulinic Acid-Enriched Dillenia indica L. Bark Extract Attenuates UVB-Induced Skin Aging via KEAP1-Mediated Antioxidant Pathways. Antioxidants 2025, 14, 1144. https://doi.org/10.3390/antiox14091144
Song B-R, Kim S, Lee S-H. Betulinic Acid-Enriched Dillenia indica L. Bark Extract Attenuates UVB-Induced Skin Aging via KEAP1-Mediated Antioxidant Pathways. Antioxidants. 2025; 14(9):1144. https://doi.org/10.3390/antiox14091144
Chicago/Turabian StyleSong, Bo-Rim, Sunghwan Kim, and Sang-Han Lee. 2025. "Betulinic Acid-Enriched Dillenia indica L. Bark Extract Attenuates UVB-Induced Skin Aging via KEAP1-Mediated Antioxidant Pathways" Antioxidants 14, no. 9: 1144. https://doi.org/10.3390/antiox14091144
APA StyleSong, B.-R., Kim, S., & Lee, S.-H. (2025). Betulinic Acid-Enriched Dillenia indica L. Bark Extract Attenuates UVB-Induced Skin Aging via KEAP1-Mediated Antioxidant Pathways. Antioxidants, 14(9), 1144. https://doi.org/10.3390/antiox14091144