Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury
Abstract
1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Animals
2.3. Network Pharmacology
2.3.1. Prediction and Screening of Potential Targets for ST in ALI
2.3.2. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) Enrichment Analyses
2.3.3. Molecular Docking
2.4. Preparation and Characterization of ST DPI
2.4.1. Ultrasonic-Assisted Antisolvent Preparation of ST DPI
2.4.2. Characterization of ST DPI
2.4.3. In Vitro Deposition Study
2.5. Pharmacokinetic Study
2.6. Pharmacodynamic Evaluation of ST DPI in ALI
2.6.1. In Vitro Anti-Inflammatory Analysis
2.6.2. Pharmacodynamic Study
3. Results and Discussion
3.1. Predicting Targets for ST in ALI Treatment via Network Pharmacology
3.1.1. Target Prediction, Screening, and the PPI Network
3.1.2. GO Biological Function and KEGG Enrichment Analysis
3.1.3. Molecular Docking Simulation
3.2. Powder Characteristics of ST DPI
3.2.1. Powder Characterization
3.2.2. Aerodynamic Particle Size Distribution
3.3. Pharmacokinetic Analysis
3.3.1. Pharmacokinetics of ST Intravenous and Inhaled Administration
3.3.2. Pharmacokinetic Parameters of ST
3.3.3. Discussion of ST Pseudo-Absorption Peak
3.4. Pharmacodynamics of ST in the Treatment of ALI
3.4.1. Anti-Inflammatory Effects of ST at the Cellular Level
3.4.2. Lung Wet–Dry Weight Ratio and Lung Histopathological Observation and Score
3.4.3. Levels of Inflammatory Factors and Oxidative Factors
3.4.4. WB Validates the Mechanism of ST in ALI: The Positive Feedback of the MAPK Pathway on Cell Apoptosis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ALI | Acute lung injury |
ST | Sinapine thiocyanate |
DPI | Dry powder inhaler |
SSA | Sinapis Semen Albae |
LPS | Lipopolysaccharides |
PBS | Phosphate-buffered saline |
IL-1β | Interleukin-1β |
IL-6 | Interleukin-6 |
TNF-α | Tumor necrosis factor-α |
NF-κB | Nuclear factor kappa-B |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
JNK1 | C-Jun N-terminal kinase 1 |
MEKK1 | MAPK kinase kinase 1 |
p38 | p38 mitogen-activated protein kinase |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
IACUC | Institutional Animal Care and Use Committee |
PPI | Protein–protein interaction |
BP | Biological process |
CC | Cellular component |
MF | Molecular function |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
GO | Gene Ontology |
SEM | Scanning electron microscopy |
TGA | Thermal gravimetric analyzer |
DSC | Differential scanning calorimetry |
DVS | Dynamic moisture adsorption |
XRD | X-ray diffractometer |
FTIR | Fourier transform infrared |
FPD | Fine particle dose |
ED | Emitted dose |
FPF | Fine particle fraction |
MMAD | Median aerodynamic diameter |
GSD | Geometric standard deviation |
DDU | Delivered dose uniformity |
WB | Western blot |
References
- Chen, Y.; Li, X.; Xiao, K.; Dou, Z.; Wang, Y.; Lu, Y.; Jia, Y. A Textual Research on the Main Drug of Sanfutie, Semen Sinapis Albae. China’s Naturop. 2022, 30, 74–76. [Google Scholar] [CrossRef]
- Wu, Y.; Dai, Z.; Chen, X.; Luo, Y. Textual Research on Materia Medica of Sinapis Semen. China Mod. Med. 2022, 29, 28–30. [Google Scholar] [CrossRef]
- Dang, R.; Guan, H.D.; Wang, C.H. Sinapis Semen: A Review on Phytochemistry, Pharmacology, Toxicity, Analytical Methods and Pharmacokinetics. Front. Pharmacol. 2023, 14, 1113583. [Google Scholar] [CrossRef]
- Liu, Y.; Yin, H.L.; Li, C.; Jiang, F.; Zhang, S.J.; Zhang, X.R.; Li, Y.L. Sinapine Thiocyanate Ameliorates Vascular Endothelial Dysfunction in Hypertension by Inhibiting Activation of the NLRP3 Inflammasome. Front. Pharmacol. 2021, 11, 620159. [Google Scholar] [CrossRef]
- Shi, J.; Song, X.; Liu, X.; Chen, H.; Yang, X.; Yang, S.; Shen, L.; Wan, K. Pharmacodynamic Study of Sinapine Thiocyanate Dissoluble Microneedle for Acupoint Administration Against Bronchial Asthma. China Pharm. 2022, 33, 2728–2732. [Google Scholar] [CrossRef]
- Shi, Y. Effect of White Mustard Seed on Attenuating Antioxidation and Aβ Toxicityin the C.elegan. Master’s Thesis, Hubei University of Traditional Chinese Medicine, Wuhan, China, 2023. [Google Scholar]
- Li, M.; Qi, J.; Wu, Q.; Liu, L. Study on the Scavenging Effect of Superoxide Free Radicals by Sinapine Cyanide Sulfonafe. Chin. Wild Plant Resour. 2012, 31, 11–12. [Google Scholar] [CrossRef]
- Guan, H.D.; Lin, Q.Y.; Ma, C.; Ju, Z.C.; Wang, C.H. Metabolic Profiling and Pharmacokinetic Studies of Sinapine Thiocyanate by UHPLC-Q/TOF-MS and UHPLC-MS/MS. J. Pharm. Biomed. Anal. 2022, 207, 114431. [Google Scholar] [CrossRef]
- Mokra, D.; Kosutova, P. Biomarkers in Acute Lung Injury. Respir. Physiol. Neurobiol. 2015, 209, 52–58. [Google Scholar] [CrossRef]
- Liu, D.J.; Weng, S.Y.; Fu, C.J.; Guo, R.J.; Chen, M.; Shi, B.B.; Weng, J.T. Autophagy in Acute Lung Injury. Cell Biochem. Biophys. 2024, 83, 1415–1425. [Google Scholar] [CrossRef]
- Mokra, D. Acute Lung Injury—From Pathophysiology to Treatment. Physiol. Res. 2020, 69, 353–366. [Google Scholar] [CrossRef]
- Imai, Y.; Kuba, K.; Neely, G.G.; Yaghubian-Malhami, R.; Perkmann, T.; van Loo, G.; Ermolaeva, M.; Veldhuizen, R.; Leung, Y.H.; Wang, H.; et al. Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury. Cell 2008, 133, 35–49. [Google Scholar] [CrossRef]
- Kellner, M.; Noonepalle, S.; Lu, Q.; Srivastava, A.; Zemskov, E.; Black, S.M. ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). Adv. Exp. Med. Biol. 2017, 967, 105–137. [Google Scholar] [CrossRef] [PubMed]
- Lewis, S.R.; Pritchard, M.W.; Thomas, C.M.; Smith, A.F. Pharmacological Agents for Adults with Acute Respiratory Distress Syndrome. Cochrane Database Syst. Rev. 2019, 7, CD004477. [Google Scholar] [CrossRef] [PubMed]
- Nanchal, R.S.; Truwit, J.D. Recent Advances in Understanding and Treating Acute Respiratory Distress Syndrome. F1000Research 2018, 7, 1322. [Google Scholar] [CrossRef]
- Mokra, D.; Mikolka, P.; Kosutova, P.; Mokry, J. Corticosteroids in Acute Lung Injury: The Dilemma Continues. Int. J. Mol. Sci. 2019, 20, 4765. [Google Scholar] [CrossRef]
- Zhang, J.Q.; Ge, P.; Liu, J.; Luo, Y.L.; Guo, H.Y.; Zhang, G.X.; Xu, C.M.; Chen, H.L. Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: An Overview on Mechanistic Insights and Clinical Benefit. Int. J. Mol. Sci. 2023, 24, 12138. [Google Scholar] [CrossRef]
- Spies, C.M.; Strehl, C.; van der Goes, M.C.; Bijlsma, J.W.J.; Buttgereit, F. Glucocorticoids. Best Pract. Res. Clin. Rheumatol. 2011, 25, 891–900. [Google Scholar] [CrossRef]
- Qiao, Q.; Li, X.N.; Ou, X.J.; Liu, X.; Fu, C.S.; Wang, Y.; Niu, B.N.; Kong, L.; Yang, C.L.; Zhang, Z.P. Hybrid Biomineralized Nanovesicles to Enhance Inflamed Lung Biodistribution and Reduce Side Effect of Glucocorticoid for Ards Therapy. J. Control. Release 2024, 369, 746–764. [Google Scholar] [CrossRef]
- Jin, Y.; Li, M. Pulmonary Drug Delivery Systems and Progress in Their Applications to Lung Disease Treatment. J. Int. Pharm. Res. 2015, 42, 289–295. [Google Scholar] [CrossRef]
- Velaga, S.P.; Djuris, J.; Cvijic, S.; Rozou, S.; Russo, P.; Colombo, G.; Rossi, A. Dry Powder Inhalers: An Overview of the In Vitro Dissolution Methodologies and Their Correlation with the Biopharmaceutical Aspects of the Drug Products. Eur. J. Pharm. Sci. 2018, 113, 18–28. [Google Scholar] [CrossRef]
- Zhang, Y.; Hu, X.; Yu, M.; Wang, D. Advance in Dry Powder Inhalants. Chin. J. Pharm. 2020, 18, 296–303. [Google Scholar] [CrossRef]
- Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; et al. Tcmsp: A Database of Systems Pharmacology for Drug Discovery from Herbal Medicines. J. Cheminform. 2014, 6, 13. [Google Scholar] [CrossRef] [PubMed]
- Daina, A.; Michielin, O.; Zoete, V. Swisstargetprediction: Updated Data and New Features for Efficient Prediction of Protein Targets of Small Molecules. Nucleic Acids Res. 2019, 47, 357–364. [Google Scholar] [CrossRef]
- Smith, K.M.; Mrozek, J.D.; Simonton, S.C.; Bing, D.R.; Meyers, P.A.; Connett, J.E.; Mammel, M.C. Prolonged Partial Liquid Ventilation Using Conventional and High-Frequency Ventilatory Techniques: Gas Exchange and Lung Pathology in an Animal Model of Respiratory Distress Syndrome. Crit. Care Med. 1997, 25, 88–97. [Google Scholar] [CrossRef]
- Li, S.X.; Wang, K.; Jiang, K.; Xing, D.M.; Deng, R.H.; Xu, Y.; Ding, Y.; Guan, H.D.; Chen, L.L.; Wang, D.D.; et al. Brazilin-Ce Nanoparticles Attenuate Inflammation by De/ Anti-phosphorylation of IKKβ. Biomaterials 2024, 305, 122466. [Google Scholar] [CrossRef]
- Spalinger, M.R.; Schwarzfischer, M.; Scharl, M. The Role of Protein Tyrosine Phosphatases in Inflammasome Activation. Int. J. Mol. Sci. 2020, 21, 5481. [Google Scholar] [CrossRef]
- Su, Z.; Burchfield, J.G.; Yang, P.; Humphrey, S.J.; Yang, G.; Francis, D.; Yasmin, S.; Shin, S.Y.; Norris, D.M.; Kearney, A.L.; et al. Global Redox Proteome and Phosphoproteome Analysis Reveals Redox Switch in Akt. Nat. Commun. 2019, 10, 5486. [Google Scholar] [CrossRef]
- Ke, J.M.; Li, S.; Zi, M.M.; Zhang, J.; Huang, S.; Luo, W.H.; Han, H.L.; Zhang, J.W.; Peng, C. Preparation, Quality Evaluation and Preliminary Pharmacokinetic-Pharmacodynamic Studies of Synephrine Dry Powder Inhaler. Drug Deliv. 2025, 32, 2486346. [Google Scholar] [CrossRef]
- Lu, P.; Li, J.W.; Liu, C.X.; Yang, J.; Peng, H.; Xue, Z.F.; Liu, Z.D. Salvianolic Acid B Dry Powder Inhaler for the Treatment of Idiopathic Pulmonary Fibrosis. Asian J. Pharm. Sci. 2022, 17, 447–461. [Google Scholar] [CrossRef]
- Singh, G. Resveratrol: Nanocarrier-based delivery systems to enhance its therapeutic potential. Nanomedicine 2020, 15, 2801–2817. [Google Scholar] [CrossRef]
- Kim, T.H.; Shin, S.; Landersdorfer, C.B.; Chi, Y.H.; Paik, S.H.; Myung, J.; Yadav, R.; Horkovics-Kovats, S.; Bulitta, J.B.; Shin, B.S. Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans. AAPS J. 2015, 17, 1210–1223. [Google Scholar] [CrossRef] [PubMed]
- Kim, T.H.; Shin, S.; Bashir, M.; Chi, Y.H.; Paik, S.H.; Lee, J.H.; Choi, H.J.; Choi, J.H.; Yoo, S.D.; Bulitta, J.B.; et al. Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats. Xenobiotica 2014, 44, 913–925. [Google Scholar] [CrossRef] [PubMed]
- Hu, Y.; Sheng, Y.; Liu, P.; Sun, J.; Tang, L. The pharmacokinetics and tissue distribution of curcumin following inhalation administration in rats-A comparative analysis with oral and intravenous routes. Biomed. Chromatogr. 2024, 38, e6003. [Google Scholar] [CrossRef]
- Sun, Q.; Liang, J.; Zhang, Q.; Wang, X.; Zhao, N.; Meng, F. Pharmacokinetics and Tissue Distribution of Itampolin A following Intragastric and Intravenous Administration in Rats Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry. Molecules 2024, 29, 2652. [Google Scholar] [CrossRef]
- Lee, J.B.; Zhou, S.; Chiang, M.; Zang, X.; Kim, T.H.; Kagan, L. Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling. Biopharm. Drug Dispos. 2020, 41, 192–205. [Google Scholar] [CrossRef]
- Guo, X.; Lu, H.; Lin, Y.; Chen, B.; Wu, C.; Cui, Z.; Wang, Y.; Xu, Y. Skin penetration of topically applied white mustard extract and its effects on epidermal Langerhans cells and cytokines. Int. J. Pharm. 2013, 457, 136–142. [Google Scholar] [CrossRef]
- Farkhondeh, T.; Mehrpour, O.; Buhrmann, C.; Pourbagher-Shahri, A.M.; Shakibaei, M.; Samarghandian, S. Organophosphorus Compounds and MAPK Signaling Pathways. Int. J. Mol. Sci. 2020, 21, 4258. [Google Scholar] [CrossRef]
- Yue, J.C.; López, J.M. Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci. 2020, 21, 2346. [Google Scholar] [CrossRef]
- Yi, Y.J.; Zhou, B.; Man, T.J.; Xu, Z.H.; Tang, H.; Li, J.; Sun, Z. Resveratrol Inhibits Nasopharyngeal Carcinoma (NPC) by Targeting the MAPK Signaling Pathway. Anti-Cancer Agents Med. Chem. 2024, 24, 1207–1219. [Google Scholar] [CrossRef]
- Kabe, Y.; Ando, K.; Hirao, S.; Yoshida, M.; Handa, H. Redox Regulation of Nf-Kappab Activation: Distinct Redox Regulation between the Cytoplasm and the Nucleus. Antioxid. Redox Signal. 2005, 7, 395–403. [Google Scholar] [CrossRef]
- Deshmukh, P.; Unni, S.; Krishnappa, G.; Padmanabhan, B. The Keap1-Nrf2 Pathway: Promising Therapeutic Target to Counteract Ros-Mediated Damage in Cancers and Neurodegenerative Diseases. Biophys. Rev. 2017, 9, 41–56. [Google Scholar] [CrossRef] [PubMed]
- Lyu, T.; Cheng, S.; Yang, D.; Li, D. Targeted Intervention of Traditional Chinese Medicine in Pulmonary Diseases based on p38MAPK Signaling Pathway. Guid. J. Tradit. Chin. Med. Pharm. 2020, 26, 129–132. [Google Scholar] [CrossRef]
- Fulmer, G.R.; Miller, A.J.M.; Sherden, N.H.; Gottlieb, H.E.; Nudelman, A.; Stoltz, B.M.; Bercaw, J.E.; Goldberg, K.I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29, 2176–2179. [Google Scholar] [CrossRef]
- Gottlieb, H.E.; Kotlyar, V.; Nudelman, A. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities. J. Org. Chem. 1997, 62, 7512–7515. [Google Scholar] [CrossRef] [PubMed]
Parameters | α | β | γ | A | B | D |
---|---|---|---|---|---|---|
Intravenous | 2.92 ± 0.88 | 0.39 ± 0.23 | 0.12 ± 0.09 | −70.71 ± 41.48 | 4.57 ± 182.80 | 66.14 ± 169.74 |
Inhaled | 3.02 ± 0.70 | 0.11 ± 0.29 | 0.23 ± 0.25 | −26.43 ± 15.64 | 12.40 ± 15.25 | 14.04 ± 18.10 |
Parameter | Intragastric | Inhaled | Intravenous |
---|---|---|---|
AUC0–t (μg/L·h) | 41.44 ± 23.86 | 111.7 ± 63.42 | 135.5 ± 38.37 |
AUC0–∞ (μg/L·h) | 43.27 ± 23.62 | 114.8 ± 62.98 | 145.1 ± 41.28 |
MRT0–t (h) | 5.574 ± 0.796 | 6.386 ± 1.799 | 3.033 ± 0.267 |
MRT0–∞ (h) | 7.273 ± 2.044 | 8.03 ± 2.859 | 4.105 ± 0.615 |
t1/2 (h) | 4.830 ± 2.337 | 4.433 ± 1.391 | 2.345 ± 0.684 |
Tmax (h) | 2.167 ± 1.472 | 1.833 ± 1.169 | 0.958 ± 0.102 |
Cmax (μg/L) | 8.74 ± 5.359 | 21.48 ± 15.02 | 41.30 ± 11.12 |
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Li, Z.; Wang, C.; Xu, H.; Wu, Q.; Peng, N.; Zhang, L.; Wang, H.; Wu, L.; Li, Z.; Yang, Q.; et al. Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury. Pharmaceutics 2025, 17, 909. https://doi.org/10.3390/pharmaceutics17070909
Li Z, Wang C, Xu H, Wu Q, Peng N, Zhang L, Wang H, Wu L, Li Z, Yang Q, et al. Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury. Pharmaceutics. 2025; 17(7):909. https://doi.org/10.3390/pharmaceutics17070909
Chicago/Turabian StyleLi, Zixin, Caifen Wang, Huipeng Xu, Qian Wu, Ningning Peng, Lu Zhang, Hui Wang, Li Wu, Zegeng Li, Qinjun Yang, and et al. 2025. "Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury" Pharmaceutics 17, no. 7: 909. https://doi.org/10.3390/pharmaceutics17070909
APA StyleLi, Z., Wang, C., Xu, H., Wu, Q., Peng, N., Zhang, L., Wang, H., Wu, L., Li, Z., Yang, Q., & Zhang, J. (2025). Three-Compartment Pharmacokinetics of Inhaled and Injected Sinapine Thiocyanate Manifest Prolonged Retention and Its Therapeutics in Acute Lung Injury. Pharmaceutics, 17(7), 909. https://doi.org/10.3390/pharmaceutics17070909