Investigation of the Molecular Mechanisms Underlying the Therapeutic
Effect of Perilla frutescens L. Essential Oil on Acute Lung Injury Using
Gas Chromatography-Mass Spectrometry and Network Pharmacology

Hou      Chen; Lu      Bai; Yanqiong      Shi; Xiaofei      Zhang; Xuan      Wang; Yujiao      Wang; Jiadong      Hu; Peijie      Zhou

doi:10.2174/0113862073244521231003071900

Abstract

Objective: The present study aimed to investigate the molecular mechanism through which Perilla essential oil treats acute lung injury (ALI) through network pharmacology, molecular docking, and in vitro assays.

Methods: Relevant ALI targets of the active ingredients of Perilla essential oil were predicted using the SwissTargetPrediction database and meta TarFisher database. These ALI targets were then screened using GeneCards and DisGeNET, and differentially expressed ALI target genes were identified using the Gene Expression Omnibus (GEO) database. Next, key targets were enriched using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction network analysis was performed to obtain targets with the highest degree values for molecular docking with Perilla essential oil active ingredients. For in vitro experiments, lipopolysaccharide (LPS) was used to induce an ALI inflammation model using RAW264.7 cells. The model cells were then treated with Perilla essential oil to detect the protein expression levels of vascular endothelial factor (NO), tumor necrosis factor (TNF-α), and p65 nuclear transcription factor in them.

Results: Sixty-eight key targets of Perilla oil were identified for the treatment of ALI. These targets were found to be involved in biological processes related to peptides, response to lipopolysaccharides, the positive regulation of cytokine production, etc., using GO. The signaling pathways found to be associated with the targets included the AGE-RAGE signaling pathway in diabetic complications, the NF-kappa B signaling pathway, and small cell lung cancer and other inflammatory signaling pathways. The five key targets that showed good binding activity with Perilla oil active ingredients included TNF, RELA, PARP1, PTGS2, and IRAK4. In vitro assays showed that Perilla essential oil could significantly reduce NO and TNF-α levels and inhibit the phosphorylation of nuclear transcription factor P65, thus inhibiting the activation of NF-κB signaling pathway.

Conclusion Perilla essential oil can play a role in the treatment of ALI by inhibiting the activation of the NF-κB signaling pathway and preventing an excessive inflammatory response. This study thus provides a reference for the in-depth study of the mechanisms through which Perilla essential oil treats ALI.

« Previous Next »

Graphical Abstract

[1]
Wang, Y.; Yuan, Y.; Wang, W.; He, Y.; Zhong, H.; Zhou, X.; Chen, Y.; Cai, X.J.; Liu, L. Mechanisms underlying the therapeutic effects of Qingfeiyin in treating acute lung injury based on GEO datasets, network pharmacology and molecular docking. Comput. Biol. Med.,  2022, 145, 105454.
 [http://dx.doi.org/10.1016/j.compbiomed.2022.105454] [PMID: 35367781]

[2]
Zhu, H.; Wang, S.; Shan, C.; Li, X.; Tan, B.; Chen, Q.; Yang, Y.; Yu, H.; Yang, A. Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach. Respir. Res.,  2021, 22(1), 188.
 [http://dx.doi.org/10.1186/s12931-021-01781-1] [PMID: 34183011]

[3]
Qi, J.J. Effects of cold exposure on TLR4/NF-κB signaling pathway in mice with endotoxic acute lung injury; Yanbian University, 2020. 

[4]
Wang, H.F. Mechanisms of NLRP1 inflammatory vesicles via TLR4/NF-кB pathway in acute lung injury; Hainan Medical College, 2022. 

[5]
Fan, E.; Brodie, D.; Slutsky, A.S. Acute respiratory distress syndrome. JAMA,  2018, 319(7), 698-710.
 [http://dx.doi.org/10.1001/jama.2017.21907] [PMID: 29466596]

[6]
Jiao, R.; Han, Z.; Ma, J.; Wu, S.; Wang, Z.; Zhou, G.; Liu, X.; Li, J.; Yan, X.; Meng, A. Irisin attenuates fine particulate matter induced acute lung injury by regulating Nod2/NF-κB signaling pathway. Immunobiology,  2023, 228(3), 152358.
 [http://dx.doi.org/10.1016/j.imbio.2023.152358] [PMID: 37003140]

[7]
Zhou, Q.; He, D.X.; Deng, Y.L.; Wang, C.L.; Zhang, L.L.; Jiang, F.M.; Irakoze, L.; Liang, Z.A. MiR-124-3p targeting PDE4B attenuates LPS-induced ALI through the TLR4/NF-κB signaling pathway. Int. Immunopharmacol.,  2022, 105, 108540.
 [http://dx.doi.org/10.1016/j.intimp.2022.108540] [PMID: 35063752]

[8]
Zhou, P.; Wang, X.; Zhao, Y.; She, X.; Jia, Y.; Wang, W.; Li, J.; Luo, X. Evaluation of the mechanism of action of rosemary volatile oil in the treatment of Alzheimer’s disease using gas chromatography-mass spectrometry analysis and network pharmacology. Comb. Chem. High Throughput Screen.,  2023, 26(13), 2321-2332.
 [http://dx.doi.org/10.2174/1386207325666220930091758] [PMID: 36200249]

[9]
Li, S.; Zhang, B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin. J. Nat. Med.,  2013, 11(2), 110-120.
 [http://dx.doi.org/10.1016/S1875-5364(13)60037-0] [PMID: 23787177]

[10]
Mutlu-Ingok, A.; Devecioglu, D.; Dikmetas, D.N.; Karbancioglu-Guler, F.; Capanoglu, E. Antibacterial, antifungal, antimycotoxigenic, and antioxidant activities of essential oils: An updated review. Molecules,  2020, 25(20), 4711.
 [http://dx.doi.org/10.3390/molecules25204711] [PMID: 33066611]

[11]
Lucca, L.G.; Romão, P.R.T.; Vignoli-Silva, M.; da Veiga-Junior, V.F.; Koester, L.S. In vivo acute anti-inflammatory activity of essential oils: A review. Mini Rev. Med. Chem.,  2022, 22(11), 1495-1515.
 [http://dx.doi.org/10.2174/1389557521666211123091541] [PMID: 34814816]

[12]
de Andrade, T.; Brasil, G.; Endringer, D.; da Nóbrega, F.; de Sousa, D. Cardiovascular activity of the chemical constituents of essential oils. Molecules,  2017, 22(9), 1539.
 [http://dx.doi.org/10.3390/molecules22091539] [PMID: 28926969]

[13]
Amorati, R.; Foti, M.C.; Valgimigli, L. Antioxidant activity of essential oils. J. Agric. Food Chem.,  2013, 61(46), 10835-10847.
 [http://dx.doi.org/10.1021/jf403496k] [PMID: 24156356]

[14]
de Sousa, D.; Silva, R.; Silva, E.; Gavioli, E. Essential oils and their constituents: An alternative source for novel antidepressants. Molecules,  2017, 22(8), 1290.
 [http://dx.doi.org/10.3390/molecules22081290] [PMID: 28771213]

[15]
Gioffrè, G.; Ursino, D.; Labate, C.; Giuffrè, A. The peel essential oil composition of bergamot fruit (Citrus bergamia, Risso) of Reggio Calabria (Italy): A review. Emir. J. Food Agric.,  2021, 32, 835-845.

[16]
Said-Al Ahl, H.A.H.; Sabra, A.S.; Gendy, A.S.H.; Astatkie, T. Essential oil content and concentration of constituents of lemon balm (melissa officinalis L.) at different harvest dates. J. Essent. Oil-Bear. Plants,  2018, 21(5), 1410-1417.
 [http://dx.doi.org/10.1080/0972060X.2018.1553636]

[17]
Verzera, A.; Russo, C.; Rosa, G.L.; Bonaccorsi, I.; Cotroneo, A. Influence of cultivar on lemon oil composition. J. Essent. Oil Res.,  2001, 13(5), 343-347.
 [http://dx.doi.org/10.1080/10412905.2001.9712228]

[18]
Donelian, A.; Carlson, L.H.C.; Lopes, T.J.; Machado, R.A.F. Comparison of extraction of patchouli (Pogostemon cablin) essential oil with supercritical CO2 and by steam distillation. J. Supercrit. Fluids,  2009, 48(1), 15-20.
 [http://dx.doi.org/10.1016/j.supflu.2008.09.020]

[19]
Ebrahimi, S.; Paryad, E.; Ghanbari Khanghah, A.; Pasdaran, A.; Kazemnezhad Leili, E.; Sadeghi Meibodi, A.M. The effects of lavandula aromatherapy on pain relief after coronary artery bypass graft surgery: A randomized clinical trial. Appl. Nurs. Res.,  2022, 68, 151638.
 [http://dx.doi.org/10.1016/j.apnr.2022.151638] [PMID: 36473717]

[20]
McDonnell, B.; Newcomb, P. Trial of essential oils to improve sleep for patients in cardiac rehabilitation. J. Altern.,  2022, 25(12), 1193-1199.

[21]
Tarik, A.; Fatouma, M.; Baghouz, A.; Montassir, Z.; Attahar, W. Essential oils rich in pulegone for insecticide purpose against legume bruchus species: Case of Ziziphora hispanica L. and Mentha pulegium L. AIMS Agric. Food,  2022, 8, 105-118.

[22]
Wang, X.F.; Li, H.; Jiang, K.; Wang, Q.Q.; Zheng, Y.H.; Tang, W.; Tan, C.H. Anti-inflammatory constituents from Perilla frutescens on lipopolysaccharide-stimulated RAW264.7 cells. Fitoterapia,  2018, 130, 61-65.
 [http://dx.doi.org/10.1016/j.fitote.2018.08.006] [PMID: 30121232]

[23]
Li, Y.Y.; Wei, K.Q.; Wu, J.; Wei, Z.Z. Introduction of medicinal plant Perilla genes into tobacco to interfere with smoking-related lung injury in rats. Nat. Prod. Res.,  2016, 28(12), 1891-1895.

[24]
Wang, F.Y.; Li, S.C.; Wang, X.R. Effects of Dunhuang ancient formula “Zishu Decoction” on histomorphological changes of lung in rats with chronic bronchitis. Gansu Zhongyi Xueyuan Xuebao,  2008, (02), 5-8.

[25]
Wang, Y.Q.; Xing, F.Y.; Liu, F.L. Pharmacological study on the cough suppressing, expectorant and asthma calming effects of Perilla frutescens. Zhongnan Pharmacology.,  2003, (03), 135-138.

[26]
Wang, W.J.; Liu, X.M.; Zhang, G.Q. Study on the effect of perilla frutescens polysaccharide on airway inflammatory response and airway remodeling in rats with chronic obstructive pulmonary disease through Wnt/PCP pathway. J. Chin. Med.,  2021, 27(10), 37-41. [J].

[27]
Cheng, D.W. Study on preparation and quality standards of compound apricot cough syrup. Asia-Pacific Traditional Medicine.,  2013, 9(11), 38-39.

[28]
Chen, F.; Liu, S.; Zhao, Z.; Gao, W.; Ma, Y.; Wang, X.; Yan, S.; Luo, D. Ultrasound pre-treatment combined with microwave-assisted hydrodistillation of essential oils from Perilla frutescens (L.) Britt. leaves and its chemical composition and biological activity. Ind. Crops Prod.,  2020, 143, 111908.
 [http://dx.doi.org/10.1016/j.indcrop.2019.111908]

[29]
Wei, C.L.; Zhang, C.W.; Guo, B.L. Exploring the factors influencing the chemotypes and components of the volatile oil of Perilla frutescens I--different growth and development stages. J. Tradit.,  2017, 42(04), 712-718.

[30]
Hu, J.H.; Liu, L.L.; Zhang, Y.J.; Xiao, W. Determination of cafferic acid and rosmarinic acid in Perilla frutescens leaves and Schizonepeta tenuifolia by HPLC. Chin. Herb. Med.,  2015, 46, 2155-2159.

[31]
Han, L.; Wang, Q.Y.; Lin, H. Comparison of the clinical effects of paediatric sensitization oral liquid and paediatric quick-acting cold granules in the treatment of wind-cold flu. Chin. Contemp. Med.,  2015, 22(5), 149-150.

[32]
Feng, S.H.; Shen, Q.; Chen, S. Essential oil profiles of 168 perilla cultivars by head space solid phase micro-extraction gas chromatography mass spectrometry. J. Essent. Oil-Bear. Plants,  2019, 22(6), 1519-1536.
 [http://dx.doi.org/10.1080/0972060X.2019.1692698]

[33]
Ahmed, H.M.; Al-Zubaidy, A.M.A. Exploring natural essential oil components and antibacterial activity of solvent extracts from twelve Perilla frutescens L. Genotypes. Arab. J. Chem.,  2020, 13(10), 7390-7402.
 [http://dx.doi.org/10.1016/j.arabjc.2020.08.016]

[34]
Xu, X.; Tang, Z.; Liang, Y. Comparative analysis of plant essential oils by GC-MS coupled with integrated chemometric resolution methods. Anal. Methods,  2010, 2(4), 359.
 [http://dx.doi.org/10.1039/b9ay00213h]

[35]
Fang, X.; Abbott, J.; Cheng, L.; Colby, J.K.; Lee, J.W.; Levy, B.D.; Matthay, M.A. Human mesenchymal stem (stromal) cells promote the resolution of acute lung injury in part through lipoxin A4. J. Immunol.,  2015, 195(3), 875-881.
 [http://dx.doi.org/10.4049/jimmunol.1500244] [PMID: 26116507]

[36]
Liu, S; Wang, Z; Zhu, R; Wang, F; Cheng, Y; Liu, Y Three differential expression analysis methods for RNA sequencing: limma, EdgeR, DESeq2. J. Vis. Exp, 2021, (175)

[37]
Otasek, D.; Morris, J.H.; Bouças, J.; Pico, A.R.; Demchak, B. Cytoscape Automation: Empowering workflow-based network analysis. Genome Biol.,  2019, 20(1), 185.
 [http://dx.doi.org/10.1186/s13059-019-1758-4] [PMID: 31477170]

[38]
Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res.,  2021, 49(D1), D605-D612.
 [http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]

[39]
Sang, L.; Sun, L.; Wang, A.; Zhang, H.; Yuan, Y. The N6-methyladenosine features of mRNA and aberrant expression of m6A modified genes in gastric cancer and their potential impact on the risk and prognosis. Front. Genet.,  2020, 11, 561566.
 [http://dx.doi.org/10.3389/fgene.2020.561566] [PMID: 33329697]

[40]
Wu, T.; Hu, E.; Xu, S.; Chen, M.; Guo, P.; Dai, Z.; Feng, T.; Zhou, L.; Tang, W.; Zhan, L.; Fu, X.; Liu, S.; Bo, X.; Yu, G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation,  2021, 2(3), 100141.
 [http://dx.doi.org/10.1016/j.xinn.2021.100141] [PMID: 34557778]

[41]
Zhong, H.; Zhao, M.; Wu, C.; Zhang, J.; Chen, L.; Sun, J. Development of oxoisoaporphine derivatives with topoisomerase I inhibition and reversal of multidrug resistance in breast cancer MCF-7/ADR cells. Eur. J. Med. Chem.,  2022, 235, 114300.
 [http://dx.doi.org/10.1016/j.ejmech.2022.114300] [PMID: 35339100]

[42]
Fanelli, V.; Ranieri, V.M. Mechanisms and clinical consequences of acute lung injury. Ann. Am. Thorac. Soc.,  2015, 12(Suppl. 1), S3-S8.
 [http://dx.doi.org/10.1513/AnnalsATS.201407-340MG] [PMID: 25830831]

[43]
Gaab, J.; Rohleder, N.; Heitz, V.; Engert, V.; Schad, T.; Schürmeyer, T.H.; Ehlert, U. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology,  2005, 30(2), 188-198.
 [http://dx.doi.org/10.1016/j.psyneuen.2004.06.008] [PMID: 15471616]

[44]
Shi, J.R.; Mao, L.G.; Jiang, R.A.; Qian, Y.; Tang, H.F.; Chen, J.Q. Monoammonium glycyrrhizinate inhibited the inflammation of LPS-induced acute lung injury in mice. Int. Immunopharmacol.,  2010, 10(10), 1235-1241.
 [http://dx.doi.org/10.1016/j.intimp.2010.07.004] [PMID: 20637836]

[45]
Wang, Y.; Hu, B.; Feng, S.; Wang, J.; Zhang, F. Target recognition and network pharmacology for revealing anti-diabetes mechanisms of natural product. J. Comput. Sci.,  2020, 45, 101186.
 [http://dx.doi.org/10.1016/j.jocs.2020.101186]

[46]
Chin, Y.F.; Tang, W.F.; Chang, Y.H.; Chang, T-Y.; Lin, W-C.; Lin, C-Y.; Yang, C-M.; Wu, H-L.; Li, P-C.; Sun, J-R.; Hsu, S-C.; Lee, C-Y.; Lu, H-Y.; Chang, J-Y.; Jheng, J-R.; Chen, C.C.; Kau, J-H.; Huang, C-H.; Chiu, C-H.; Hung, Y-J.; Tsai, H-P.; Horng, J-T. Orally delivered perilla (Perilla frutescens) leaf extract effectively inhibits SARS-CoV-2 infection in a Syrian hamster model. Yao Wu Shi Pin Fen Xi,  2022, 30(2), 252-270.
 [http://dx.doi.org/10.38212/2224-6614.3412]

[47]
Millar, M.W.; Fazal, F.; Rahman, A. Therapeutic targeting of NF-κB in acute lung injury: A double-edged sword. Cells,  2022, 11(20), 3317.
 [http://dx.doi.org/10.3390/cells11203317] [PMID: 36291185]

[48]
Malaviya, R.; Laskin, J.D.; Laskin, D.L. Anti-TNFα therapy in inflammatory lung diseases. Pharmacol. Ther.,  2017, 180, 90-98.
 [http://dx.doi.org/10.1016/j.pharmthera.2017.06.008] [PMID: 28642115]

[49]
Shen, W.; Gan, J.; Xu, S.; Jiang, G.; Wu, H. Penehyclidine hydrochloride attenuates LPS-induced acute lung injury involvement of NF-κB pathway. Pharmacol. Res.,  2009, 60(4), 296-302.
 [http://dx.doi.org/10.1016/j.phrs.2009.04.007] [PMID: 19386282]

[50]
McVey, M.J.; Steinberg, B.E.; Goldenberg, N.M. Inflammasome activation in acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2021, 320(2), L165-L178.
 [http://dx.doi.org/10.1152/ajplung.00303.2020] [PMID: 33296269]

[51]
Jiang, B.; Chu, Z.X. Nitric oxide and inflammation. Foreign Medicine,  1998, 1998(01), 44-47.

[52]
Hayden, M.S.; Ghosh, S. Regulation of NF-κB by TNF family cytokines. Semin. Immunol.,  2014, 26(3), 253-266.
 [http://dx.doi.org/10.1016/j.smim.2014.05.004] [PMID: 24958609]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/0113862073244521231003071900	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Investigation of the Molecular Mechanisms Underlying the Therapeutic Effect of Perilla frutescens L. Essential Oil on Acute Lung Injury Using Gas Chromatography-Mass Spectrometry and Network Pharmacology

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract