Analysis of the Mechanism of <i>Salvia miltiorrhiza</i> in the Treatment of Pancreatic Cancer Based on Network Pharmacology

Xueling Tan; Jiajun Chen; Yuting Bai; Xin Chen

doi:doi:10.11648/j.bs.20230903.11

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Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology

Xueling Tan, Jiajun Chen, Yuting Bai, Xin Chen

Published in Biomedical Sciences (Volume 9, Issue 3)

Received: 5 July 2023 Accepted: 19 July 2023 Published: 27 July 2023

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Abstract

Objective: To explore the potential molecular mechanism of Salvia miltiorrhiza in the treatment of pancreatic cancer using network pharmacology. Methods: The active components and their corresponding core targets in Salvia miltiorrhiza were screened by TCMSP database, and the corresponding gene Symbol of core targets was obtained by using Uniprot database. The gene targets for pancreatic cancer were searched from Gene Cards, OMIM, TTD and DrugBank databases. The potential targets of Salvia miltiorrhiza were matched with pancreatic cancer gene targets using Venn diagram, and the active components-targets network of Salvia miltiorrhiza and the active components-targets network of Salvia miltiorrhiza were mapped using Cytoscape software. The DAVID database was used to perform Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the potential mechanisms of targets. Results: A total of 65 active components of Salvia miltiorrhiza were screened, corresponding to 118 targets. A total of 2167 pancreatic cancer disease targets were screened, and 75 Salvia miltiorrhiza-pancreatic cancer crossover targets were obtained. Six core targets were obtained by PPI network analysis. Luteolin, tanshinone, quercetin and dihydrodanshinolide were the main active components, and ESR1, JUN, CDKN1A, MAPK14, MYC and TP53 were the main core targets. The results of GO analysis showed that the cellular components where the 75 targets of Salvia miltiorrhiza for pancreatic cancer therapy function are mainly the nucleus, membrane rafts, spindle, and membrane microdomains. The biological processes are mainly in response to radiation, response to xennobiotic stimulus, gland development, and so on. Molecular functions include DNA binding transcription factors, specific RNA polymerase II binding transcription factors, and regulation of kinase activity. 75 targets of Salvia miltiorrhiza for pancreatic cancer treatment are mainly through PI3K/Akt signaling pathway, cancer signaling pathway, pancreatic cancer signaling pathway, HIF-1 signaling pathway and other pathways to regulate tumor immune response, induce apoptosis, promote cell cycle arrest, and tumor metastasis, promote cell cycle arrest and tumor metastasis. Conclusions: This study reveals that Salvia miltiorrhiza may regulate multiple signaling pathways through multiple targets, thus acting as a therapeutic agent for pancreatic cancer, which also provides theoretical support for the clinical discovery of alternative drugs for pancreatic cancer treatment.

Published in	Biomedical Sciences (Volume 9, Issue 3)
DOI	10.11648/j.bs.20230903.11
Page(s)	53-59
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Network Pharmacology, Pancreatic Cancer, Mechanism, Salvia miltiorrhiza

References

[1]	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021, 71 (3): 209-249.
[2]	Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer Statistics, 2021. CA Cancer J Clin 2021, 71 (1): 7-33.
[3]	Xu Y, Oliverson BG, Simmons DL: Trifunctional inhibition of COX-2 by extracts of Lonicera japonica: direct inhibition, transcriptional and post-transcriptional down regulation. J Ethnopharmacol 2007, 111 (3): 667-670.
[4]	Kao ST, Liu CJ, Yeh CC: Protective and immunomodulatory effect of flos Lonicerae japonicae by augmenting IL-10 expression in a murine model of acute lung inflammation. J Ethnopharmacol 2015, 168: 108-115.
[5]	Mussard E, Jousselin S, Cesaro A, Legrain B, Lespessailles E, Esteve E, Berteina-Raboin S, Toumi H: Andrographis Paniculata and Its Bioactive Diterpenoids Protect Dermal Fibroblasts Against Inflammation and Oxidative Stress. Antioxidants (Basel) 2020, 9 (5).
[6]	Kumar RA, Sridevi K, Kumar NV, Nanduri S, Rajagopal S: Anticancer and immunostimulatory compounds from Andrographis paniculata. J Ethnopharmacol 2004, 92 (2-3): 291-295.
[7]	Song X, Zhang Y, Dai E, Du H, Wang L: Mechanism of action of celastrol against rheumatoid arthritis: A network pharmacology analysis. Int Immunopharmacol 2019, 74: 105725.
[8]	Kashyap D, Sharma A, Tuli HS, Sak K, Mukherjee T, Bishayee A: Molecular targets of celastrol in cancer: Recent trends and advancements. Crit Rev Oncol Hematol 2018, 128: 70-81.
[9]	Yuan F, Zhao ZT, Jia B, Wang YP, Lei W: TSN inhibits cell proliferation, migration, invasion, and EMT through regulating miR-874/HMGB2/β-catenin pathway in gastric cancer. Neoplasma 2020, 67 (5): 1012-1021.
[10]	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.
[11]	Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T, Rosen N, Kohn A, Twik M, Safran M et al: GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford) 2017, 2017.
[12]	Amberger JS, Hamosh A: Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes. Curr Protoc Bioinformatics 2017, 58: 1.2.1-1.2.12.
[13]	Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res 2002, 30 (1): 412-415.
[14]	Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J: DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 2006, 34 (Database issue): D668-672.
[15]	Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P et al: STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019, 47 (D1): D607-d613.
[16]	Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt H: Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci 2022, 43 (2): 136-150.
[17]	Li S, Zhang B: Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med 2013, 11 (2): 110-120.
[18]	Zhang B, Wang X, Li S: An Integrative Platform of TCM Network Pharmacology and Its Application on a Herbal Formula, Qing-Luo-Yin. Evid Based Complement Alternat Med 2013, 2013: 456747.
[19]	Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R: ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 2015, 12 (10): 573-583.
[20]	Omarjee S, Jacquemetton J, Poulard C, Rochel N, Dejaegere A, Chebaro Y, Treilleux I, Marangoni E, Corbo L, Romancer ML: The molecular mechanisms underlying the ERα-36-mediated signaling in breast cancer. Oncogene 2017, 36 (18): 2503-2514.
[21]	Seeliger H, Pozios I, Assmann G, Zhao Y, Müller MH, Knösel T, Kreis ME, Bruns CJ: Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma. BMC Cancer 2018, 18 (1): 1049.
[22]	Behrens A, Jochum W, Sibilia M, Wagner EF: Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene 2000, 19 (22): 2657-2663.
[23]	Gartel AL, Tyner AL: The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 2002, 1 (8): 639-649.
[24]	Georgakilas AG, Martin OA, Bonner WM: p21: A Two-Faced Genome Guardian. Trends Mol Med 2017, 23 (4): 310-319.
[25]	Xie D, Lan L, Huang K, Chen L, Xu C, Wang R, Shi Y, Wu X, Wang L, Liu Y et al: Association of p53/p21 expression and cigarette smoking with tumor progression and poor prognosis in non-small cell lung cancer patients. Oncol Rep 2014, 32 (6): 2517-2526.
[26]	Han J, Wang F, Yuan SQ, Guo Y, Zeng ZL, Li LR, Yang J, Wang DS, Liu MY, Zhao H et al: Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer. BMC Cancer 2014, 14: 650.

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APA Style

Xueling Tan, Jiajun Chen, Yuting Bai, Xin Chen. (2023). Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomedical Sciences, 9(3), 53-59. https://doi.org/10.11648/j.bs.20230903.11

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ACS Style

Xueling Tan; Jiajun Chen; Yuting Bai; Xin Chen. Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomed. Sci. 2023, 9(3), 53-59. doi: 10.11648/j.bs.20230903.11

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AMA Style

Xueling Tan, Jiajun Chen, Yuting Bai, Xin Chen. Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomed Sci. 2023;9(3):53-59. doi: 10.11648/j.bs.20230903.11

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@article{10.11648/j.bs.20230903.11,
  author = {Xueling Tan and Jiajun Chen and Yuting Bai and Xin Chen},
  title = {Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology},
  journal = {Biomedical Sciences},
  volume = {9},
  number = {3},
  pages = {53-59},
  doi = {10.11648/j.bs.20230903.11},
  url = {https://doi.org/10.11648/j.bs.20230903.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bs.20230903.11},
  abstract = {Objective: To explore the potential molecular mechanism of Salvia miltiorrhiza in the treatment of pancreatic cancer using network pharmacology. Methods: The active components and their corresponding core targets in Salvia miltiorrhiza were screened by TCMSP database, and the corresponding gene Symbol of core targets was obtained by using Uniprot database. The gene targets for pancreatic cancer were searched from Gene Cards, OMIM, TTD and DrugBank databases. The potential targets of Salvia miltiorrhiza were matched with pancreatic cancer gene targets using Venn diagram, and the active components-targets network of Salvia miltiorrhiza and the active components-targets network of Salvia miltiorrhiza were mapped using Cytoscape software. The DAVID database was used to perform Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the potential mechanisms of targets. Results: A total of 65 active components of Salvia miltiorrhiza were screened, corresponding to 118 targets. A total of 2167 pancreatic cancer disease targets were screened, and 75 Salvia miltiorrhiza-pancreatic cancer crossover targets were obtained. Six core targets were obtained by PPI network analysis. Luteolin, tanshinone, quercetin and dihydrodanshinolide were the main active components, and ESR1, JUN, CDKN1A, MAPK14, MYC and TP53 were the main core targets. The results of GO analysis showed that the cellular components where the 75 targets of Salvia miltiorrhiza for pancreatic cancer therapy function are mainly the nucleus, membrane rafts, spindle, and membrane microdomains. The biological processes are mainly in response to radiation, response to xennobiotic stimulus, gland development, and so on. Molecular functions include DNA binding transcription factors, specific RNA polymerase II binding transcription factors, and regulation of kinase activity. 75 targets of Salvia miltiorrhiza for pancreatic cancer treatment are mainly through PI3K/Akt signaling pathway, cancer signaling pathway, pancreatic cancer signaling pathway, HIF-1 signaling pathway and other pathways to regulate tumor immune response, induce apoptosis, promote cell cycle arrest, and tumor metastasis, promote cell cycle arrest and tumor metastasis. Conclusions: This study reveals that Salvia miltiorrhiza may regulate multiple signaling pathways through multiple targets, thus acting as a therapeutic agent for pancreatic cancer, which also provides theoretical support for the clinical discovery of alternative drugs for pancreatic cancer treatment.},
 year = {2023}
}

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TY  - JOUR
T1  - Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology
AU  - Xueling Tan
AU  - Jiajun Chen
AU  - Yuting Bai
AU  - Xin Chen
Y1  - 2023/07/27
PY  - 2023
N1  - https://doi.org/10.11648/j.bs.20230903.11
DO  - 10.11648/j.bs.20230903.11
T2  - Biomedical Sciences
JF  - Biomedical Sciences
JO  - Biomedical Sciences
SP  - 53
EP  - 59
PB  - Science Publishing Group
SN  - 2575-3932
UR  - https://doi.org/10.11648/j.bs.20230903.11
AB  - Objective: To explore the potential molecular mechanism of Salvia miltiorrhiza in the treatment of pancreatic cancer using network pharmacology. Methods: The active components and their corresponding core targets in Salvia miltiorrhiza were screened by TCMSP database, and the corresponding gene Symbol of core targets was obtained by using Uniprot database. The gene targets for pancreatic cancer were searched from Gene Cards, OMIM, TTD and DrugBank databases. The potential targets of Salvia miltiorrhiza were matched with pancreatic cancer gene targets using Venn diagram, and the active components-targets network of Salvia miltiorrhiza and the active components-targets network of Salvia miltiorrhiza were mapped using Cytoscape software. The DAVID database was used to perform Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the potential mechanisms of targets. Results: A total of 65 active components of Salvia miltiorrhiza were screened, corresponding to 118 targets. A total of 2167 pancreatic cancer disease targets were screened, and 75 Salvia miltiorrhiza-pancreatic cancer crossover targets were obtained. Six core targets were obtained by PPI network analysis. Luteolin, tanshinone, quercetin and dihydrodanshinolide were the main active components, and ESR1, JUN, CDKN1A, MAPK14, MYC and TP53 were the main core targets. The results of GO analysis showed that the cellular components where the 75 targets of Salvia miltiorrhiza for pancreatic cancer therapy function are mainly the nucleus, membrane rafts, spindle, and membrane microdomains. The biological processes are mainly in response to radiation, response to xennobiotic stimulus, gland development, and so on. Molecular functions include DNA binding transcription factors, specific RNA polymerase II binding transcription factors, and regulation of kinase activity. 75 targets of Salvia miltiorrhiza for pancreatic cancer treatment are mainly through PI3K/Akt signaling pathway, cancer signaling pathway, pancreatic cancer signaling pathway, HIF-1 signaling pathway and other pathways to regulate tumor immune response, induce apoptosis, promote cell cycle arrest, and tumor metastasis, promote cell cycle arrest and tumor metastasis. Conclusions: This study reveals that Salvia miltiorrhiza may regulate multiple signaling pathways through multiple targets, thus acting as a therapeutic agent for pancreatic cancer, which also provides theoretical support for the clinical discovery of alternative drugs for pancreatic cancer treatment.
VL  - 9
IS  - 3
ER  -

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Author Information

Xueling Tan

Department of Clinical Laboratory, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, China
Jiajun Chen

Department of Clinical Laboratory, Gaoping District People’s Hospital of Nanchong, Nanchong, China
Yuting Bai

Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
Xin Chen

Department of Rehabilitation Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, China

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Plain Text BibTeX RIS

APA Style

Xueling Tan, Jiajun Chen, Yuting Bai, Xin Chen. (2023). Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomedical Sciences, 9(3), 53-59. https://doi.org/10.11648/j.bs.20230903.11

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ACS Style

Xueling Tan; Jiajun Chen; Yuting Bai; Xin Chen. Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomed. Sci. 2023, 9(3), 53-59. doi: 10.11648/j.bs.20230903.11

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AMA Style

Xueling Tan, Jiajun Chen, Yuting Bai, Xin Chen. Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology. Biomed Sci. 2023;9(3):53-59. doi: 10.11648/j.bs.20230903.11

Copy | Download

@article{10.11648/j.bs.20230903.11,
  author = {Xueling Tan and Jiajun Chen and Yuting Bai and Xin Chen},
  title = {Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology},
  journal = {Biomedical Sciences},
  volume = {9},
  number = {3},
  pages = {53-59},
  doi = {10.11648/j.bs.20230903.11},
  url = {https://doi.org/10.11648/j.bs.20230903.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bs.20230903.11},
  abstract = {Objective: To explore the potential molecular mechanism of Salvia miltiorrhiza in the treatment of pancreatic cancer using network pharmacology. Methods: The active components and their corresponding core targets in Salvia miltiorrhiza were screened by TCMSP database, and the corresponding gene Symbol of core targets was obtained by using Uniprot database. The gene targets for pancreatic cancer were searched from Gene Cards, OMIM, TTD and DrugBank databases. The potential targets of Salvia miltiorrhiza were matched with pancreatic cancer gene targets using Venn diagram, and the active components-targets network of Salvia miltiorrhiza and the active components-targets network of Salvia miltiorrhiza were mapped using Cytoscape software. The DAVID database was used to perform Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the potential mechanisms of targets. Results: A total of 65 active components of Salvia miltiorrhiza were screened, corresponding to 118 targets. A total of 2167 pancreatic cancer disease targets were screened, and 75 Salvia miltiorrhiza-pancreatic cancer crossover targets were obtained. Six core targets were obtained by PPI network analysis. Luteolin, tanshinone, quercetin and dihydrodanshinolide were the main active components, and ESR1, JUN, CDKN1A, MAPK14, MYC and TP53 were the main core targets. The results of GO analysis showed that the cellular components where the 75 targets of Salvia miltiorrhiza for pancreatic cancer therapy function are mainly the nucleus, membrane rafts, spindle, and membrane microdomains. The biological processes are mainly in response to radiation, response to xennobiotic stimulus, gland development, and so on. Molecular functions include DNA binding transcription factors, specific RNA polymerase II binding transcription factors, and regulation of kinase activity. 75 targets of Salvia miltiorrhiza for pancreatic cancer treatment are mainly through PI3K/Akt signaling pathway, cancer signaling pathway, pancreatic cancer signaling pathway, HIF-1 signaling pathway and other pathways to regulate tumor immune response, induce apoptosis, promote cell cycle arrest, and tumor metastasis, promote cell cycle arrest and tumor metastasis. Conclusions: This study reveals that Salvia miltiorrhiza may regulate multiple signaling pathways through multiple targets, thus acting as a therapeutic agent for pancreatic cancer, which also provides theoretical support for the clinical discovery of alternative drugs for pancreatic cancer treatment.},
 year = {2023}
}

Copy | Download

TY  - JOUR
T1  - Analysis of the Mechanism of Salvia miltiorrhiza in the Treatment of Pancreatic Cancer Based on Network Pharmacology
AU  - Xueling Tan
AU  - Jiajun Chen
AU  - Yuting Bai
AU  - Xin Chen
Y1  - 2023/07/27
PY  - 2023
N1  - https://doi.org/10.11648/j.bs.20230903.11
DO  - 10.11648/j.bs.20230903.11
T2  - Biomedical Sciences
JF  - Biomedical Sciences
JO  - Biomedical Sciences
SP  - 53
EP  - 59
PB  - Science Publishing Group
SN  - 2575-3932
UR  - https://doi.org/10.11648/j.bs.20230903.11
AB  - Objective: To explore the potential molecular mechanism of Salvia miltiorrhiza in the treatment of pancreatic cancer using network pharmacology. Methods: The active components and their corresponding core targets in Salvia miltiorrhiza were screened by TCMSP database, and the corresponding gene Symbol of core targets was obtained by using Uniprot database. The gene targets for pancreatic cancer were searched from Gene Cards, OMIM, TTD and DrugBank databases. The potential targets of Salvia miltiorrhiza were matched with pancreatic cancer gene targets using Venn diagram, and the active components-targets network of Salvia miltiorrhiza and the active components-targets network of Salvia miltiorrhiza were mapped using Cytoscape software. The DAVID database was used to perform Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to predict the potential mechanisms of targets. Results: A total of 65 active components of Salvia miltiorrhiza were screened, corresponding to 118 targets. A total of 2167 pancreatic cancer disease targets were screened, and 75 Salvia miltiorrhiza-pancreatic cancer crossover targets were obtained. Six core targets were obtained by PPI network analysis. Luteolin, tanshinone, quercetin and dihydrodanshinolide were the main active components, and ESR1, JUN, CDKN1A, MAPK14, MYC and TP53 were the main core targets. The results of GO analysis showed that the cellular components where the 75 targets of Salvia miltiorrhiza for pancreatic cancer therapy function are mainly the nucleus, membrane rafts, spindle, and membrane microdomains. The biological processes are mainly in response to radiation, response to xennobiotic stimulus, gland development, and so on. Molecular functions include DNA binding transcription factors, specific RNA polymerase II binding transcription factors, and regulation of kinase activity. 75 targets of Salvia miltiorrhiza for pancreatic cancer treatment are mainly through PI3K/Akt signaling pathway, cancer signaling pathway, pancreatic cancer signaling pathway, HIF-1 signaling pathway and other pathways to regulate tumor immune response, induce apoptosis, promote cell cycle arrest, and tumor metastasis, promote cell cycle arrest and tumor metastasis. Conclusions: This study reveals that Salvia miltiorrhiza may regulate multiple signaling pathways through multiple targets, thus acting as a therapeutic agent for pancreatic cancer, which also provides theoretical support for the clinical discovery of alternative drugs for pancreatic cancer treatment.
VL  - 9
IS  - 3
ER  -

Copy | Download