Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

Jianwei Xiao; Xinmin Huang; Xu Cai; Yiwei Hong; Zhenbo Yan; Xinpeng Chen

doi:doi:10.11648/j.ajbio.20241203.12

Research Article |

| Peer-Reviewed

Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

Jianwei Xiao

, Xinmin Huang

, Xu Cai

, Yiwei Hong

, Zhenbo Yan

, Xinpeng Chen^*

Published in American Journal of BioScience (Volume 12, Issue 3)

Received: 6 May 2024 Accepted: 31 May 2024 Published: 13 June 2024

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

Objective: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.Methods: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.Results: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. Conclusion: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.

Published in	American Journal of BioScience (Volume 12, Issue 3)
DOI	10.11648/j.ajbio.20241203.12
Page(s)	90-100
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

Rheumatoid Arthritis, Molecular Docking, Molecular Dynamics, Curcumin, ALOX5

References

[1]	Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016; 388(10055): 2023-2038. https://doi.org/10.1016/s0140-6736(16)30173-8
[2]	McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365(23): 2205-2219. https://doi.org/10.1056/nejmra1004965
[3]	Gheorghe KR, Korotkova M, Catrina AI, et al. Expression of 5-lipoxygenase and 15-lipoxygenase in rheumatoid arthritis synovium and effects of intraarticular glucocorticoids. Arthritis Res Ther. 2009; 11(3): R83. https://doi.org/10.1186/ar2717
[4]	Mengli Wu, et al. The role of leukotriene B4 in the pathogenesis of rheumatoid arthritis. Chinese Journal of Immunology. 2014, 30(05): 689-693. https://doi.org/10.3969/j.issn.1000-484X.2014.05.028
[5]	Smolen JS, van der Heijde D, Machold KP, et al. Proposal for a new nomenclature of disease-modifying antirheumatic drugs [J]. Ann Rheum Dis. 2014; 73(1): 3-5. https://doi.org/10.1136/annrheumdis-2013-204317 PMID: 24072562.
[6]	Kuttan G, Kumar KB, Guruvayoorappan C, et al. Antitumor, anti-invasion, and antimetastatic effects of curcumin. Adv Exp Med Biol. 2007; 595: 173-184. https://doi.org/10.1007/978-0-387-46401-5_6
[7]	Xiao J, Cai X, Zhou W, et al. Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/miR-126-5p/PIAS2 axis. Bioengineered. 2022; 13(4): 10973-10983. https://doi.org/10.1080/21655979.2022.2066760
[8]	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(W1): W357-W364. https://doi.org/10.1093/nar/gkz382
[9]	Keiser MJ, Roth BL, Armbruster BN et al. Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 2007; 25(2): 197-206. https://doi.org/10.1038/nbt1284
[10]	Jiménez J, Doerr S, Martínez-Rosell G et al. DeepSite: protein-binding site predictor using 3D-convolutional neural networks. Bioinformatics. 2017; 33(19): 3036-3042. https://doi.org/10.1093/bioinformatics/btx350
[11]	MALDE A K, ZUO L, BREEZE M, et al. An automated force field topology builder (ATB) and repository: Version 1.0. Journal of Chemical Theory and Computation, 2011, 7(12): 4026-4037. https://doi.org/10.1021/ct200196m
[12]	Kumari R, Kumar R; Open Source Drug Discovery Consortium, Lynn A. g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model. 2014; 54(7): 1951-1962. https://doi.org/10.1021/ci500020m
[13]	Hamzehzadeh L, Atkin SL. The versatile role of curcumin in cancer prevention and treatment. A focus on PI3K/AKT pathway. J Cell Physiol. 2018; 233(10): 6530–6537. https://doi.org/10.1002/jcp.26620
[14]	Murray-Stewart T, Casero RA. Regulation of polyamine metabolism by curcumin for cancer prevention and therapy. Med Sci. 2017; 5(4): E38:38. https://doi.org/10.3390/medsci5040038
[15]	Zhang S, Zou J, Li P, et al. Curcumin protects against atherosclerosis in apolipoprotein E-knockout mice by inhibiting toll-like receptor 4 expression. J Agric Food Chem. 2018; 66(2): 449–456. https://doi.org/10.1021/acs.jafc.7b04260
[16]	Chen M, du ZY, Zheng X, et al. Use of curcumin in diagnosis, prevention, and treatment of Alzheimer’s disease. Neural Regen Res. 2018; 13(4): 742–752. https://doi.org/10.4103/1673-5374.230303
[17]	Zhuyong Li, Liqiang Wen, et al. The effect of curcumin on inhibiting the proliferation of rheumatoid arthritis synovial fibroblasts [J]. Lingnan Journal of Emergency Medicine. 2018, 06: 564-566+576. https://doi.org/10.3969/j.issn.1671-301X.2018.06.019
[18]	Al-Madol MA, Shaqura M, John T, et al. Comparative Expression Analyses of Pro- versus Anti-Inflammatory Mediators within Synovium of Patients with Joint Trauma, Osteoarthritis, and Rheumatoid Arthritis. Mediators Inflamm. 2017; 2017: 9243736. https://doi.org/10.1155/2017/9243736
[19]	Rådmark O, Werz O, Steinhilber D, et al. 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim Biophys Acta. 2015; 1851(4): 331-339. https://doi.org/10.1016/j.bbalip.2014.08.012
[20]	Živković NP, Petrovečki M, Lončarić ČT, et al. Positron emission tomography-computed tomography and 4-hydroxynonenal-histidine immunohistochemistry reveal differential onset of lipid peroxidation in primary lung cancer and in pulmonary metastasis of remote malignancies. Redox Biol. 2017; 11: 600-605. https://doi.org/10.1016/j.redox.2017.01.005
[21]	Berbée JFP, Mol IM, Milne GL, et al. Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia. Atherosclerosis. 2017; 264: 100-107. https://doi.org/10.1016/j.atherosclerosis.2017.06.916
[22]	Chao H, Liu Y, Fu X, et al. Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson's disease. Exp Neurol. 2018; 300: 74-86. https://doi.org/10.1016/j.expneurol.2017.10.031
[23]	Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017; 482(3): 419-425. https://doi.org/10.1016/j.bbrc.2016.10.086
[24]	Singh NK, Rao GN. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res. 2019; 73: 28-45. https://doi.org/10.1016/j.plipres.2018.11.001
[25]	Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007; 357(18): 1841-1854. https://doi.org/10.1056/NEJMc073333
[26]	Gürsel T, Firat S, Ercan ZS. Increased serum leukotriene B4 level in the active stage of rheumatoid arthritis in children. Prostaglandins Leukot Essent Fatty Acids. 1997; 56(3): 205-207. https://doi.org/10.1016/s0952-3278(97)90535-4
[27]	Zheng LX, Li KX, Hong FF, Yang SL. Pain and bone damage in rheumatoid arthritis: role of leukotriene B4. Clin Exp Rheumatol. 2019; 37(5): 872-878.
[28]	Chen M, Lam BK, Kanaoka Y, et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med. 2006; 203(4): 837-842. https://doi.org/10.1084/jem.20052371
[29]	Lin HC, Lin TH, Wu MY, et al. 5-Lipoxygenase inhibitors attenuate TNF-α-induced inflammation in human synovial fibroblasts. PLoS One. 2014; 9(9): e107890. https://doi.org/10.1371/journal.pone.0107890

Cite This Article

Plain Text BibTeX RIS

APA Style

Xiao, J., Huang, X., Cai, X., Hong, Y., Yan, Z., et al. (2024). Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. American Journal of BioScience, 12(3), 90-100. https://doi.org/10.11648/j.ajbio.20241203.12

Copy | Download

ACS Style

Xiao, J.; Huang, X.; Cai, X.; Hong, Y.; Yan, Z., et al. Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. Am. J. BioScience 2024, 12(3), 90-100. doi: 10.11648/j.ajbio.20241203.12

Copy | Download

AMA Style

Xiao J, Huang X, Cai X, Hong Y, Yan Z, et al. Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. Am J BioScience. 2024;12(3):90-100. doi: 10.11648/j.ajbio.20241203.12

Copy | Download

@article{10.11648/j.ajbio.20241203.12,
  author = {Jianwei Xiao and Xinmin Huang and Xu Cai and Yiwei Hong and Zhenbo Yan and Xinpeng Chen},
  title = {Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments
},
  journal = {American Journal of BioScience},
  volume = {12},
  number = {3},
  pages = {90-100},
  doi = {10.11648/j.ajbio.20241203.12},
  url = {https://doi.org/10.11648/j.ajbio.20241203.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajbio.20241203.12},
  abstract = {Objective: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.Methods: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.Results: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. Conclusion: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.
},
 year = {2024}
}

Copy | Download

TY  - JOUR
T1  - Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

AU  - Jianwei Xiao
AU  - Xinmin Huang
AU  - Xu Cai
AU  - Yiwei Hong
AU  - Zhenbo Yan
AU  - Xinpeng Chen
Y1  - 2024/06/13
PY  - 2024
N1  - https://doi.org/10.11648/j.ajbio.20241203.12
DO  - 10.11648/j.ajbio.20241203.12
T2  - American Journal of BioScience
JF  - American Journal of BioScience
JO  - American Journal of BioScience
SP  - 90
EP  - 100
PB  - Science Publishing Group
SN  - 2330-0167
UR  - https://doi.org/10.11648/j.ajbio.20241203.12
AB  - Objective: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.Methods: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.Results: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. Conclusion: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.

VL  - 12
IS  - 3
ER  -

Copy | Download

Author Information

Jianwei Xiao

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0000-0002-1178-538X
Xinmin Huang

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0009-0003-3183-8869
Xu Cai

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0000-0002-8553-1585
Yiwei Hong

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0009-0006-6399-0277
Zhenbo Yan

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0000-0002-7954-5358
Xinpeng Chen

Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China

Contact Email

http://orcid.org/0009-0009-0732-6066

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Xiao, J., Huang, X., Cai, X., Hong, Y., Yan, Z., et al. (2024). Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. American Journal of BioScience, 12(3), 90-100. https://doi.org/10.11648/j.ajbio.20241203.12

Copy | Download

ACS Style

Xiao, J.; Huang, X.; Cai, X.; Hong, Y.; Yan, Z., et al. Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. Am. J. BioScience 2024, 12(3), 90-100. doi: 10.11648/j.ajbio.20241203.12

Copy | Download

AMA Style

Xiao J, Huang X, Cai X, Hong Y, Yan Z, et al. Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments. Am J BioScience. 2024;12(3):90-100. doi: 10.11648/j.ajbio.20241203.12

Copy | Download

@article{10.11648/j.ajbio.20241203.12,
  author = {Jianwei Xiao and Xinmin Huang and Xu Cai and Yiwei Hong and Zhenbo Yan and Xinpeng Chen},
  title = {Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments
},
  journal = {American Journal of BioScience},
  volume = {12},
  number = {3},
  pages = {90-100},
  doi = {10.11648/j.ajbio.20241203.12},
  url = {https://doi.org/10.11648/j.ajbio.20241203.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajbio.20241203.12},
  abstract = {Objective: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.Methods: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.Results: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. Conclusion: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.
},
 year = {2024}
}

Copy | Download

TY  - JOUR
T1  - Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

AU  - Jianwei Xiao
AU  - Xinmin Huang
AU  - Xu Cai
AU  - Yiwei Hong
AU  - Zhenbo Yan
AU  - Xinpeng Chen
Y1  - 2024/06/13
PY  - 2024
N1  - https://doi.org/10.11648/j.ajbio.20241203.12
DO  - 10.11648/j.ajbio.20241203.12
T2  - American Journal of BioScience
JF  - American Journal of BioScience
JO  - American Journal of BioScience
SP  - 90
EP  - 100
PB  - Science Publishing Group
SN  - 2330-0167
UR  - https://doi.org/10.11648/j.ajbio.20241203.12
AB  - Objective: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.Methods: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.Results: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. Conclusion: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.

VL  - 12
IS  - 3
ER  -

Copy | Download