Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Towards Further Understanding the Role of Curcumin in Wound Healing: A Systems Biology Approach

Author(s): Anukriti, Naveen Dhingra*, Ravindra Bhardaj, Uma Bhardwaj* and Anupam Dhasmana

Volume 20, Issue 11, 2023

Published on: 12 September, 2022

Page: [1744 - 1756] Pages: 13

DOI: 10.2174/1570180819666220801111246

Price: $65


Background: Curcumin, a polyphenolic compound present in the turmeric plant (Curcuma longa) is well known for its anti-aging, anti-tumor, anti-inflammatory, anti-mutagenic and antioxidative properties due to which turmeric has been used as a medicinal plant from ages.

Objective: Our current study aims at finding the most potent targets of curcumin displaying efficient binding by using various systems biology tools. Around 560 genes related to wound healing are extracted from PubMed using the combination of words like wound healing, curcumin, Homo sapiens, etc.

Methods: For the investigation of the mechanism of curcumin interference at the system level, proteinprotein interaction network (PPIN) of the proteins involved in the wound healing process was generated using the STRING database. The noise of the data generated in PPIN was removed by modulation of the network with the help of Molecular Complex Detection (MCODE) and finding the seed proteins. GO enrichment analysis along with network topology analysis and molecular docking will help in pinpointing the most important and efficient curcumin binding proteins.

Results: The findings of this study shows that besides SCR, PPARG and MAPK3, AKT3 is one of the novel targets for wound healing as the binding affinity of AKT3 is -4.53 Kcal/mol, which is close to SRC with the highest binding affinity with binding energy of -6.6 Kcal/mol. The binding energy of PPARG was -6.2 Kcal/mol and for MAPK3 the binding energy was -5.95 Kcal/mol. Besides AKT3, FLT4 and RPS6KB1 were also the novel targets of curcumin with binding affinities of -4.13 Kcal/mol and -4.04 Kcal/mol. In network analysis, we obtained PIK3R1 as a connector node which acted as a hub node with highest betweenness score.

Conclusion: From the results obtained, we can say that curcumin finds its role in all four stages of wound healing and it also prevents the healing cells from turning into tumors.

Keywords: String DB, cytoscape, protein-protein interactions, AKT3, polyphenolic, protein interaction.

Graphical Abstract
Gupta, S.C.; Patchva, S.; Koh, W.; Aggarwal, B.B. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin. Exp. Pharmacol. Physiol., 2012, 39(3), 283-299.
[] [PMID: 22118895]
Park, M.J.; Kim, E.H.; Park, I.C.; Lee, H.C.; Woo, S.H.; Lee, J.Y.; Hong, Y.J.; Rhee, C.H.; Choi, S.H.; Shim, B.S.; Lee, S.H.; Hong, S.I. Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitor, p21WAF1/CIP1, p27KIP1 and p53. Int. J. Oncol., 2002, 21(2), 379-383.
[] [PMID: 12118335]
Yang, X.; Thomas, D.P.; Zhang, X.; Culver, B.W.; Alexander, B.M.; Murdoch, W.J.; Rao, M.N.A.; Tulis, D.A.; Ren, J.; Sreejayan, N. Curcumin inhibits platelet-derived growth factor-stimulated vascular smooth muscle cell function and injury-induced neointima formation. Arterioscler. Thromb. Vasc. Biol., 2006, 26(1), 85-90.
[] [PMID: 16239599]
Choi, B.H.; Kim, C.G.; Lim, Y.; Shin, S.Y.; Lee, Y.H. Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett., 2008, 259(1), 111-118.
[] [PMID: 18006147]
van de Vyver, M.; Idensohn, P.J.; Niesler, C.U. A regenerative approach to the pharmacological management of hard-to-heal wounds. Biochimie, 2022, 194, 67-78.
[] [PMID: 34982983]
Kant, V.; Kumari, P.; Jitendra, D.K.; Ahuja, M.; Kumar, V. Nanomaterials of natural bioactive compounds for wound healing: Novel drug delivery approach. Curr. Drug Deliv., 2021, 18(10), 1406-1425.
[] [PMID: 34325636]
Kesić, S. Systems biology, emergence and antireductionism. Saudi J. Biol. Sci., 2016, 23(5), 584-591.
[] [PMID: 27579007]
Dhingra, N.; Kar, A.; Sharma, R. Towards further understanding the structural requirements of combretastatin-like chalcones as inhibitors of microtubule polymerization. Curr. Computeraided Drug Des., 2020, 16(2), 155-166.
[] [PMID: 30574854]
Dhasmana, A.; Uniyal, S. Anukriti; Kashyap, V.K.; Somvanshi, P.; Gupta, M.; Bhardwaj, U.; Jaggi, M.; Yallapu, M.M.; Haque, S.; Chauhan, S.C. Topological and system-level protein interaction network (PIN) analyses to deduce molecular mechanism of curcumin. Sci. Rep., 2020, 10(1), 12045.
[] [PMID: 32694520]
Yadav, B.S.; Tripathi, V. Recent advances in the system biology-based target identification and drug discovery. Curr. Top. Med. Chem., 2018, 18(20), 1737-1744.
[] [PMID: 30360719]
Ahmed, M.M.; Tazyeen, S.; Haque, S.; Sulimani, A.; Ali, R.; Sajad, M.; Alam, A.; Ali, S.; Bagabir, H.A.; Bagabir, R.A.; Ishrat, R. Network-based approach and IVI methodologies, a combined data investigation identified probable key genes in cardiovascular disease and chronic kidney disease. Front. Cardiovasc. Med., 2022, 8(8), 755321.
[] [PMID: 35071341]
Caglar, H.O. Bioinformatics analysis of recurrent deletion regions in neuroblastoma. Med. Oncol., 2022, 39(3), 31.
[] [PMID: 35059899]
Tang, M.; Liu, P.; Wu, X.; Gong, J.; Weng, J.; Gao, G.; Liu, Y.; Gan, L. COL3A1 and its related molecules as potential biomarkers in the development of human ewing’s sarcoma. BioMed Res. Int., 2021, 2021(20), 7453500.
[] [PMID: 35047627]
Sabe, V.T.; Ntombela, T.; Jhamba, L.A.; Maguire, G.E.M.; Govender, T.; Naicker, T.; Kruger, H.G. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review. Eur. J. Med. Chem., 2021, 224(224), 113705.
[] [PMID: 34303871]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[] [PMID: 10592235]
UniProt Consortium. UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res., 2019, 47(D1), D506-D515.
[] [PMID: 30395287]
Yang, J.; Zhang, Y. Protein structure and function prediction using i-tasser. CurrProtoc Bioinformatics, 2015, 52, 5.8.1-5.815.
Xu, D.; Zhang, Y. Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys. J., 2011, 101(10), 2525-2534.
[] [PMID: 22098752]
Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; de Bakker, P.I.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Calpha geometry: Phi,psi and Cbeta deviation. Proteins, 2003, 50(3), 437-450.
[] [PMID: 12557186]
Chin, C.H.; Chen, S.H.; Wu, H.H.; Ho, C.W.; Ko, M.T.; Lin, C.Y. cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol., 2014, 8, S11.
[] [PMID: 25521941]
Watts, D.J.; Strogatz, S.H. Collective dynamics of -small-world networks. Nature, 1998, 393(6684), 440-442.
Buchanan, M.; Caldarelli, G.; Rios, P.D.L.; Rao, F.; Vendruscolo, M. Networks in Cell Biology; Cambridge University Press, 2010.
Stokman, F.N. Networks: SocialInternational Encyclopedia of the Social & Behavioral Sciences; , 2001, pp. 10509-10514.
Yu, H.; Kim, P.M.; Sprecher, E.; Trifonov, V.; Gerstein, M. The importance of bottlenecks in protein networks: Correlation with gene essentiality and expression dynamics. PLOS Comput. Biol., 2007, 3(4), e59.
[] [PMID: 17447836]
Gu, S.; Dai, H.; Zhao, X.; Gui, C.; Gui, J. AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling. Aging (Albany NY), 2020, 12(8), 6928-6946.
[] [PMID: 32291381]
Huang, H.; Cui, W.; Qiu, W.; Zhu, M.; Zhao, R.; Zeng, D.; Dong, C.; Wang, X.; Guo, W.; Xing, W.; Li, X.; Li, L.; Tan, Y.; Wu, X.; Chen, L.; Fu, X.; Luo, D.; Xu, X. Impaired wound healing results from the dysfunction of the Akt/mTOR pathway in diabetic rats. J. Dermatol. Sci., 2015, 79(3), 241-251.
[] [PMID: 26091964]
Danilevicz, C.K.; Wagner, V.P.; Ferreira, N.; Bock, H.; Salles Pilar, E.F.; Webber, L.P.; Schmidt, T.R.; Alonso, E.C.P.; de Mendonça, E.F.; Valadares, M.C.; Marreto, R.N.; Martins, M.D. Curcuma longa L. effects on Akt/mTOR pathway and NF-κB expression during skin wound healing: An immunohistochemical study. Appl. Immunohistochem. Mol. Morphol., 2021, 29(10), e92-e100.
[] [PMID: 34261975]
Hassan, W.U.; Greiser, U.; Wang, W. Role of adipose-derived stem cells in wound healing. Wound Repair Regen., 2014, 22(3), 313-325.
[] [PMID: 24844331]
Yi, Y.S.; Kim, H.G.; Kim, J.H.; Yang, W.S.; Kim, E.; Jeong, D.; Park, J.G.; Aziz, N.; Kim, S.; Parameswaran, N.; Cho, J.Y. Syk-MyD88 axis is a critical determinant of inflammatory-response in activated macrophages. Front. Immunol., 2021, 12(12), 767366.
[] [PMID: 35003083]
Liu, C.; Wang, M.; Lv, H.; Liu, B.; Ya, X.; Zhao, W.; Wang, W. CEACAM6 promotes cholangiocarcinoma migration and invasion by inducing epithelial-mesenchymal transition through inhibition of the SRC/PI3K/AKT signaling pathway. Oncol. Lett., 2022, 23(1), 39.
[] [PMID: 34966455]
Park, S.H.; Choi, H.J.; Yang, H.; Do, K.H.; Kim, J.; Lee, D.W.; Moon, Y. Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor γ. J. Biol. Chem., 2010, 285(46), 35330-35339.
[] [PMID: 20829347]
Siersbaek, R.; Nielsen, R.; Mandrup, S. PPARgamma in adipocyte differentiation and metabolism--novel insights from genome-wide studies. FEBS Lett., 2010, 584(15), 3242-3249.
[] [PMID: 20542036]
Thiruvengadam, M.; Venkidasamy, B.; Subramanian, U.; Samynathan, R.; Ali Shariati, M.; Rebezov, M.; Girish, S.; Thangavel, S.; Dhanapal, A.R.; Fedoseeva, N.; Lee, J.; Chung, I.M. Bioactive compounds in oxidative stress-mediated diseases: Targeting the nrf2/are signaling pathway and epigenetic regulation. Antioxidants, 2021, 10(12), 1859.
[] [PMID: 34942962]
Sudhesh, D.S.; Zainal, A.S.A.; Farghadani, R.; Othman, I.; Naidu, R. Receptor tyrosine kinases and their signaling pathways as therapeutic targets of curcumin in cancer. Front. Pharmacol., 2021, 12, 772510.

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy