Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 28;27(1):167.
doi: 10.3390/molecules27010167.

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Seyed Hossein Shahcheraghi  1 , Fateme Salemi  2 , Niloufar Peirovi  3 , Jamshid Ayatollahi  1 , Waqas Alam  4 , Haroon Khan  4 , Luciano Saso  5
Affiliations
Review

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Seyed Hossein Shahcheraghi et al. Molecules. .

Abstract

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc-curcumin Zn (II)-curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc-curcumin Zn (II)-curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

Keywords: Nrf2 regulation; anticancer effect; curcumin; future prospect; mechanistic insight.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Anti-tumorigenesis effect of curcumin via targeting different pathways including inhibition of ROS (reactive oxygen species); RNS (reactive nitrogen species); NFкB (nuclear factor kappa B); Nrf2 (NF-E2-related factor 2); HO-1(heme oxygenase-1); GST (glutathione S-transferase); GR (glutathione reductase).
Figure 2
Figure 2
Schematic representation ofNrf2regulation viaKEAP1 Pathway.Nrf2 is consistently ubiquitinated by KEAP1 and destroyed in the cytosol proteasome at normal conditions. During stress, the KEAP1-Nrf2 connection is disrupted, allowing free NRF2 to translocate into the nucleus. Nrf2 then forms heterodimers with sMaf and binds to ARE sites in antioxidant and detoxification genes’ regulatory regions. Nrf2;(nuclearerythroid2likefactor-2); KEAP1(Kelch-likeECH-associatedprotein1); AR (antioxidant response element);sMafs;(small musculoaponeuroticfibrosarcoma oncogene family).
Figure 3
Figure 3
Structures of Curcumin and its different analogues.
See this image and copyright information in PMC

References

    1. Agarwal N.B., Jain S., Agarwal N.K., Mediratta P.K., Sharma K.K. Modulation of pentylenetetrazole-induced kindling and oxidative stress by curcumin in mice. Phytomedicine. 2011;18:756–759. doi: 10.1016/j.phymed.2010.11.007. - DOI - PubMed
    1. Ibrahim S.G., El-Emam S.Z., Mohamed E.A., Abd Ellah M.F. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties. Int. Immunopharmacol. 2020;80:106131. doi: 10.1016/j.intimp.2019.106131. - DOI - PubMed
    1. Liao L., Shi J., Jiang C., Zhang L., Feng L., Liu J., Zhang J. Activation of anti-oxidant of curcumin pyrazole derivatives through preservation of mitochondria function and Nrf2 signaling pathway. Neurochem. Int. 2019;125:82–90. doi: 10.1016/j.neuint.2019.01.026. - DOI - PubMed
    1. Tan W., Lu J., Huang M., Li Y., Chen M., Wu G., Gong J., Zhong Z., Xu Z., Dang Y. Anti-cancer natural products isolated from chinese medicinal herbs. Chin. Med. 2011;6:27. doi: 10.1186/1749-8546-6-27. - DOI - PMC - PubMed
    1. Trujillo J., Granados-Castro L.F., Zazueta C., Andérica-Romero A.C., Chirino Y.I., Pedraza-Chaverrí J. Mitochondria as a target in the therapeutic properties of curcumin. Arch. Pharm. 2014;347:873–884. doi: 10.1002/ardp.201400266. - DOI - PubMed

MeSH terms