Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

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.

Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats

“…CUR upregulated Nrf2/HO-1 and prevented oxidative stress in the testis of cadmium-intoxicated mice [ 68 ]. The ability of CUR to upregulate Nrf2 signaling has been investigated in different in vitro and in vivo models (reviewed in [ 69 ]). In consistence with the results of antioxidant enzymes, N-CUR was more effective in upregulating testicular Nrf2/HO-1 signaling in CuSO 4 -administered rats.…”

Neuroprotective effect of Ginsenoside Re against neurotoxin‑induced Parkinson's disease models via induction of Nrf2

“…Nrf2 is a key component of the oxidative stress response and regulates the expression of antioxidant and cytoprotective genes ( 29 ). To determine whether Nrf2 is modulated by Rot and/or Re treatment, western blot analysis of SH-SY5Y subcellular fractions was performed.…”

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

“…Many different compounds like anethole derivatives such as anethole trithione, dithiolethiones, curcumin, isothiocyanates, caffeic acid, phenethyl esters, flavon derivatives, and triterpenoids (Figure 1) have been found to stimulate ARE and the phase II detoxifying enzymes [75,76].…”