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.
Highlights
As a major monomer constituent in turmeric derived from Curcuma Longa rhizomes, curcumin has shown a variety of potential bioactivities such as anti-inflammatory, antioxidant and anti-infective properties, with few side effects [1,2,3,4,5,6,7]
The kidney is adversely affected by renal excision since 5/6 nephrectomy (5/6NX) procedure imposes oxidative stress, increased glomerular filtration rate (GFR) and hypertensive nephropathy
The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway have been shown to improve insulin resistance
Summary
As a major monomer constituent in turmeric derived from Curcuma Longa rhizomes, curcumin has shown a variety of potential bioactivities such as anti-inflammatory, antioxidant and anti-infective properties, with few side effects [1,2,3,4,5,6,7]. Dose–response studies suggest that these analogs activate Nrf by multiple mechanisms, including the sensitivity to activation, reflected in EC50 values and the extent of activation influenced by a broad range of substituent on the aromatic rings of these enones [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Copolymer 3a was identified as the most potentcomponent in PEGylated curcumin, strengthening Nrf2-dependent NQO1 production in a dose-dependent pattern [30]
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