The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications

Abstract

Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells' redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin.

Keywords: Keap1-Nrf2; antioxidant enzymes; catalase; curcumin; diabetes; hypoxia-inducible factor 1 (HIF-1); oxidative stress.

Figure 1

Domain structure of Nrf2. The seven functional domains (Neh1–7) and their positions.

Figure 2

Post-translational phosphorylation and acetylation of Nrf2. Phosphorylation of Nrf2 is performed at Ser/Thr residues by multiple protein kinases to activate Nrf2-related responses to oxidative stresses (green circles) or proteasomal degradation by a Cullin1/Rbx1 complex (red circles). Acetylation of Nrf2 at several Lys residues by transcriptional co-activators p300 and CREB-binding protein (CBP); p300/CBP has a boosting effect on Nrf2 for binding DNA (blue diamond).

Figure 3

Molecular regulation of the Keap1-Nrf2 pathway. A variety of factors and pathways are involved in regulating the function of the Keap1-Nrf2 pathway, which can be modulated through various factors in the cell.

Figure 4

Dual-edge sward functioning of Nrf2 with tumor cells and crosstalk between Nrf2 and HIF-1 activation. Under hypoxia and in the presence of oxidative stress, Nrf2 and HIF1 both enhance the tumor malignancy in tumor cells, but Nrf2 activation in the tumor microenvironment (TME) triggers anticancer immunity, thus suppressing tumors.

Figure 5

Anti-inflammatory effects of curcumin through modulation on Nrf2 and HIF1. Considering their correlation, modulation of Nrf2 and HIF-1 signaling pathways reduces diabetic complications by balancing ROS levels.