Promising tools into oxidative stress: A review of non-rodent model organisms

Abstract

Oxidative stress is a crucial concept in redox biology, and significant progress has been made in recent years. Excessive levels of reactive oxygen species (ROS) can lead to oxidative damage, heightening vulnerability to various diseases. By contrast, ROS maintained within a moderate range plays a role in regulating normal physiological metabolism. Choosing suitable animal models in a complex research context is critical for enhancing research efficacy. While rodents are frequently utilized in medical experiments, they pose challenges such as high costs and ethical considerations. Alternatively, non-rodent model organisms like zebrafish, Drosophila, and C. elegans offer promising avenues into oxidative stress research. These organisms boast advantages such as their small size, high reproduction rate, availability for live imaging, and ease of gene manipulation. This review highlights advancements in the detection of oxidative stress using non-rodent models. The oxidative homeostasis regulatory pathway, Kelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), is systematically reviewed alongside multiple regulation of Nrf2-centered pathways in different organisms. Ultimately, this review conducts a comprehensive comparative analysis of different model organisms and further explores the combination of novel techniques with non-rodents. This review aims to summarize state-of-the-art findings in oxidative stress research using non-rodents and to delineate future directions.

Keywords: Antioxidant mechanism; High-throughput screening; Non-rodent model organisms; Oxidative stress; Reactive oxygen species; Redox signaling pathway.

Graphical abstract

Fig. 1

Common redox fluorescence probes loaded in non-rodent models. (A) DCFH-DA; (B) Amplex Red®; (C) DHE; (D) MitoSOX; (E) MitoB. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Common redox biosensors in non-rodent models. (A) roGFP2; (B) Hyper; (C) roGFP2-Orp1; (D) roGFP2-Grx1.

Fig. 3

Chemical mechanism of redox signaling based on cysteine oxidation. GSH: Glutathione; Grx: Glutaredoxin; Trx: Thioredoxin.

Fig. 4

Schematic domains of Nrf2 and isoforms found in different organisms. RARα: retinoic acid receptor α; KKKK: lysine-rich α-helix; BR: basic region; ER: endoplasmic reticulum; NHB1/2: N-terminal homology box1/2. The numbers marked in the C-terminal are the length of amino acids.

Fig. 5

Schematic domains of Keap1 protein in different organisms. NTR: N-terminal region; CTR: C-terminal region; CTD: C-terminal tail. Three sensor cysteines, Cys151, Cys273, and Cys288, are highlighted.

Fig. 6

“Keap1-Nrf2” system in different organisms.

Fig. 7

Multiple regulation of Nrf2 activity. (A) GSK-3β-dependent phosphorylation and inhibited by PI3K/Akt pathway. (B) Direct phosphorylation by PKC, AMPK, CK2,and P38 MAPK. (C) P97-dependent Nrf2 degradation. (D) Sirt1-Nrf2 positive feedback loop. (E) Interplay between NF-κB and Keap1-Nrf2 pathway. (F) P62-dependent Keap1 degradation.

Fig. 8

Scheme of IIS and SKN-1/Nrf2 pathways in C. elegans. The critical cysteines, Cys663, Cys364, Cys905, Cys213, and Cys173, involved in the P38 MAPK pathway are highlighted.

Fig. 9

Multiple factors of model organisms to be considered in redox biology research.