Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives

Abstract

Ischemia reperfusion injury is a complex process consisting of a seemingly chaotic but actually organized and compartmentalized shutdown of cell function, of which oxidative stress is a key component. Studying oxidative stress, which results in an imbalance between reactive oxygen species (ROS) production and antioxidant defense activity, is a multi-faceted issue, particularly considering the double function of ROS, assuming roles as physiological intracellular signals and as mediators of cellular component damage. Herein, we propose a comprehensive overview of the tools available to explore oxidative stress, particularly in the study of ischemia reperfusion. Applying chemistry as well as biology, we present the different models currently developed to study oxidative stress, spanning the vitro and the silico, discussing the advantages and the drawbacks of each set-up, including the issues relating to the use of in vitro hypoxia as a surrogate for ischemia. Having identified the limitations of historical models, we shall study new paradigms, including the use of stem cell-derived organoids, as a bridge between the in vitro and the in vivo comprising 3D intercellular interactions in vivo and versatile pathway investigations in vitro. We shall conclude this review by distancing ourselves from "wet" biology and reviewing the in silico, computer-based, mathematical modeling, and numerical simulation options: (a) molecular modeling with quantum chemistry and molecular dynamic algorithms, which facilitates the study of molecule-to-molecule interactions, and the integration of a compound in a dynamic environment (the plasma membrane...); (b) integrative systemic models, which can include many facets of complex mechanisms such as oxidative stress or ischemia reperfusion and help to formulate integrated predictions and to enhance understanding of dynamic interaction between pathways.

Keywords: ROS; animal models; antioxidant factors; ischemia-reperfusion injury; molecular modeling models; organoids; oxidative stress.

Scheme 1

Concepts of ROS generation and antioxidant control in DNA injury.

Scheme 2

Main enzymes involved in enzymatic antioxidant system.

Scheme 3

Interest of in vivo, ex vivo, and in vitro models, depending on their physiological relevance and their scientific target.

Scheme 4

Interest and limits of organoids.

Scheme 5

Schematic view of a lipid bilayer membrane under oxidative stress in the presence of two antioxidants located in different regions, namely, in contact with the polar head group region or embedded in between the lipid tails for both the prototypical flavonoid antioxidant (quercetin, in yellow) and vitamin E (green). Due to possible noncovalent interaction between both antioxidants, regeneration processes are possible by electron or H-atom transfer, see text. The positioning of both antioxidants is obtained from MD simulations, according to the methodology described in Fabre G. et al. [67].