an-experimental-human-diep-flap-model-to-investigate-preservation

An Experimental Human DIEP Flap Model to Investigate Preservation Strategies for Vascularized Composite Allografts and Free Flaps

Recently, preservation approaches such as cytoprotective agents injection, ex vivo machine perfusion, and supercooling have emerged as strategies to ...

Université Côte d'Azur, CNRS, LP2M

Disorders characterized by ischemia/reperfusion (I/R) are the most common causes of debilitating diseases and death in stroke, cardiovascular ischemia, acute kidney injury or organ transplantation. In the latter example the I/R step defines both the amplitude of the damages to the graft and the functional recovery outcome. During transplantation the kidney is subjected to blood flow arrest followed by a sudden increase in oxygen supply at the time of reperfusion. This essential clinical protocol causes massive oxidative stress which is at the basis of cell death and tissue damage. The involvement of both reactive oxygen species (ROS) and nitric oxides (NO) has been shown to be a major cause of these cellular damages. In fact, in non-physiological situations, these species escape endogenous antioxidant control and dangerously accumulate in cells. In recent years, the objective has been to find clinical and pharmacological treatments to reduce or prevent the appearance of oxidative stress in ischemic pathologies. This is very relevant because, due to the increasing success of organ transplantation, clinicians are required to use limit organs, the preservation of which against oxidative stress is crucial for a better outcome. This review highlights the key actors in oxidative stress which could represent new pharmacological targets.

Targeting oxidative stress, a crucial challenge in renal transplantation outcome.

Intracellular metabolism is a crucial regulator of macrophage function. Recent evidence revealed that the polyamine pathway and subsequent hypusination of eukaryotic initiation factor 5A (eIF5A) are master regulators of immune cell functions. In brown adipose tissue (BAT), macrophages show an impressive degree of heterogenicity, with specific subsets supporting adaptive thermogenesis during cold exposure. In this review, we discuss the impact of polyamine metabolism on macrophage diversity and function, with a particular focus on their role in adipose tissue homeostasis. Thus, we highlight the exploration of how polyamine metabolism in macrophages contributes to BAT homeostasis as an attractive and exciting new field of research.

Polyamine metabolism in macrophage-adipose tissue function and homeostasis.

Ischemia/reperfusion (I/R) refers to the interruption or reduction of blood flow followed by its sudden restoration, resulting in significant oxidative stress, particularly in the kidneys, which are highly oxygen-dependent and metabolically active. During I/R, excessive production of reactive oxygen species (ROS) is triggered by mitochondrial dysfunction and activation of oxidases. Cellular antioxidant defences which attempt to neutralise ROS can become overwhelmed, resulting in oxidative stress that damages macromolecules and ultimately impairs cell function and survival. In kidney transplantation, ROS-induced I/R injury contributes to delayed graft function and chronic graft loss. In this context, inhibition of eIF5A hypusination using the deoxyhypusine synthase inhibitor GC7 protects kidney against I/R injury, potentially by reducing oxidative stress. However, the exact mechanisms and dynamics of this antioxidant protection remain to be elucidated. Using a mouse model of renal I/R and equivalent in vitro cell model, we analyzed the concomitance between protection against oxidative stress due to GC7 treatment and recovery of renal function or cell survival. In addition, we analyzed proteome modulation due to GC7 treatment to unravel pathways involved in its protective effect, and we defined the impact of GC7 on ROS productions and on antioxidant defences. We demonstrated that GC7 protected against I/R-induced injury and anoxia/reoxygenation in both in vivo and in vitro models by conditioning the cells and organ to resist stress. From a mechanistic point of view, we showed that the protective effects of GC7 were largely attributed to the enhancement of antioxidant defences, mainly through sustained catalase activity, which was mandatory in kidney cells to survive in the face of ROS production. Overall, GC7 is a clinical candidate for reducing oxidative damage in kidney transplantation, particularly for organs from marginal donors. Its ability to reprogram redox and metabolic pathways early after treatment supports its use to improve graft survival and function.

Article	Year
Targeting oxidative stress, a crucial challenge in renal transplantation outcome. Free radical biology & medicine\| PubMed ID: 33892115	2021
Polyamine metabolism in macrophage-adipose tissue function and homeostasis. Trends in endocrinology and metabolism: TEM\| PubMed ID: 38897879	2024
Inhibition of eIF5A hypusination enhances antioxidant defense to prevent kidney Ischemia/Reperfusion injury. Redox biology\| PubMed ID: 40789258	2025

Didier F. Pisani

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