Special issue on “AGEs and ALEs: chemistry, physiopathology and molecular strategies for their inhibition”

Advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) are widely studied as reporters of oxidative and glycoxidative damage. Besides being considered as reliable biomarkers of oxidative damage, more recently, AGEs and ALEs have also been recognized as important pathogenetic factors of some oxidative stress-based diseases. Hence, AGEs/ALEs are now considered as promising drug targets, and a substantial effort is now dedicated, on one hand, to better understand the molecular effects and mechanisms of AGEs and ALEs on cell signaling pathways in pathophysiology, and on the other, to delve into the molecular strategies aimed at preventing, reducing, or removing these protein oxidation products.

The chemistry and physiopathology of AGEs and ALEs, as well as the molecular strategies for their inhibition, has been a hot topic within the COST Action CM1001 entitled “Chemistry of non-enzymatic protein modification – modulation of protein structure and function”, since its launch in 2010. The COST Action CM1001 (http://users.unimi.it/cm1001/) has as a major goal the scientific advancement in the area of protein modification, using an interdisciplinary approach and, therefore, to contribute to the development of new technologies in this field. This includes the identification of prominent or new post-translational protein modification products and the development of sophisticated methods for their detection. CM1001 comprises four different working groups and the special issue here reported represents the results obtained by the group chaired by Prof. Grzegorz Bartosz and entitled “Prevention of post‐translational protein modification and removal of products”.

The special issue, consisting of seven reviews, can be divided into three parts, which are linked together: the first part gives an overview of the chemistry of AGEs and ALEs together with their mechanisms of formation. The second part mainly focuses on the biological responses of such protein adducts, as well as of their precursors in physiopathology. The third part is devoted to the molecular strategies so far reported in the literature and used to inhibit AGEs and ALEs formation as well to constrain their biological effects.

In a more detail, the first review “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation” by Giulio Vistoli et al. [1] is a comprehensive review of the chemical pathways leading to AGEs and ALEs formation. In particular, the aim of this paper is to group the main AGEs and ALEs and to describe, for each of them, the precursors and mechanisms of formation.

A general overview on the involvement of AGEs in physiopathology is reported in the paper entitled “Molecular effects of advanced glycation end products (AGEs) on cell signalling pathways, ageing and pathophysiology” by Olgica Nedić et al [2]. The paper firstly introduces the effects of AGEs on cell signaling pathways, then reports the contribution of AGEs to ageing and pathophysiology and finally introduces the reduction of the accumulation of AGEs as a strategy for the improvement of health span. An insight into the effect of AGEs/ALEs and aldehydes into diabetes and related disorders is treated in the paper “Reactive aldehydes – second messengers of free radicals in diabetes mellitus” by M. Jaganjac et al [3]. The review discusses the role of oxidative stress and in particular of reactive aldehydes as well as of ALEs and AGEs in the onset, progression, and complications of diabetes. Two papers deal with the role of AGEs in specific pathologies. The paper by Delminda Neves “Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction” describes the deposition of AGEs in corpus cavernosum, leading to inhibition of nitric oxide synthases, and means of pharmacological intervention in this process [4]. The role of AGEs and receptors for AGEs (RAGEs) in pregnancy, especially complicated by preeclampsia and diabetes, as well as the usefulness of AGEs and RAGEs as diagnostic and prognostic tools in preeclampsia is discussed in the review by Luis Guedes-Martins et al. “AGEs, contributors to placental bed vascular changes leading to preeclampsia” [5]. A more specific review of the effects of oxidative stress, high glucose, and AGEs on the activity of sarco/endoplasmic reticulum Ca²⁺-ATPase is then reported in the paper entitled “Impairment of calcium ATPases by high glucose and potential pharmacological protection” by Lubica Horáková et al. [6].

The review “Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products” by Giancarlo Aldini et al. [7] focuses on the different molecular strategies so far reported for inhibiting AGEs/ALEs formation. Molecules able to counteract the formation of AGEs and ALEs such as antioxidants, metal-ion chelators, and sequestering agents of AGEs and ALEs precursors are firstly considered. Then, after detailed description on the physiological pathways of AGEs and ALEs removal, the molecular approaches used for stimulating the degradation of these oxidative derivatives are shown. The third part is devoted to molecular strategies aimed at blocking the ligand–RAGE axis and consists of inactivating RAGE by antagonists or by down-regulating the RAGE expression.

We hope that this summary of the current state of knowledge on the formation, properties, physiological role of AGEs and ALEs, their contribution to pathologies and aging, and of means of counteracting their accumulation will be useful for researchers working in relevant fields and attractive for newcomers.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.