Reactive Oxygen Comes of Age: Mechanism-Based Therapy of Diabetic End-Organ Damage

Abstract

Reactive oxygen species (ROS) have been mainly viewed as unwanted byproducts of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general. A New Approach to Diabetes Mellitus and Reactive Oxygen Species Diabetes mellitus (DM) and its related end-organ damage, such as diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy, are major causes of death and long-term disability. Their underlying mechanisms are incompletely understood, which is why none of the current antidiabetic therapies target the underlying causes or are curative, but focus instead on normalizing surrogate parameters or risk factors such as blood glucose or hypertension [1]. Hence, our lack of mechanistic understanding of lifestyle change-resistant diabetic end-organ damage, together with the increasing prevalence of DM, represent a significant major unmet medical need. One mechanism that has been suggested for decades to cause pancreatic b cell dysfunction and diabetic end-organ damage is 'oxidative stress' (see Glossary), originally defined as an overproduction of reactive oxygen species (ROS). Antioxidants were considered the obvious therapeutic countermeasure but, clinically, have consistently disappointed [2]. Even worse, meta-analyses of clinical trials show that antioxidants may not only be ineffective, but harmful, and even increase mortality [2]. Recently, however, important conceptual breakthroughs in our understanding of ROS in general and DM in particular explain the failure of antioxidants and point towards entirely different mechanism-based and possibly curative therapeutic approaches. Our new understanding of ROS requires that many long-held misconceptions, such as the 'redox balance hypothesis' and the view that ROS are primarily stressors, disease triggers, and metabolic waste products, must be overcome. Instead, the many physiological roles of ROS and the existence of at least seven evolutionarily conserved ROS-producing enzymes (NOX1-5,

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

“…We began with a seed gene-based approach, based on clinically validated proteins. Noxs were suggested by GWAS in old [5] but not in younger patients [68] and are the only known enzyme family solely dedicated to ROS formation [69]. The NO-cGMP pathway is important for blood pressure regulation and its dysfunction a hallmark of hypertension [70].…”

Redox Nanomedicine Cures Chronic Kidney Disease (CKD) by Mitochondrial Reconditioning

“…Recent understanding about the pivotal role of ROS as secondary messengers in cellular signaling to control processes like metabolism, energetics, cell survival, and death lead to a paradigm shift to the traditional "oxidants are bad -antioxidants are good" based simplistic view of redox biology [6][7][8][9][10]. Apathy towards the paradox between lethality of excessive intracellular ROS (oxidative distress) and beneficial role of low concentration ROS (oxidative eustress) is the major underlying reason behind the failure of conventional antioxidant therapies using natural or synthetic antioxidants (e.g., α-tocopherol, ascorbic acid, -carotene, curcumin, and numerous polyphenols present in the diet) that along with scavenging intracellular free radicals in a stoichiometric way, insulates redox signaling [10][11][12]. Moreover, meta-analyses of clinical trials show that conventional antioxidants are not only ineffective, but harmful, and even increase mortality [12,13].…”

“…Apathy towards the paradox between lethality of excessive intracellular ROS (oxidative distress) and beneficial role of low concentration ROS (oxidative eustress) is the major underlying reason behind the failure of conventional antioxidant therapies using natural or synthetic antioxidants (e.g., α-tocopherol, ascorbic acid, -carotene, curcumin, and numerous polyphenols present in the diet) that along with scavenging intracellular free radicals in a stoichiometric way, insulates redox signaling [10][11][12]. Moreover, meta-analyses of clinical trials show that conventional antioxidants are not only ineffective, but harmful, and even increase mortality [12,13]. The understanding that proper cell functioning critically requires a dynamic balance between oxidative eustress and distress (i.e., cellular redox homeostasis) forms the conceptual framework of redox medicine, a novel therapeutics that passivates the oxidative distress while maintains the normal redox circuitry [10,12,[14][15][16].…”

“…Moreover, meta-analyses of clinical trials show that conventional antioxidants are not only ineffective, but harmful, and even increase mortality [12,13]. The understanding that proper cell functioning critically requires a dynamic balance between oxidative eustress and distress (i.e., cellular redox homeostasis) forms the conceptual framework of redox medicine, a novel therapeutics that passivates the oxidative distress while maintains the normal redox circuitry [10,12,[14][15][16]. The cellular redox dynamics and its regulations, however, are still largely elusive because of the lack of effective pharmacological interventions [17].…”

Effects of Rutin on Wound Healing in Hyperglycemic Rats

“…Both diabetes and wounds can induce oxidative stress, especially hyperglycemia, which enhances the generation of free radicals and reduces anti-oxidation capabilities. Free radicals destroy the ability of β-cells to secrete insulin and increase the incidence of diabetes complications [ 3 , 4 ]. In addition, long-term exposure of cells and tissues to the hyperglycemic environment affects the metabolism of proteins and lipids, induces the production of reactive oxygen species (ROS), promotes inflammation, increases the risk of wound ulcers, and delays wound healing [ 4 ].…”