An increasing body of evidence from animal models, human specimens and cell lines points to reactive oxygen species as likely involved in the pathways, which convey both extracellular and intracellular signals to the nucleus, under a variety of pathophysiological conditions. Indeed, reactive oxygen species (ROS), in a concentration compatible with that detectable in human pathophysiology, appear able to modulate a number of kinases and phosphatases, redox sensitive transcription factors and genes. This type of cell signalling consistently implies the additional involvement of other bioactive molecules that stem from ROS reaction with cell membrane lipids. The present review aims to comprehensively report on the most recent knowledge about the potential role of ROS and oxidised lipids in signal transduction processes in the major events of cell and tissue pathophysiology. Among the lipid oxidation products of ROS-dependent reactivity, which appear as candidates for a signalling role, there are molecules generated by oxidation of cholesterol, polyunsaturated fatty acids and phospholipids, as well as lysophosphatidic acid and lysophospholipids, platelet activating factor-like lipids, isoprostanes, sphingolipids and ceramide.

Muscle protein wasting in cancer cachexia is a critical problem. The underlying mechanisms are still unclear, although the ubiquitin-proteasome system has been involved in the degradation of bulk myofibrillar proteins. The present work has been aimed to investigate whether autophagic degradation also plays a role in the onset of muscle depletion in cancer-bearing animals and in glucocorticoid-induced atrophy and sarcopenia of aging. The results show that autophagy is induced in muscle in three different models of cancer cachexia and in glucocorticoid-treated mice. In contrast, autophagic degradation in the muscle of sarcopenic animals is impaired but can be reactivated by calorie restriction. These results further demonstrate that different mechanisms are involved in pathologic muscle wasting and that autophagy, either excessive or defective, contributes to the complicated network that leads to muscle atrophy. In this regard, particularly intriguing is the observation that in cancer hosts and tumor necrosis factor α-treated C2C12 myotubes, insulin can only partially blunt autophagy induction. This finding suggests that autophagy is triggered through mechanisms that cannot be circumvented by using classic upstream modulators, prompting us to identify more effective approaches to target this proteolytic system.

An increasing number of reports underscore the frequent association of fibrosclerotic diseases of lung, liver, arterial wall, brain, etc., with the accumulation of oxidatively modified lipids and proteins. A cause-and-effect relationship has been proposed between cellular oxidative damage and increased fibrogenesis based on the fact that experimental treatment with antioxidants either prevents or quenches the fibrotic process. With some peculiarities in the different organs, fibrosclerosis is essentially the result of the interaction of macrophages and extracellular matrix-producing cells. The cross-talk is mediated by fibrogenic cytokines, among which the most important appears to be transforming growth factor beta1 (TGF-beta1). This report describes treatment of different types of macrophage, of both human and murine origin, with 4-hydroxy-2,3-nonenal (HNE) a major aldehyde end product of membrane lipid oxidation found consistently to induce both mRNA expression and synthesis of TGF-beta1. Since increased HNE levels have been demostrated in the cirrhotic liver and in the oxidatively modified low-density human lipoproteins associated with atherosclerosis, the up-regulation of macrophage TGF-beta1 by HNE appears to be involved in the pathogenesis of these and similar diseases characterized by fibrosclerosis.

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